Scientists are one step closer to mimicking the way biological systems interact and process information in the body -- a vital step toward developing new forms of biorobotics and novel treatment approaches for several muscle-related health problems such as muscular degenerative disorders, arrhythmia and limb loss.

Using cardiac muscle cells and cardiac fibroblasts -- cells found in connective heart tissue -- researchers at the University of Notre Dame have created a "living diode," which can be used for cell-based information processing, according to a recent study in Advanced Biosystems. Bioengineers created the muscle-based circuitry through a novel, self-forming, micro patterning approach.

Using muscle cells opens the door to functional, biological structures or "computational tissues" that would allow an organ to control and direct mechanical devices in the body. The design arranges the two types of cells in a rectangular pattern, separating excitable cells from nonexcitable cells, allowing the team to transduce electrical signals unidirectionally and achieve a diode function using living cells. In addition to the diode-like function, the natural pacing ability of the muscle cells allowed Pinar Zorlutuna, assistant professor of aerospace and mechanical engineering, and her team to pass along information embedded in the electrical signals by modulating the frequency of the cells' electrical activity. Zorlutuna's research was funded by the National Science Foundation.

"Muscle cells have the unique ability to respond to external signals while being connected to fibroblasts internally through intercellular junctions. By combining these two cell types, we have the ability to initiate, amplify and propagate signals directionally," said Zorlutuna, who is also director of the Tissue Engineering Laboratory at the university. "The success of these muscle-cell diodes offers a path toward linking such cell-based circuitry to a living system -- and creating functional control units for biomedical engineering applications such as bioactuators or biosensors."

The team's work presents a new option in biocomputing, which has focused primarily on using gene circuitries of genetically modified single-cells or neuronal networks doped with chemical additives to create information processing systems. The single-cell options are slower to process information since they relay on chemical processes, and neuronal-based approaches can misfire signals, firing backward up to 10 percent of the time.

Zorlutuna explores biomimetic environments in order to understand and control cell behavior. She also studies cell-cell and cell-environment interactions through tissue and genetic engineering, and micro- and nanotechnology at the Notre Dame Center for Nano Science and Technology. She is a researcher at the University's Center for Stem Cells and Regenerative Medicine and the Harper Cancer Research Institute.

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Materials provided by University of Notre Dame. Note: Content may be edited for style and length.

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Researchers develop 'living diode' using cardiac muscle cells - Science Daily

Home Bone Health Stem cell technique may aid in bone repair

A new method for repairing damaged bones with stem cell and carbon material has been developed by researchers working with the Ulsan National Institute of Science and Technology (UNIST). The method involves using stem cells from human bone marrow and carbon sheets with photocatalytic properties, and may help to create better treatments for bone injuries like periodontal disease and fractures.

During their study, researchers found that carbon nitride sheets that absorb red light encourage proliferation and growth of bone, as well as osteogenic differentiation. Human bone marrow stem cells have previously been used in the treatment of fractures, as they promote bone regeneration even in patients who have lost large areas of bone because of trauma or disease. The use of carbon nitride sheets alongside the bone marrow stem cells in this study were an attempt to accelerate the regeneration process.

Researchers found that when the carbon nitride was exposed to red light, it absorbed the light and emitted fluorescence, which is already known to expedite bone regeneration. The study also showed proliferation in osteogenic differentiation genes and accelerated bone formation in cells that were cultured in the lab.

This new stem cell research shows that coupling human bone marrow stem cells with carbon nitride could prove to be an effective way to create new bone material in areas that are lacking. With further research, this method could soon be applied to helping to heal bone fractures and wear-and-tear related to diseases like osteoporosis, as well as used to create new joints and teeth.

Related: Improve bone density and reduce the risk of osteoporosis with lifestyle changes

Related Reading:

Eat these foods for strong bones

Six tips to improve your bone health

New Stem Cell Technique Shows Promise for Bone Repair

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Stem cell technique may aid in bone repair - Bel Marra Health

After a spinal cord injury, many of the nerve fibers at the injury site lose their insulating layer of myelin. As a result, the fibers are no longer able to properly transmit signals between the brain and the spinal cord contributing to paralysis. Unfortunately, the spinal cord lacks the ability to restore these lost myelin-forming cells after trauma.

Tissue engineering in the spinal cord involves the implantation of scaffold material to guide cell placement and foster cell development. These scaffolds can also be used to deliver stem cells at the site of injury and maximize their regenerative potential.

When the spinal cord is damagedeither accidentally (car accidents, falls) or as the result of a disease (multiple sclerosis, infections, tumors, severe forms of spinal bifida, etc.)it can result in the loss of sensation and mobility and even in complete paralysis.

For publications on spinal cord injuries, please click here.

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Spinal Cord Injury and Stem Cell Therapy

Bangladesh News 24 hours

Bangladesh performs 25th bone marrow transplants in the first-ever centre Bangladesh News 24 hours In bone marrow transplantation, doctors replace damaged or destroyed marrow the soft and spongy tissue inside bones with healthy bone marrow stem cells to treat different types of blood cancer, certain genetic blood and immunity disorders like ... and more »

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Bangladesh performs 25th bone marrow transplants in the first-ever centre - Bangladesh News 24 hours

(WXYZ) - When we get sick, it's common for us to reach for some medicine or maybe even have surgery to deal with disease or pain, but what if you could use your own healthy cells to fight back instead?

Right now, there's a procedure being performed in metro Detroit where healthy stem cells are stored so they can be reintroduced to your system and potentially have life changing or life saving benefits.

Dr. Michael Schenden is the first plastic surgeon in the US to perform the Forever Labs stem cell collection. He starts by harvesting her bone marrow to save those healthy stem cells.

"They should be available for many, many different medical applications is a wonderful thing," says Dr. Schenden.

The company behind this procedure is based in Ann Arbor and it's called Forever Labs.

We're told about 30 people have decided to store their stem cells this way. Sonja Michelsen is one of them. She had her daughter in her early 40s and felt like storing her own stem cells could pay off in the future.

"I want to be able to be here with her throughout her life," she says.

She knows there's no guarantee banking her stem cells will help her in the future, but she sees it as an investment that could pay off if her health takes a turn.

"To have that peace of mind that you do have something to use down the road .. is huge," she says.

Steven Clausnitzer is CEO of Forever Labs. He says by re-introducing your own healthy cells, you may be able to fight disease in the future.

"There are a number of ways people are already using these cells. Maybe the most promising .. orthopedic surgeons .. are reintroducing them into joints in lieu of surgery," he says.

Clausnitzer says there are about 500 clinical trials right now that are using stem cells that, one day, may be able to treat everything from osteoarthritis to multiple scleroses to cardiovascular disease.

This kind of stem cell banking is a 15 minute outpatient procedure. It starts with a local anesthetic in the lower back.

He says the number of your stem cells diminishes with age, as does their therapeutic quality.

"My stem cells were stored at 38. I'm going to turn 40 this year. I rest assured knowing I have my 38-year-old stem cells rendered biologically inert. They're no longer aging .. even as I do," says Clausnitzer.

Mark Katakowski is president of Forever Labs. He says his research showed him the rejuvenating and healing power of stem cells in animals. He believes it can have the same effect in humans.

He says the best time to store the stem cells is when you're young.

"There's a slower decline between 20 and 40 years-old and then it picks up. When you put them in the right place at the right time, they can actually improve recovery in a bunch of therapeutic applications," he says.

Katakowski says there's no limit as to how long they can be stored.

Should a person pass away, their stored stem cells would be destroyed unless arrangements have been made for them to be given to a family member.

At this point, the procedure is not FDA approved. The Forever Labs stem cell collection isn't covered by insurance. It costs around $3,500 to have the procedure done and $250 a year for storage.

The company says it plans to bring the first clinical trials for longevity to market in the next 7-10 years, once there is a large enough differential time between when our first clients stored their cells and can then reintroduce.

It says its goal is that its clientele will be able to participate in the first longevity based human trials utilizing autologous stem cell treatments of healthy individuals.

To learn more about Forever Labs, go to: https://www.foreverlabs.co/

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Can storing your stem cells be the key to fighting disease and living longer? - WXYZ

Induced pluripotent stem cells don't increase genetic mutations Science Daily Using skin cells from the same donor, they created genetically identical copies of the cells using both the iPSC and the subcloning techniques. They then sequenced the DNA of the skin cells as well as the iPSCs and the subcloned cells and determined ...

