Induced pluripotent stem cells made to produce insulin and CRISPR, used to correct a genetic defect, cured Wolfram syndrome in mice.

Using induced pluripotent stem cells (iPSCs) produced from the skin of a patient with a rare, genetic form of insulin-dependent diabetes called Wolfram syndrome, researchers transformed the human stem cells into insulin-producing cells and used CRISPR-Cas9 to correct a genetic defect that had caused the syndrome. They then implanted the cells into lab mice and cured the unrelenting diabetes in those models.

The findings, from researchers at Washington University School of Medicine in St. Louis, US, suggest this CRISPR-Cas9 technique may hold promise as a treatment for diabetes, particularly the forms caused by a single gene mutation and it also may be useful one day in some patients with the more common forms of diabetes, such as type 1 and type 2.

This is the first time CRISPR has been used to fix a patients diabetes-causing genetic defect and successfully reverse diabetes, said co-senior investigator Dr Jeffrey Millman, an assistant professor of medicine and of biomedical engineering at Washington University. For this study, we used cells from a patient with Wolfram syndrome because, conceptually, we knew it would be easier to correct a defect caused by a single gene. But we see this as a stepping stone toward applying gene therapy to a broader population of patients with diabetes.

Wolfram syndrome is caused by mutations to a single gene, providing the researchers an opportunity to determine whether combining stem cell technology with CRISPR to correct the genetic error also might correct the diabetes caused by the mutation.

Researchers at Washington University School of Medicine in St. Louis have transformed stem cells into insulin-producing cells. They used the CRISPR gene-editing tool to correct a defect that caused a form of diabetes, and implanted the cells into mice to reverse diabetes in the animals. Shown is a microscopic image of insulin-secreting beta cells (insulin is green) that were made from stem cells produced from the skin of a patient with Wolfram syndrome [credit: Millman lab Washington University].

Millman and his colleagues had previously discovered how to convert human stem cells into pancreatic beta cells. When such cells encounter blood sugar, they secrete insulin. Recently, these researchers developed a new technique to more efficiently convert human stem cells into beta cells that are considerably better at controlling blood sugar.

In this study, they took the additional steps of deriving these cells from patients and using the CRISPR-Cas9 gene-editing tool on those cells to correct a mutation to the gene that causes Wolfram syndrome (WFS1). Then, the researchers compared the gene-edited cells to insulin-secreting beta cells from the same batch of stem cells that had not undergone editing with CRISPR.

In the test tube and in mice with a severe form of diabetes, the newly grown beta cells that were edited with CRISPR more efficiently secreted insulin in response to glucose. Diabetes disappeared in mice with the CRISPR-edited cells implanted beneath the skin and the animals blood sugar levels remained in normal range for the entire six months they were monitored. Animals receiving unedited beta cells remained diabetic. Although their newly implanted beta cells could produce insulin, it was not enough to reverse their diabetes.

We basically were able to use these cells to cure the problem, making normal beta cells by correcting this mutation, said co-senior investigator Dr Fumihiko Urano, the Samuel E. Schechter Professor of Medicine and a professor of pathology and immunology. Its a proof of concept demonstrating that correcting gene defects that cause or contribute to diabetes in this case, in the Wolfram syndrome gene we can make beta cells that more effectively control blood sugar. Its also possible that by correcting the genetic defects in these cells, we may correct other problems Wolfram syndrome patients experience, such as visual impairment and neurodegeneration.

Were excited about the fact that we were able to combine these two technologies growing beta cells from induced pluripotent stem cells and using CRISPR to correct genetic defects, Millman said. In fact, we found that corrected beta cells were indistinguishable from beta cells made from the stem cells of healthy people without diabetes.

Moving forward, the process of making beta cells from stem cells should get easier, the researchers said. For example, the scientists have developed less intrusive methods, making iPSCs from blood and they are working on developing stem cells from urine samples.

The study is published in Science Translational Medicine.

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Induced pluripotent stem cells and CRISPR reversed diabetes in mice - Drug Target Review

Skin Stem Cells Comments Off on Induced pluripotent stem cells and CRISPR reversed diabetes in mice – Drug Target Review | April 24th, 2020

Most breast cancers utilize the female hormone estrogen to grow, so drug-induced estrogen deprivation is used as a treatment in many patients. However, cancer will recur in one-third of these patients. A research team at Dartmouths and Dartmouth-Hitchcocks Norris Cotton Cancer Center, led by Todd W. Miller, PhD, is trying to understand why dormant breast cancer cells survive despite being starved of estrogen. The team discovered that an anti-diabetes drug, metformin, which is being tested in many clinical trials as an anti-cancer agent, actually activated fat metabolism that protected dormant breast cancer cells during estrogen deprivation. The findings suggest that the drug has context-dependent effects on cancer cells. The results, entitled AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells, are newly published online inClinical Cancer Research, a journal of the American Association for Cancer Research.

Knowledge that metformin has context-dependent effects on cancer cells will inform a better understanding of ongoing and prior clinical trials testing metformin, and help shape the design of trials moving forward. Our study indicates that the development of drugs targeting fat metabolism is warranted for breast cancer. Most excitingly, anti-angina drugs that block fat metabolism may be quickly repurposed as potential treatments for cancer and tested in clinical trials, says Miller.

Next steps include clinical trials testing drugs that block fat metabolism in breast cancer. Were also designing preclinical studies to further dissect the roles of fat metabolism in breast and other cancers, with the goal of identifying more refined therapeutic targets that will selectively kill cancer cells and not harm healthy cells, notes Miller.

Reference:Hampsch, et al. (2020) AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells. Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-20-0269.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Team Reveal Key to the Survival of Dormant Breast Cancer Cells - Technology Networks

Skin Stem Cells Comments Off on Team Reveal Key to the Survival of Dormant Breast Cancer Cells – Technology Networks | April 24th, 2020

Findings confirmed that patient-specific autologous dendritic cell vaccines (DCV) induced a different immune response associated with longer survival than autologous tumor cell vaccines (TCV)

IRVINE, Calif.--(BUSINESS WIRE)-- AIVITA Biomedical, Inc., a biotechnology company specializing in innovative cell therapy applications, announced today the publication of a paper titled, Cytokine network analysis of immune responses before and after autologous dendritic cell and tumor cell vaccine immunotherapies in a randomized trial, in the Journal of Translational Medicine. Robert O. Dillman, M.D., chief medical officer at AIVITA, and Gabriel I Nistor, M.D., chief scientific officer at AIVITA, authored the article.

The publication provides insight into the innate and adaptive immune responses induced by patient-specific autologous dendritic cell vaccines (DCV) and autologous tumor cell vaccines (TCV), and their impact on survival. DCV was associated with a multipronged innate and adaptive immune response and correlated with improved survival compared to TCV.

In a randomized Phase 2 trial conducted in patients with melanoma, blood samples were obtained at one week before and one week after a course of three weekly injections, which either included dendritic cells loaded ex vivo with antigens from autologous irradiated tumor-initiating cells (DCV), or autologous irradiated tumor-initiating cells alone (TCV). Cytokine network analysis techniques used to analyze the serologic immune responses generated by each immunotherapy confirmed they triggered differing responses. The results help provide insight into a potential underlying immunologic mechanism of action that contributes to improved survival in DCV-treated patients.

This analysis reinforces conclusions from our patient-specific cancer vaccine survival data, which suggested that ex-vivo processing of the same tumor antigens by autologous dendritic cells induces a more advantageous immune response than antigen-only based tumor cell vaccines, said Dr. Nistor. This is reassuring as we continue to further optimize our unique approach in which we use enhanced autologous dendritic cells for targeting each patients own tumor.

AIVITA is currently conducting three independent clinical studies investigating its platform immunotherapy in patients with ovarian cancer, glioblastoma and melanoma. AIVITA uses 100% of proceeds from the sale of its ROOT of SKIN skincare line to support the development of its cancer therapeutic pipeline.

About AIVITAS Clinical Trials

OVARIAN CANCER

AIVITAs ovarian Phase 2 double-blind study is active and enrolling approximately 99 patients who are being randomized in a 2:1 ratio to receive either the autologous tumor-initiating cell-targeting immunotherapy or autologous monocytes as a comparator.

Patients eligible for randomization and treatment will be those (1) who have undergone debulking surgery, (2) for whom a cell line has been established, (3) who have undergone leukapheresis from which sufficient monocytes were obtained, (4) have an ECOG performance grade of 0 or 1 (Karnofsky score of 70-100%), and (5) who have completed primary therapy. The trial is not open to patients with recurrent ovarian cancer.

For additional information about AIVITAs AVOVA-1 trial patients can visit: http://www.clinicaltrials.gov/ct2/show/NCT02033616

GLIOBLASTOMA

AIVITAs glioblastoma Phase 2 single-arm study is active and is enrolling approximately 55 patients to receive the tumor-initiating cell-targeting immunotherapy.

Patients eligible for treatment will be those (1) who have recovered from surgery such that they are about to begin concurrent chemotherapy and radiation therapy (CT/RT), (2) for whom an autologous tumor cell line has been established, (3) have a Karnofsky Performance Status of > 70 and (4) have undergone successful leukapheresis from which peripheral blood mononuclear cells (PBMC) were obtained that can be used to generate dendritic cells (DC). The trial is not open to patients with recurrent glioblastoma.

For additional information about AIVITAs AV-GBM-1 trial please visit: http://www.clinicaltrials.gov/ct2/show/NCT03400917

MELANOMA

AIVITAs melanoma Phase 1B open-label, single-arm study will establish the safety of administering anti-PD1 monoclonal antibodies in combination with AIVITAs tumor-initiating cell-targeting immunotherapy in patients with measurable metastatic melanoma. The study will also track efficacy of the treatment for the estimated 14 to 20 patients. This trial is not yet open for enrollment.

Patients eligible for treatment will be those (1) for whom a cell line has been established, (2) who have undergone leukapheresis from which sufficient monocytes were obtained, (3) have an ECOG performance grade of 0 or 1 (Karnofsky score of 70-100%), (4) who have either never received treatment for metastatic melanoma or were previously treated with enzymatic inhibitors of the BRAF/MEK pathway because of BRAF600E/K mutations and (5) are about to initiate anti-PD1 monotherapy.

For additional information about AIVITAs AV-MEL-1 trial please visit: http://www.clinicaltrials.gov/ct2/show/NCT03743298

About AIVITA Biomedical

AIVITA Biomedical is a privately held company engaged in the advancement of commercial and clinical-stage programs utilizing curative and regenerative medicines. Founded in 2016 by pioneers in the stem cell industry, AIVITA Biomedical utilizes its expertise in stem cell growth and directed, high-purity differentiation to enable safe, efficient and economical manufacturing systems which support its therapeutic pipeline and commercial line of skin care products. All proceeds from the sale of AIVITAs skin care products support the treatment of people with cancer.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200423005260/en/

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AIVITA Biomedical Publishes Study Comparing Immune Responses and Associated Survivals Induced by Dendritic and Tumor Cell Vaccines - BioSpace

Skin Stem Cells Comments Off on AIVITA Biomedical Publishes Study Comparing Immune Responses and Associated Survivals Induced by Dendritic and Tumor Cell Vaccines – BioSpace | April 24th, 2020

Good morning,

Crucial data gaps are hurting Canadas ability to fight the COVID-19 pandemic, leaving Canadians in the dark about who is being infected or struggling with the devastated economy.

Canada has a long-standing problem of information gaps, The Globe and Mail found in a year-long series, and that has left us vulnerable during public health crises before. But now, these blind spots could blunt the federal economic rescue effort, hide inequities in deaths from the disease and slow our emergence from self-isolation in the months ahead.

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Father Victor Fernandes puts on personal protection equipment prior to visiting with a patient in the COVID-19 intensive care unit at St. Paul's hospital in downtown Vancouver on April 21, 2020.

JONATHAN HAYWARD/The Canadian Press

This is the daily Morning Update newsletter. If youre reading this on the web, or it was forwarded to you from someone else, you can sign up for Morning Update and more than 20 more Globe newsletters on our newsletter signup page.

Nova Scotia shooting: Premier Stephen McNeil is urging his mourning province to help investigators unravel questions around a gunmans weekend rampage. A new tip line was created specifically for the killings. He acknowledged there is anger over the RCMPs decision not to use the provincial emergency alert system during the 12-hour manhunt, but he asked people to be patient, and wait for answers.

New details are emerging about the chaos that ensued as police tried to capture the killer disguised as an RCMP officer. Audio recordings of first responders communicating on two-way radios provide a glimpse of frantic attempts to help the first victims in the village of Portapique.

A couple pays their respects at a memorial in Portapique, N.S., on April 22, 2020.

Andrew Vaughan/The Canadian Press

Economy: Saskatchewan has laid out a detailed, comprehensive plan to reopen its economy, and is the first province in the country to do so. On May 4, the five phases will begin, opening non-essential medical procedures, and the reopening of provincial parks, campgrounds and golf courses.

In Quebec, Premier Franois Legault is preparing to lay the groundwork next week for a plan to gradually restart the provinces economy and get children back to school.

Rent: Ottawa is proposing to offer commercial rent relief, in the form of loans for landlords of small and medium-sized businesses, that would cover up to 75 per cent of tenants payments for three months, according to sources familiar with the negotiations.

When it comes to investment properties, small landlords across Canada might not qualify for government assistance and are scrambling to figure out how to accommodate rent reductions while making their mortgage payments.

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World news:

Researchers at the University of Oxford are racing to develop a vaccine for COVID-19 and plan to make a million doses of it this summer. The team has been working since January, and clinical trials involving more than 500 volunteers began yesterday. The testing is expected to take several months, but the researchers have already teamed up with manufacturers globally to produce the doses September and millions more by the end of the year. The Globes Paul Waldie reports.

An aerial view of people queuing outside a bank in downtown Quito, Ecuador, on April 22, 2020.

RODRIGO BUENDIA/AFP/Getty Images

Got a news tip that youd like us to look into? E-mail us at tips@globeandmail.com Need to share documents securely? Reach out via SecureDrop

Scheer, Tories refrain from criticizing MP accused of racist comments: People of Asian descent have faced a spike in hate crimes and slurs since the COVID-19 pandemic began in China last year and experts say the comments from an elected official give licence for the attacks to continue.

Child protection organizations seeing significant uptick in predators: In dark-web forums, sexual predators are increasingly discussing the COVID-19 pandemic as an opportunity to exploit children online as they spend more time out of school and on the internet.

Ontarios Serious Fraud Office investigates Bondfield: A special unit of Ontario police officers and prosecutors launched the investigation in 2019, looking into allegations of wrongdoing by a major builder of hospitals, transit stations and other public infrastructure across the province.

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Parents of teen girls killed by Paul Bernardo seek to obtain his file with the parole board: The two families filed for judicial review this month after their requests for the documents under access to information legislation were denied.

MPs seek to overcome hurdle in getting WHO adviser to testify: A parliamentary committee scrutinizing the response to the pandemic is working to get key World Health Organization adviser Bruce Aylward to testify. The WHOs legal counsel has said that Dr. Aylward cannot testify unless he receives authorization from WHO Director-General Tedros Adhanom Ghebreyesus.

World stocks fall on worries over EU stimulus details, coronavirus drug: Global shares fell on Friday, spurred by delays to an agreement on divisive details of the European Unions stimulus package and doubts about progress in the development of drugs to treat COVID-19. In Europe, Britains FTSE 100 was down 0.93 per cent around 6 a.m. ET. Germanys DAX and Frances CAC 40 fell 1.07 per cent and 1.03 per cent, respectively. In Asia, Japans Nikkei fell 0.86 per cent. Hong Kongs Hang Seng fell 0.61 per cent. New York futures were flat. The Canadian dollar was trading at 71.05 U.S. cents.

Canada must protect itself from Americas response to COVID-19

Robyn Urback: It is not implausible that Mr. Trump would retaliate in some sort of petty but potentially grave economic way on supply lines for essential goods, for example if Canada refuses to lift restrictions on non-essential travel if and when the President decides that time is up.

This Ramadan, in solitude, will be more meaningful than ever

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Fatima Al Fahim: But the pandemic need not dampen Ramadan spirits. Physical distancing gives us a reminder of the true meaning of the holy month.

The world has a big China problem now

Campbell Clark: We dont know precisely what happened in China in the early days of COVID-19, but we know some whistle-blowers were stifled and, for whatever reason, officials waited for days to tell the world after learning they faced a serious epidemic.

By Brian Gable

Brian Gable/The Globe and Mail

What you really need is a room edit, not a reno

Especially while in isolation, you may be looking for curatorial guidance, but are keen to avoid the expense of a full interiors overhaul. Some people would rather rip out a wall or buy a bigger house, when all it often takes is reimaging and reworking what you already have, says Joanna Teplin, the Nashville co-founder of the Home Edit. If you want to remodel, read about how you might be able to make the change with what you already have.

Snuppy, right, the first male dog cloned from adult cells by somatic nuclear cell transfer, and the male Afghan hound from which an adult skin cell was taken to clone Snuppy, are seen in this handout photo released in Seoul on Aug. 3, 2005.

