The kidney is made up of about a million tiny units that filter blood, rid the body of undesired waste products while holding back blood cells and valuable proteins, and control the bodys fluid content. Key to each of these units is a structure known the glomerulus, in which podocyte cells wrap themselves tightly around a tuft of capillaries separated only by a thin membrane composed of extracellular matrix, and leave slits between them to build an actual filtration barrier. Podocytes are the target of many congenital or acquired kidney diseases, and they are often harmed by drugs.

To build an in vitro model of the human glomerulus to probe deeper into its function and vulnerabilities to disease and drug toxicities, researchers have been attempting to engineer human stem cells that in theory can give rise to any mature cell type so that they form into functional podocytes. These cell culture efforts, however, so far have failed to produce populations of mature podocytes pure enough as to be useful for modeling glomerular filtration.

A team led by Donald Ingber, Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) and Founding Director of Harvards Wyss Institute of Biologically Inspired Engineering, now reports a solution to this challenge in Nature Biomedical Engineering, which enables the differentiation of human induced pluripotent stem (iPS) cells into mature podocytes with more than 90 percent efficiency.

Linking the differentiation process with organ-on-a-chip technology pioneered by his team, the researchers went on to engineer the first in vitro model of the human glomerulus, demonstrating effective and selective filtration of blood proteins and podocyte toxicity induced by a chemotherapy drug in vitro.

Ingber is also theJudah Folkman Professor of Vascular Biologyat Harvard Medical School (HMS) and the Vascular Biology Program at Boston Childrens Hospital.

The development of a functional human kidney glomerulus chip opens up an entirely new experimental path to investigate kidney biology, carry out highly personalized modeling of kidney diseases and drug toxicities, and the stem cell-derived kidney podocytes we developed could even offer a new injectable cell therapy approach for regenerative medicine in patients with life-threatening glomerulopathies in the future, said Ingber.

Ingbers team has engineered multiple organs-on-chips that accurately mimic human tissue and organ-level physiology. These platforms are currently being evaluated by the Food and Drug Administration (FDA) as a tool to more effectively study the effects of potential chemical and biological hazards found in foods, cosmetics or dietary supplementsthan existing culture systems or animal models. In 2013, his team developed an organ-on-a-chip microfluidic culture device that modeled the human kidneys proximal tubule, which is anatomically connected to the glomerulus and salvages ions from urinary fluid.

Now, with the teams newly engineered human kidney glomerulus-on-a-chip, researchers also can get in vitro access to the kidneys core filtration mechanisms that are critical for drug clearance and pharmacokinetics, in addition to studying human podocytes at work.

To generate almost pure populations of human podocytes in cell culture, Samira Musah, the studys first author and HMS Deans Postdoctoral Fellow who is working with Ingber at the Wyss Institute, leveraged pieces of the stem cell biologists arsenal, and merged them with snippets taken from Ingbers past research on how cells in the body respond to adhesive factors and physical forces in their tissue environments.

Our method not only uses soluble factors that guide kidney development in the embryo but, by growing and differentiating stem cells on extracellular matrix components that are also contained in the membrane separating the glomerular blood and urinary systems, we more closely mimic the natural environment in which podocytes are induced and mature, said Musah. We even succeeded in inducing much of this differentiation process within a channel of the microfluidic chip, whereby applying cyclical motions that mimic the rhythmic deformations living glomeruli experience due to pressure pulses generated by each heartbeat, we achieve even greater maturation efficiencies.

The complete microfluidic system closely resembles a living, three-dimensional cross-section of the human glomerular wall. It consists of an optically clear, flexible, polymeric material the size of a computer memory chip in which two closely opposed microchannels are separated by a porous, extracellular matrix-coated membrane that corresponds to the kidneys glomerular basement membrane. In one of the membrane-facing channels, the researchers grow glomerular endothelial cells to mimic the blood microvessel compartment of glomeruli. The iPS cells are cultured on the opposite side of the membrane in the other channel that represents the glomerulus urinary compartment, where they are induced to form a layer of mature podocytes that extend long cellular processes through the pores in the membrane and contact the underlying endothelial cells. In addition, the devices channels are rhythmically stretched and relaxed at a rate of one heart beat per second by applying cyclic suction to hollow chambers placed on either side of the cell-lined microchannels to mimic physiological deformations of the glomerular wall.