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Induced pluripotent stem cells don't increase genetic mutations - Science Daily

PARIS and STOCKHOLM, Feb. 9, 2017 /PRNewswire/ -- Laboratoire Fleur de Sants new Champagne Collection uses Extrait de Champagne, fueled by grape seed Phyto-StemCell's Resveratrol, for the ultimate antioxidant protection and photo-aging prevention. By reinforcing the skin's structural matrix (collagen and elastin) and stimulating its natural regeneration process, this powerful antioxidant postpones skin aging and leaves it smooth and even toned. One more reason to love Champagne!

"Antioxidant rich, Champagne extract is used in our products because it's incredibly effective at protecting and nourishing your skin. We believe that beautiful, healthy skin is worth celebrating every day," says Mathias Tonnesson, CEO of Laboratoire Fleur de Sant.

Champagne takes on a whole new meaning in skin care

The most famous sparkling wine in the world isn't just for drinking any more.

Fleur de Sant has captured its essence for the ultimate global anti-aging range of products. Extremely rich in antioxidants (Resveratrol), Champagne is one of the most beneficial ingredients protecting skin from free radicals and stress to which we are exposed every day by breathing in pollution or being unprotected from UV light.

By counteracting these factors, Champagne extract reduces the damaging marks photo-aging leaves on your skin (wrinkles, sagging skin, dark spots). It works by restoring the skin's structural tissue collagen and elastin to make it more resistant to various environmental aggressors. Antioxidants, which Champagne owes to grape seed extract, are of the highest potency, being at least 20 times more powerful than Vitamin C or E. In Fleur de Sant products, the exclusive Extrait de Champagne is further enhanced by grape seed Phyto-StemCell Infusion, which together deliver tremendously strong anti-aging force.

For more information about Fleur de Sant Champagne Collection, visit http://www.fleurdesante.com/products/

What makes phyto-stem cells so special?

Phyto-stem cells counteract the negative effect of the UV light, help maintain skin stem cell's functions and reinforce their capacity to grow, which in turn slows down the skin aging process. On top of this, they accelerate regeneration and the tissue building functions of skin, resulting in restoration of firmness and wrinkle reduction.

About Laboratoire Fleur de Sant

Fleur de Sant was founded in 1980, with the distinction of being the only brand in the world to utilize Swedish and French medicinal flowers in their beneficial formulations. The tradition continues as the brand is experiencing a re-birth with CEO Mathias Tonnesson. His passion to create skin care with "every detail considered" sees the latest clinically proven collections containing antioxidant-rich Champagne extract, plant stem cell-boosted flowers, and airless packaging that makes every formulation more effective. 95% natural and never tested on animals, Fleur de Sant is more than premium skin care it is the result of one man's passion to create products made from love.

Visit: http://www.fleurdesante.com

Contact: Mathias Tonnesson CEO, Laboratoire Fleur de Sant +1 (646) 893-4100Ext: 100 145363@email4pr.com

To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/celebrate-your-skin-with-champagne--phyto-stemcells-300404181.html

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Celebrate Your Skin with Champagne & Phyto-StemCells - PR Newswire (press release)

For many people suffering from disabling conditions, such as Parkinsons disease, spinal injury and paralysis, heart disease, and even cancer, announcements in the press around breakthroughs in stem cell research undoubtedly bring hope.

Keeping the balance between hope and hype is a difficult one, particularly when there are vulnerable and suffering people relying on the hope medical research offers. As Australian of the Year, Emeritus Professor Alan Mackay-Sim, stated in his acceptance speech, there are now many clinical trials being performed in Australia and around the globe, to determine whether the delivery of certain types of cells, including some grown from stem cells, into the spinal column can allow patients with spinal cord injury to regain function.

For these individuals, even a small gain of functionis a major advance. However, as yet there is no stem cell silver bullet.

And stem cells that have shown promise can also cause complications. It was also reported a paraplegic woman developed a growth in her spine many years after an unsuccessful spinal stem cell treatmentHence, more research to test these and other types of cells in well-run clinical trials is required to move from anecdote to safe and effective therapies.

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:The future of stem cells: tackling hype versus hope

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Hype versus hope: Deciphering news about stem cell breakthroughs - Genetic Literacy Project

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Quebec family hopes to raise awareness for patients in need with stem cell registry drive Globalnews.ca Natasha Camacho-Gomes (middle right, standing) organized a bone marrow registry drive Saturday, Feb. 4, 2017 to raise awareness for patients in need. Her Fianc Kevin Butterfill is one of those patients. He was diagnosed with leukemia in January.

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Quebec family hopes to raise awareness for patients in need with stem cell registry drive - Globalnews.ca

BUCKEYE, AZ - As the saying goes: "blood is thicker than water." But when it comes to bone marrow, it is truer than ever especially because family is usually the only people to turn to for a match.

But, one Buckeye family is finding that the phrase could not be more perfectfor them because a brother has been serving as the lifeline for his sibling over the last few years.

Gloria Mesquias calls her 11-year-old son, Shaun, "the warrior."

"He takes every jab he gets and just rolls through," said Mesquias.

Shaun's 13-year-old brother Malik is called "the hero."

"They are actually like night and day, "Mesquias said. "They're brothers."

The three of them, and other supportive family members, have spent months at Phoenix Children's Hospital. Shaun has a condition where his body isn't producing new blood cells.

"He was diagnosed with severe aplastic anemia," Mesquias said.

That happened when he was just about 1 year old. Ever since then, he's been in and out of the hospital.

But, Malikhas served as a bone marrow and stem cell donor to his b brother not once, not twice but, three different times.

And the fight for this little warrior, is not over yet. If his treatment goes well over the next few days, he will have a fourth surgery on Wednesday; another stem cell transplant.

Mesquias doing this all as a single mother. She also has a 5-year-old daughter, who has not seen Shaun since before Christmas.

"She understand;she gets it," Mesquias explained. "She knows brother is sick and she knows mom is here with Shaun."

But, while she tries to keep it together, all of the stress and days away from home are weighing on Mesquias. But, it's something she will never let her family see.

"At night time, I can go in the restroom and cry my eyes out or ball my face out in the pillow," Mesquias said. "But, I just don't do it in front of him."

So, the boys' Buckeye teacher, Carrie Brown, has also taken action to try and do something special for the family.

"She would never ask for help," Brown said. "She's not that kind of person. So, I just thought that this was one thing that I could do to relieve some of the worry that she has and to give her a little bit of comfort."

Brown started a GoFundMe page to try and help the family who has given so much to each other.

And Mesquias said she is making sure all of them get out of that hospital together.

"He has his moments too where he says he wants to go home," Mesquias explained. "And... I'm like, 'I'm not going home until you're going home. So, we're good."

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Buckeye boy donates bone marrow to sick brother - ABC15 Arizona - ABC15 Arizona

Bone marrow is a soft, spongy material found in your large bones. It makes more than 200 billion new blood cells every day, including red blood cells, white blood cells, and platelets. But for people with bone marrow disease, including several types of cancer, the process doesnt work properly. Often, a bone marrow transplant is a persons best chance of survival and a possible cure. The good news is that donating bone marrow can be as easy and painless as giving blood.

A bone marrow transplant replaces diseased bone marrow with healthy tissue, usually stem cells found in the blood. Thats why bone marrow transplants are also called stem cell transplants. In an allogeneic transplantation (ALLO transplant), blood stem cells from the bone marrow are transplanted from a donor into the patient. The donor stem cells can come from either the blood that circulates throughout another persons body or from umbilical cord blood.

But theres a catch. Before a person receives an ALLO transplant, a matching donor must be found using human leukocyte antigen (HLA) typing. This special blood test analyzes HLAs, which are specific proteins on the surface of white blood cells and other cells that make each persons tissue type unique. HLA-matched bone marrow is less likely to cause a possible side effect of transplantation called graft vs. host disease (GVHD). GVHD is when immune cells in the transplanted tissue recognize the recipients body as foreign and attack it.

Only about 30% of people who need a transplant can find an HLA-matched donor in their immediate family. For the remaining 70% of people, doctors need to find HLA-matched bone marrow from other donors. In 2016, that equals about 14,000 people from very young children up to older adults in the United States who need to find a donor outside of their close family.