Seoul National University via Reuters

Snuppy worlds first cloned dog is born

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If he were born today, Snuppy would be dubbed, in internet lingo, a very good pupper or an excellent doggo. Instead, Snuppy, the first successful clone of a dog, had to settle for merely being hailed as a breakthrough in biotechnology. A team of 45 South Korean researchers, led by stem-cell researcher Hwang Woo-suk, produced the pup using a process called somatic cell nuclear transfer with a cell from the ear of a male Afghan dog, Tai. Snuppy was named for Seoul National University (SNU) and puppy. While other mammals had been cloned successfully starting with Dolly the sheep in 1996 cloning mans best friend proved more challenging. The achievement suggested that, given time and expertise, almost any mammal could be reproduced. Defying concerns that clones would be rife with ailments, Snuppy was generally healthy. He fathered 10 pups by artificial insemination and produced, by stem-cell clone, a litter with three surviving pups. Snuppy died of cancer, a common fate in dogs, just days after his 10th birthday in 2015. Jessie Willms

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Morning Update: Canadas data gaps are hurting our ability to fight the pandemic - The Globe and Mail

Skin Stem Cells Comments Off on Morning Update: Canadas data gaps are hurting our ability to fight the pandemic – The Globe and Mail | April 24th, 2020

New research results show promise in treating people who are blind.

The National Eye Institute funded the study, which is research considered to be ethical.

Dr. David Prentice of the Charlotte Lozier Institute says there have been discussions over using adult stem cells to restore sight, which he calls a different tack for advancing science and medicine.

It's still an ethical way to go about this, he observes. There's no embryonic stem cells, no fetal tissue, none of this unethical type of research direction.

What the scientists did was turn a skin cell directly into a photoreceptor for vision then transplanted it.

Prenticeadvises the testing is very preliminary after the experiment on mice.

But what they find was when they transplanted this newly formed type of vision cell into the eyes of these blind mice, he says, they restored their vision.

The researchers applied chemicals that transformed one cell type into another needed for vision, and there is now potential to help people with all forms of vision blindness or vision correction, which would include macular degeneration and other retinal disorders.

Editor's note: Original posting attribute comments to wrong person.

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Lozier praises promising, and ethical, blindness study - OneNewsNow

Skin Stem Cells Comments Off on Lozier praises promising, and ethical, blindness study – OneNewsNow | April 24th, 2020

Just because you cant head to a nail salon right now doesnt mean you should neglect your hands, feet and nails. Plus, the excessive hand washing youve been doing still the most reliable way to protect yourself and your family from Covid-19 can also strip skin of its natural oils and leave it dry. Heres what you can do:

If youre lazy, just use a body scrub in the shower, starting from the feet up. But for a little DIY pampering, start with a foot soak to soften rough heels and soles, then use a foot scrub.

This is important, especially for the hands, as the skin there is thinner than the rest of the body. Its also one of the first places to show signs of ageing. Plus, if the skin on your hands and feet are extremely dry, it could develop micro cracks that allow germs in, making you unwell.

Did you know that massaging cuticle oil on your cuticles and nails every day can improve blood flow to the nail matrix (the root), which makes your nails strong and healthy? If you tend to forget, keep the bottle by your WFH work desk or at your bedside as a nightly reminder.

Here are seven treats to get your hands, feet and nails looking great, when youre stuck at home:

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The Body Shop ? Almond Hand And Nail Cream 30ml 95.000 Order WA : 0878 8850 6509 #thebodyshop #bodybutter #vitamin #moisturizer #showergel #edt #parfum #bodymist #sabunmandi #sabuncair #makeup #teatree #vitamine #strawberry #vanilla #mango #tbs #thebodyshopsurabaya #thebodyshopalmondhandcream #handcreamthebodyshop #almondhandcream #almond #pelembab #thebodyshop #handcream #krimtangan #pelembabtangan Pelembap khusus tangan dan kuku dengan aroma sweet almond. Membantu membuat tangan dan kuku menjadi lembap, lembut, dan tampak sehat.

A post shared by haii rek ? (@mbakaysurabaya) on Feb 27, 2020 at 11:38am PST

Sweet almond oil and shea butter nourish skin, strengthen nails, and keep your hands soft.

Available atwww.thebodyshop.com/en-sg/and when stores re-open, at The Body Shop.

Not everyone likes using a thick, heavy cream, especially when you dont have the aircon on when you work from home. The heat just makes it all the more sticky.

This lotion is lightweight yet intensively hydrates hands with organic shea butter, USDA-certified organic jojoba seed oil and rice bran oil, yet remains lightweight on the skin.

The latter ingredient contains vitamin E, which protects your hands against UV damagewhich helps give added projection if you work by the window.

Available atwww.thann.com.sg

ALSO READ:9 nail products to help you get a salon-quality manicure at home

A five-oil blend of jojoba, sunflower, argan, pomegranate and tamu moisturise dry cuticles, keeping nails healthy, and soothing skin. We love the rollerball for fuss-free application and the delicate citrus and rose geranium scent.

Available atwww.net-a-porter.com

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#???? #??? . ???? ????? ??!! ???? ????, ???? ????, ???? ????, ????? #legspa #?? #????? #cureprogram #?????? #?

A post shared by ???(????PT? WEgym) (@n___hyunwoo) on Feb 15, 2019 at 11:14pm PST

You wear the mask like socks that reach up to mid-shin, taping the tabs down for a snug fit. The inside of the mask contains its formula of 7 essential oils and 11 herbs (including spearmint, eucalyptus, grapefruit, bergamot, juniper and thyme) to relieve tired feet and legs, and keep them soft and hydrated.

Available atwww.ksisters.sg

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I’m not a big “exfoliate in the shower person,”but the smell of this product is divine and makes me want to buff my bits? @aesopskincare #aesop #aesopbodyscrub #aesopredemptionbodyscrub #aesopscrub #bodyscrub #skincare #beauty #aesopskincare #scrub

A post shared by Susan B (@susybliving) on May 17, 2019 at 9:40am PDT

For quick exfoliation in the shower, use this creamy body scrub. It contains finely milled pumice stone and bamboo stem to gently buff away dead skin cells and dirt. Skin feels smoother and softer, from top to toe.

Available atwww.aesop.com/sg/andwww.net-a-porter.com

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So for those of who missed my stories early last week, I wanted to start a fun @drunkelephant tag myself so I came up with #silisaturday ? I have been really enjoying lathering myself up with the new Sili Body Lotion. It is so light, absorbs quickly into the skin but your skin is still left feeling hydrated & soft - no greasy residue, which is something I hate in a lot of body lotions / body butters. There is a very subtle sweet almond scent but you have to really look for it in order to smell it. I remember opening the bottle to smell it and didn’t at first; but the smell was more noticeable once I started actually applying it. I can’t wait to get my hands on the rest of the new hair & body collection - I’ll have a review up soon of the Marula Detangler Spray once I’ve used it a bit more to really get a solid opinion! ? . . Show me your #silisaturday photos & I will be sharing them on my stories! ?? . . #drunkelephant #drunkelephantskincare #drunkelephantforlife #drunkelephantsili #silibodylotion #skin #cleanbeauty #cleanskincare #acleanbreak #skincare #skincareroutine #skincareproducts #skincaretips #skincarejunkie #skincarecommunity #skincareroutines #skincareblogger #skincaretipsandtricks #skincareaddict #skincarelover #skincareobsessed #skincareregime #skincarereview

A post shared by Jennifer (@makeupxdanseee) on Apr 4, 2020 at 11:55am PDT

A body lotion is the easiest way to ensure that every bit of skin gets hydration, not just your hands and feet. This one contains nourishing plant oils and butters, together with amino acids, ceramides and antioxidants that lock in moisture, soothe dryness and itch, and protect skin from free radical damage.

Available atwww.sephora.sgand when stores re-open, at Sephora.

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Werbung- Happy Sunday Ihr Lieben ? was macht Ihr heute? Bei uns ist es recht kühl und Dauerregen? Ideales Wetter für ein bisschen Me-Time zuhause. Sonntag ist eh immer mein Pflege-Tag mit Masken, Baden, Peelings und Co. Ich habe vor kurzem diese neuen Gold Masken für Hände und Füße?von Starskin zugeschickt bekommen. Kennt Ihr die Marke schon? Benutzt Ihr solche Hand & Fuß Masken? Ich habe das tatsächlich noch nie probiert ? Bin immer zu ungeduldig für sowas. PS: Es freut mich, dass soviele beim Gewinnspiel mitmachen ? Daher kommt wahrscheinlich auch schon nächste Woche das nächste für Euch ??Ich wünsche Euch einen schönen Sonntag ?? #instabeauty #instamakeup #makeup #makeupadicct #makeupjunkie #skincare #starskin #starskingold #starskinsquad #starskinmask #starskinbeauty #beautyaddict #beautyjunkie #beautyblogger_de #bblogger #cosmetics #cosmetic #highendlove #blogger_de #starskinthegoldmask

A post shared by I L O N K A T I M M (@highendloveblog) on Aug 18, 2019 at 3:17am PDT

An intensive treatment for your hands, the mask contains two layers: The inner layer contains Bulgarian rose, shea butter and rose hip oil to nourish while the outer protective foil creates a warming effect to enhance absorption of the active ingredients. Hands are soft, supple and conditioned in 15 minutes.

Available atwww.sephora.sgand when stores re-open, at Sephora.

For the latest updates on the coronavirus, visithere.

This article was first published in Her World Online.

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How to care for your nails at home now that you can't go to the salon - AsiaOne

Skin Stem Cells Comments Off on How to care for your nails at home now that you can’t go to the salon – AsiaOne | April 24th, 2020

- Phase 3 REACH2 data demonstrate that ruxolitinib (Jakafi) improves outcomes across a range of efficacy measures in patients with steroid-refractory acute graft-versus-host disease (GVHD) compared to best available therapy (BAT)

- Results show a significantly greater overall response rate (ORR) in patients treated with ruxolitinib (62%) compared to BAT (39%) 1,2

- GVHD is a serious and common complication of allogeneic stem cell transplants with a one-year mortality rate as high as 80% in patients who develop acute GVHD3-5

- The results, published in The New England Journal of Medicine, were also selected for an oral presentation during the Presidential Symposium at the European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting to be held 30 August to 2 September in Madrid, Spain

Incyte (Nasdaq:INCY) today announced that data from the Phase 3 REACH2 study have been published in The New England Journal of Medicine demonstrating that ruxolitinib (Jakafi) improves outcomes across a range of efficacy measures in patients with steroid-refractory acute graft-versus-host disease (GVHD) compared to best available therapy (BAT). The results of REACH2, the first Phase 3 study of ruxolitinib in acute GVHD to have met its primary endpoint, reinforce findings from the previously-reported Phase 2 REACH1 study.

In REACH2, patients treated with ruxolitinib experienced a significantly greater overall response rate (ORR) vs. BAT (62% vs. 39%; p<0.001) at Day 28, the primary endpoint of the study. For the key secondary endpoints, patients treated with ruxolitinib maintained significantly higher durable ORR (40% vs. 22%; p<0.001) at Day 56. In addition, ruxolitinib was associated with longer median failure free survival (FFS) than BAT (5.0 months vs. 1.0 months; hazard ratio 0.46, 95% CI, 0.35 to 0.60) and showed a positive trend with other secondary endpoints, including duration of response1,2.

No new safety signals were observed, and the ruxolitinib safety profile in REACH2 was consistent with that seen in previously reported studies in steroid-refractory acute GVHD. The most frequently reported adverse events among study participants were thrombocytopenia and anemia. While 38% and 9% of patients required ruxolitinib and BAT dose modifications, the number of patients who discontinued treatment due to AEs was low (11% and 5%, respectively)1,2.

"The results from the REACH2 study reinforce findings from the pivotal REACH1 trial and demonstrate the potential that ruxolitinib has to effectively and safely improve outcomes for patients with GVHD," said Peter Langmuir, M.D., Group Vice President, Oncology Targeted Therapies, Incyte. "We are committed to continuing our research in GVHD with the goal of providing more effective treatment options for patients living with this disease, and look forward to the results of the REACH3 study in steroid-refractory chronic GVHD later this year."

The REACH2 data were also accepted as an oral presentation as part of the Presidential Symposium at the European Society for Blood and Marrow Transplantation (EBMT) Annual Meeting to be held 30 August to 2 September in Madrid, Spain.

"Patients with acute graft-versus-host disease face life-threatening challenges with limited treatment options, particularly for the nearly half of individuals who do not respond to initial steroid therapy," said Robert Zeiser, University Hospital Freiburg, Department of Haematology, Oncology and Stem Cell Transplantation, Freiburg, Germany. "These new data from REACH2 showing superiority of ruxolitinib over current standard-of-care therapies add to a growing body of evidence on how targeting the JAK pathway can be an effective strategy in this difficult-to-treat condition."

In 2019, Jakafi (ruxolitinib) was approved by the U.S. Food and Drug Administration for the treatment of steroid-refractory acute GVHD in adult and pediatric patients 12 years and older, based on the positive results of the Phase 2 REACH1 trial6. The Phase 3 REACH3 study in patients with steroid-refractory chronic GVHD is ongoing and results are expected in the second half of this year. Jakafi is marketed by Incyte in the U.S.; ruxolitinib (Jakavi) is licensed to Novartis ex-U.S.

The NEJM publication of the REACH2 results is available online.

Story continues

About REACH2

REACH2 (NCT02913261), a randomized, open-label, multicenter Phase 3 study sponsored by Novartis and conducted in collaboration with and co-funded by Incyte , is evaluating the safety and efficacy of ruxolitinib compared with best available therapy in patients with steroid-refractory acute GVHD.

The primary endpoint was overall response rate (ORR) at Day 28, defined as the proportion of patients demonstrating a best overall response (complete response or partial response). Secondary endpoints include durable ORR at Day 56, ORR at Day 14, duration of response, overall survival and event-free survival, among others. For more information about the study, please visit https://clinicaltrials.gov/ct2/show/NCT02913261.

About REACH

The REACH clinical trial program evaluating ruxolitinib in patients with steroid-refractory GVHD, includes the randomized pivotal Phase 3 REACH2 and REACH3 trials, conducted in collaboration with Novartis. The ongoing REACH3 trial is evaluating patients with steroid-refractory chronic GVHD with results expected later this year. For more information about the REACH3 study, please visit https://clinicaltrials.gov/ct2/show/NCT03112603.

The REACH program was initiated with the Incyte-sponsored REACH1 trial, a prospective, open-label, single-cohort, multicenter, pivotal Phase 2 trial (NCT02953678) evaluating Jakafi in combination with corticosteroids in patients with steroid-refractory grade II-IV acute GVHD. For more information about the study, including trial results, please visit https://clinicaltrials.gov/show/NCT02953678.

About Jakafi (ruxolitinib)

Jakafi is a first-in-class JAK1/JAK2 inhibitor approved by the U.S. FDA for the treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea, in adults with intermediate or high-risk myelofibrosis (MF), including primary MF, post-polycythemia vera MF and post-essential thrombocythemia MF and for the treatment of steroid-refractory acute GVHD in adult and pediatric patients 12 years and older.

Jakafi is marketed by Incyte in the United States and by Novartis as Jakavi (ruxolitinib) outside the United States. Jakafi is a registered trademark of Incyte Corporation. Jakavi is a registered trademark of Novartis AG in countries outside the United States.

Important Safety Information

Jakafi can cause serious side effects, including:

Low blood counts: Jakafi (ruxolitinib) may cause your platelet, red blood cell, or white blood cell counts to be lowered. If you develop bleeding, stop taking Jakafi and call your healthcare provider. Your healthcare provider will perform blood tests to check your blood counts before you start Jakafi and regularly during your treatment. Your healthcare provider may change your dose of Jakafi or stop your treatment based on the results of your blood tests. Tell your healthcare provider right away if you develop or have worsening symptoms such as unusual bleeding, bruising, tiredness, shortness of breath, or a fever.

Infection: You may be at risk for developing a serious infection during treatment with Jakafi. Tell your healthcare provider if you develop any of the following symptoms of infection: chills, nausea, vomiting, aches, weakness, fever, painful skin rash or blisters.

Skin cancers: Some people who take Jakafi have developed certain types of non-melanoma skin cancers. Tell your healthcare provider if you develop any new or changing skin lesions.

Increases in cholesterol: You may have changes in your blood cholesterol levels. Your healthcare provider will do blood tests to check your cholesterol levels during your treatment with Jakafi.

The most common side effects of Jakafi include: for certain types of MF and PV - low platelet or low red blood cell counts, bruising, dizziness, headache, and diarrhea; and for acute GVHD low platelet, red or white blood cell counts, infections, and fluid retention.

These are not all the possible side effects of Jakafi. Ask your pharmacist or healthcare provider for more information. Tell your healthcare provider about any side effect that bothers you or that does not go away.

Before taking Jakafi, tell your healthcare provider about: all the medications, vitamins, and herbal supplements you are taking and all your medical conditions, including if you have an infection, have or had tuberculosis (TB), or have been in close contact with someone who has TB, have or had hepatitis B, have or had liver or kidney problems, are on dialysis, have a high level of fat in your blood (high blood cholesterol or triglycerides), had skin cancer or have any other medical condition. Take Jakafi exactly as your healthcare provider tells you. Do not change or stop taking Jakafi without first talking to your healthcare provider.

Women should not take Jakafi while pregnant or planning to become pregnant. Do not breast-feed during treatment with Jakafi and for 2 weeks after the final dose.

Full Prescribing Information, which includes a more complete discussion of the risks associated with Jakafi, is available at http://www.jakafi.com.

About Incyte

Incyte is a Wilmington, Delaware-based, global biopharmaceutical company focused on finding solutions for serious unmet medical needs through the discovery, development and commercialization of proprietary therapeutics. For additional information on Incyte, please visit Incyte.com and follow @Incyte.