This in vitro system allows us to effectively recapitulate the filtration of small substances contained in blood into the urinary compartment while retaining large proteins in the blood compartment just like in our bodies, and we can visualize and monitor the damage inflicted by drugs that cause breakdown of the filtration barrier in the kidney, said Musah.

The study was also co-authored by Wyss Institute Core Faculty member George Church, who also is Professor of Genetics at HMS and Professor of Health Sciences and Technology at Harvard and the Massachusetts Institute of Technology (MIT), and who served as a co-mentor of Musah with Ingber. Other authors include Akiko Mammoto and Tadanori Mammoto, who at the time of the study were Instructors in the Vascular Biology Program and Department of Surgery at Boston Childrens Hospital, as well as Thomas Ferrante, Sauveur Jeanty, Kristen Roberts, Seyoon Chung, Richard Novak, Miles Ingram, Tohid Fatanat-Didar, Sandeep Koshy, and James Weaver.

Funding for the study was provided by the Defense Advanced Research Projects Agency (DARPA). Musah was supported by a HMS Deans Postdoctoral Fellowship, Postdoctoral Enrichment Program Award from the Burroughs Wellcome Fund, UNCF-Merck Postdoctoral Fellowship, and an NIH/NIDDK Nephrology Training Grant.

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Engineering human stem cells to model the kidney's filtration barrier on a chip - Harvard School of Engineering and Applied Sciences

IPS Cell Therapy Comments Off on Engineering human stem cells to model the kidney’s filtration barrier on a chip – Harvard School of Engineering and Applied Sciences | May 10th, 2017

CAMBRIDGE, Mass. and CROMWELL, Conn., May 04, 2017 (GLOBE NEWSWIRE) -- Cellaria, LLC, a scientific innovator that develops revolutionary new patient-specific models for challenging diseases, and Biological Industries USA (BI-USA), a subsidiary of Biological Industries (Israel), today announced a new sales and marketing agreement to promote custom stem cell services. The partnership combines BI-USAs strength in stem cell culture media and manufacturing with Cellarias comprehensive Stem Cell Services program, which includes industry leading RNA reprogramming and custom differentiation services. Together, the companies will offer one of the industrys most innovative and comprehensive stem cell service offerings available to biotechnology companies and academic institutions.

As part of the agreement, Cellaria will distribute BI-USAs stem cell media offering, including its NutriStem hPSC Medium, a cGMP xeno-free media specifically designed for human pluripotent stem cell culture. Cellaria will also incorporate the product into its stem cell services. BI-USA will market Cellaria's customized stem cell services, establishing an integrated, single source solution for iPS cell line derivation, culture maintenance, banking, characterization and differentiation services.

BI is one of the most respected names in life sciences today, said David Deems, chief executive officer at Cellaria. The companys strong market presence and innovative media products will enhance our stem cell and RNA reprogramming service offerings and significantly increase the availability and appeal of our combined offerings.

This is an important partnership for us, added Tanya Potcova, chief executive officer of BI-USA. In combination, our teams bring a wealth of stem cell experience but also share a common goal of creating higher quality, more consistent research outcomes for researchers in the life sciences field. We are pleased to be working with the team at Cellaria to put the best possible tools and support in the hands of our present and future customers.

Please visit Cellaria and BI at the International Society of Stem Cell Research Annual Meeting in Boston, MA June 14-17, 2017 at booth# 407.

About Cellaria Cellaria creates high quality, next generation in vitro disease models that reflect the unique nature of a patients biology. All models begin with tissue from a patient, capturing clinically relevant details that inform model characterization. For cancer, Cellarias cell models exhibit molecular and phenotypic characteristics that are highly concordant to the patient. For RNA-mediated iPS cell line derivation and stem cell services, Cellarias cell models enable interrogation of patient and disease-specific mechanisms of action. Cellarias innovative products and services help lead the research community to more personalized therapeutics, revolutionizing and accelerating the search for a cure. For more information, visitwww.cellariabio.com.