The National Marrow Donor Program (NMDP) has a registry of potential donors that might be the match a patient needs. Heres how the donation process works:

You register with the NMDP online or in person at a donor center. You can find a center by calling the toll-free number 1-800-MARROW2.

You collect cells from your cheek with a cotton swab or provide a small blood sample. This is done by following directions in a mail-in kit or at a donor center. The sample is analyzed to determine your HLA type, which is recorded in the NMDP national database.

If an HLA match is made with a patient in need, the NMDP contacts you. A donor center takes a new sample of your blood, which is sent to the patients transplant center to confirm the HLA match. Once doctors confirm the match, youd meet with a counselor from the NMDP to talk about the procedures, benefits, and risks of the donation process. You then decide whether youre comfortable with donating.

If you agree to donate bone marrow, youll likely do whats called a peripheral blood stem cell (PBSC) collection. Heres how it works:

For 5 days leading up to the donation, youll get a daily 5-minute injection of granulocyte colony-stimulating factor (G-CSF), a white blood cell growth hormone.

On day 5, a trained health care provider will place a needle in each of your arms. One needle will remove blood, and a machine circulates the blood and collects the stem cells. Your blood then is returned to your body through the second needle. The process takes about 3 hours and may be repeated on a second donation day. Side effects include headaches, bone soreness, and discomfort from the needles during the process.

Although less common, some donors may be asked to undergo a bone marrow harvest, during which doctors take bone marrow from the back of a donors hip bone during surgery. Donors usually go home the same day of the surgery and can return to normal activity within 1 week. Common side effects include nausea, headache, and fatigue, most often related to the anesthesia. Bruising or discomfort in the lower back is also common.

The end result? You could help cure someones disease.

More:
Donating Bone Marrow | Cancer.Net

In August, 2011 an all natural rejuvenating serum that uses your own adult stem cells to decrease wrinkles and increase moisture retention and elasticity was launched in the United States, and subsequently in Australia. This is a mocha based fusion of the world's most restorative ingredients and a blend of six cytokines that stimulate the proliferation and migration of the skin's stem cells by more than 225%.

There are a number of stem cell based serums and skin care products that have appeared on the marketplace over the past few years, and they constitute a novel frontier in skin care. Although many of them are nothing more than simple skin care products with misleading or spurious stem cell claims, a few are legitimate products. The legitimate ones are all based on the use of compounds called cytokines, which are growth factors supporting the functions of stem cells in the skin. Some of them contain an extract from apple stem cells, whose effectiveness really remains to be proven there is an obvious difference between human skin and an apple! Others contained cytokines from human stem cells. The latter are obviously the premium products.

One of the questions the developers of this product asked was: Of all the natural compounds and herbal extracts known to benefit the skin, which do so by supporting the natural role of stem cells in the skin? Are there natural compounds that can support the intrinsic ability of the skin to renew itself? They studied a broad array of plants and herbal extracts for their effect on the proliferation and differentiation of human skin stem cells grown in vitro, and they discovered a handful of natural compounds that have an effect on the very stem cells of your skin. By supporting the natural role of your skins stem cells, you support the process of rejuvenation of your skin from within.......the way nature intended. These compounds include AFA, the same product from which stem cell nutrition is derived.

AFA alone increased the proliferation of skin stem cells by nearly 100% in the study. Other natural ingredients include: Aloe vera (which increased skin stem cell proliferation by 87%) and a proprietary fucoidan that increased proliferation by 55%. When blended together, the effect of these plants on skin stem cell proliferation was further synergistically increased by ingredients like vanilla, maqui berry, cacao, old mans weed and others. All these ingredients taken together constitute the Stem Cell Complex unique to this product with a Stem Cell Index exceeding 250%

Hyaluronic acid is part of the infrastructure (skeleton of the skin) and is one of the main components forming the matrix of the skin. One of the main roles of hyaluronic acid is to retain moisture in the skin. Good hydration is the hallmark of young skin, and it comes from the presence of hyaluronic acid. Recently a group of scientists discovered that as we age, although we continue to produce hyaluronic acid, its structure is less and less branched. The highly branched hyaluronic acid in young skin allows for greater retention of water in the skin. Since these branches are formed of a derivative of glucosamine, scientists discovered that the best results are obtained when this derivative of glucosamine is applied on the skin, instead of hyaluronic acid itself. This product is the first in the US to contain that very derivative of glucosamine, produced by fermentation.

An all-natural formula Of all the stem cell based skin care products, this is the only one that is truly natural ......even though many make the claim. In essence, all skin care products are oils blended with water extracts of various plants. Since oil and water do not mix, it is necessary to use compounds called emulsifiers that can dissolve in both water and in lipids, thereby helping to create an emulsion. There are very few natural emulsifiers and none that are known to be effective at making a cold emulsion which is essential to the preservation of all the delicate actives found in herbal extracts. This is the only skin care product made cold with an all-natural emulsification system. Products like glycerin are relatively natural and can be used as emulsifiers; however, they are known for their drying effect on the skin. There is no glycerin here. Once produced, natural skin care products are essentially food for bacteria, so they need to be preserved. And this is the biggest challenge, as there are virtually no natural preservatives commercially available. Although the best products claim to have none of the dangerous carcinogenic parabens, they have other compounds just as dangerous such as phenoxyethanol and various forms of benzoic acid, all known to be irritants to the skin. The developers asked the question, Where in nature can we find natural antibacterial compounds? They harvested several flowers known to grow in very moist areas while blooming for weeks, unaffected by bacterial or fungal growth, and they extracted their antibacterial power. To this they added a proprietary process called SoniPure that inactivates bacteria by the use of sound waves a breakthrough innovative process. So this skin serum is 100% stable without delivering harmful compounds to your skin.

The developers intention was to create a product to restructure the skin from within in order to increase water retention and skin elasticity, which in turn would naturally reduce wrinkles and fine lines and this is exactly what was demonstrated in an independent clinical trial. It was shown to increase water retention by 30% and skin elasticity by 10% and to reduce wrinkles by an average of 25% in 28 days. Some people saw significant benefits after only 7 days, while others report wrinkle reduction by as much as 75%. In all participants, wrinkle reduction was already statistically significant after 7 days. So you can easily see how both the developmental process and the resulting formula ensure that this product is undeniably second-to-none in stem cell based skin care.

In healthy individuals, skin youthfulness is maintained by epidermal stem cells which self-renew and generate daughter cells that become new skin. Therefore, part of skin aging is caused by impaired adult stem cell mobilization from the bone marrow and the reduced number of adult stem cells able to respond to repair signals. This means that, if we increase the number of circulating adult stem cells, we can affect the epidermal stem cells. Research also shows that topical application of cytokines stimulates the migration and proliferation of skin stem cells.

In much the same way as stem cell nutrition works with adult stem cells to deliver inner wellness, the rejuvenating skin serum applies the benefits of adult stem cell science to the bodys largest organ, the skin, to achieve and maintain outer vibrance! Taking care of this organ the skin, which exposed to the elements on a continual basis is essential. The rejuvenating skin serum assists in our daily process at the skin level, by a proprietary blend of over two dozen natural ingredients found during years of searching worldwide. Each natural ingredient has been selected for its nutrient-rich attributes that fight the appearance of aging, regenerating cells, decreasing fine lines and wrinkles, increasing moisture retention and increasing skin elasticity. In addition, some of the ingredients have natural sun-protecting components.

After using stem cell serum on one side of face only for only 10 days

Your skin's response to an increase in circulating adult stem cells. The most evident visual response in people's facial skin a few weeks after taking stem cell nutrition is that - it glows. People notice a smoothness and improvement in color of their skin. Skin may also show improvements in age related and hormonal pigmentation, decreased bruising and increased elasticity and tone.

Before and after using stem cell serum

This product is second to none, and early clinical tests have demonstrated the following dramatic results: Decreased fine line & coarse wrinkles 25% in 28 days Increased moisture retention 30% in 28 days Increased elasticity 10% in 28 days

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Rejuvenating Skin Serum - Stem Cell Nutrition

Some of the promise of stem cell therapy has been realized. A prime example is bone marrow transplantation. Even here, however, manyproblems remain to be solved.