Forward-Looking Statements

Except for the historical information set forth herein, the matters set forth in this press release, including statements about the REACH2 data, when results from the REACH3 study will be available, the effect of the REACH2 results on patients with GVHD, and the overall REACH program, contain predictions, estimates and other forward-looking statements.

These forward-looking statements are based on the Companys current expectations and subject to risks and uncertainties that may cause actual results to differ materially, including unanticipated developments in and risks related to: unanticipated delays; further research and development and the results of clinical trials possibly being unsuccessful or insufficient to meet applicable regulatory standards or warrant continued development; the ability to enroll sufficient numbers of subjects in clinical trials; determinations made by the FDA; the Companys dependence on its relationships with its collaboration partners; the efficacy or safety of the Companys products and the products of the Companys collaboration partners; the acceptance of the Companys products and the products of the Companys collaboration partners in the marketplace; market competition; sales, marketing, manufacturing and distribution requirements; greater than expected expenses; expenses relating to litigation or strategic activities; and other risks detailed from time to time in the Companys reports filed with the Securities and Exchange Commission, including its Form 10-K for the year ended December 31, 2019. The Company disclaims any intent or obligation to update these forward-looking statements.

References

View source version on businesswire.com: https://www.businesswire.com/news/home/20200422005739/en/

Contacts

Incyte Contacts Media Jenifer Antonacci+1 302 498 7036jantonacci@incyte.com

Catalina Loveman+1 302 498 6171cloveman@incyte.com

Investors Michael Booth, DPhil+1 302 498 5914mbooth@incyte.com

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Incyte Announces Pivotal REACH2 Study Data Published in NEJM Highlight Superior Efficacy of Ruxolitinib (Jakafi) versus Best Available Therapy in...

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CRISPR corrects genetic defect so cells can normalize blood sugar

Researchers at Washington University School of Medicine in St. Louis have transformed stem cells into insulin-producing cells. They used the CRISPR gene-editing tool to correct a defect that caused a form of diabetes, and implanted the cells into mice to reverse diabetes in the animals. Shown is a microscopic image of insulin-secreting beta cells (insulin is green) that were made from stem cells produced from the skin of a patient with Wolfram syndrome.

Using induced pluripotent stem cells produced from the skin of a patient with a rare, genetic form of insulin-dependent diabetes called Wolfram syndrome, researchers transformed the human stem cells into insulin-producing cells and used the gene-editing tool CRISPR-Cas9 to correct a genetic defect that had caused the syndrome. They then implanted the cells into lab mice and cured the unrelenting diabetes in those mice.

The findings, from researchers at Washington University School of Medicine in St. Louis, suggest the CRISPR-Cas9 technique may hold promise as a treatment for diabetes, particularly the forms caused by a single gene mutation, and it also may be useful one day in some patients with the more common forms of diabetes, such as type 1 and type 2.

The study is published online April 22 in the journal Science Translational Medicine.

Patients with Wolfram syndrome develop diabetes during childhood or adolescence and quickly require insulin-replacement therapy, requiring insulin injections multiple times each day. Most go on to develop problems with vision and balance, as well as other issues, and in many patients, the syndrome contributes to an early death.

This is the first time CRISPR has been used to fix a patients diabetes-causing genetic defect and successfully reverse diabetes, said co-senior investigator Jeffrey R. Millman, PhD, an assistant professor of medicine and of biomedical engineering at Washington University. For this study, we used cells from a patient with Wolfram syndrome because, conceptually, we knew it would be easier to correct a defect caused by a single gene. But we see this as a stepping stone toward applying gene therapy to a broader population of patients with diabetes.

Wolfram syndrome is caused by mutations to a single gene, providing the researchers an opportunity to determine whether combining stem cell technology with CRISPR to correct the genetic error also might correct the diabetes caused by the mutation.

A few years ago, Millman and his colleagues discovered how to convert human stem cells into pancreatic beta cells. When such cells encounter blood sugar, they secrete insulin. Recently, those same researchers developed a new technique to more efficiently convert human stem cells into beta cells that are considerably better at controlling blood sugar.

In this study, they took the additional steps of deriving these cells from patients and using the CRISPR-Cas9 gene-editing tool on those cells to correct a mutation to the gene that causes Wolfram syndrome (WFS1). Then, the researchers compared the gene-edited cells to insulin-secreting beta cells from the same batch of stem cells that had not undergone editing with CRISPR.

In the test tube and in mice with a severe form of diabetes, the newly grown beta cells that were edited with CRISPR more efficiently secreted insulin in response to glucose. Diabetes disappeared quickly in mice with the CRISPR-edited cells implanted beneath the skin, and the animals blood sugar levels remained in normal range for the entire six months they were monitored. Animals receiving unedited beta cells remained diabetic. Their newly implanted beta cells could produce insulin, just not enough to reverse their diabetes.

We basically were able to use these cells to cure the problem, making normal beta cells by correcting this mutation, said co-senior investigator Fumihiko Urano, MD, PhD, the Samuel E. Schechter Professor of Medicine and a professor of pathology and immunology. Its a proof of concept demonstrating that correcting gene defects that cause or contribute to diabetes in this case, in the Wolfram syndrome gene we can make beta cells that more effectively control blood sugar. Its also possible that by correcting the genetic defects in these cells, we may correct other problems Wolfram syndrome patients experience, such as visual impairment and neurodegeneration.

In the future, using CRISPR to correct certain mutations in beta cells may help patients whose diabetes is the result of multiple genetic and environmental factors, such as type 1, caused by an autoimmune process that destroys beta cells, and type 2, which is closely linked to obesity and a systemic process called insulin resistance.

Were excited about the fact that we were able to combine these two technologies growing beta cells from induced pluripotent stem cells and using CRISPR to correct genetic defects, Millman said. In fact, we found that corrected beta cells were indistinguishable from beta cells made from the stem cells of healthy people without diabetes.

Moving forward, the process of making beta cells from stem cells should get easier, the researchers said. For example, the scientists have developed less intrusive methods, making induced pluripotent stem cells from blood and they are working on developing stem cells from urine samples.

In the future, Urano said, we may be able to take a few milliliters of urine from a patient, make stem cells that we then can grow into beta cells, correct mutations in those cells with CRISPR, transplant them back into the patient, and cure their diabetes in our clinic. Genetic testing in patients with diabetes will guide us to identify genes that should be corrected, which will lead to a personalized regenerative gene therapy.

Maxwell KG, Augsornworawat P, Velazco-Cruz L, Kim MH, Asada R, Hogrebe NJ, Morikawa S, Urano F, Millman JR. Gene-edited human stem cell-derived cells from a patient with monogenic diabetes reverse pre-existing diabetes in mice. Science Translational Medicine, published online April 22, 2020.

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of General Medical Sciences, the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH). Grant numbers R01 DK114233, DK112921, TR002065, TR002345, T32 DK108742, R25 GM103757, T32 DK007120, P30 DK020579, P30 CA91842, UL1 TR000448 and UL1 TR002345. Additional assistance was provided by the Washington University Genome Engineering and iPSC Center, the Washington University Diabetes Center, and the Washington University Institute of Clnical and Translational Science, with additional funding from the JDRF, the Washington University Center of Regenerative Medicine, startup funds from the Washington University School of Medicine Department of Medicine, the Unravel Wolfram Syndrome Fund, Silberman Fund, Stowe Fund, Ellie White Foundation for Rare Genetic Disorders, Eye Hope Foundation, Snow Foundation, Feiock Fund, Childrens Discovery Institute, Manpei Suzuki Diabetes Foundation, and a JSPS Overseas Research Fellowship.

Washington University School of Medicines 1,500 faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Childrens hospitals. The School of Medicine is a leader in medical research, teaching and patient care, ranking among the top 10 medical schools in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Childrens hospitals, the School of Medicine is linked to BJC HealthCare.

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Diabetes reversed in mice with genetically edited stem cells derived from patients - Washington University School of Medicine in St. Louis

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Whether you're still completing a lengthy beauty routine each morning or your beloved products are collecting dust, there's one base makeup item that both can simplify things and persuade the fresh-faced crew to change their tune: BB cream. First developed in South Korea, this all-in-one product can replace your foundation and also your serum, moisturizer, primer, and sometimes even sunblock saving you time, money, and effort.

"Beauty balms" (i.e., "BB") are typically more sheer than traditional foundations (and even most tinted moisturizers), and are easy to apply with a brush, sponge, or even your fingers. Nearly all formulas include some form of SPF to protect against the sun, as well as active ingredients to help treat common skin concerns. Now, this versatility could explain why they seem to be flying off the (virtual) shelves at Sephora, but we picked out 12 popular options that get an A+ from us and other shoppers, too.

Here are the top-rated BB creams you can still nab at Sephora ahead.

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12 Top-Rated BB Creams That Can Simplify Your Beauty Routine and Protect Skin, Too - POPSUGAR

Skin Stem Cells Comments Off on 12 Top-Rated BB Creams That Can Simplify Your Beauty Routine and Protect Skin, Too – POPSUGAR | April 22nd, 2020

5 tips to help clients get glowing skin in coronavirus lockdownFor many clients, achieving glowy skin in between facial appointments is sometimes easier said than done. Even with a consistentskincare routineand plenty of hydration, its easy for clients to feel like their skin isnt as radiant as it could be, especially inCovid-19 lockdown.

Help clients achieve and maintain a dewy complexion until they can see you again using make-up and skincare brandInika Organics top tips.

As you know, the first step to achieving glowing skin is to thoroughly remove all make-up and surface debris with a gentle, natural remover likePhytoactive Micellar Rosewater.

Clients should be using a product that hydrates the skin as it cleanses, removing all traces of make-up, SPF, sweat, grime and environmental pollutants. They also need to soak a cotton pad with the remover and gently wipe the face, repeating this process until the pad comes away clean.

They then need to double cleanse using a product likePhytofuse Renew Camellia Oil Cleanser, which is enriched with Rose of Jericho extract to help brighten skin and even out texture.

Once or twice a week your clients should be removing dead skin cells with a natural exfoliant. For example, Inika OrganicsPhytofuse Renewal Caviar Lime Exfoliatorwhisks away dead cells and encourages faster cell turnover, leaving skin smooth and radiant.

Ingredients such as micronised bamboo stem and pumice will deeply purify pores and refine skin texture, while natural fruit AHAs from Australian caviar lime dissolve dead cells in an instant.

Hydration is the key to unlocking radiant skin, so getting clients to invest in the rightfacial moisturiseris key they need to smooth in a few drops of a powerful facial oil likePhyto-Active Rosehip Oil Blend. Rosehip oil is extremely beneficial for skin as it provides gentle hydration, oil management, brightening of dark spots and reduced healing times.

Once your clients facial oil has been absorbed, they should then prep skin for make-up (if they decide to put some on) by massaging in a hydrating primer blended with ingredients such as hyaluronic acid, jojoba oil and kangaroo paw extract. This type of primer (i.e.Certified Organic Pure Perfection Primer)will give an even, hydrated canvas.

Build on your base with a dusting ofBaked Mineral Illuminisorin a peachy-nude shade, which is ideal for creating a glowing look. Illuminisors should be applied over the high points of the face, including the brow bone, bridge of the nose and apples of the cheeks.

Get clients to finish with a liquid highlighter that adds soft shimmer and highlights their best features. Products likeLimited Edition Liquid Glow Illuminisorcan be dabbed onto the outer edges of the eyes, cupids bow, apples of the cheeks and the bridge of the nose for an ethereal glow.

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Send clients this easy5-minute everyday make-up routinewhich they can practice at home.

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5 tips to help clients get glowing skin in coronavirus lockdown - Professional Beauty

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The report aims to provide an overview of global Autologous Stem Cell and Non-Stem Cell Based Therapies Market with detailed market segmentation by product/application and geography. The global Autologous Stem Cell and Non-Stem Cell Based Therapies Market is expected to witness high growth during the forecast period. The report provides key statistics on the Market status of the Autologous Stem Cell and Non-Stem Cell Based Therapies players and offers key trends and opportunities in the market.

Autologous stem-cell transplantation is the autologous transplantation of stem cells. User preserves his own cells which can be used later. This is considered to be one of the effective and safer way to treat the diseases such as cancer. It is safer technology when compared with allogeneic and xeno transplants. IT reduces the risk of disease transmission, bio-incompatibility, and immunological reactions.

Download a Sample Report Explore further @https://www.theinsightpartners.com/sample/TIPRE00006725

The Autologous Stem Cell and Non-Stem Cell Based Therapies market is anticipated to grow in the forecast period owing to driving factors such as rising prevalence of cancer and diabetes, growing geriatric population, favorable reimbursement scenarios across several countries.

Top Dominating Key Players:

The Global Autologous Stem Cell and Non-Stem Cell Based Therapies market is segmented on the basis of application and end user. Based on application the market is segmented into Neurodegenerative, Cardiovascular, Cancer & Autoimmune, Skin and Infectious Diseases. Based on end user, the market is segmented into hospital and research institute.

The report provides a detailed overview of the industry including both qualitative and quantitative information. It provides overview and forecast of the global Autologous Stem Cell and Non-Stem Cell Based Therapies market based on various segments. It also provides market size and forecast estimates from year 2017 to 2027 with respect to five major regions, namely; North America, Europe, Asia-Pacific (APAC), Middle East and Africa (MEA) and South & Central America. The Autologous Stem Cell and Non-Stem Cell Based Therapies market by each region is later sub-segmented by respective countries and segments. The report covers analysis and forecast of 18 countries globally along with current trend and opportunities prevailing in the region.

The report analyzes factors affecting Autologous Stem Cell and Non-Stem Cell Based Therapies market from both demand and supply side and further evaluates market dynamics effecting the market during the forecast period i.e., drivers, restraints, opportunities, and future trend. The report also provides exhaustive PEST analysis for all five regions namely; North America, Europe, APAC, MEA and South & Central America after evaluating political, economic, social and technological factors effecting the Autologous Stem Cell and Non-Stem Cell Based Therapies market in these regions.

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Autologous Stem Cell and Non-Stem Cell Based Therapies Market Analysis with Key Players, Applications, Trends and Forecast to 2027 - Jewish Life News

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Reprinted with permission fromWorld At Large, a news website which covers politics, nature, science, health, and travel.

Age-related macular degeneration (MD) is a variety of ocular disease that affects so many millions of people, its downright characterized as nothing more than the process of aging.

In fact, the study of MD has proven itself to be so fruitful for understanding aging as a whole, MD has become one of the first places that scientists have looked to in order to attempt to repair the damage of aging and restoring youthful, or normal function.

Now in a new paper published in Nature, researchers demonstrate an alternative to stem cells by creating replacement photoreceptors from skin fibroblast cells via pharmacological-conversiona process that promises to be cheaper, faster, and unburdened by ethical and legal restrictions.

Containing the genetic code for every protein we need to build and repair our cells, DNA can become damaged over time through the stresses of life. Similarly to how scratches or cracks in a CD prevent lasers from reading the information on the disk, damaged DNA becomes difficult, and even impossible for our RNA (which you could imagine as the laser inside the CD player) to read the genetic information contained therein.

WATCH: Blind Man Develops Smart Cane That Uses Google Maps and Sensors to Identify Ones Surroundings

The photoreceptor is the neuron in the eye that turns on visual circuity in response to light which enables us to have vision, says Sai Chavala, Ph.D. and author of the new paper.

The loss of photoreceptors can result in MD and other retinal diseases that lead to irreversible blindness. In this new study, however, cells called fibroblasts can be chemically reprogrammed to produce photoreceptor-like cells that are now shown to restore vision in mice.

Fibroblasts are cells that help maintain the structural integrity of connective tissues, and a reduction in fibroblast cell count leads to wrinkled skin.

Sai Chavala and colleagues from the Center for Retina Innovation in Dallas, Texas, found a set of five compounds that can drive embryonic fibroblast cells to convert themselves into retinal, rod-like, photoreceptors in both mice and human cells.

Stem cell-based strategies are extremely exciting, Dr. Chavala tells World at Large, but adds that generating these cells can be cumbersome and time-consuming. Describing his strategy of chemically reprogramming existing cells as a breakthrough, Chavala added that the generation of the photoreceptors using his method requires a fraction of the time.

In the study, these converted photoreceptors were transplanted into the eyes of 14 blind mice to see if they would restore vision.

CHECK OUT: LEGO Unveils New Bricks That Will Help Teach Blind Children to Read Braille

Owing to their nature, mice with working vision prefer dark spaces, and so a test of whether or not the transplant was a success was fairly straight forward; create a bright space and a dark space and wait to see which one was preferred by the mice.

Six mice were found to not only have restored visual function and reflexesnotably in the pupilbut they also preferred to spend their time in the dark space. Chavala hypothesizes that it could have been down to how many of the chemically-reprogrammed cells survived the transplant into the retina that determined whether vision was restored in the mice or not.

What makes interventions like thesewhich involve creating brand new cells to replace the damaged onesso effective and exciting in the field of aging is that they present an alternative to natural replication by bypassing the difficulties that our own cells have with trying to repair themselves from DNA that features double-strand breaks or other blemishes.

Adding that these conversions of fibroblasts to photoreceptors has also been done in humans, Chavala detailed why he believes the treatments and future research to spring from this discovery are going to change the field of ophthalmology.

CHECK OUT: In World First Blind People Have Their Vision Restored Thanks to Stem Cells From Deceased Organ Donors

We [] believe this can be a game changer in the field of regenerative ophthalmology. We also believe this is a platform technology and have already started establishing protocols to generate retinal ganglion cells valuable for patients suffering from glaucoma, says Chavala.