About Biological Industries Biological Industries (BI) is one of the worlds leading and trusted suppliers to the life sciences industry, with over 35 years experience in cell culture media development and cGMP manufacturing. BIs products range from classical cell culture media to supplements and reagents for stem cell research and potential cell therapy applications, to serum-free, xeno-free media. BI is committed to a Culture of Excellence through advanced manufacturing and quality-control systems, regulatory expertise, in-depth market knowledge, and extensive technical customer-support, training, and R&D capabilities.

Biological Industries USA (BI-USA) is the US commercialization arm of BI, with facilities in Cromwell, Connecticut. Members of the BI-USA team share a history and expertise of innovation and success in the development of leading-edge technologies in stem cell research, cellular reprogramming, and regenerative medicine. For more information, visit http://www.bioind.com or connect onLinkedIn,Twitter, andFacebook.

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Cellaria and Biological Industries USA Partner on Stem Cell Media ... - Yahoo Finance

IPS Cell Therapy Comments Off on Cellaria and Biological Industries USA Partner on Stem Cell Media … – Yahoo Finance | May 5th, 2017

Colorado State University is one of multiple research institutions that uses stem cells from aborted fetal tissue to research HIV and AIDS, a practice some say is unnecessary and immoral, but researchers say is essential.

Emily Faulkner, a senior biology major at CSU and founder of the anti-abortion group, CSU Students for Life, has been advocating against the Universitys use of fetal tissue for moral and legal reasons. Faulkner believes the University has illegally obtained fetal tissue for research and still could be after similar allegations against Planned Parenthood and CSU arose in 2015.

Earlier this semester, Faulkner hung posters that said CSU buys trafficked baby parts but says they were ripped down an hour later.

For a community that expresses tolerance for (many other communities) it seems to be very intolerant of the pro-life community, Faulkner said. Its really hard to open peoples minds to actually see whats going on, especially when theres so much intolerance.

In January, a Republican panel from the House of Representatives released a report suggesting some Planned Parenthood clinics and firms sold fetal tissue for profit, which is illegal under federal law. The report concluded over a year-long investigation after similar allegations against Planned Parenthood arose in 2015.

The report cited documents indicating the University paid the tissue procurement organizations StemExpress and Advanced Bioscience Resources $2,000 and $100,000, respectively, for fetal tissue between 2010 and 2015. It is illegal to buy fetal tissue, but federal law does not specify how much can be charged for shipping and handling. The report questions whether or not ABR and StemExpress donated the fetal tissue or sold it for profit.

Faulkner brought up CSUs use of fetal tissue this semester in response to the report. She and CSU Students for Life collected signatures on a petition that asked CSU President Tony Frank to investigate whether or not CSU was involved in illegal obtainment of fetal tissue and to acknowledge its use in research.

In response to the 2015 allegations, Frank wrote to Rep. Doug Lamborn stating that CSU was compliant with all state and federal laws in acquiring fetal tissue. According to Executive Director of Public Affairs and Communications, Mike Hooker, and the Vice President for Research, Alan Rudolph, the University has continued to follow the state and federal laws.

(Part of) my job as an institutional official is making sure that we sustain the highest standards for practice even beyond what the feds recommend, Rudolph said.

In addition to legal concerns, Faulkner also has moral concerns. She said that though abortion may be legal, that does not mean it is right. She expressed concern about fetal tissue and organs being harvested from late-term fetuses with beating hearts.

Its quite inhumane, Faulkner said. Were talking about actual human beings that have livers, brains and hearts. Theyre actually living, breathing beings.