Challenges facing stem cell therapy include the following:

Adult stem cells Tissue-specific stem cells in adult individuals tend to be rare. Furthermore, while they can regenerate themselves in an animal or person they are generally very difficult to grow and to expand in the laboratory. Because of this, it is difficult to obtain sufficient numbers of many adult stem cell types for study and clinical use. Hematopoietic or blood-forming stem cells in the bone marrow, for example, only make up one in a hundred thousand cells of the bone marrow. They can be isolated, but can only be expanded a very limited amount in the laboratory. Fortunately, large numbers of whole bone marrow cells can be isolated and administered for the treatment for a variety of diseases of the blood. Skin stem cells can be expanded however, and are used to treat burns. For other types of stem cells, such as mesenchymal stem cells, some success has been achieved in expanding the cellsin vitro, but application in animals has been difficult. One major problem is the mode of administration. Bone marrow cells can be infused in the blood stream, and will find their way to the bone marrow. For other stem cells, such as muscle stem cells, mesenchymal stem cells and neural stem cells, the route of administration in humans is more problematic. It is believed, however, that once healthy stem cells find their niche, they will start repairing the tissue. In another approach, attempts are made to differentiate stem cells into functional tissue, which is then transplanted. A final problem is rejection. If stem cells from the patients are used, rejection by the immune system is not a problem. However, with donor stem cells, the immune system of the recipient will reject the cells, unless the immune system is suppressed by drugs. In the case of bone marrow transplantation, another problem arises. The bone marrow contains immune cells from the donor. These will attack the tissues of the recipient, causing the sometimes deadly graft-versus-host disease.

Pluripotent stem cells All embryonic stem cell lines are derived from very early stage embryos, and will therefore be genetically different from any patient. Hence, immune rejection will be major issue. For this reason, iPS cells, which are generated from the cells of the patient through a process of reprogramming, are a major breakthrough, since these will not be rejected. A problem however is that many iPS cell lines are generated by insertion of genes using viruses, carrying the risk of transformation into cancer cells. Furthermore, undifferentiated embryonic stem cells or iPS cells form tumors when transplanted into mice. Therefore, cells derived from embryonic stem cells or iPS cells have to be devoid of the original stem cells to avoid tumor formation. This is a major safety concern.

A second major challenge is differentiation of pluripotent cells into cells or tissues that are functional in an adult patient and that meet the standards that are required for 'transplantation grade' tissues and cells.

A major advantage of pluripotent cells is that they can be grown and expanded indefinitely in the laboratory. Therefore, in contrast to adult stem cells, cell number will be less of a limiting factor. Another advantage is that given their very broad potential, several cell types that are present in an organ might be generated. Sophisticated tissue engineering approaches are therefore being developed to reconstruct organs in the lab.

While results from animal models are promising, the research on stem cells and their applications to treat various human diseases is still at a preliminary stage. As with any medical treatment, a rigorous research and testing process must be followed to ensure long-term efficacy and safety.

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Stem Cell FAQ

Some cells are visible to the unaided eye

The smallest objects that the unaided human eye can see are about 0.1 mm long. That means that under the right conditions, you might be able to see an ameoba proteus, a human egg, and a paramecium without using magnification. A magnifying glass can help you to see them more clearly, but they will still look tiny.

Smaller cells are easily visible under a light microscope. It's even possible to make out structures within the cell, such as the nucleus, mitochondria and chloroplasts. Light microscopes use a system of lenses to magnify an image. The power of a light microscope is limited by the wavelength of visible light, which is about 500 nm. The most powerful light microscopes can resolve bacteria but not viruses.

To see anything smaller than 500 nm, you will need an electron microscope. Electron microscopes shoot a high-voltage beam of electrons onto or through an object, which deflects and absorbs some of the electrons. Resolution is still limited by the wavelength of the electron beam, but this wavelength is much smaller than that of visible light. The most powerful electron microscopes can resolve molecules and even individual atoms.

The label on the nucleotide is not quite accurate. Adenine refers to a portion of the molecule, the nitrogenous base. It would be more accurate to label the nucleotide deoxyadenosine monophosphate, as it includes the sugar deoxyribose and a phosphate group in addition to the nitrogenous base. However, the more familiar "adenine" label makes it easier for people to recognize it as one of the building blocks of DNA.

No, this isn't a mistake. First, there's less DNA in a sperm cell than there is in a non-reproductive cell such as a skin cell. Second, the DNA in a sperm cell is super-condensed and compacted into a highly dense form. Third, the head of a sperm cell is almost all nucleus. Most of the cytoplasm has been squeezed out in order to make the sperm an efficient torpedo-like swimming machine.

The X chromosome is shown here in a condensed state, as it would appear in a cell that's going through mitosis. It has also been duplicated, so there are actually two identical copies stuck together at their middles. A human sperm cell contains just one copy each of 23 chromosomes.

A chromosome is made up of genetic material (one long piece of DNA) wrapped around structural support proteins (histones). Histones organize the DNA and keep it from getting tangled, much like thread wrapped around a spool. But they also add a lot of bulk. In a sperm cell, a specialized set of tiny support proteins (protamines) pack the DNA down to about one-sixth the volume of a mitotic chromosome.

The size of the carbon atom is based on its van der Waals radius.

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An adult stem cell is thought to be an undifferentiated cell, found among differentiated cells in a tissue or organ. The adult stem cell can renew itself and can differentiate to yield some or all of the major specialized cell types of the tissue or organ. The primary roles of adult stem cells in a living organism are to maintain and repair the tissue in which they are found. Scientists also use the term somatic stem cell instead of adult stem cell, where somatic refers to cells of the body (not the germ cells, sperm or eggs). Unlike embryonic stem cells, which are defined by their origin (cells from the preimplantation-stage embryo), the origin of adult stem cells in some mature tissues is still under investigation.

Research on adult stem cells has generated a great deal of excitement. Scientists have found adult stem cells in many more tissues than they once thought possible. This finding has led researchers and clinicians to ask whether adult stem cells could be used for transplants. In fact, adult hematopoietic, or blood-forming, stem cells from bone marrow have been used in transplants for more than 40 years. Scientists now have evidence that stem cells exist in the brain and the heart, two locations where adult stem cells were not at firstexpected to reside. If the differentiation of adult stem cells can be controlled in the laboratory, these cells may become the basis of transplantation-based therapies.

The history of research on adult stem cells began more than 60 years ago. In the 1950s, researchers discovered that the bone marrow contains at least two kinds of stem cells. One population, called hematopoietic stem cells, forms all the types of blood cells in the body. A second population, called bone marrow stromal stem cells (also called mesenchymal stem cells, or skeletal stem cells by some), were discovered a few years later. These non-hematopoietic stem cells make up a small proportion of the stromal cell population in the bone marrow and can generate bone, cartilage, and fat cells that support the formation of blood and fibrous connective tissue.

In the 1960s, scientists who were studying rats discovered two regions of the brain that contained dividing cells that ultimately become nerve cells. Despite these reports, most scientists believed that the adult brain could not generate new nerve cells. It was not until the 1990s that scientists agreed that the adult brain does contain stem cells that are able to generate the brain's three major cell typesastrocytes and oligodendrocytes, which are non-neuronal cells, and neurons, or nerve cells.

Adult stem cells have been identified in many organs and tissues, including brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis. They are thought to reside in a specific area of each tissue (called a "stem cell niche"). In many tissues, current evidence suggests that some types of stem cells are pericytes, cells that compose the outermost layer of small blood vessels. Stem cells may remain quiescent (non-dividing) for long periods of time until they are activated by a normal need for more cells to maintain tissues, or by disease or tissue injury.

Typically, there is a very small number of stem cells in each tissue and, once removed from the body, their capacity to divide is limited, making generation of large quantities of stem cells difficult. Scientists in many laboratories are trying to find better ways to grow large quantities of adult stem cells in cell culture and to manipulate them to generate specific cell types so they can be used to treat injury or disease. Some examples of potential treatments include regenerating bone using cells derived from bone marrow stroma, developing insulin-producing cells for type1 diabetes, and repairing damaged heart muscle following a heart attack with cardiac muscle cells.

Scientists often use one or more of the following methods to identify adult stem cells: (1) label the cells in a living tissue with molecular markers and then determine the specialized cell types they generate; (2) remove the cells from a living animal, label them in cell culture, and transplant them back into another animal to determine whether the cells replace (or "repopulate") their tissue of origin.