In addition to bypassing the ethical and political restrictions and hiccups with using embryonic human stem cells, the process takes two weeks, costs less, and is more scalable than using stem cells.

WATCH: Hundreds of People Are Being Cured of Blindness Every Day With Cheap, Minutes-Long Surgery

It is intriguing to postulate that the addition of other molecules or modifications to the culture conditions can yield other types of neurons beneficial for a variety of neurological diseases, he adds, discussing possible alternatives to photoreceptor generation from fibroblasts.

Finally, Chavala is rapidly approaching human trials and hopes to have an FDA-approved treatment out the other end of the pipeline in 2-3 years, saying he is thrilled with the possibility of allowing millions of people to regain their lost vision.

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Irreversible No Longer: Blind Mice See Again Thanks To New Method of Synthesizing Lost Cells - Good News Network

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First Posted: Apr 20, 2020 06:30 AM EDT

Almost every month, a new beauty fad takes over the world. Beauty products with activated charcoal have become a household name since it hit the market. Thanks to its ability to unclog pores and remove dirt, bacteria, and all kinds of nasties on the skin's surface, the ingredient has made a name for itself in the beauty world.

By definition, activated charcoal is charcoal that has been treated so it can attract and trap toxins in our bodies before they are absorbed. On the skin's surface, it acts as a magnet for oils, dead skin cells, and dirt from environmental exposure.

Charcoal is known for its diverse uses--whitening teeth and reducing acne, leaving your skin bright and clear. Here are some products with activated charcoal that you must have:

(Photo: Amazon)

Biore's Deep Pore Charcoal Cleanse formula is a dermatologically tested product that lifts away dirt and oil on the skin without all the harsh chemicals. It comes in an easy-to-use pump bottle that provides just the right amount of product for every wash.

Biore's cleansing formula leaves your skin glowing and bright with a cooling menthol effect. It's oil-free, vegan-friendly, cruelty-free, and paraben-free. So if you're looking for something that leaves your face feeling deeply clean, then this product is perfect for you.

(Photo: Amazon)

Biore's Cleansing Pore Strips work like magic in extracting all that unwanted dirt in clogged pores. A strip could easily remove all those nasty blackheads from your nose. The cleansing pore strips are easy to apply and will leave your skin feeling spotless.

For best results, it is recommended to wash your face with warm water to relax and open up the pores before applying a strip. It is also advised to dry your hands before using the piece as it does not stick well to wet surfaces.

(Photo: Amazon)

Colgate's Charcoal Toothpaste effectively whitens teeth and removes impurities that can contribute to surface stain. The product has a great texture and suds up well. Colgate's formula contains micro polishers that leave a whiter, brighter smile, and long-lasting fresh breath.The formula contains essential ingredients to keep your teeth safe from cavities. Use daily for best results.

(Photo: Amazon)

M3 Natural Activated Charcoal Scrub is an all-natural scrub that can be used on the body and the face. The formula is infused with dead sea salt that's effective for extracting and removing excess oil and dirt deep inside the pores. It also contains collagen and stem cells to deliver a powerful anti-aging effect.

The product has been admired for being friendly to acne-prone skin. It's safe, natural, and proven effective. A jar of M3's Activated Charcoal Scrub provides about a month's worth of product.

For best results, apply on damp skin with a circular scrubbing motion. Using a body brush can also increase the scrubbing effect and stimulation to provide a healthy and glowing complexion.

Looking for other products? Check these out:

TagsAmazon, amazon deals, beauty products, activated charcoal

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The report aims to provide an overview of global Autologous Stem Cell and Non-Stem Cell Based Therapies Market with detailed market segmentation by product/application and geography. The global Autologous Stem Cell and Non-Stem Cell Based Therapies Market is expected to witness high growth during the forecast period. The report provides key statistics on the Market status of the Autologous Stem Cell and Non-Stem Cell Based Therapies players and offers key trends and opportunities in the market.

Autologous stem-cell transplantation is the autologous transplantation of stem cells. User preserves his own cells which can be used later. This is considered to be one of the effective and safer way to treat the diseases such as cancer. It is safer technology when compared with allogeneic and xeno transplants. IT reduces the risk of disease transmission, bio-incompatibility, and immunological reactions.

Download a Sample Report Explore further @https://www.theinsightpartners.com/sample/TIPRE00006725

The Autologous Stem Cell and Non-Stem Cell Based Therapies market is anticipated to grow in the forecast period owing to driving factors such as rising prevalence of cancer and diabetes, growing geriatric population, favorable reimbursement scenarios across several countries.

Top Dominating Key Players:

The Global Autologous Stem Cell and Non-Stem Cell Based Therapies market is segmented on the basis of application and end user. Based on application the market is segmented into Neurodegenerative, Cardiovascular, Cancer & Autoimmune, Skin and Infectious Diseases. Based on end user, the market is segmented into hospital and research institute.

The report provides a detailed overview of the industry including both qualitative and quantitative information. It provides overview and forecast of the global Autologous Stem Cell and Non-Stem Cell Based Therapies market based on various segments. It also provides market size and forecast estimates from year 2017 to 2027 with respect to five major regions, namely; North America, Europe, Asia-Pacific (APAC), Middle East and Africa (MEA) and South & Central America. The Autologous Stem Cell and Non-Stem Cell Based Therapies market by each region is later sub-segmented by respective countries and segments. The report covers analysis and forecast of 18 countries globally along with current trend and opportunities prevailing in the region.

The report analyzes factors affecting Autologous Stem Cell and Non-Stem Cell Based Therapies market from both demand and supply side and further evaluates market dynamics effecting the market during the forecast period i.e., drivers, restraints, opportunities, and future trend. The report also provides exhaustive PEST analysis for all five regions namely; North America, Europe, APAC, MEA and South & Central America after evaluating political, economic, social and technological factors effecting the Autologous Stem Cell and Non-Stem Cell Based Therapies market in these regions.

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Autologous Stem Cell and Non-Stem Cell Based Therapies Market Analysis and 2027 Forecasts for United States, Europe, Japan and China Markets - Science...

Skin Stem Cells Comments Off on Autologous Stem Cell and Non-Stem Cell Based Therapies Market Analysis and 2027 Forecasts for United States, Europe, Japan and China Markets – Science… | April 19th, 2020

When our panelists were asked which innovation showed the best results, scalp injections of platelet-rich plasma (PRP) for hair growth was at the top of many lists. You get significant benefits with very little downside, Dr. Schultz says. First, your blood is drawn and spun in a centrifuge to separate the PRP, which is then injected all over your scalp. Using your bloods growth factors to stimulate collagen and follicles lets your own body work its magic, says dermatologist Mona Gohara, M.D.

Another new option is a laser called Lutronic KeraLase ($750 to $1,000 per treatment), which is paired with a synthetic growth factor serum. The device stamps across your scalp, stimulating the area and creating tiny channels in the follicles, where the serum is then applied. It delivers active ingredients where theyre needed, says dermatologist Jeanine Downie, M.D. The serum can contain even more growth factors than a persons own PRP, plus stem cells to help hair growth, she says. Nutrafol for Women (Buy It, $79 $88 for 1 month, nutrafol.com), a supplement brand for hair loss, also garnered multiple mentions from our panel. Ive seen promising results, especially in conjunction with the above treatments, Dr. Downie says.

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The Best Face and Body Skin-Care Products for 2020 - Shape Magazine

Skin Stem Cells Comments Off on The Best Face and Body Skin-Care Products for 2020 – Shape Magazine | April 18th, 2020

Northwestern University scientists received top honors from the Clinical Research Forum as part of its 2020 Top Ten Clinical Research Achievement Awards program, taking home the associations highest honor and capturing more finalist nominations than any other institution.

The remarkable success of these brilliant and dedicated investigators shows the strength and breadth of Northwesterns clinical research program and demonstrates our shared commitment as an institution to groundbreaking science that transforms human health, said Eric G. Neilson, MD, vice president for medical affairs and Lewis Landsberg Dean, Northwestern University Feinberg School of Medicine.

John Rogers, PhD, the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering and Neurological Surgery, was awarded the prestigious Herbert Pardes Clinical Research Excellence Award for the research study that best shows a high degree of innovation and creativity, advances science and has an impact upon human disease.

Richard Burt, MD, chief of Immunotherapy and Autoimmune Diseases in the Department of Medicine, was chosen to receive the Distinguished Clinical Research Award. Norrina Allen, PhD, associate professor of Preventive Medicine in the Division of Epidemiology, and Daniela Matei, MD, the Diana, Princess of Wales Professor of Cancer Research and a professor of Medicine in the Division of Hematology and Oncology, were also named to the list of top 20 finalists.

Rogers and Burt are members of the Northwestern University Clinical and Translational Sciences (NUCATS) Institute. The Clinical Research Forum, an organization dedicated to supporting the clinical translational research enterprise and promoting understanding and support for clinical research and its impact on health and healthcare, celebrates outstanding research accomplishments that exemplify innovation and impact on human disease.

Northwestern studies honored by the Clinical Research Forum are:

Skin-like Devices for Wireless Monitoring of Vital Signs in Neonatal Intensive Care (John Rogers, PhD), published in Science. Reporting on the development and validation of a pair of soft, flexible wireless sensors that replace the tangle of wire-based sensors that currently monitor babies in hospitals neonatal intensive care units. The study concluded that that the wireless sensors provided data as precise and accurate as that from traditional monitoring systems, and were gentler on a newborns fragile skin and allow for more skin-to-skin contact with the parent, which has been shown to improve the health of infants and promote emotional bonding.

Hematopoietic Stem Cell Transplantation for Frequently Relapsing Multiple Sclerosis (Richard Burt, MD), published in JAMA. Reporting the success of a process called hematopoietic stem cell transplantation, which temporarily shuts down and reboots patients immune systems with the application of a patients own stem cells, this study demonstrated significant improvement over the current therapies. The study found benefits for patients which no drug had been able to accomplish before.

Associations of Dietary Cholesterol or Egg Consumption with Incident Cardiovascular Disease and Mortality (Norrina Allen, PhD), published in JAMA.

The results of this large study found that adults who ate more eggs and dietary cholesterol had a significantly higher risk of cardiovascular disease and death from any cause.

The study suggested that current U.S. dietary guideline recommendations for dietary cholesterol and eggs, one of the richest sources of dietary cholesterol among all commonly consumed foods, may need to be re-evaluated.

Adjuvant Chemotherapy plus Radiation for Locally Advanced Endometrial Cancer (Daniela Matei, MD), published in New England Journal of Medicine.

This study found that radiation combined with chemotherapy did not increase recurrence-free survival in women with stage III/IVA endometrial cancer, normally the standard of care in these cases.

Endometrial cancer, which begins in the uterus, is the most common gynecologic cancer with most cases occurring in women after age 55, and both occurrence of and mortality from the disease are rising.

Nominees and Top Ten Awardees were announced at the end of January, and the Herbert Pardes Clinical Research Excellence Award and the Distinguished Clinical Research Achievement Awards were announced virtually on April 15.

Learn more about Northwestern University Feinberg School of Medicine at https://www.feinberg.northwestern.edu/.

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Northwestern Scientists Awarded Top Honors for Achievement in Clinical Research - Northwestern University NewsCenter

Skin Stem Cells Comments Off on Northwestern Scientists Awarded Top Honors for Achievement in Clinical Research – Northwestern University NewsCenter | April 17th, 2020

We've all been talking about Sandra Bullock's beauty for several years now, and we still aren't sure how she manages to look stunning in every single photo of hers. Although she dismissed the idea of having plastic surgery, she does affirm that just like almost every Hollywood celebrity, the Bird Box actress uses natural remedies and a particular treatment which even surprised Ellen Degeneres!

Apparently, yes. In 2018, The Oceans 8 star revealed on The Ellen Show that she gets her foreskin facial also famously known as EGF serum by New York-based celebrity beautician, Georgia Louise who also treats stars like Katy Perry, Cate Blanchett, and Emma Stone.

The480 treatment which has the stem cells from foreskin Korean babies is what makes her skin to look younger and fuller. Approved by the state Department for control over products and medicines, Louise wanted to give Sandra something that would prevent her from undergoing any needles or lasers.

Related:Even Kim Kardashian Has Big Beauty Regrets

"I wanted to give Sandra something that would change her skin without having to go through the lasers and would provide long-term results," George Louise told to People. "In her case, the effect of the procedure seems to work great."

"It's this way in which one forces through micro-needlingit's a little roller, I think many of you know it," She said. "It pushes through the skin, ruptures the collagen and boosts it and you look like a burn victim for a day."

Apart from using the strange serum, Bullock also practices wipes her face with slices of fruits that leaves her skin looking fresh and toned. She uses anti-aging cosmetics as well to smooth out those fine lines and conceal the dark circles but avoids using it heavily on her face.

In fact, the one thing which she never forgets is quality cleansing, and she achieves that by using a sponge made of flannel fabric.

Related:10 Weird Beauty Techniques From Around The World

The 55-year-old actress refrains from using bright shades but instead opts for natural skin tones that make her look more elegant and quintessential. All she uses is a moisturizing cream, a neutral eye shadow, lip gloss, blush and, mascara, and she's good to go.

According to Popsugar, Sandra Bullock often consumes lean proteins in her diet and her menu usually consists of salads, steamed rice, tea and, fresh juices. Emirates Woman reports that Bullock sticks to her lean diet for six days a week but gives her body the freedom to indulge in the things that make her (everyone) happy such as chocolates and sweets.

CBS News reports that Bullock enjoys chicken and turkey meals that are sugar and gluten-free and that she eats throughout the day to maintain her metabolism.

Related:Anna Hathaway Reveals These Simple Yet Stunning Beauty Secrets

Apart from all that, the Speed actress's main beauty secret is apples! She eats apples and honey to overcome her sweet cravings.

"I start Friday night and I end Saturday night." She told InStyle.

She has a simple mantra to keep her healthy and young and that's to eat 5 times a day, eat in small portions, drink a lot of water and to avoid eating after 6 pm.

"There's always cardio like dance, jump roping or rebounding," Bullock told Women's Health. "Then we alternate between 10-minute intervals of high-intensity cardio and strength training moves that focus on different body parts."

Well, it's not easy for a Hollywood Star to maintain their health in between their sleepless nights and busy schedules but Bullock does it all with a strong mindset.

"I never did anything according to what anyone else wanted. That's why I think I am happy," She continued, adding. "I know when I'm getting ready to mess up, I'm going to do it full-on. I now know that anything sweet, really sweet, that I have was nothing that I planned."

And that's about all the hacks we know about the mother of two's everlasting beauty.

Next:Here Are 15 Things Sandra Bullock Has Been Up To Since Bird Box

Selena Gomez Sues Gaming Company For Stealing Her Look- While Instagram Users Accuse Her Of Stealing Someone Elses

Aaliyah Salia is the author of the 13: We all Start as Strangers, a poet, freelance writer, Vlogger, Travel Enthusiast, Script Writer, Proofreader, and Gamer. She has written many fanfictions on the online writing platform called Wattpad and is a Level 2 Seller on Fiverr.

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All The Hacks You Need To Know About Sandra Bullock's Beauty - TheThings

Skin Stem Cells Comments Off on All The Hacks You Need To Know About Sandra Bullock’s Beauty – TheThings | April 17th, 2020

Abstract

The skin constantly renews itself throughout adult life, and the hair follicle undergoes a perpetual cycle of growth and degeneration. Stem cells (SCs) residing in the epidermis and hair follicle ensure the maintenance of adult skin homeostasis and hair regeneration, but they also participate in the repair of the epidermis after injuries. We summarize here the current knowledge of epidermal SCs of the adult skin. We discuss their fundamental characteristics, the methods recently designed to isolate these cells, the genes preferentially expressed in the multipotent SC niche, and the signaling pathways involved in SC niche formation, SC maintenance, and activation. Finally, we speculate on how the deregulation of these pathways may lead to cancer formation.

Keywords: hair follicle, multipotency, self-renewal, cell fate determination, Wnt signaling, Bmp, cancer

Skin and its appendages ensure a number of critical functions necessary for animal survival. Skin protects animals from water loss, temperature change, radiation, trauma, and infections, and it allows animals to perceive their environment through tactile sense. Through camouflage, the skin provides protection against predators, and it also serves as decoration for social and reproductive behavior.

Adult skin is composed of a diverse organized array of cells emanating from different embryonic origins. In mammals, shortly after gastrulation, the neurectoderm cells that remain at the embryo surface become the epidermis, which begins as a single layer of unspecified progenitor cells. During development, this layer of cells forms a stratified epidermis (sometimes called interfollicular epidermis), the hair follicles (HRs), sebaceous glands, and, in nonhaired skin, the apocrine (sweat) glands. Mesoderm-derived cells contribute to the collagen-secreting fibroblasts of the underlying dermis, the dermovasculature that supplies nutrients to skin, arrector pili muscles that attach to each hair follicle (HF), the subcutaneous fat cells, and the immune cells that infiltrate and reside in the skin. Neural crestderived cells contribute to melanocytes, sensory nerve endings of the skin, and the dermis of the head. Overall, approximately 20 different cell types reside within the skin.

In the adult, many different types of stem cells (SCs) function to replenish these various cell types in skin as it undergoes normal homeostasis or wound repair. Some SCs (e.g., those that replenish lymphocytes) reside elsewhere in the body. Others (e.g., melanoblasts and epidermal SCs) reside within the skin itself. This review concentrates primarily on epidermal SCs, which possess two essential features common to all SCs: They are able to self-renew for extended periods of time, and they differentiate into multiple lineages derived from their tissue origin (Weissman et al. 2001).