Faulkner said fetal tissue should not be necessary for research on curing or preventing HIV and AIDS, as there is also gene replacement therapy, which takes HIV out of infected cells, and pre-exposure prophylaxis treatment, which consists of taking a pill daily to prevent HIV. Faulkner also said that researchers could use induced pluripotent stem cells (iPS cells) created from adult cells instead of stem cells from fetal tissue.

Pluripotent cells have the ability to become any cell in the body. However, according to Rudolph, iPS stem cells from adults cannot be used in CSUs research on curing and bettering HIV and AIDS, which is conducted by CSU virology professor Ramesh Akkina.

Fetal tissue research, especially the work that Ramesh does, cannot currently be done any other way, Rudolph said.

Akkina uses stem cells from fetal tissue to recreate human immune systems in mice, which Rudolph said are multicellular systems. Akkinas humanized mice can be used to study the effects of countermeasures, including therapeutics, antibodies, vaccines or biologics, on a human immune system meant to improve or cure HIV.

Rudolph said that while scientists are looking into how to conduct research on HIV and AIDS using iPS stem cells, the cells are more limited in their ability to create other types of cells than stem cells from fetal tissue are. He said that cells from fetal tissue are so far back in their development that they have the ability to create complex functions that are lost when cells become older. Cells are more pluripotent.

Faulkner said she hopes that scientists research and work with iPS stem cells.

The lives of those affected by HIV/AIDS are very important, but so are the lives of the unborn, Faulkner wrote in a message to the Collegian. We cannot forget equality for all.

Collegian reporter MQ Borocz can be reached at news@collegian.com or on Twitter @MQBorocz22.

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CSU's use of fetal tissue for HIV/AIDS research sparks controversy - Rocky Mountain Collegian

IPS Cell Therapy Comments Off on CSU’s use of fetal tissue for HIV/AIDS research sparks controversy – Rocky Mountain Collegian | May 5th, 2017

Details WhaTech Channel: Industrial Market Research Published: 04 May 2017 Submitted by John Vardon WhaTech Premium News from QY Research Groups Viewed: 7 times

This report studies the global Regenerative Medicine market, analyzes and researches the Regenerative Medicine development status and forecast in United States, EU, Japan, China, India and Southeast Asia.Learn details of the Size, Status and Forecast 2022

What is Regenerative Medicine?

Download Report atwww.qyresearchgroups.com/request-sample/339736

History

Applications

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This report focuses on the top players in global market, like

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Table of Contents

Global Regenerative Medicine Market Size, Status and Forecast 2022 1 Industry Overview of Regenerative Medicine 1.1 Regenerative Medicine Market Overview 1.1.1 Regenerative Medicine Product Scope 1.1.2 Market Status and Outlook 1.2 Global Regenerative Medicine Market Size and Analysis by Regions 1.2.1 United States 1.2.2 EU 1.2.3 Japan 1.2.4 China 1.2.5 India 1.2.6 Southeast Asia 1.3 Regenerative Medicine Market by Type 1.3.1 Cell Therapy 1.3.2 Tissue Engineering 1.3.3 Biomaterial 1.3.4 Others 1.4 Regenerative Medicine Market by End Users/Application 1.4.1 Dermatology 1.4.2 Cardiovascular 1.4.3 CNS

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1.4.4 Orthopedic 1.4.5 Others

2 Global Regenerative Medicine Competition Analysis by Players 2.1 Regenerative Medicine Market Size (Value) by Players (2016 and 2017) 2.2 Competitive Status and Trend 2.2.1 Market Concentration Rate 2.2.2 Product/Service Differences 2.2.3 New Entrants 2.2.4 The Technology Trends in Future

3 Company (Top Players) Profiles 3.1 Acelity 3.1.1 Company Profile 3.1.2 Main Business/Business Overview 3.1.3 Products, Services and Solutions 3.1.4 Regenerative Medicine Revenue (Value) (2012-2017) 3.1.5 Recent Developments 3.2 DePuy Synthes 3.2.1 Company Profile 3.2.2 Main Business/Business Overview 3.2.3 Products, Services and Solutions 3.2.4 Regenerative Medicine Revenue (Value) (2012-2017) 3.2.5 Recent Developments 3.3 Medtronic 3.3.1 Company Profile 3.3.2 Main Business/Business Overview