Importantly, scientists must demonstrate that a single adult stem cell can generate a line of genetically identical cells that then gives rise to all the appropriate differentiated cell types of the tissue. To confirm experimentally that a putative adult stem cell is indeed a stem cell, scientists tend to show either that the cell can give rise to these genetically identical cells in culture, and/or that a purified population of these candidate stem cells can repopulate or reform the tissue after transplant into an animal.

As indicated above, scientists have reported that adult stem cells occur in many tissues and that they enter normal differentiation pathways to form the specialized cell types of the tissue in which they reside.

Normal differentiation pathways of adult stem cells. In a living animal, adult stem cells are available to divide for a long period, when needed, and can give rise to mature cell types that have characteristic shapes and specialized structures and functions of a particular tissue. The following are examples of differentiation pathways of adult stem cells (Figure 2) that have been demonstrated in vitro or in vivo.

Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image. ( 2008 Terese Winslow)

Transdifferentiation. A number of experiments have reported that certain adult stem cell types can differentiate into cell types seen in organs or tissues other than those expected from the cells' predicted lineage (i.e., brain stem cells that differentiate into blood cells or blood-forming cells that differentiate into cardiac muscle cells, and so forth). This reported phenomenon is called transdifferentiation.

Although isolated instances of transdifferentiation have been observed in some vertebrate species, whether this phenomenon actually occurs in humans is under debate by the scientific community. Instead of transdifferentiation, the observed instances may involve fusion of a donor cell with a recipient cell. Another possibility is that transplanted stem cells are secreting factors that encourage the recipient's own stem cells to begin the repair process. Even when transdifferentiation has been detected, only a very small percentage of cells undergo the process.

In a variation of transdifferentiation experiments, scientists have recently demonstrated that certain adult cell types can be "reprogrammed" into other cell types in vivo using a well-controlled process of genetic modification (see Section VI for a discussion of the principles of reprogramming). This strategy may offer a way to reprogram available cells into other cell types that have been lost or damaged due to disease. For example, one recent experiment shows how pancreatic beta cells, the insulin-producing cells that are lost or damaged in diabetes, could possibly be created by reprogramming other pancreatic cells. By "re-starting" expression of three critical beta cell genes in differentiated adult pancreatic exocrine cells, researchers were able to create beta cell-like cells that can secrete insulin. The reprogrammed cells were similar to beta cells in appearance, size, and shape; expressed genes characteristic of beta cells; and were able to partially restore blood sugar regulation in mice whose own beta cells had been chemically destroyed. While not transdifferentiation by definition, this method for reprogramming adult cells may be used as a model for directly reprogramming other adult cell types.

In addition to reprogramming cells to become a specific cell type, it is now possible to reprogram adult somatic cells to become like embryonic stem cells (induced pluripotent stem cells, iPSCs) through the introduction of embryonic genes. Thus, a source of cells can be generated that are specific to the donor, thereby increasing the chance of compatibility if such cells were to be used for tissue regeneration. However, like embryonic stem cells, determination of the methods by which iPSCs can be completely and reproducibly committed to appropriate cell lineages is still under investigation.

Many important questions about adult stem cells remain to be answered. They include:

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Progress in basic research, starting with the work on neural stem cells in the middle 1990's to embryonic stem (ES) cells and induced pluripotent stem (iPS) cells at present, will lead the cell therapy (regenerative medicine) of various organs, including the central nervous system to a big medical field in the future. The author's group transplanted iPS cell-derived retinal pigment epithelial (RPE) cell sheets to the eye of a patient with exudative age-related macular degeneration (AMD) in 2014 as a clinical research. Replacement of the RPE with the patient's own iPS cell-derived young healthy cell sheet will be one new radical treatment of AMD that is caused by cellular senescence of RPE cells. Since it was the first clinical study using iPS cell-derived cells, the primary endpoint was safety judged by the outcome one year after surgery. The safety of the cell sheet has been confirmed by repeated tumorigenisity tests using immunodeficient mice, as well as purity of the cells, karyotype and genetic analysis. It is, however, also necessary to prove the safety by clinical studies. Following this start, a good strategy considering cost and benefit is needed to make regenerative medicine a standard treatment in the future. Scientifically, the best choice is the autologous RPE cell sheet, but autologous cell are expensive and sheet transplantation involves a risky part of surgical procedure. We should consider human leukocyte antigen (HLA) matched allogeneic transplantation using the HLA 6 loci homozyous iPS cell stock that Prof. Yamanaka of Kyoto University is working on. As the required forms of donor cells will be different depending on types and stages of the target diseases, regenerative medicine will be accomplished in a totally different manner from the present small molecule drugs. Proof of concept (POC) of photoreceptor transplantation in mouse is close to being accomplished using iPS cell-derived photoreceptor cells. The shortest possible course for treatment is now being investigated in preclinical research. Among the mixture of rod and cone photoreceptors in the donor cells, the percentage of cone photoreceptors is still low. Donor cells with more. cone photoreceptors will be needed. If that will work well, photoreceptor transplantation will be the first example of neural network reconstruction in the central nervous system. These efforts will reach to variety of retinal cell transplantations in the future.

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Our skin is an extremely important and multi-faceted organ. It protects our insides by providing a cover for our body and is responsible for preventing pathogens entering our organism. The skin also fulfills other important roles by regulating body temperature, in the area of metabolism, and for our sensitivity to touch and stimuli.

In addition, our skin also contains a large quantity of autologous stem cells (so-called adult stem cells). Autologous stem cells are on the one hand relevant for the external appearance of the skin, and on the other hand they offer a great deal of positive therapeutic potential in the area of regenerative medicine.

If we bear in mind what kind of functions our skin has, it becomes obvious why we should be paying special attention to its health.

Already in the traditional European medicine there was the tenet As inside, so outside. Even in modern science we know that it is important to distinguish between cause and effect and that many degenerative processes inside the body manifest externally.

For example, various factors can lead to a massive acceleration of the per se normal skin aging: Stress, overload and unhealthy diet can cause hormonal dysfunction, which in turn leads to premature aging and tissue slackening. Certain lifestyle habits such as tanning booths as well as smoking can cause skin damages over time, which can often make people concerned look more than 10 years older than they actually are.

Our therapeutic approach is not only to treat the symptom (= premature aging of the skin), but the cause (= e.g., hormone deficiency) as far as possible. Combinations of both the therapy of the cause and targeted local treatments can be useful, especially when a large distress is present and/or the skin damages are very advanced.

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We use the autologous substances for our skin treatments. We never use artificial fillers (e.g., silicone) or Botox, because their side effects often lead to a worsening of skin quality.

When we are young, the body still has enough stem cells and produces sufficient growth factors and hormones, however, as the years pass, the body produces less of them. This wear process can be accelerated by stress, overwork, poor nutrition and certain lifestyle habits. The external signs of premature aging appear, such as wrinkles, slackening of tissue, sagging cheeks and greying of the skin.

All types of treatment offered by our clinic serve the purpose of giving your skin back a certain amount of quality, elasticity and freshness by targeted application of the autologous substances or substances similar to the bodys own.

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Skin Regeneration with Stem Cells, Growth Factors ...

Scientists have discovered a new type of stem cell in the skin that acts surprisingly like certain stem cells found in embryos: both can generate fat, bone, cartilage, and even nerve cells. These newly-described dermal stem cells may one day prove useful for treating neurological disorders and persistent wounds, such as diabetic ulcers, says Freda Miller, an HHMI international research scholar.

Miller and her colleagues first saw the cells several years ago in both rodents and people, but only now confirmed that the cells are stem cells. Like other stem cells, these cell scan self-renew and, under the right conditions, they can grow into the cell types that constitute the skins dermal layer, which lies under the surface epidermal layer. We showed that these cells are, in fact, the real thing, says Miller, a professor at the University of Toronto and a senior scientist in the department of developmental biology at the Hospital for Sick Children in Toronto. The dermal stem cells also appear tohelp form the basis for hair growth.The new work was published December 4, 2009, in the journal Cell Stem Cells.

Stem cell researchers like to talk about building organs in a dish. You can imagine, if you have all the right playersdermal stem cells and epidermal stem cellsworking together, you could do that with skin in a very real way.