Mature epidermis is a stratified squamous epithelium whose outermost layer is the skin surface. Only the innermost (basal) layer is mitotically active. The basal layer produces, secretes, and assembles an extracellular matrix (ECM), which constitutes much of the underlying basement membrane that separates the epidermis from the dermis. The most prominent basal ECM is laminin5, which utilizes 31-integrin for its assembly. As cells leave the basal layer and move outward toward the skin surface, they withdraw from the cell cycle, switch off integrin and laminin expression, and execute a terminal differentiation program. In the early stages of producing spinous and granular layers, the program remains transcriptionally active. However, it culminates in the production of dead flattened cells of the cornified layer (squames) that are sloughed from the skin surface, continually being replaced by inner cells moving outward ().

Epidermal development and hair follicle morphogenesis. The surface of the early embryo is covered by a single layer of ectodermal cells that adheres to an underlying basement membrane of extracellular matrix. As development proceeds, the epidermis progressively stratifies and acquires layers of terminally differentiating cells that are required to establish a functional barrier. During embryonic development, some of the undifferentiated basal cells are instructed by the underlying dermis (signal 1) to adopt a hair follicular fate. Subsequently, the epidermis sends a message to the dermis (signal 2) to make the dermal papilla (DP). Finally, the DP sends a message to the developing follicle (signal 3), allowing its growth and differentiation to form the discrete lineages of the hair follicle and its hair. Encased by a basement membrane, the basal layer of the follicle is referred to as the outer root sheath (ORS). At the base of the mature follicle is the highly proliferative compartment called the matrix (Mx). Matrix cells differentiate to form the concentric rings of differentiating cells that give rise to the hair shaft, its channel (the inner root sheath, IRS), and the companion layer. Hair follicles also contain sebaceous glands to ensure the water impermeability of the hair and lubricate the hair channel and skin surface.

The major structural proteins of the epidermis are keratins, which assemble as obligate heterodimers into a network of 10-nm keratin intermediate filaments (IFs) that connect to 64-integrin-containing hemidesmosomes that anchor the base of the epidermis to the laminin5-rich, assembled ECM. Keratin IFs also connect to intercellular junctions called desmosomes, composed of a core of desmosomal cadherins. Together, these connections to keratin IFs provide an extensive mechanical framework to the epithelium (reviewed in Omary et al. 2004). The basal layer is typified by the expression of keratins K5 and K14 (also K15 in the embryo), whereas the intermediate suprabasal (spinous) layers express K1 and K10. Desmosomes connected to K1/K10 IFs are especially abundant in suprabasal cells, whereas basal cells possess a less robust network of desmosomes and K5/K14. Rather, basal cells utilize a more dynamic cytoskeletal network of microtubules and actin filaments that interface through -and -catenins to E-cadherin-mediated cell-cell (adherens) junctions, in addition to the 1-integrin-mediated cell-ECM junctions (reviewed in Green et al. 2005, Perez-Moreno et al. 2003). Filaggrin and loricrin are produced in the granular layer. The cornified envelope seals the epidermal squames and provides the barrier that keeps microbes out and essential fluids in (Candi et al. 2005, Fuchs 1995) (). The program of terminal differentiation in the epidermis is governed by a number of transcription factor families, including AP2, AP1, C/EBPs, Klfs, PPARs, and Notch (reviewed in Dai & Segre 2004).

Although the molecular mechanisms underlying the process of epidermal stratification are still unfolding, several studies have recently provided clues as to how this might happen. Increasing evidence suggests the transcription factor p63 might be involved. Mice null for the gene encoding p63 present an early block in the program of epidermal stratification (Mills et al. 1999, Yang et al. 1999).

There are several possible mechanisms by which stratification could be achieved with an inner layer of mitotically active cells and suprabasal differentiating layers. In the first mechanism, a proliferating basal cell progressively weakens its attachment to the basement membrane and to its neighbors and is pushed off the basal layer and up into the spinous layer. In vitro studies demonstrated that this process, referred to as delamination, effectively allows stratification (Vaezi et al. 2002, Watt & Green 1982). A possible alternative to delamination is that basal cells in a stratifying tissue might orient their mitotic plane of division perpendicular to the underlying basement membrane, which would consequently place one of the two daughter cells in the suprabasal layer.

Recent studies in mice suggest that during embryonic development in skin, the majority of mitotic cells within the epidermis go from having their spindle plane parallel to the basement membrane to a perpendicular orientation (Lechler & Fuchs 2005, Smart 1970). In these perpendicular orientations, the apical centriole associates with a complex containing Nuclear Mitotic Apparatus protein, partitioning-defective protein 3, atypical protein kinase C, Inscuteable, and partner of inscuteable. The association with this cortical complex is intriguing because most of these evolutionarily conserved proteins have been shown genetically to be essential for the asymmetric cell divisions that occur in Drosophila neuroblasts and in Caenorhabditis elegans embryos (Cowan & Hyman 2004, Wodarz 2005). Although many features of the underlying mechanism remain to be addressed, proper spindle orientation appears to require 1-integrin and -catenin, further underscoring the importance of basement membrane and adherens junctions in the establishment of epidermal polarity and tissue architecture (Lechler & Fuchs 2005). More studies are now needed to determine the respective role of asymmetrical cell division and delamination during development, skin homeostasis, and pathological conditions such as wound healing.

The development of HFs involves a temporal series of epithelial-mesenchymal interactions (reviewed in Hardy 1992) (). First, the dermis signals to the overlying epidermis to make an appendage. In response, the epidermis then transmits a signal to instruct the underlying dermal cells to condense and form the dermal papilla (DP). Another signal is then sent from the DP to promote the proliferation and elaborate differentiation required to form the epidermal appendage.

The process of HF development has been divided into discrete stages distinguished by their morphological and biochemical differences (Paus et al. 1999). The first morphological sign of HF development is the formation of a hair placode, in which the basal epithelium becomes elongated and invaginates at sites where dermal condensates form. As the developing follicle extends downward and en-wraps the DP, the cells at the base maintain a highly proliferative state. During follicle maturation, these proliferating (matrix) cells begin to differentiate into the inner root sheath (IRS), which is the envelope for the future hair shaft and is marked by the expression of the transcription factor GATA3 and the structural protein trichohyalin (Kaufman et al. 2003, O'Guin et al. 1992). The outer layer of cells becomes the outer root sheath (ORS), which is contiguous with the epidermis and is surrounded externally by the basement membrane. The ORS expresses K5 and K14, similar to the interfollicular epidermis. As the follicle continues to widen, a new inner core of cells appears and begins to express the hair keratin genes of the hair shaft (reviewed in Omary et al. 2004). By postnatal day 8 in mice, follicle downgrowth is complete, and for the next 7 days, matrix cells proliferate and differentiate into the six concentric layers of the IRS and hair shaft ().

At postnatal day 16, proliferation in the matrix ceases, and the lower two-thirds of the HF rapidly degenerates by a process involving apoptosis (catagen stage). An epithelial strand surrounded by the retracting basement membrane draws the DP upward, where in backskin it comes to rest just below the base of this permanent segment of the HF called the bulge. This resting stage is referred to as telogen. In the first hair cycle, telogen lasts approximately one day, but in subsequent cycles, this phase becomes increasingly extended, suggesting the need to reach a biochemical threshold before the next hair cycle can be activated. The new cycle of hair regeneration (anagen) begins with the emergence of a proliferating hair germ, and the progression to form the mature follicle bears a significant resemblance to embryonic folliculogenesis (Muller-Rover et al. 2001) (). The periodic cycling of hair growth and degeneration persists throughout the life of the animal and implicates the existence of SCs to fuel the regenerative process.

The hair follicle cycle. When matrix cells exhaust their proliferative capacity or the stimulus required for it, hair growth stops. At this time, the follicle enters a destructive phase (catagen), leading to the degeneration of the lower two-thirds of the follicle. The upper third of the follicle remains intact as a pocket of cells surrounding the old hair shaft (club hair). The base of this pocket is known as the bulge, which is the natural reservoir of hair follicle stem cells (SCs) necessary to form a new hair follicle. After catagen, the bulge cells enter a quiescent stage (telogen), in which the DP is now in close contact with bulge SCs. In the mouse, the first telogen lasts approximately one day, after which all the hair follicles synchronously enter a new cycle of regeneration and hair growth (anagen stage). The bulge as a structure develops when the new hair must emerge from the original orifice, which is often shared by the old club hair. Subsequent hair cycles involve increasingly longer telogen phases, resulting in considerably less synchronous hair cycles.

The molecular mechanisms that govern HF morphogenesis and cycling are still poorly understood, but genetic studies in mice reveal the importance of Wnt/-catenin, bone morphogenetic protein (Bmp), sonic hedgehog (Shh), fibroblast growth factor (Fgf), epidermal growth factor receptor (Egf), NFkB, and Notch signaling pathways (reviewed in Millar 2002, Schmidt-Ullrich & Paus 2005).

The adult skin epithelium is composed of molecular building blocks, each of which consists of a pilosebaceous unit (HF and sebaceous gland) and its surrounding interfollicular epidermis (IFE). The IFE contains its own progenitor cells to ensure tissue renewal in the absence of injury, and HFs contain multipotent SCs that are activated at the start of a new hair cycle and upon wounding to provide cells for HF regeneration and repair of the epidermis.

The IFE, which generates the lipid barrier of adult skin, constantly renews its surface throughout the entire life of the animal and also undergoes reepithelialization after wound injuries. These renewing and repairing activities of the skin epidermis imply the existence of SCs to ensure these critical functions. Histological analysis has shown that mouse epidermis is organized in stacks of cells with a hexagonal surface area lying on a bed of ten basal cells (Mackenzie 1970; Potten 1974, 1981). This structure was hypothesized to function as an epidermal proliferative unit (EPU) with one putative SC per unit. Researchers tested experimentally the existence of EPUs using lineage-tracing analyses. The first type of lineage tracing was performed by infecting cultured mouse and human keratinocytes with a retrovirus expressing LacZ and grafting these marked keratinocytes onto immunodeficient mice. Alternatively, mice were directly infected with LacZ-virus in skin, following dermabrasion (Ghazizadeh & Taichman 2001, Kolodka et al. 1998, Mackenzie 1997). Analysis of the chimeric skin revealed the presence of discrete columns of blue cells from the basal cells to the most differentiated uppermost layer of cells. These findings demonstrate that EPUs exist in the basal IFE and can be maintained individually as a separate unit for extended periods of time. Such domains can be explained by a mechanism whereby basal cells divide asymmetrically relative to the basement membrane to maintain a proliferative daughter and give rise to a differentiating daughter cell overlying it (Lechler & Fuchs 2005).

Self-renewal within the epidermis has also been studied using genetic fate mapping, which circumvents the wound response generated in transplantation experiments (Ro & Rannala 2004). In this case, transgenic mice were engineered to express a mutant form of green fluorescent protein (GFP) that cannot be translated owing to the presence of a stop codon in the EGFP-coding sequence. Subsequently, the mice received topical application of a mutagen to induce mutations that can remove the stop codon and restore expression of a functional GFP protein. These sporadic mutations resulted in patches of GFP-positive cells within the IFE, allowing the visualization of EPU columns. Although elegant, these experiments did not address how many SCs are present in each EPU and where the SCs reside within the unit.

In human skin, the epidermis is thicker and undulates to form deep epidermal ridges (rete ridges) that extend downward in the epidermis and help to anchor the epidermis to the dermis. Used only sparingly, SCs have been proposed to cycle less frequently. The infrequently cycling cells within the IFE are located at the base of these ridges, which is conveniently in a more protected site than elsewhere within the IFE (Lavker & Sun 1982).

To identify characteristics of IFE SCs, researchers have turned toward in vitro experiments. Cultured human IFE keratinocytes expressing the highest level of 1-integrin have the highest proliferative potential in vitro (Jones & Watt 1993). Other genes have also been shown to be preferentially expressed in 1-enriched human keratinocytes, underscoring the biochemical distinctions of this population of basal cells (Legg et al. 2003). As would be expected, the 1-bright cells are found in the basal layer, but interestingly, they reside in clusters (Jones et al. 1995). Additionally, the 1-bright cells do seem to reside at the base of the deepest epidermal ridges of palmoplantar skin, consistent with the location of slow-cycling SCs observed by Lavker & Sun (1982). Elsewhere, however, the 1-bright clusters reside outside these zones, in a seemingly more compromised position for SCs. Hence, the extent to which 1-integrin levels define the distinguishing features of IFE SCs must await further studies. In this effort, additional markers are needed to enrich the purification and analyses of IFE cells with high proliferative potential. Such markers should also help in defining the location and the number of IFE SCs within their functional EPU columns and in discerning the extent to which less frequent cycling is a measure of stemness within the IFE population. A final issue to be resolved is the extent to which cells with high proliferative potential in the basal layer of the IFE are able to contribute to other cell lineages, i.e., those of the sebaceous gland and HF.

In the mid-1970s, Rheinwald & Green (1975) defined culture conditions allowing the growth of human IFE SCs in vitro. This seminal discovery allowed the propagation of keratinocytes from severely burned patients and their subsequent grafting as sheets of autologous cultured cells that were functional in reepithelializing the damaged skin (Gallico et al. 1984, O'Connor et al. 1981, Pellegrini et al. 1999, Ronfard et al. 2000). In the past 25 years, this technology has saved many lives. Although the patient's repaired skin epithelium does not regenerate sweat glands or HFs, it does have a normal epidermis, which can undergo wound repair.

When plated at low cell density, cultured human keratinocytes can form three types of colonies: (a) highly proliferative colonies (holoclones) of small round cells that present an undifferentiated morphology and that can be passaged long-term, (b) aborted colonies (paraclones) displaying large flat morphology typical of terminally differentiated cells, and (c) relatively small heterogeneous colonies (meroclones) of limited proliferative potential that become senescent after a few rounds of passaging (Barrandon & Green 1987). Although the term holoclone refers only to the proliferative capacity of the colony, the progeny of a single epidermal holoclone in vitro can re-form a functional and renewable epidermis in vivo (Rochat et al. 1994). This implies that at least some cells within holoclones possess the fundamental characteristics of a SC in that they can self-renew and differentiate into a functional tissue. By contrast, meroclones have been likened to so-called transit-amplifying cells, i.e., cells with a limited number of cell divisions before they commit to terminally differentiate. Although the precise physiological relevance of these cultured populations of cells remains to be determined, the in vitro description of their clonal properties has served as a useful foundation for the analyses of SCs in vivo.

In the hair follicle, SCs reside in a discrete microenvironment called the bulge, located at the base of the part of the follicle that is established during morphogenesis but does not degenerate during the hair cycle. Bulge SCs are more quiescent than other cells within the follicle. However, during the hair cycle, bulge SCs are stimulated to exit the SC niche, proliferate, and differentiate to form the various cell types of mature HFs. In addition, to provide cells during HF regeneration, the bulge SC is a reservoir of multipotent SCs that can be recruited during wound healing to help the repair of the epidermis. We summarize here the recent progress in the functional and molecular characterization of bulge SCs.

For many years, it was thought that the SCs that regenerate HFs during the hair cycle are the highly proliferative matrix cells (Kligman 1959). This model was later challenged when Montagna & Chase (1956) observed that X-ray irradiation kills the matrix cells, but hairs can still re-form from cells within the ORS. The ability of the upper ORS to act in concert with the DP to make HFs was further substantiated by dissection and transplantation experiments (Jahoda et al. 1984; Oliver 1966, 1967).

Mathematical modeling has supported the notion that SCs may be used sparingly and hence divide less frequently than their progeny (Potten et al. 1982). This notion was bolstered by administering repeated doses of marked nucleotide analogs such as BrdU or 3[H]-thymidine to label the S-phase cycling cells of the skin (pulse period) and then following the fate of the incorporated label over time (chase period). The differentiating cells are sloughed from the skin surface, and the more proliferative cells dilute their label as they divide, marking the least proliferative cells as label-retaining cells (LRCs) (Bickenbach 1981).

To locate HF LRCs, Lavker and colleagues (Cotsarelis et al. 1990) administrated BrdU for a week in newborn mice and then analyzed label retention in the skin after four weeks of chase. The majority of LRCs in the skin resided in a specialized region at the base of the permanent segment of the HF. Known as the bulge, this region was described more than a century ago by histologists (Stohr 1903). Within the ORS, the bulge resides just below the sebaceous gland at a site where the arrector pili muscle attaches to the follicle (). Although its origins are likely to be traced to the early stages of HF embryogenesis, the bulge acquires its distinctive appearance when the first postnatal hair germ emerges before the prior club hair has been shed (). During the first telogen phase, a single layer of quiescent cells surround the old club hair; as the new hair cycle initiates, the bulge acquires a second layer of cells (Blanpain et al. 2004).

Although generally quiescent, bulge cells can be prompted to proliferate artificially in response to mitogenic stimuli such as phorbol esters (TPA) or naturally at the start of each hair cycle. In an elegant double-label study to demonstrate a precursor-product relation, Taylor et al. (2000) showed that when BrdU-labeled LRCs in the bulge are exposed to a brief pulse of a second nucleotide label, they incorporate 3[H]-thymidine as they exit and proliferate to develop the new hair germ. To directly determine whether the bulge region contains SCs, Barrandon and coworkers (Kobayashi et al. 1993) dissected rat and human HFs and assessed the growth potential of different HF segments in vitro. In rat-whisker follicles, 95% of the derived holoclones came from cells of the bulge segments, whereas less than 5% of the growing colonies could be derived from the matrix region. In adult human skin, keratinocytes with high proliferative potential were also found within bulge segments, but the zone of clonogenic cells was broader, extending from the bulge to the lower ORS (Rochat et al. 1994). In this regard, in adult human skin, the bulge is notably a less distinctive structure than it is in rodents.