READ MORE atwww.qyresearchgroups.com/report/global-regenerative-medicine-market-size-status-and-forecast-2022

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Latest report on regenerative medicine market just published - WhaTech

IPS Cell Therapy Comments Off on Latest report on regenerative medicine market just published – WhaTech | May 4th, 2017

Thursday, May 4, 2017 11:31 AM UTC

CAMBRIDGE, Mass. and CROMWELL, Conn., May 04, 2017 -- Cellaria, LLC, a scientific innovator that develops revolutionary new patient-specific models for challenging diseases, and Biological Industries USA (BI-USA), a subsidiary of Biological Industries (Israel), today announced a new sales and marketing agreement to promote custom stem cell services. The partnership combines BI-USAs strength in stem cell culture media and manufacturing with Cellarias comprehensive Stem Cell Services program, which includes industry leading RNA reprogramming and custom differentiation services. Together, the companies will offer one of the industrys most innovative and comprehensive stem cell service offerings available to biotechnology companies and academic institutions.

As part of the agreement, Cellaria will distribute BI-USAs stem cell media offering, including its NutriStem hPSC Medium, a cGMP xeno-free media specifically designed for human pluripotent stem cell culture. Cellaria will also incorporate the product into its stem cell services. BI-USA will market Cellaria's customized stem cell services, establishing an integrated, single source solution for iPS cell line derivation, culture maintenance, banking, characterization and differentiation services.

BI is one of the most respected names in life sciences today, said David Deems, chief executive officer at Cellaria. The companys strong market presence and innovative media products will enhance our stem cell and RNA reprogramming service offerings and significantly increase the availability and appeal of our combined offerings.

This is an important partnership for us, added Tanya Potcova, chief executive officer of BI-USA. In combination, our teams bring a wealth of stem cell experience but also share a common goal of creating higher quality, more consistent research outcomes for researchers in the life sciences field. We are pleased to be working with the team at Cellaria to put the best possible tools and support in the hands of our present and future customers.

Please visit Cellaria and BI at the International Society of Stem Cell Research Annual Meeting in Boston, MA June 14-17, 2017 at booth# 407.

About Cellaria Cellaria creates high quality, next generation in vitro disease models that reflect the unique nature of a patients biology. All models begin with tissue from a patient, capturing clinically relevant details that inform model characterization. For cancer, Cellarias cell models exhibit molecular and phenotypic characteristics that are highly concordant to the patient. For RNA-mediated iPS cell line derivation and stem cell services, Cellarias cell models enable interrogation of patient and disease-specific mechanisms of action. Cellarias innovative products and services help lead the research community to more personalized therapeutics, revolutionizing and accelerating the search for a cure. For more information, visitwww.cellariabio.com.

About Biological Industries Biological Industries (BI) is one of the worlds leading and trusted suppliers to the life sciences industry, with over 35 years experience in cell culture media development and cGMP manufacturing. BIs products range from classical cell culture media to supplements and reagents for stem cell research and potential cell therapy applications, to serum-free, xeno-free media. BI is committed to a Culture of Excellence through advanced manufacturing and quality-control systems, regulatory expertise, in-depth market knowledge, and extensive technical customer-support, training, and R&D capabilities.

Biological Industries USA (BI-USA) is the US commercialization arm of BI, with facilities in Cromwell, Connecticut. Members of the BI-USA team share a history and expertise of innovation and success in the development of leading-edge technologies in stem cell research, cellular reprogramming, and regenerative medicine. For more information, visit http://www.bioind.com or connect onLinkedIn,Twitter, andFacebook.

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Cellaria and Biological Industries USA Partner on Stem Cell Media and Research - EconoTimes

IPS Cell Therapy Comments Off on Cellaria and Biological Industries USA Partner on Stem Cell Media and Research – EconoTimes | May 4th, 2017

(EnviroNews World News) Kobe, Japan For more than two million Americans, straight lines may look wavy and the vision in the center of their eye may slowly disappear. Its called age-related macular degeneration (AMD), and there is no cure. But that may change soon.