Freda D. Miller

Though this research focuses on the skin, Miller has spent her career searching for cures for neurological diseases such as Parkinsons. About a decade ago, she decided to find an easily accessible cell that could be coaxed into making nerves. Brain stem cells, some of which can grow into nerves, lie deep in the middle of the organ and are too difficult to reach if the scientists eventually wanted to cultivate the cells from individual patients. I thought, This is blue sky stuff, but you never know. She searched the literature and found that amphibians can regenerate nerves in their skin. She also found published hints that mammalian nerve cells could do the same.

Her team looked in the dermal layer of the skin in both mice and people. Hair follicles and sweat glands are rooted in the dermis, a thick layer of cells that also help support and nourish blood vessels and touch-perceiving nerves. In 2001, Millers team hit paydirt when they discovered cells that respond to the same growth factors that make brain stem cells differentiate. She named them skin-derived precursors (SKPs, or skips).

Miller soon discovered that the cells act like neural crest cells from embryosstem cells that generate the entire peripheral nervous system and part of the headin that they could turn into nerves, fat, bone, and cartilage.That gave us the idea that these were some kind of embryonic-like precursor cell that migrated into the skin of the embryo, Miller said. But instead of disappearing as the embryo develops, the cells survive into adulthood.

Even though the SKPs acted like stem cells in Petri dishes, Miller didnt know if they behaved the same way in the body. We were obviously very excited about these cells, she said. The problem was, cells can do all kinds of weird things in culture dishes that look right but really arent. We thought, Maybe were being deceived.So lab member Jeffrey Biernaskie put the cells through their paces, performing a series of experiments to test whether the SKPs indeed acted like stem cells in the body.

Earlier work in the lab had shown that the SKPs produce a transcription factor called SOX2, which is produced in many types of stem cells. The team used genetically engineered mice with SOX2 genes tagged with green fluorescent protein, which allowed them to track where SOX2 was expressed in the animals. They found that about 1% of skin cells from adult mice contained the SOX2-making cells, and they were concentrated in the bulb at the base of hair follicles.When the team cultured these cells, they began behaving like SKPs.

Next, the scientists decided to see if the cells would not just settle at the base of hair follicles but grow new hair. They took the fluorescent cells, mixed them with epidermal cellswhich make up the majority of cells in a hair follicleand transplanted the mixture under the skin of hairless mice. These mice began growing hair, and analysis showed the green cells migrated to their home base in the bulb of the new hair follicles. The team also transplanted rat SKP cells under the skin of mice. The cells behaved exactly like dermal stem cellsthey spread out through the dermis and differentiated into various dermal cell types, including fat cells and dermal fibroblasts, which form the structural framework of the dermal layer. Intriguingly, the mice that carried transplanted rat SKPs also grew longer, thicker,rat-like hair, instead of short, thin mouse hair. These cells are instructive, they tell the epidermal cellswhich form the bulk of the hair follicleto make bigger, rat-like hair follicles, Miller said. There are a lot of jokes in my lab about bald men running around with rat hair on their heads.

Finally, the team gave mice small puncture wounds and then transplanted their fluorescent SKPs next to the wound. Within a month, many transplanted cells appeared in the scar, showing they had contributed to wound healing. The SKPs were also found in new hair follicles in the healed skin.

The cells behavior both in wound healing and hair growth led the team to conclude that the SKPs are, in fact, dermal stem cells. Miller said the finding complements work by HHMI investigator Elaine Fuchs, who found epidermal stem cells, which help renew the top layer of skin. Combining the evidence from the two labs suggests a possible path to baldness treatments, Miller saidthe dermal stem cells at the base of the hair follicle seem to be signaling the epidermal cells that form the shaft of the follicle to grow hair. But much about the signaling mechanism remains unknown.

Miller wants to investigate less cosmetic applications, such as treating nerve and brain diseases. Experiments she published between 2005 and 2007 showed that SKPs can grow into nerves and help repair spinal cord damage in rats. Her lab is continuing to pursue that research. She is also searching for signals that could trigger the dermal stem cells to rev up their innate wound-healing ability. If such a signal can be found and mimicked, Miller can envision one day treating chronic woundssuch as diabetic ulcerswith a topical cream. Such a treatment is years or decades away, she said, but now researchers know which cell types to focus on. Another possibility: improving skin grafts, which today consist of only epidermal, not dermal, cells. While skin grafts can dramatically help burn victims, those grafts dont function like normal skin.

Stem cell researchers like to talk about building organs in a dish, said Miller. You can imagine, if you have all the right playersdermal stem cells and epidermal stem cellsworking together, you could do that with skin in a very real way.

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Combined NSC transplantation and VPA administration improves functional recovery of hind limbs without CST axon reextension. As VPA has been shown to have effects that are likely to be beneficial to treatment of the injured CNS, such as neuroprotection (2731), induction of neuronal differentiation (26), and promotion of neurite outgrowth (32), we examined the response of SCI model mice to different combinations of VPA administration and NSC transplantation. We prepared NSCs from embryonic forebrains of 3 different Tg mouse lines ubiquitously expressing either GFP (GFP-Tg) (33), GFP and LUC (GFP.LUC-Tg), or GFP, LUC, and the diphtheria toxin (DT) receptor human heparin-binding EGF-like growth factor (TR6) (TR6.GFP.LUC-Tg) (see Methods). The expression of GFP, LUC, and TR6 in NSCs enabled us to distinguish transplanted cells from host cells, to trace the survival of transplanted cells based on LUC activity in a noninvasive fashion, and to specifically ablate transplanted cells (see below), respectively. To obtain a homogeneous population of NSCs, we used adherent monolayer culture (3436). The embryonic forebrains were dissociated and cultured with EGF and basic FGF (bFGF) (36) (Supplemental Figure 1, A and B; supplemental material available online with this article; doi:10.1172/JCI42957DS1). These cells uniformly expressed the stem cell markers Sox2 and nestin but did not express differentiation markers (Supplemental Figure 1, C and D). Under the appropriate conditions for each lineage, these NSCs differentiated into neurons, astrocytes, or oligodendrocytes (Supplemental Figure 1, E and F). NSCs from different Tg mice behaved similarly in these culture conditions (data not shown). NSCs that had been cultured and passaged 510 times in the presence of both EGF and bFGF to maintain the undifferentiated state were used for transplantation studies.

Undifferentiated NSCs were transplanted into the SCI epicenter 7 days after injury. Nontransplanted control and transplanted mice were then intraperitoneally administered VPA or saline daily for 7 days (Figure 1A), whereafter we monitored their hind limb motor function using the open field locomotor scale (BBB score) (79, 37) for 6 weeks. Remarkably, we found that the simultaneous treatment of SCI model mice with NSCs and VPA resulted in a dramatic recovery of hind limb function compared with either treatment alone (Figure 1B and Supplemental Videos 14). There were no significant differences among the data obtained from each SCI model mouse group transplanted with the 3 distinct NSCs. Functional recovery of each treated SCI model mouse reached a plateau at around 6 weeks, the level of which was sustained for more than 3 months. Since mice treated with VPA alone showed no further improvement compared with untreated mice, it is most likely that VPA affected the function of transplanted cells.

A combination of NSC transplantation and VPA administration improves functional recovery of hind limbs without CST axon reextension. (A) Schematic of the NSC transplantation and VPA injection protocol. (B) Time course of functional recovery of hind limbs after SCI. GFP-NSCs, GFP.LUC-NSCs, and TR6.GFP.LUC-NSCs were transplanted into the SCI epicenter 7 days after injury as indicated. Combined treatment with NSC transplantation and VPA administration resulted in the greatest functional recovery. Data represent mean SEM. **P < 0.001 compared with SCI models with no treatment; *P < 0.01 compared with SCI models with no treatment (repeated measures ANOVA). NSC+VPA, total n = 21. (C) Representative pictures of BDA-labeled CST fibers at 5 mm rostral and 5 mm caudal to the lesion site. BDA was injected into the motor cortices 12 weeks after SCI. 2 weeks after the injection, mice were fixed and spinal cord sections were stained. Representative results for a GFP-NSCtransplanted spinal cord are shown. Blue, Hoechst nuclear staining. Scale bar: 20 m. (D) Quantification of the labeled CST fibers in the spinal cords of intact mice, SCI mice receiving no treatment, and SCI mice undergoing combined NSC/VPA treatment. Eight 30-mthick serial parasagittal sections from individual spinal cords were evaluated. The x axis indicates specific locations along the rostrocaudal axis of the spinal cord, and the y axis indicates the ratio of the number of BDA-labeled fibers at the indicated site to that at 6 mm rostral to the lesion site (Th9). **P < 0.001 compared with SCI models without treatment; *P = 0.188 There is no significant difference in the number of BDA-labeled fibers between NSC+VPA-treated mice (blue line) and SCI model mice with no treatment (yellow line) (repeated measures ANOVA). All data shown are from at least 3 experiments in parallel conditions, with error bars representing SEM.