Early studies involving reepithelialization during wound repair led researchers to posit that HFs may have the capacity to regenerate epidermis upon injury (Argyris 1976). To evaluate whether bulge LRCs have this capacity, Taylor et al. (2000) extended their double-labeling techniques to wound-healing experiments. Indeed, following a wound, BrdU-labeled cells derived from the bulge could be found proliferating within the epidermis near the HF orifice (infundibulum).

Fuchs and coworkers (Tumbar et al. 2004) recently adapted the nucleotide pulse-chase experiments to the protein level by engineering mice expressing a tetracycline-regulated histone H2B-GFP protein in their skin epithelium. In the absence of tetracycline, all the skin epithelial nuclei were green with H2B-GFP expression, but when tetracycline was administered, the gene was shut off, and after four weeks, only the bulge cells still labeled brightly with H2B-GFP protein (). Upon wounding, H2B-GFP-positive cells were detected in the epidermis and infundibulum, confirming the ability of bulge LRCs to reepithelialize the epidermis in response to injury (Tumbar et al. 2004). Upon activation of the hair cycle, the emerging hair germ displayed H2B-GFP-positive cells with much weaker fluorescence than the bulge, suggesting that they were derived from the bulge LRCs. These findings support the studies of Barrandon, demonstrating the ability of bulge cells to regenerate the HF during the normal hair cycle.

The bulge stem cells (SCs). Bulge (Bu) SCs are more quiescent than are other keratinocytes with proliferative potential in the skin. Tumbar et al. (2004) developed a strategy for conducting fluorescent pulse-chase experiments in mice engineered to express a tetracycline-regulatable H2B-GFP transgene. After labeling all the skin epithelial cells with H2B-GFP, a four-week chase resulted in significant H2B-GFP-label retention only in the bulge (a). Label-retaining cells (LRCs) could be found along the basal layer of cells that express 64-integrins, as well as in a suprabasal location within the bulge (b). Bulge SCs express a high level of the cell surface protein CD34, which has been used with 6-integrin to isolate basal and suprabasal bulge cells, using flow cytometry (Blanpain et al. 2004, Trempus et al. 2003). [The approximate fluorescence of the outer root sheath (ORS) and interfollicular epidermis (IFE) cells is also indicated on the FACS profile.] Tissues were counterstained with Dapi (blue) to mark the nuclei. Abbreviations used: Cb, club hair; HF, hair follicle; SG, sebaceous gland.

Several lines of evidence suggest that there is a continuous flux of bulge cells throughout the growing stage of the hair cycle. During the anagen phase of the backskin hair cycle, Tumbar et al. (2004) detected a trail of H2B-GFP-positive cells along the lower ORS. Although these cells were less bright than their bulge LRC counterparts, the results were intriguing in light of rat-whisker bulge transplantation and clonogenic experiments performed by Barrandon and colleagues (Oshima et al. 2001). Based on these seminal studies, researchers proposed that SCs migrate from the bulge along the basal layer of the ORS to the matrix, where they proliferate and differentiate to produce the hair and IRS. Although the hair cycle of whisker follicles differs from those in the backskin in that the growing stage is longer and follicles transit from mid-catagen directly to anagen, a common theme for SC movement and activation likely applies for HFs, irrespective of whether they are whisker or pelage follicles.

In the past ten years, researchers have made considerable strides in isolating and purifying cells from the HF bulge. Given the complexity of the skin, purification of bulge cells using flow cytometry (FACS) has focused on isolating bulge cells in the simpler, telogen-phase follicles, where the quiescent bulge marks the base. Kaur and colleagues (Li et al. 1998) have employed conjugated antibodies against 6-integrin and anti-CD71 (antitransferin Ab or 10G7) to show that 6-bright, CD71-dim cells from skin possess similar colony-forming efficiency but higher long-term growth potential than the rest of the population. Bulge LRCs share this expression pattern and are enriched in the 6-bright, CD71-dim population by approximately twofold (Tani et al. 2000). Other markers such as S100A4 and S100A6 proteins (Ito & Kizawa 2001), K19 (Michel et al. 1996), K15 (Lyle et al. 1998), and CD34 (Trempus et al. 2003) have also been reported to exhibit preferential expression in the bulge. Although most of these antibodies have not proven useful for isolating living bulge cells by FACS, CD34 is an exception. CD34-positive cells are enriched tenfold for LRCs, and they form larger colonies than unfractionated epidermis (Trempus et al. 2003).

When transgenic expression of a basal epidermal marker (K14-GFP) is used in conjunction with antibodies against 6-integrin and CD34, purification of bulge cells is enhanced substantially (Blanpain et al. 2004). On the basis of differential 6 expression, the CD34/K14-GFP-positive cells from the inner and outer layers of the mature bulge can also be fractionated (). Bulge cells have also been purified from K15-GFP-transgenic skin in conjunction with 6-integrin antibodies (Morris et al. 2004), and when tetracycline-regulatable H2B-GFP mice are employed for bulge purification, a 70-fold enrichment of bulge LRCs can be achieved over unfractionated skin epithelial cells (Tumbar et al. 2004). In all three of these methods for obtaining bulge cells with high purity, bulge cells form large colonies that can be passaged in vitro (Morris et al. 2004, Tumbar et al. 2004). This is true for both the inner and the outer layer of the bulge (Blanpain et al. 2004) (). Clonogenicity studies further demonstrate that a large colony derived from a single bulge cell can give rise to multiple large colonies upon passaging, implying the occurrence of SC self-renewal in vitro (Blanpain et al. 2004, Claudinot et al. 2005).

The two major properties of SCs are their abilities to self-renew and to differentiate along multiple lineages. To address the differentiation potential of bulge SCs, researchers have used a variety of methods, including (a) transplantation studies of microdissected HF segments, (b) direct transplantation and clonal analysis of isolated bulge cells, and (c) genetic fate mapping in mice.

In pioneering studies, Oshima et al. (2001) generated chimeric rodent-whisker follicles by removing the unlabeled bulge of a wild-type vibrissae follicle, replacing it with a lacZ-expressing bulge microdissected from a transgenic mouse-whisker follicle and transplanting the chimeric follicle into the kidney capsule and/or embryonic backskin from immunodeficient mice. Thirty days after transplantation, lacZ-marked cells were detected in the epidermis, sebaceous gland, and HFs (Oshima et al. 2001). Morris et al. (2004) have obtained similar results using 105-FACS-isolated K15-GFP-tagged bulge cells transplanted into immunodeficient mice.

In the experiments of Barrandon and coworkers, temporal analysis of anagen-phase chimeric whisker follicles revealed a downward flux of lacZ-positive cells originating from the transplanted bulge, migrating to the matrix and subsequently differentiating into one of the six concentric rings of IRS and hair shaft lineages. Although at reduced frequency, cells residing in the lower HF were also able to differentiate into multiple skin cell lineages (Oshima et al. 2001). These findings support the view that SCs migrate from the bulge to the base of the follicle before they differentiate and lose their potential. As outlined above, it still remains to be resolved as to whether a continuous downward flux of bulge cells occurs only in whiskers or human HFs, in which the hair cycle displays a prolonged anagen phase, or whether it is a feature common to all HFs.

The studies above beautifully underscore the potential of cells within the bulge region to differentiate along the three different lineages afforded to the skin keratinocyte. However, they do not address whether the bulge consists of multiple types of unipotent progenitors, each of which are able to differentiate along one lineage, or whether individual bulge cells possess multipotency, the ability to differentiate along any of the three lineages. To date, technical hurdles have precluded testing for multipotency using in vivo clonal analyses. However, in the past few years, researchers have employed clonal analyses in vitro to demonstrate definitively the multipotency of bulge cells when passaged in vitro (Blanpain et al. 2004, Claudinot et al. 2005).

In the first study, Fuchs and coworkers (Blanpain et al. 2004) placed isolated K14-GFP-tagged bulge cells in culture to obtain individual holoclones. After short-term expansion, the descendents from a single bulge cell were then transplanted onto the backs of nude mice. The progeny of single bulgederived holoclones each gave rise to GFP-positive HFs, IFE, sebaceous gland, and even bulge SCs (Blanpain et al. 2004). Similar results were obtained by Barrandon and coworkers (Claudinot et al. 2005), who were able to generate thousands of HFs from the progeny of a single cultivated rat-whisker SC. These experiments provide compelling evidence in support of the notion that cells within the adult follicle bulge possessing the classical criteria of bona fide multipotent SCs. That the inner bulge layer also has this capacity further suggests that even when bulge cells detach from the basal lamina and appear to undergo early commitment to the HF lineage, the process is reversible, at least after in vitro culture (Blanpain et al. 2004).

Under normal circumstances, the bulge acts as a reservoir of follicle SCs, and only in response to injury has it been shown to mobilize and function as a multipotent SC reservoir. Whether there are other multipotent SCs in adult skin remains to be demonstrated. However, there is substantial evidence that unipotent SCs exist in other locations in the skin. Fate-mapping experiments using a Cre recombinase that permanently marks bulge cells reveal that under physiological conditions, the IFE contains only rare patches of -galactosidase-positive cells derived from bulge cells. These data reinforce the notion postulated above on the basis of EPU columns: Normal IFE homeostasis is controlled by the presence of unipotent progenitors that reside within the IFE (Ito et al. 2005, Levy et al. 2005, Morris et al. 2004). That bulge SCs are not necessary for epidermal homeostasis is perhaps best exemplified by the fact that palmoplantar skin lacks HFs altogether, as do a number of genetic hair disorders, yet epidermal homeostasis and wound repair can still take place (Montagna et al. 1954).

To determine which genes and signaling pathways operate within the bulge SCs, researchers have performed transcriptional profiling on isolated telogen-phase bulge cells (Blanpain et al. 2004, Morris et al. 2004, Tumbar et al. 2004). In most cases, these profiles have been compared with those of basal epidermal cells, which have proliferative capacity but are thought to contain few if any multipotent SCs. Notably, most of the transcripts upregulated in either the Tumbar or Morris arrays were upregulated in the Blanpain array, which encompassed a considerably larger gene set compared with the two earlier studies. Blanpain et al. (2004) list 56 transcripts that scored as upregulated in bulge cells irrespective of the isolation method, hair cycle stage, or attachment to the basal lamina and that can be viewed as a molecular signature of bulge cells.

Interestingly, 14% of genes found to be upregulated in other types of SCs (hematopoeitic SC, neuronal SC, and embryonic SC) (Ivanova et al. 2002, Ramalho-Santos et al. 2002) were also found to be a part of the bulge signature (Blanpain et al. 2004), suggesting that certain genes within this list are likely involved in the unique properties common to many if not all SCs. Related to this issue are the important similarities recently uncovered between these mouse bulge SC profiles and those of human bulge SCs (Ohyama et al. 2006). Although some differences were noted (CD34, for example, extends to the lower ORS in human follicles), this similarity bodes well for future clinical studies aimed at improving the potential of skin SCs for therapeutic purposes.

The bulge signature now provides a constellation of markers that should enable researchers to examine the extent to which bulge cells retain their program of gene expression as they respond to natural stimuli, e.g., during the hair cycle and upon injury, and as they exit the niche to migrate and/or differentiate along particular lineages. The list should also be useful in examining how the bulge cells change their properties in response to various genetic manipulations. Through such future examinations, scientists should begin to uncover the extent to which the bulge signature is a reflection of the quiescence of these SCs and identify the subset of these genes involved in self-renewal and in suppression of lineage determination irrespective of whether a skin SC is quiescent or proliferative.

Although these studies are in their infancy, a few important lessons are already emerging. One intriguing aspect of the transcriptional profiling conducted on the bulge to date is the high degree to which the bulge signature is maintained in both anagen and telogen stages of the hair cycle and in basal and suprabasal bulge layers (Blanpain et al. 2004). These findings underscore the powerful influence that the microenvironment of the bulge niche has on its residents. In turn, for a bulge SC to become mobilized and exit the niche, this dominance must be overcome.

Although researchers are conducting additional experiments to dissect the molecular significance of the bulge signature, it is tempting to speculate on the roles of various transcripts that are either up- or downregulated preferentially in the bulge. To this end, a number of bulge signature genes encode cell adhesion, cytoskeleton, and ECM components. We posit that these genes may reflect the specialized microenvironment that must be suitable not only for maintaining their SC characteristics within the niche, but also for allowing bulge SCs to exit their niche and migrate during wound repair and/or in hair regrowth.

The bulge signature also provides a battery of candidate genes likely to play a role in SC quiescence. Most notable are the many upregulated genes encoding cell-cycle inhibitory factors, such as Cdkn1b (p27), Cdkn1c (p57), and Cdkn2b (p15), and the numerous downregulated genes encoding cell-cycle-promoting factors, such as Ki67, proliferating cell nuclear antigen, cyclins (Cyclin D1, D2, A2, B1) and cyclin-dependent kinases, and cell-division-cycle-related genes (Cdc2a, 2b, 6, 7, 25c) (Blanpain et al. 2004, Morris et al. 2004, Tumbar et al. 2004). Although the cell cycle is typically thought to be regulated largely at the posttranslational level, the transcriptional regulation of these cell-cycle genes suggests that the quiescent nature of the bulge is governed by unique operational control mechanisms.

Finally, another interesting set of bulge signature genes contains those that are likely involved in maintaining the SCs in an undifferentiated, growth-inhibited state. Of these genes, it is particularly interesting that many components of the Wnt/-catenin signaling pathway (Tcf3; Tcf4; Dkk-3; sFRP1; Fzd 2, 3, 7; Dab2; Ctbp2) and the TGF-/Bmp signaling pathways (Ltbp1, 2, 3; Tgf-2; Gremlin) are upregulated in the bulge. These pathways are discussed individually in the sections below.

The Wnt/-catenin signaling pathway is conserved throughout the eukaryotic kingdom, where it controls a myriad of different cellular decisions during embryonic and postnatal development (). Wnt deregulation leads to an imbalance of proliferation and differentiation, often resulting in cancers (Reya et al. 2001).

The Wnt/-catenin signaling pathway during hair follicle (HF) morphogenesis and regeneration. (a) Schematic of the canonical Wnt pathway (for more details, see http://www.stanford.edu/%7Ernusse/). In the absence of a Wnt signal, the excess of cytoplasmic -catenin is targeted for degradation through its association with a multiprotein complex. Upon binding Wnt, its activated receptor complex recruits certain key components of the -catenin degradation targeting machinery. Stabilized free cytoplasmic -catenin is now translocated to the nucleus, where it can associate with transcription factors of the LEF/TCF family to transactivate the expression of their target genes. (b) Loss- and gain-of-function studies in mice have highlighted the different functions of Wnt/-catenin signaling during morphogenesis and adult skin homeostasis. During HF morphogenesis, Wnt/-catenin is required to specify the HF (placode) fate in the undifferentiated basal epidermis. During the adult hair cycle, Wnt/-catenin is required to maintain HF stem cell (SC) identity. As judged by a Wnt reporter transgene, an increase in Wnt signaling promotes SC activation to initiate the growth of a new hair during the telogen-to-anagen transition. An even stronger signal appears to be involved later at the transition of matrix cells to commit to terminally differentiate specifically along the hair shaft lineage. (c) When a constitutively active form of -catenin is expressed for sustained periods in skin epidermis, mice develop de novo HFs from the interfollicular epidermis (IFE), outer root sheath (ORS), and sebaceous glands (SGs). Eventually, these mice develop HF tumors called pilomatricoma, which consist of immortalized matrix-like cells at the periphery, and pure hair cells in the centers (no inner root sheath or companion layer cells). Visualization was enhanced by breeding the K14-N mice on a background of K14-GFP mice. (d) The different signal strengths of Wnt reporter gene activity, combined with the -catenin dosage dependency associated with these different outcomes in mice, can be explained by a model whereby the effective strength of Wnt signaling controls the behavior and fate of the follicle SC. Note: The so-called gradient of Wnt activity refers to the status of Tcf/Lef/-catenin transcriptional activity within the cell, which in fact could be achieved as a gradient, without even involving a Wnt per se. DP, dermal papilla.

Wnts compose a large family of cysteine-rich secreted glycoproteins that activate Frizzled receptors, which in turn stimulate a cascade of events culminating in the stabilization and accumulation of cytoplasmic -catenin. Normally, cellular -catenin is complexed with E-cadherin and -catenin at adherens junctions, and free cytoplasmic -catenin is degraded by the proteasome. Upon Wnt signaling, excess -catenin is no longer degraded, and it is free to complex with and activate members of the Tcf/Lef1 family of transcription factors (Logan & Nusse 2004) ().

The sonic hedgehog (Shh) signaling pathway during hair follicle morphogenesis and adult hair cycle. (a) Schematic of the Shh pathway. In the absence of Shh, its receptor Patched (Ptch) inhibits Smoothened (Smo) activity. Upon Shh binding, Ptch can no longer repress Smo, which activates the translocation of Gli into the nucleus, allowing it to transactivate its target genes. (b) The role of Shh in the hair follicle. Loss-of-function studies in mice have revealed the importance of Shh in sustaining proliferation in the embryonic and adult hair germ. Gain-of-function studies underscore the striking relation between basal cell carcinomas and deregulation of the Shh pathway. (c) Shh is not expressed in the quiescent bulge stem cells. During hair regeneration, there is a lag before Shh is strongly activated in the developing hair germ. Sustained expression of Shh seems to rely on close association with the dermal papilla (DP). Both in embryonic development and the adult, Shh appears to act downstream of the Wnt/-catenin signaling pathway. Bu, bulge; HG, hair germ.