A surgical team at Kobe City Medical Center General Hospital in Japan recently injected 250,000 retinal pigment epithelial (RPE) cells into the right eye of a man in his 60s. The cells were derived from donor stem cells stored at Kyoto University. It marked the first time that retinal cells derived from a donors skin have been implanted in a patients eye. The skin cells had been reprogrammed into induced pluripotent stem cells (iPS), which can be grown into most cell types in the body.

The procedure is part of a safety study authorized by Japans Ministry of Health that will involve five patients. Each will be followed closely for one year and continue to receive follow-up exams for three additional years. Project leader Dr. Masayo Takahashi at Riken, a research institution that is part of the study, told the Japan Times, A key challenge in this case is to control rejection. We need to carefully continue treatment.

A previous procedure on a different patient in 2014 used stem cells from the individuals own skin. Two years later, the patient reported showing some improvement in eyesight. But the procedure cost $900,000, leading the study team to move forward using donor cells. They expect the costs to come down to less than $200,000.

Among people over 50 in developed countries, AMD is the leading cause of vision loss. According to the National Eye Institute, 14 percent of white Americans age 80 or older will suffer some form of AMD. The condition is almost three times more common among white adults than among people of color. Women of all races comprise 65 percent of AMD cases.

The lack of a cure has led some to try unproven treatments. Three elderly women lost their sight after paying $5,000 each for a stem cell procedure at a private clinic in Florida. Clinic staff used liposuction to remove fat from the womens bellies. They then extracted stem cells from the fat, which were injected into both eyes of each patient in the same procedure, resulting in vision loss in both eyes. Two of the three victims agreed to a lawsuit settlement with the company that owned the clinic.

Stem cell therapy is still at an early stage. As of January 2016, 10 clinical uses have been approved around the world, all using adult stem cells. These include some forms of leukemia and bone marrow disease, Hodgkin and non-Hodgkin lymphoma and some rare inherited disorders including sickle cell anemia. Stem cell transplants are now often used to treat multiple myeloma, which strikes more than 24,000 people a year in the U.S.

Clinical trials to treat type 1 diabetes, Parkinsons disease, stroke, brain tumors and other conditions are being conducted. The first patient in a nationwide clinical study to receive stem cell therapy for heart failure recently underwent the procedure at the University of Wisconsin School of Medicine and Public Health. An experimental treatment at Keck Medical Center of USC last year on a paralyzed patient restored the 21-year-old mans use of his arms and hands. Harvard scientists see stem cell biology as a path to counter aging and extend human lifespans. But the International Society for Stem Cell Research warns that there are many challenges ahead before these treatments are proven safe and effective.

The U.S. Food and Drug Administration (FDA) regulates stem cells to ensure that they are safe and effective for their intended use. But, that doesnt stop some clinics from preying on worried patients. The FDA warns on its website that the hope that patients have for cures not yet available may leave them vulnerable to unscrupulous providers of stem cell treatments that are illegal and potentially harmful.

While there is yet no magic cure for AMD, the Japan study and others may one day lead there. The Harvard Stem Cell Institute (HSCI) in Boston is currently researching retina stem cell transplants. One approach uses gene therapy to generate a molecule that preserves healthy vision. Another involves Muller cells, which give fish the ability to repair an injured retina.

But these therapies are far off. We are at about the halfway mark, but there is still a precipitous path ahead of us, Takahashi said.

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World's 1st Stem Cell Transplant from Donor to Man's Eye Shows Promise of Restoring Sight - EnviroNews (registration) (blog)

IPS Cell Therapy Comments Off on World’s 1st Stem Cell Transplant from Donor to Man’s Eye Shows Promise of Restoring Sight – EnviroNews (registration) (blog) | April 27th, 2017

Organ transplant rejection might eventually be preventable by giving recipients an immune-suppressing vaccine derived from induced pluripotent stem cells, according to a study led by Japanese researchers.