We next sought to determine the basis for this improvement in locomotor function. Since transplanted NSCs have been reported to play a supportive role in the reextension of injured axons (14), we analyzed whether CST axons were regenerated by anterograde labeling using biotinylated dextran amine (BDA) (6, 16, 17). Because BDA was injected into the motor cortex, only the axons of first-order neurons in the CST could be visualized (Figure 1C). In our SCI model mice, the caudal part of the injured site was completely devoid of CST axons (Figure 1, C and D), and the same was true in mice that had undergone combined NSC transplantation and VPA administration (Figure 1, C and D). These data indicated that CST axons did not reextend in mice treated with both NSCs and VPA and therefore that some other mechanism was responsible for the animals dramatic functional locomotor improvement.

Transplanted NSCs encompass the lesion site and extend their processes. Given that host CST axon reextension was not involved in the observed hind limb recovery, we decided to focus on the transplanted cells. We analyzed the migration, morphology, neuronal marker expression, and viability of these cells after coadministration with VPA. Transplant-derived cells migrated to both rostral and caudal areas and displayed processes that extended into the gray matter and dorsal funiculus within 5 weeks of transplantation (Figure 2). Between 20% and 40% of the transplanted cells were found to be surviving in the injured spinal cord after 8 weeks, and 17% still remained viable more than 1 year after transplantation (data not shown). About 20% of the surviving cells had differentiated into microtubule-associated protein 2positive (MAP2-positive) neurons with elongated processes within 5 weeks after transplantation (Figure 2, B and C, and Figure 3, E and F). Survival of the transplanted NSCs was not significantly influenced by VPA administration (Supplemental Figure 8).

Transplanted NSCs migrate from the injection site and encompass the lesion site. Representative results of GFP-NSCtransplanted SCI model mice are shown. (A) A series of immunostaining images of injured spinal cord at 6 weeks after injury. SCI mice received combination treatment with NSC transplantation and VPA administration. Specimens were picked up every 150 m and stained with anti-GFP (green) and MAP2 (not shown) antibodies and Hoechst (blue). The epicenter of the SCI is indicated (*). Scale bar: 1 mm. (B and C) Higher-magnification images of the white boxes in A. GFP-positive transplanted NSCs differentiated into MAP2-positive neurons and extended their processes. Scale bar: 50 m.

VPA promotes neuronal differentiation of transplanted NSCs. Representative results of GFP-NSCtransplanted SCI model mice are shown. (A) Confocal images of NSCs 1 week after transplantation into the injured spinal cords. Spinal cord sections from VPA-treated (+) and untreated () mice were stained with anti-GFP (green), anti-doublecortin (DCX) (immature neuronal marker, red) and anti-GFAP (magenta) antibodies, and Hoechst (blue). VPA administration resulted in an increase in the number of DCX-positive neuronal precursors among transplanted cells (lower panel). Scale bar: 20 m. (BD) The percentages of DCX-, GFAP-, and MBP-positive cells in GFP-positive transplanted cells were quantified. **P < 0.01; *P < 0.05 compared with controls (Students t test). (E) Confocal images of NSCs 5 weeks after transplantation into injured spinal cords. Spinal cord sections from VPA-treated (+) and untreated () mice were stained with anti-GFP (green), anti-MAP2 (neuronal marker, red) and anti-GFAP (magenta) antibodies, and Hoechst (blue). VPA administration increased the numbers of MAP2-positive neurons (lower panel). Scale bar: 20 m. (F and G) The percentages of cells positive for MAP2 or GFAP in GFP-positive transplanted cells in E were quantified. **P < 0.01; *P < 0.05 compared with control (Students t test). All data shown in BD, F, and G are from at least 15 confocal images of 3 individuals in parallel experiments, with error bars representing the SD.

HDAC inhibition promotes neuronal differentiation of NSCs and is critical for transplantation-induced hind limb recovery. In contrast to previous studies, which have indicated that very few transplanted NSCs differentiate into neurons in the injured CNS environment (8, 10, 11, 20), many neurons were observed in the spinal cord after coadministration with VPA. We next examined in more detail the contribution of VPA to differentiation of cultured and transplanted NSCs. To analyze differentiation in vitro, NSCs were treated with either VPA or valpromide (VPM), an amide analog of VPA that is also an antiepileptic but is not an HDAC inhibitor (24), under differentiation culture conditions. VPA enhanced histone acetylation (Supplemental Figure 2A) and promoted neuronal differentiation and neurite outgrowth of the NSCs (Supplemental Figure 3, AC); it also inhibited astrocytic and oligodendrocytic differentiation of NSCs (Supplemental Figure 3, DG). A different HDAC inhibitor, trichostatin A (TSA), also enhanced histone acetylation (Supplemental Figure 2A) and neuronal differentiation of NSCs (not shown) (26). In contrast, VPM neither enhanced histone acetylation nor induced neuronal differentiation, suggesting that HDAC inhibition has an important role in regulating fate determination in NSCs.

We then assessed the histone acetylation status and differentiation profiles of transplanted NSCs. VPA administration enhanced histone acetylation in transplanted cells in the spinal cord (Supplemental Figure 2, B and C). When we examined the differentiation status of transplanted cells 1 week after transplantation, neuronal but not glial differentiation was greatly enhanced by VPA administration (Figure 3, AD, and Supplemental Figure 4A). A similar differentiation tendency of transplanted NSCs to that at 1 week was observed at 5 weeks after transplantation: there was a dramatic increase in the number of cells positive for MAP2 (a relatively late differentiation marker of neurons in comparison with DCX) in VPA-administered mice (Figure 3, EG, and Supplemental Figure 4B). Furthermore, VPM administration to the SCI mice neither promoted neuronal differentiation nor enhanced hind limb motor function, suggesting that HDAC inhibition has an essential role in regulating fate determination of transplanted NSCs and improvement of motor function in vivo (Supplemental Figure 5, AC). In light of the above findings that the percentage of neurons generated from transplanted NSCs increased dramatically with VPA administration, whereas those of astrocytes and oligodendrocytes declined, we anticipated that these neurons would be likely to play a major role in regenerating the disrupted neuronal circuitry of the injured spinal cord.

Transplant-derived neurons reconstruct disrupted neuronal circuits in a relay manner. We next asked how the disrupted neuronal circuits were regenerated following the combined treatment with NSC transplantation and VPA administration. Wheat germ agglutinin (WGA), which can be transsynaptically transported, is one of the best known tracers of neural pathways (38). WGA protein can be transferred across synapses to second- and third-order neurons, permitting functional neuronal circuits to be tracked in the CNS. We injected WGA-expressing adenoviruses into the motor cortex of mouse brain 12 weeks after SCI. In uninjured mice, WGA was detected as intracellular granule-like structures in neurons localized in the ventral horn throughout the spinal cord (Figure 4, A and B). In untreated SCI model mice, WGA granules were almost completely absent from the caudal region below the injured site (Figure 4, A and C). Surprisingly, although we could not observe CST axonal reextension through the lesion site (Figure 1, C and D), WGA granules were clearly present in caudal large neurons located in the spinal cords of mice treated with both NSC and VPA (Figure 4, A and D). Intriguingly, moreover, transplant-derived neurons in or close to the lesion site contained WGA granules (Figure 4E), which were received from more rostral neurons. These data imply that WGA was conveyed through the lesion site to the caudal area via transplant-derived neurons. Considering this finding, together with the fact that WGA could be detected in caudal neurons without CST axonal reextension in mice that had undergone the combined treatment, it seemed conceivable that the transplant-derived neurons reconstructed the disrupted neuronal circuits, thereby acting as relays for transmitting signals between endogenous neurons whose interconnection had been abolished by the injury. In mice that received NSC transplantation alone after SCI, the percentage of WGA-positive cells among MAP2ab-positive cells in the caudal region was higher than that in untreated mice (Figure 4C) but lower than that in mice receiving combined NSC transplantation and VPA administration (Supplemental Figure 6), reflecting the degree of hind limb functional improvement (Figure 1C).