In the skin, Wnt and -catenin play diverse roles in HF morphogenesis, SC maintenance and/or activation, hair shaft differentiation, and also pilomatricoma tumor formation in mice and humans (Alonso & Fuchs 2003). Activation of Wnt/-catenin signaling is critical during the first stage of HF morphogenesis, as evidenced by the absence of placode formation on conditional ablation of -catenin (Huelsken et al. 2001) or constitutive expression of a soluble Wnt inhibitor (Dkk1) (Andl et al. 2002). Although the source and identity of the putative Wnt signal required to induce placode formation remain elusive, it may be the first dermal signal to instruct epidermal cells to make hair. Consistent with this notion is the activation in both the placode and the postnatal hair germ of a Wnt reporter gene driving lacZ under the control of an enhancer composed of multimerized binding sites for the Lef1/Tcf DNA-binding proteins that interact with and are activated by association with -catenin (DasGupta & Fuchs 1999, Reya & Clevers 2005) (). Nuclear -catenin and Lef1 expression are also seen in embryonic placodes and postnatal hair germs at this time (Merrill et al. 2004, van Genderen et al. 1994, Zhou et al. 1995). Noggin, a soluble inhibitor of Bmps, is expressed by the mesenchymal condensate and is required in the early stage of HF morphogenesis and cycling. It appears to act at least in part by promoting expression of Lef1 (Botchkarev et al. 2001, Jamora et al. 2003).

Transgenic mouse studies support a role for Wnt signaling in the specification of HF development. Mice expressing a constitutively stabilized -catenin (>N-catenin) display de novo HFs (Gat et al. 1998) (), whereas mice lacking Lef1 (van Genderen et al. 1994) or -catenin (Huelsken et al. 2001) or overexpressing the Wnt inhibitor Dkk1 exhibit a paucity of follicles (Andl et al. 2002).

Postnatally, the strongest Wnt signal is associated with the terminally differentiating cortical cells of the hair shaft (DasGupta & Fuchs 1999) (). The hair keratin genes possess Lef1/Tcf DNA-binding domains and are bona fide targets for Wnt-mediated gene expression (Merrill et al. 2001, Zhou et al. 1995). This lineage of the matrix cells appears to be particularly singled out for robust Wnt signaling, as K14-N-catenin transgenic mice develop pilomatricomas, which are pure tumor masses of cortical cells (Gat et al. 1998). Similarly, the majority of human pilomatricomas possess N-terminal stabilizing mutations in the coding sequence of the -catenin gene (Chan et al. 1999, Xia et al. 2006).

In contrast to the cortical cells, the bulge is largely silent for Wnt reporter activity (DasGupta & Fuchs 1999). Microarray data suggest that the bulge is normally in a Wnt-inhibited environment, showing an upregulation of genes encoding putative Wnt-inhibitory factors (sFRP1, Dkk3, Wif) and a downregulation of genes encoding Wnt-promoting factors in the bulge (Wnt3, Wnt3a). However, bulge SCs express a number of frizzled surface receptors (Fz2, 3, and 7) to enable them to receive Wnt signals as well as Wnt-signaling-related transcription factors (Tcf3, Tcf4, Tle1, Ctbp2) to enable them to transmit a Wnt signal (see Tumbar et al. 2004). In this regard, Tcf3 is intriguing, as it has been shown to act as a repressor in the absence of Wnt signaling (Merrill et al. 2001, 2004). Taken together, these findings suggest that bulge SCs are in a quiescent, Wnt-inhibited state and that Wnt signaling plays a key role in driving these cells along at least one hair differentiation lineage ().

Several studies suggest that the role of Wnt signaling in the postnatal HF may be even broader. The involvement of Wnts in HF morphogenesis suggests that Wnt signaling may be important for activating bulge SCs. Consistent with this notion is the presence of a few Wnt-reporter-driven, LacZ-positive bulge cells at the beginning of the hair cycle (DasGupta & Fuchs 1999). The number of activated bulge cells can be considerably enhanced by breeding the Wnt-reporter mice on the background of K14-N-catenin mice; at most stages of the hair cycle, however, the bulge remains silent for Wnt-reporter activity (DasGupta & Fuchs 1999, Merrill et al. 2001).

By inducing the expression of stabilized -catenin in telogen-phase follicles, several groups have observed precocious activation of hair regeneration (Lo Celso et al. 2004, Lowry et al. 2005, Van Mater et al. 2003), in a fashion reminiscent of the de novo follicle morphogenesis that occurs in the IFE (Gat et al. 1998). Despite the premature transition from telogen to anagen, the K14-N-catenin bulge reenters its relatively quiescent state once the follicle has grown downward (Lowry et al. 2005). These findings imply that some additional factor(s) is required in addition to elevated Wnt signaling to change the status of Lef1/Tcf-regulated genes (including TopGal) and activate bulge SCs. It is tempting to speculate that this signal emanates from the DP, given the close proximity of the DP to the bulge prior to the start of the hair cycle. One candidate may be the Bmp-inhibitor Noggin, produced by the DP and shown to be required for Lef1 expression in the embryonic hair placode and in the matrix cells as well (Andl et al. 2004, Botchkarev et al. 1999, Jamora et al. 2003, Kobielak et al. 2003). Fgf7 and Fgf10 are additional candidates known to be expressed in the bulge and to have an impact on follicle morphogenesis (Guo et al. 1993, Petiot et al. 2003).

Despite the continuous presence of an elevated level of stabilized -catenin, the size of the SC niche does not change over time (Lowry et al. 2005). This means that if elevated -catenin promote the self-renewal of bulge SCs, it must be accompanied by an increase in the rate at which SCs exit the niche. Two factors consistent with this notion are that the rate of BrdU-label retention is reduced and the level of BrdU-label incorporation is enhanced in the K14-N-catenin bulge. That said, this increased proliferation appears to be manifested in precocious SC activation, as it was not accompanied by a noticeable increase in the length of the hair or the cellularity of HFs.

To understand how -catenin elevation can promote SC activation in the bulge, Lowry et al. (2005) conducted microarray analyses on telogen- or anagen-phase SCs isolated from N-catenin or wild-type follicles. Intriguingly, some telogen-phase bulge genes affected by N-catenin were similarly affected in the normal anagen-phase bulge, suggesting the transgene-induced changes may reflect natural changes that occur in the telogen-to-anagen transition of the hair cycle. Although further studies are needed to assess the extent to which this is the case, genes that surfaced in these arrays and that may play a role in Wnt-mediated bulge SC activation include Cyclin D2 (Ccnd2), Sox4, and Biglycan (Lowry et al. 2005). Another protein upregulated in the early anagen bulge appears to be the transcriptional corepressor Hairless, which has been proposed to function by blocking the expression of the soluble Wnt inhibitor Wise, which in turn may lead to Wnt-mediated SC activation (Beaudoin et al. 2005). An additional interesting twist is the recent study reporting that Shh is a downstream target of Wnt-mediated activation of follicle SCs (Silva-Vargas et al. 2005). Shh is particularly intriguing as a Wnt candidate, as it would integrate these two key signaling pathways essential for HF morphogenesis. That said, on the basis of the differential expression of direct Wnt target genes and Shh, it seems unlikely that Shh is a direct target for Wnt signaling in bulge cells (Lowry et al. 2005). We discuss the Shh pathway in greater depth below.

In summary, these findings delineate sequential roles for Wnt signaling in temporally regulating follicle SC lineages, perhaps in a fashion that depends on the level of the signal: (a) -catenin stabilization promotes bulge SC activation, proliferation, and induction of follicle regeneration; (b) -catenin stabilization promotes the specification of matrix cells to terminally differentiate along the hair (cortical) cell lineage; (c) -catenin stabilization promotes de novo HF morphogenesis; and (d) constitutively active -catenin expression results in pilomatricoma hair tumors. The particular fate selected by a follicle cell appears to depend on a constellation of intrinsic and extrinsic factors, which together influence the status of Tcf/Lef1-regulated genes. At the Wnt-inhibited end of the spectrum is SC quiescence, and at the constitutive Wnt end is tumorigenesis ().

Similar to Wnt/-catenin, Shh is an ancient signaling pathway involved in cell fate specification and proliferation during animal development (Taipale & Beachy 2001). The Shh transmembrane receptor is Patched (Ptch), which is active in the absence of Shh (). Ptch functions by inhibiting Smoothened (Smo), which is essential to transduce the Shh signal through the Gli family of transcription factors to induce target gene expression. Ptch itself is a Shh target gene, resulting in the localized sequestration of Shh and the restriction of long-range signaling (Casali & Struhl 2004).

Given the prominence of the Shh pathway in development and proliferation, it is not surprising to find that when deregulated, this pathway leads to tumorigenesis. Rubin et al. (2005) illuminated its importance in skin with the finding that Ptch1 gene mutations cause basal cell nevus syndrome, a hereditary predisposition to basal cell carcinomas (BCCs), the most common type of skin cancer in humans. In the skin, Ptch acts as a tumor suppressor gene, as loss of heterozygosity at the Ptch locus (chromosome 9q22.3) has been observed in sporadic BCC and BCCs isolated from patients with basal cell nevus syndrome (Gailani et al. 1996, Hahn et al. 1996, Johnson et al. 1996, Unden et al. 1996). Activating mutations in Smo have also been detected in sporadic BCCs (Xie et al. 1998), and overexpression of Shh, Smo, Gli1, or Gli2 leads to BCCs in mice (Dahmane et al. 1997, Grachtchouk et al. 2000, 2003; Hutchin et al. 2005; Oro et al. 1997; Xie et al. 1998). Recently, Vidal et al. (2005) demonstrated that an HMG transcription box factor, Sox9, is also upregulated in BCC, and epistasis experiments suggest that Sox9 is downstream of the Shh signaling pathway in skin.

BCCs are thought to be derived from HFs, and consistent with this notion, Shh is expressed in the hair placodes of embryonic skin (St-Jacques et al. 1998) (). As revealed by Ptch expression, Shh is likely to signal in both the epithelial hair germ and its underlying mesenchymal condensate, suggesting its potential role in the epithelial-mesenchymal cross talk essential for follicle formation (Oro & Higgins 2003, Oro et al. 1997). Loss-of-function mutations in Shh are still permissive for hair germ formation, placing Shh genetically downstream of Wnt and Noggin signaling (). However, placodes fail to develop further, thus positioning Shh upstream from the proliferative cascade essential for HF morphogenesis (Chiang et al. 1999, St-Jacques et al. 1998, Wang et al. 2000). Mice deficient in Gli2 present a phenotype similar to Shh-null mice, suggesting that Shh acts mainly through Gli2 in HF (Mill et al. 2003).

Shh signaling is also important for follicle regeneration during the adult hair cycle. Although not expressed in the bulge, Shh is expressed in the matrix and in the developing germ, where it becomes polarized to one side during anagen progression (). The mechanisms underlying this exquisite restriction in expression are not understood, but Shh signaling is likely to span the matrix, as evidenced by Ptch expression (Gat et al. 1998, Oro & Higgins 2003). As would be predicted from the relative roles of Shh and Wnt signaling in embryonic skin, anti-Shh antibodies delivered to postnatal follicles block anagen progression (Wang et al. 2000), and similarly the Shh inhibitor cyclopamine blocks hair regeneration (Silva-Vargas et al. 2005). Conversely, Shh or small-molecule Shh agonists accelerate the progression from telogen to anagen (Paladini et al. 2005, Sato et al. 1999).

Whereas Shh plays a role in matrix cell proliferation in the hair cycle, Indian hedgehog (Ihh) is expressed in the sebaceous gland. Additionally, both human and mouse sebaceous tumors overexpress Ihh but not Shh. In normal sebaceous glands, Ihh is expressed in differentiating sebocytes, and nuclear Gli1 is present in sebocyte progenitors (Niemann et al. 2003). In vitro inhibition of hedgehog signaling inhibits growth and stimulates differentiation of sebocytes, suggesting a paracrine mechanism by which Ihh secreted by differentiated sebocytes stimulates proliferation of sebocyte precursors (Niemann et al. 2003). Transgenic overexpression of the other members of Shh family shows that Desert hedgehog is a functional homolog to Shh in the skin (Adolphe et al. 2004).

Bmps are secreted proteins that activate signal transduction by binding to a transmembrane receptor complex composed of Bmpr1a and Bmpr1b receptors. Upon ligand binding, Bmpr1b phosphorylates the cytoplasmic tail of Bmpr1a, which in turns phosphorylates the R-Smad DNA-binding protein (Smad 1, 5, and 8), which in turn complexes with one of its partner Smads (typically Smad 4) to translocate to the nucleus and mediate target gene expression (Shi & Massague 2003) ().

Bone morphogenetic protein (BMP) signaling pathway during hair follicle morphogenesis and differentiation. (a) Schematic of the BMP pathway. The extracellular availability of BMP proteins is tightly regulated by soluble BMP inhibitors such as Noggin. BMP dimers bind a heterodimeric receptor complex (BMPR-I and BMPR-II) that phosphorylates and activates R-Smad (Smads 1, 5, and 8), which then associates with its co-Smad (Smad 4) partner. Once activated, the R-Smad/co-Smad complex is translocated into the nucleus, where it transactivates its target genes. (b) Role of BMPs in hair follicle morphogenesis. BMP signals are transmitted to and from the overlying epidermis to underlying dermal condensates. Although the role these BMP signals play is not fully understood, this exchange of signaling is thought to play a role in the early specification of sites of hair follicle morphogenesis. As dermal condensates form, they express the BMP-inhibitor Noggin, which is required for normal follicle development and permissive for Lef1 expression and Wnt signaling. Later, as follicle maturation has progressed, the activation of BMP receptor signaling is essential for the matrix cells to differentiate to form the hair shaft and its inner root sheath (IRS) channel. BMP signaling also regulates epidermal proliferation in the skin. DP, dermal papilla.

Bmpr1a is expressed throughout most of the developing skin epithelium. The pattern of Bmp expression is particularly elaborate in the HF. In early skin development, Bmp2 is expressed in the placode epithelium, whereas Bmp4 is expressed by the underlying mesenchyme (Kratochwil et al. 1996; Lyons et al. 1989, 1990; Wilson et al. 1999). In adult HFs, Bmps also appear to function in epithelial-mesenchymal interactions. In the DP, Bmp4, -6, and -7 are expressed (Kratochwil et al. 1996; Lyons et al. 1989, 1990; Rendl et al. 2005; Wilson et al. 1999), although Bmp6 may also function in bulge SC quiescence and/or maintenance (Blanpain et al. 2004). In addition, Bmps are differentially expressed in the various lineages of the HF, with Bmp7 and -8 in the IRS and Bmp2 and -4 in the hair shaft precursors.

The role for Bmp signaling in skin development begins in the neuroepithelium, when Bmp signaling specifies uncommitted ectodermal cells to become epidermis (Nikaido et al. 1999). Once the embryonic skin SC progenitor cells have been specified, the next crossroads for signaling appears to be at the juncture of hair placode formation. In a process bearing a certain resemblance to the formation of the neural tube, placode formation is dependent on Noggin, a soluble inhibitor of Bmp signaling (Botchkarev et al. 1999, Jamora et al. 2003). Conditional ablation of the Bmpr1a gene also results in the accumulation of large masses of undifferentiated, Lef1-expressing, placode-like cells, further emphasizing a role for Bmp inhibition in the early stages of HF morphogenesis (Andl et al. 2004, Kobielak et al. 2003).

The conditional targeting of the Bmpr1a gene also revealed a positive role for Bmp signaling in the differentiation of matrix cells into IRS and hair shaft lineages (Andl et al. 2004, Kobielak et al. 2003, Ming Kwan et al. 2004, Yuhki et al. 2004). Several markers of matrix cell differentiation (FoxN1/nude, Hoxc13, Msx2, and GATA3) were strongly reduced or absent following the ablation of Bmpr1a. Notably and in striking contrast, Shh and Lef1 expression was expanded, as is also seen in transgenic mice expressing Noggin under the control of the Msx2 promoter (Kulessa et al. 2000). Nuclear -catenin was also decreased in the Bmpr1a-deficient matrix cells, demonstrating that Bmp signaling lies upstream of -catenin signaling during matrix cell differentiation. These findings strengthen the view that the inhibition of Bmp signaling is required for SC activation toward the HF cell fate, whereas Bmp signaling is required for the differentiation of activated SCs to adopt one or more of the six different lineages that compose the mature HF (Kobielak et al. 2003).

Several other lines of evidence suggest that the inhibition of Bmp signaling promotes SC activation. At the conclusion of the normal hair cycle, proliferation ceases and the HF enters the destructive phase (catagen). By contrast, Bmpr1a-null ORS continues to proliferate and grow downward, leading to an accumulation of matrix cells and the formation of follicular tumors (Andl et al. 2004, Ming Kwan et al. 2004). Conversely, treatment of cultivated bulge SCs with BMP6 inhibits their proliferation and leads to a transient withdrawal from the cell cycle (Blanpain et al. 2004, Botchkarev et al. 1999).