In mice, the treatment allowed permanent acceptance of heart grafts by selectively inhibiting the immune response to the donor graft, said the study, published April 20 in Stem Cell Reports. The work might also be applicable to autoimmune diseases, the study said.

The study can be found at j.mp/ipscden. The co-first authors were Songjie Cai, Jiangang Hou, and Masayuki Fujino. The senior author was Xiao-Kang Li. All are of the National Research Institute for Child Health and Development in Tokyo.

The IPS cells were matured into donor-type regulatory dendritic cells (DCregs) which in turn caused production of tolerance-inducing regulatory T cells, or Tregs, that allow the graft to be treated as self.

While the technology looks good, a UC San Diego stem cell researcher said it faces a number of hurdles that make practical use of it difficult, especially the difficulty in producing the donor-derived regulatory cells in time to be of use in a transplant.

Use of these Tregs and immature DCregs for transplant has been investigated for several years now. In theory, they would provide a better method of preventing rejection than immunosuppressive drugs that knock down immune functioning across the board.

However, activating Tregs must be done precisely, or other T cell types will be activated, increasing the risk of rejection.

The study found that donor-type dendritic cells reliably activated Tregs and not the other types. Peptide antigens from the graft directed naive CD4+ T cells to mature into donor-specific Tregs, providing a selective immune signal to tolerate the graft.

Use of IPS cells for producing these immune regulatory cells is quite novel, said Dan Kaufman, director of cell therapy at UC San Diego, and affiliated with the universitys Sanford Stem Cell Clinical Center.

Obviously, it fits my interest in making immune cells from ES and IPS cells, Kaufman said. The ability to use these cells to suppress transplant rejection seems quite strong. I think the data is all good.

That said, the findings could be strengthened by extending the work from animals to human xenografts, he said. That would demonstrate that human IPS cells can similarly function, although it would be challenging.

Another limitation is the need to use donor-derived cells to induce immune tolerance.

How you would translate that would be unclear to me, Kaufman said.

Are you going to get a heart and then make IPS cells from that donor, which obviously you couldnt do in a reasonable time frame? Could you create a bank of these types of cells that might be suitable for certain patient populations with certain HLA types? Im not sure. I think that gets a little more speculative.

Another speculative possibility is to make the donor-derived IPS cells grow into an organ, and then also create the immune-regulating cells from these IPS cells to selectively induce tolerance.

But were still, I think, a long ways off from having IPS-derived organs, he said.

Autoimmune disease treatment with this technology is worth exploring, Kaufman said. In that case, the IPSCs would be made from the patients themselves.

More than 118,000 Americans are on the waiting list for an organ transplant, according to the Organ Procurement and Transplantation Network.

bradley.fikes@sduniontribune.com

(619) 293-1020

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Stem cell-based treatment prevents transplant rejection, in animal study - The San Diego Union-Tribune

IPS Cell Therapy Comments Off on Stem cell-based treatment prevents transplant rejection, in animal study – The San Diego Union-Tribune | April 23rd, 2017

MADISON, Wis.--(BUSINESS WIRE)--Cellular Dynamics International (CDI), a FUJIFILM company and a leading developer and manufacturer of induced pluripotent stem cells (iPS), today announced it has signed a collaboration agreement with the Harvard Stem Cell Institute (HSCI), a novel network of stem cell scientists that extends from the University to its affiliated hospitals and the biomedical industry. The objective of the new partnership is to increase the availability of iPS cells and services to the HSCI network and the research community at large.

CDI is honored and excited to partner with Harvard Stem Cell Institute, one of the worlds most prestigious research organizations, said Dr. Bruce Novich, Division President-CNBD for FUJIFILM Holdings America Corporation and Executive Vice President and General Manager of Life Science Business Division for CDI. Our goal is to make iPS cells and technology more accessible so that researchers across disciplines and the various institutions of HSCI can better pursue the promise of stem cell science and regenerative medicine.