Transplant-derived neurons reconstruct disrupted neuronal circuits in a relay manner. (A) Representative pictures of WGA-labeled neuronal cell bodies located in the ventral horn at 14 weeks after SCI. Spinal cord sections were stained with anti-WGA (red) and -MAP2ab (magenta) antibodies and Hoechst (blue). Scale bar: 20 m. Intense WGA immunoreactivity was observed as intracellular granule-like structures. Left panels show the rostral area (Th4Th7), and right panels show the caudal area (Th11 to lumbar vertebra [L] 1). In uninjured mice, WGA injected into the bilateral motor cortices was transsynaptically transported to neurons in areas rostral and caudal to the injured site (top panels). In the SCI model mice that did not receive treatment, very little WGA was observed in caudal areas (middle panels). However, in spinal cords of animals that underwent dual treatment with NSC and VPA, WGA was clearly observed in neurons in the caudal areas (bottom panels). Representative results of GFP-NSCtransplanted SCI model mice are shown. (BD) The percentages of WGA-positive cells in the neurons localized in the ventral horn were quantified. **P < 0.05 (Students t test). All data shown are from at least 30 images, containing more than 600 cells, from 3 individuals (5 images per area) in parallel experiments, with error bars representing SD. (E) Representative confocal images of WGA-labeled transplant-derived MAP2-positive neurons. Sections were stained with anti-WGA (red), anti-MAP2ab (magenta) and anti-GFP (green) antibodies, and Hoechst (blue). Granule-like WGA structures (yellow arrowheads) could be seen in the GFP and MAP2abdouble-positive transplant-derived neurons. Scale bar: 10 m.

In support of the notion of a relay function for transplant-derived neurons, immunoelectron microscopy revealed that GFP-positive transplant-derived neurons received projections from endogenous neurons (Figure 5, A and B) and that the axon terminals of transplant-derived neurons made synapses with endogenous neurons localized in the ventral horn (Figure 5, CE).

Transplant-derived neurons make synapses with endogenous neurons. (A) Immunoelectron microscopy image of a sagittal section of dual-treated (GFP-NSC and VPA) injured spinal cord (rostral area). A GFP-positive dendrite (Den) made synapses with GFP-negative endogenous axon termini (At) (yellow arrowheads). Scale bar: 1 m. (B) In other rostral regions, a dendrite of a GFP-positive transplant-derived neuron made a synapse (yellow arrowheads) with the axon terminus of a GFP-negative endogenous neuron. Scale bar: 1 m. (C) Sagittal section of dual-treated (NSC and VPA) injured spinal cord (caudal area) stained with anti-GFP antibody (dark brown). The epicenter of the SCI is indicated (*). Scale bar: 500 m. (D) High-magnification image of a large neuron localized in the ventral horn in the white rectangle in C. GFP-positive transplanted neurons extended their processes toward an endogenous neuron (yellow arrowheads). Scale bar: 100 m. (E) Immunoelectron microscopy image of the boxed area in D. GFP-positive axon termini made synapses with the dendrite of a GFP-negative endogenous large neuron (yellow arrowheads). Scale bar: 1 m.

Transplanted cells contribute directly to functional recovery of hind limb movement in SCI mice. To determine whether the transplanted cells made a direct contribution to the functional recovery of hind limbs after SCI, we performed specific ablation of transplanted cells using the toxin receptormediated cell knockout (TRECK) method (Figure 6A and refs. 39, 40). For this purpose, we prepared NSCs from the embryonic forebrains of GFP.LUC Tg and TR6.GFP.LUC Tg mice (Figure 6A and Supplemental Figure 7, A and B). Almost all of the transplanted TR6.GFP.LUC-NSCs were specifically ablated following DT administration (Figure 6, B and C). Furthermore, after ablation of the transplanted cells, the BBB scores of SCI model mice that had undergone combined TR6.GFP.LUC-NSC transplantation and VPA administration declined rapidly to levels similar to those observed in untreated and VPA onlytreated mice. These results were superimposed on the graph in Figure 1B, with the observation period extended to 12 weeks after SCI, as shown in Figure 6D (for clarity, the data for GFP-NSC.VPA and GFP.LUC-NS in Figure 1B were removed). These data indicate that the transplanted cells, in the presence of VPA, made a direct and major contribution to the functional recovery of hind limb movement in SCI model mice.

Ablation of transplanted cells abolishes hind limb motor function recovery. (A) Schematic of the protocols for NSC transplantation and for detection and ablation of transplanted cells. NSCs derived from GFP.LUC- or TR6.GFP.LUC-Tg mice were transplanted into SCI model mice 1 week after injury. VPA was intraperitoneally administered every day for 1 week. Survival of transplanted cells and locomotor function of the mice were monitored weekly for 14 weeks. (B) Survival of transplanted cells was checked every week using a bioluminescence imaging system. 6 weeks after injury (5 weeks after transplantation), each mouse received 2 DT administrations. By the following week, LUC activity had completely disappeared in mice transplanted with TR6.GFP.LUC-NSCs (lower panel). (C) Sagittal sections from SCI model mice transplanted with GFP.LUC- and TR6.GFP.LUC-NSCs 2 weeks after DT injection. All transplanted cells were ablated with DT (lower panel). Scale bar: 1 mm. (D) Time course of the changes in BBB scores in SCI model mice. The hind limb function of mice that had undergone dual treatment with TR6.GFP.LUC-NSCs and VPA dropped drastically after DT administration (black line). *P < 0.0001 compared with GFP.LUC-NSCtransplanted, VPA-administered, and DT-injected SCI model mice (blue line) (repeated measures ANOVA). Data are mean SEM. VPA, n = 8; no treatment, n = 8. (E) Twelve weeks after injury, groups of SCI model mice received NMDA injections, as indicated, into the injury epicenter, to ablate local neurons in the gray matter (blue, black, and yellow lines with triangles). *P < 0.0001 compared with non-NMDAinjected mice in each group (blue, black, and yellow lines with circles) (repeated measures ANOVA). Data represent mean SEM.

Both endogenous and transplant-derived local neurons play an important role in improving hind limb motor function. It has been shown recently that local neurons in the spinal cord play an important role in spontaneous functional recovery after SCI (41, 42). In our SCI model, we also observed slight but significant spontaneous recovery of hind limb function in untreated mice, and similar levels of recovery were sustained after ablation of transplanted cells (Figure 6D). We thus hypothesized that these recoveries were attributable to endogenous local neurons in the spinal cord. Furthermore, it seemed likely that the much higher recovery observed in mice with the combined treatment but without cell ablation (Figure 6D) was effected by transplant-derived local neurons in addition to the endogenous ones. To evaluate the involvement of these local neurons in our treatment regime, we divided each treated mouse group analyzed in Figure 6D into 2 subgroups (except for the TR6.GFP.LUC-NCStransplanted only and VPA-administered only groups). The axon-sparing excitotoxin NMDA was injected at 12 weeks after SCI into the injury epicenter in the injured spinal cords of the mice in 1 subgroup for each treatment to ablate local neurons in the gray matter (4345). In uninjured mice, NMDA injections had no significant effect on hind limb function (data not shown). However, as shown in Figure 6E, NMDA injections completely reversed both spontaneous and treatment-provoked functional recovery of hind limb movement in SCI model mice, indicating that both endogenous and transplant-derived local neurons indeed play an important role in the restoration of hind limb motor function.

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JCI - Neurons derived from transplanted neural stem cells ...

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Supported by a Science Education Partnership Award (SEPA) Grant No. R25RR023288 from the National Center for Research Resources, a component of the NIH. The contents provided here are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

APA format: Genetic Science Learning Center (2014, June 22) Stem Cells. Learn.Genetics. Retrieved September 26, 2015, from http://learn.genetics.utah.edu/content/stemcells/ MLA format: Genetic Science Learning Center. "Stem Cells." Learn.Genetics 26 September 2015 <http://learn.genetics.utah.edu/content/stemcells/> Chicago format: Genetic Science Learning Center, "Stem Cells," Learn.Genetics, 22 June 2014, <http://learn.genetics.utah.edu/content/stemcells/> (26 September 2015)

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