Similar to other major signaling pathways in skin, Notch signaling is involved in a variety of cell fate decisions across the animal kingdom. Transmembrane Notch receptors (Notch14 in mammals) bind transmembrane ligands, either Jaggeds (2) or deltas (3). Upon ligand engagement, membrane Notch receptors are sequentially cleaved, first by a metalloproteinase and then by -secretase, which releases the active Notch intracellular domain (NICD), freeing it to translocate to the nucleus and associate with the DNA-binding protein RBP-J. Upon NICD binding, RBP-J is converted from a transcriptional repressor to an activator, leading to the induction of downstream Notch target genes (Artavanis-Tsakonas et al. 1999) ().

Notch signaling pathway during epidermal stratification and hair follicle differentiation. (a) Schematic of canonical Notch signaling. Upon ligand (Jagged or Delta) binding, the Notch transmembrane receptor is cleaved by proteases (ADAM protease and -secretase), releasing the Notch intracellular domain (NICD), which can then translocate into the nucleus and associate with the DNA-binding protein RBP-Jk to permit transcription of target genes. (b) Role of Notch1 in skin development. Notch1 is cleaved and generates its active form, NICD1, which controls epidermal stratification and differentiation. Early, NICD1 is present in basal cells but later it is found primarily in suprabasal cells. Loss-of-function studies suggest that Notch1 acts as a tumor suppressor in skin epidermis to restrict proliferation to the basal layer. Notch1 also plays a role in the hair follicle, where it has been demonstrated to play a critical role in the differentiation of the inner root sheath and the hair shaft.

Multiple components of the Notch signaling pathway are expressed in embryonic and adult epidermis. During the early stage of epidermal stratification, Notch1 is expressed and active in the basal and suprabasal cells of the epidermis and sebaceous glands (Okuyama et al. 2004, Rangarajan et al. 2001) (). In the latter stages of epidermal stratification, Notch1 activity decreases in the basal layer and becomes more restricted to the spinous layer (K1-positive cells) (Okuyama et al. 2004). Loss of Notch1 function results in a defect of IFE differentiation (Rangarajan et al. 2001).

In the HF, Notch13 are expressed in proliferative matrix cells and in differentiating HF cells (Kopan & Weintraub 1993, Pan et al. 2004) (). When both Notch 1 and Notch2 or PS1 and PS2 genes involved in Notch processing are conditionally ablated in the matrix, HFs are quantitatively lost and epidermal cysts arise, underscoring the role for Notch signaling in follicle maturation and differentiation (Pan et al. 2004). The consequences of Notch1 deletion are most directly deleterious to the sebaceous glands, which are reduced in the single conditional knockout animals; in the absence of both Notch1 and Notch2, sebaceous glands are missing altogether (Pan et al. 2004). Conditional gene targeting of RBP-J also results in hair loss and epidermal cyst formation (Yamamoto et al. 2003).

Related to the natural role of Notch signaling in skin, loss of Notch 1 potentiates skin tumor development upon chemically induced carcinogenesis (Nicolas et al. 2003). Conversely, NICD overexpression in cultured cells inhibits keratinocyte proliferation, in part by upregulating the p21 target gene, which possesses a functional RBP-J-binding site within its promoter (Rangarajan et al. 2001). Although these studies point to a role for Notch in hair differentiation and inhibition of proliferation, sustained activation of Notch signaling through NICD1 overexpression in hair shaft progenitors unexpectedly promotes matrix cell proliferation and impairs hair shaft differentiation (Lin & Kopan 2003, Lin et al. 2000). These findings raise the possibility that the roles for Notch signaling in the epidermis and HF may be distinct.

Further insights into Notch signaling in the skin come from studies on chicken feather formation. As in mice, Notch1 is expressed in chick epidermal placode, and delta is expressed in the underlying mesenchyme. Delta overexpression in a small epidermal patch leads to an acceleration of feather development, whereas massive overexpression in the epidermis leads to a decrease in feather development (Crowe et al. 1998). These findings suggest a model in which Notch signaling promotes HF development in the preexisting placode but restricts neighboring cells from adopting a similar fate. The generalization of this model for other appendage development in other species requires further investigation, but the model mirrors that of Notch signaling in epidermal and neural fate specification in Drosophila.

Although loss of Notch1 in the epidermis does not impair early follicle morphogenesis, it does progressively reduce the number of HFs over time (Vauclair et al. 2005). It is still unclear what the downstream genes regulated by Notch signaling in the epidermis are, and how these genes mediate their cellular function. It also remains to be determined how Notch signaling acts in the bulge SC niche, how Notch regulates hair cycle, and how the Notch signaling pathway is connected to the other signaling pathways known to influence SC maintenance and activation.

The ends of chromosomes are called telomeres, and they consist of short, tandem DNA sequence repeats that associate with specific proteins and protect chromosome ends from degradation and recombination. Telomerase is a reverse transcriptase that synthesizes the DNA repeats to circumvent telomere shortening during DNA replication. Telomerase reverse transcriptase (TERT) is the catalytic subunit of the protein complex that makes the telomerase. Telomerase is upregulated in many human cancers, and TERT cooperates with other oncogenes to transform normal cells into tumor cells (Blackburn 2001).

TERT has been postulated to extend the proliferative potential of cells, and hence it has been speculated to play a role in SC biology. When the K5 promoter is used to drive TERT overexpression in the basal epidermal layer of transgenic mice, animals are more susceptible to skin tumorigenesis when exposed to chemical carcinogens, and they repair their wounds more rapidly (Gonzalez-Suarez et al. 2001). Conversely, mice deficient for TERC, another key component of telomerase, are resistant to skin chemical carcinogenesis (Gonzalez-Suarez et al. 2000).

In bulge SCs, increased TERT activity results in proliferation and premature entry into the anagen stage (Flores et al. 2005, Sarin et al. 2005). Flores et al. (2005) assumed that the reduced epidermal proliferation seen in TERC-null mice reflected the importance of telomerase and telomere length in bulge SC behavior. In contrast, Sarin et al. (2005) discovered surprisingly that TERC affects the skin in a fashion independent of its role in telomerase function and telomere length. Both groups have posited that TERT and TERC exert their function on the quiescent SCs within the bulge. However, given the need to sustain proliferation in the matrix cells during the growth phase of the hair cycle, it seems more plausible that a need for enhancing conventional telomerase activity would be felt by the proliferating matrix compartment rather than the infrequently cycling cells of the bulge. Additional studies are needed to clarify these conflicting results and determine the mechanism by which telomerase overexpression allows or facilitates skin carcinogenesis and SC activation.

Bulge SCs display elevated levels of several cytoskeleton-related genes known to be regulated by small G proteins of the Rho family of small GTPases. Rac is a pleiotropic regulator of actin dynamics, intercellular adhesion, and cell migration, and as such, it is expressed broadly in proliferating cells. Conditional ablation of the Rac1 gene in the proliferating keratinocytes of skin rapidly depletes the proliferative compartments, leading to a mobilization and depletion of SCs (Benitah et al. 2005).

A priori, a similar outcome might be expected for the depletion of many different types of essential epidermal genes. However, Rac1 was of particular intrigue to Watt and her colleagues (Arnold & Watt 2001, Braun et al. 2003, Frye et al. 2003, Waikel et al. 2001) because it is a negative regulator of c-Myc, whose elevated expression has been reported to deplete the population of bulge LRCs. It will be interesting in the future to see the extent to which, as posited by the authors, Rac1 may act at the nexus of the transition between the SC and its committed progeny (Benitah et al. 2005).

Given the general consensus that overexpression of c-Myc depletes bulge SCs and drives them to differentiate along the epidermal lineage (Arnold & Watt 2001, Braun et al. 2003, Frye et al. 2003, Waikel et al. 2001), it came as a surprise that conditional loss of endogenous c-Myc also leads to a loss of bulge LRCs and precocious differentiation of basal epidermal cells (Zanet et al. 2005). Although the jury is still out, one possible explanation for the seemingly disparate results between gain and loss of c-Myc function is that c-Myc acts at multiple points along the bulge SC lineages, and a perturbation at one or more of these steps may indirectly impact the behavior of SCs. Consistent with this notion is that both gain- and loss-of-function studies point to a role for c-Myc in governing the sebaceous gland lineage, which is also thought to rely on bulge SCs.

The skin epithelium is a complex tissue containing three distinct lineages that form the IFE, the HF, and the sebaceous gland.

The IFE constantly self-renews to provide a new protective layer at the skin surface, and HFs undergo a perpetual cycle of growth and degeneration to ensure the renewal of the hair pelage.

Different populations of progenitor cells contribute to lineage homeostasis, but to date, only bulge SCs have been demonstrated clonally to be multipotent with the ability to differentiate into all three differentiation lineages.

Bulge SCs can be activated and mobilized, at each cycle of hair follicle regeneration and after wound healing, to provide cells for tissue repair.

Recent progress in the isolation and molecular characterization of bulge SCs has provided new insights into the various mechanisms implicated in SC maintenance and activation.

Conserved signaling pathways regulating developmental decisions throughout the animal kingdom are reutilized during adult life to regulate the functions of skin epithelial SCs, and deregulation of these signaling pathways leads to the development of cancer in various tissues.

In this review, we try to highlight some of the significant advances made recently in skin stem cell biology, and we place them within the context of the historical foundations that made this current research possible. In closing, we offer a few of the unanswered questions in the field of skin stem cells that we think are likely to capture the attention of skin biologists in the years to come.

Do common molecular mechanisms govern the fundamental characteristics shared by adult skin SCs and other SCs, namely self-renewal and maintenance of the undifferentiated state? Comparisons of the transcriptional profiles of different types of SCs isolated directly from their respective tissues should help to identify possible candidates, as will the profiling of SCs residing in and out of their niches, and in quiescent and activated states. As candidate genes are identified, functional analyses of putative self-renewal or differentiation inhibitory SC genes in skin should reveal their importance and begin to unravel the pathways involved.

What is the mechanism by which quiescent bulge SCs are activated? Little is known about the signals needed to mobilize bulge SCs to reepithelialize epidermal wounds and to replenish the sebaceous gland. Even for the better understood process of SC activation during the hair cycle, a number of key issues remain unsolved. At the crux of the problem is whether follicle SC activation involves an intrinsic clock mechanism and/or whether it involves a signal from the DP. Although a change in the status of Lef1/Tcf/-catenin-regulated genes has been implicated in follicle SC activation, it is still not clear where a Wnt signal is involved, where it comes from, how the pathway exerts its effects, how it converges with other key signaling pathways, and how the program of gene expression is established that leads to follicle formation.

What is the relationship between the bulge SCs and the proliferative compartments of the epidermis, sebaceous gland, and HF? Do proliferating skin keratinocytes retain unipotent or even multipotent SC properties, or are they committed to embark on a terminal differentiation program? The point of no return in the skin SC field is an important one. Lineage-tracing experiments and the recent studies on asymmetric cell divisions in the skin provide new insights into these issues, but additional studies are now needed to illuminate the molecular relations between these different proliferative populations within the skin.

What is the relationship between the multipotent progenitors of embryonic skin epidermis and the multipotent SCs of the bulge? Embryonic skin effectively begins as a single layer of multipotent progenitors, but they differ from bulge SCs in their proliferative status and their lack of an apparent niche. Are bulge SCs simple quiescent counterparts of their embryonic brethren, or are there intrinsic differences between them? As methods are honed to isolate and characterize the early embryonic SCs, this relationship should become clearer. Additionally, it will be helpful to trace the development of the bulge from its early origins to its site in the postnatal follicle.

Are SCs at the root of cancers in the skin? Cancer is the result of a multistep process requiring the accumulation of mutations in several genes. For most cancers, the target cells of oncogenic mutations are unknown. Adult SCs may be the initial target cells, as they self-renew for extended periods of time, providing increased opportunity to accumulate the mutations required for cancer formation. Certain cancers contain cells with SC characteristics with high self-renewal capacities and the ability to re-form the parental tumor on transplantation. However, whether the initial oncogenic mutations arise in normal SCs or in more differentiated cells that reacquire SC-like properties remains to be determined. The demonstrations that SCs are the target cells of the initial transforming events and that cancers contain cells with SC characteristics await the development of tools allowing for the isolation and characterization of normal adult SCs. For most epithelia in which cancer arises, such isolation techniques are not available. The new methods to isolate and specifically mark skin SCs make it now possible to test experimentally the cancer SC hypothesis in the skin.

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Epidermal Stem Cells of the Skin - PubMed Central (PMC)

Skin Stem Cells Comments Off on Epidermal Stem Cells of the Skin – PubMed Central (PMC) | April 16th, 2020

Medical skin care products are used for beautifying or to address some other skin care problems. The cosmetic industry is booming and skin care forms a very huge part of this industry. The aesthetic appearance is so important that people spend a lot on skin care products and treatment. People being more technologically aware of the various new skin care products trending in the market. In addition to the aesthetic application, the medical skin care products are also used to address issues such as acne, pimples or scars.

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Medical Skin Care Products Market: Drivers and Restraints

The medical skin care products is primarily driven by the need of natural based active ingredients products which are now trending in the market. Consumers demand medical skin care products which favor health and environment. Moreover, the consumers are updated with the trends so that various companies end up providing such products to satisfy the customers. For instance, a single product face mask has thousands of different variants. This offers consumers different options to select the product depending on the skin type. Moreover, the market players catering to the medical skin care products are offering products with advanced technologies. For instance, Santinov launched the CICABEL mask using stem cell material based on advanced technologies. The stem cells used in the skin care product helps to to protect and activate the cells and promote the proliferation of skin epidermal cells and the anagenesis of skin fibrosis.

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On the basis of product type the medical skin care products market can be segmented as:

On the basis of application, the medical skin care products market can be segment as:

On the basis of distribution channel, the medical skin care products market can be segment as:

Medical Skin Care Products Market: Overview

Medical skin care products are used to address basic skin problems ranging from acne to scars. There are various advancements in the ingredients used to offer skin care products to the consumers. For instance, the use of hyaluronic acid and retinoids is the latest development in the industry. The anti-aging creams are at the forefront as the help treating issues such as wrinkles, scars, acne, and sun damage. Another, product in demand is the probiotic skincare which include lactobacillus and bifidobacterium.

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Medical Skin Care Products Market: Region-wise Outlook

In terms of geography, medical skin care products market has been divided into five regions including North- America, Asia- Pacific, Middle-East & Africa, Latin America and Europe. North America dominated the global medical skin care products market as international players are acquiring domestic companies to make their hold strong in the U.S. LOral is accelerating its U.S. market by signing a definitive agreement with Valeant Pharmaceuticals International Inc. to acquire CeraVe, AcneFree and Ambi skin-care brands for US$ 1.3 billion. The acquisition is expected LOreal to get hold of the brands in the price-accessible segment. Asia Pacific is expected to be the fastest growing region owing to the increasing disposable income and rising awareness towards the skin care products.

Medical Skin Care Products Market: Key Market Participants

Some of the medical skin care products market participants are ,

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Medical Skin Care Products Market Structure and Its Segmentation for the Forecast 2017 2025 - Curious Desk

Skin Stem Cells Comments Off on Medical Skin Care Products Market Structure and Its Segmentation for the Forecast 2017 2025 – Curious Desk | April 16th, 2020

Researchers at Lund University in Sweden have succeeded in restoring mobility and sensation of touch in stroke-afflicted rats by reprogramming human skin cells to become nerve cells, which were then transplanted into the rats' brains. The study has now been published in the Proceedings of the National Academy of Sciences (PNAS).

"Six months after the transplantation, we could see how the new cells had repaired the damage that a stroke had caused in the rats' brains," says Professor Zaal Kokaia, who together with senior professor Olle Lindvall and researcher Sara Palma-Tortosa at the Division of Neurology is behind the study.

Several previous studies from the Lund team and others have shown that it is possible to transplant nerve cells derived from human stem cells or from reprogrammed cells into brains of rats afflicted by stroke. However, it was not known whether the transplanted cells can form connections correctly in the rat brain in a way that restores normal movement and feeling.

"We have used tracking techniques, electron microscopy and other methods, such as light to switch off activity in the transplanted cells, as a way to show that they really have connected correctly in the damaged nerve circuits. We have been able to see that the fibres from the transplanted cells have grown to the other side of the brain, the side where we did not transplant any cells, and created connections. No previous study has shown this," says Zaal Kokaia, who, even though he and colleague Olle Lindvall have studied the brain for several decades, is surprised by the results.

"It is remarkable to find that it is actually possible to repair a stroke-damaged brain and recreate nerve connections that have been lost. The study kindles hope that in the future it could be possible to replace dead nerve cells with new healthy nerve cells also in stroke patients, even though there is a long way to go before achieving that," says Olle Lindvall.

The researchers have used human skin cells that have been reprogrammed in the laboratory to become nerve cells. They were then transplanted into the cerebral cortex of rats, in the part of the brain that is most often damaged after a stroke. Now the researchers will undertake further studies.

"We want to know more about how the transplanted cells affect the opposite hemisphere of the brain. We also want to take a closer look at how a transplant affects intellectual functions such as memory. In addition, we will study possible side effects. Safety is, of course, extremely important for cell transplantation if it is going to be used clinically in the future," says Zaal Kokaia.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Researchers Have Succeeded in Restoring Mobility and Sensation of Touch in Stroke-Afflicted Rats - Technology Networks

Skin Stem Cells Comments Off on Researchers Have Succeeded in Restoring Mobility and Sensation of Touch in Stroke-Afflicted Rats – Technology Networks | April 15th, 2020