Under the terms of the agreement, CDI will collaborate with HSCIs iPS Core Facility by providing iPSC technology support to the stem cell community. In addition, CDI will offer critical iPSC technology elements which may accelerate iPSC based science, technology and applications.

About Cellular Dynamics International:

Cellular Dynamics International (CDI), a FUJIFILM company, is a leading developer and supplier of human cells used in drug discovery, toxicity testing, and regenerative medicine applications. Leveraging technology that can be used to create induced pluripotent stem cells (iPSCs) and differentiated tissue-specific cells from any individual, CDI is committed to advancing life science research and transforming the therapeutic development process in order to fundamentally improve human health. The companys inventoried iCell products and donor-specific MyCell Products are available in the quantity, quality, purity, and reproducibility required for drug and cell therapy development. For more information please visitwww.cellulardynamics.com.

About Fujifilm

FUJIFILM Holdings Corporation, Tokyo, Japan brings continuous innovation and leading-edge products to a broad spectrum of industries, including: healthcare, with medical systems, pharmaceuticals and cosmetics; graphic systems; highly functional materials, such as flat panel display materials; optical devices, such as broadcast and cinema lenses; digital imaging; and document products. These are based on a vast portfolio of chemical, mechanical, optical, electronic, software and production technologies. In the year ended March 31, 2016, the company had global revenues of $22.1 billion, at an exchange rate of 112.54 yen to the dollar. Fujifilm is committed to environmental stewardship and good corporate citizenship. For more information, please visit:www.fujifilmholdings.com.

All product and company names herein may be trademarks of their registered owners.

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Cellular Dynamics International Signs Collaboration Agreement with Harvard Stem Cell Institute - Business Wire (press release)

IPS Cell Therapy Comments Off on Cellular Dynamics International Signs Collaboration Agreement with Harvard Stem Cell Institute – Business Wire (press release) | April 20th, 2017

Plasticell, a developer of cell therapies including hematopoietic cell replacement therapies, recently announced it has partnered with Kings College London to progress preclinical trials of its artificial blood platelet product, manufactured from pluripotent stem cells. The work is supported by a MedCity research grant which funds collaboration between leading SMEs and academics from London universities.

Over 10 million units of platelets are transfused worldwide each year in one of the most common procedures in clinical medicine. However, platelets derived from human donors can transmit infections and trigger serious immune reactions that eventually render the therapy ineffective (a condition known as alloimmune refractoriness). In addition, since platelet donations require pathogen testing and cannot be frozen for later use, supply shortages can occur under certain circumstances.

Plasticell has developed robust, cost-effective methods of producing functional platelets from human induced pluripotent stem cells (iPSCs) and has scaled these up to intermediate bioreactor level, allowing manufacture of product for pre-clinical studies. Kings College will contribute world-leading expertise and in vivo models to characterise the dynamics, lifespan, safety and efficacy of transfused platelets.

In addition to providing a more stable and safe supply of universal platelets, the use of iPS cells would allow us to create immunologically compatible matched platelets for patients suffering from alloimmune refractoriness, commented Dr Marina Tarunina, Principal Scientist leading the project at Plasticell.

The project is part of Plasticells hematopoietic cell therapy portfolio, which includes the expansion of umbilical cord- and bone- derived hematopoietic stem cells, and the manufacture of various blood cell types. Plasticell recently announced it had received Innovate UK funding for a 1.1M project to manufacture red blood cells from pluripotent stem cells, in collaboration with the University of Edinburgh.

About Plasticell Plasticell is a biotechnology company leading the use of high throughput technologies to develop stem cell therapies. The Companys therapeutic focus is in hematopoietic stem cell therapy, anaemia and thrombocytopenia, cancer immunotherapy and diabetes/obesity. Plasticells Combinatorial Cell Culture (CombiCult) platform technology, allows it to test very large numbers of cell culture variables in combinations to discover optimal laboratory protocols for the manipulation of stem cells and other cell cultures and has received a number of industry awards including the Queens Award for Enterprise in Innovation and the R&D 100 Award. For more information, visit http://www.plasticell.co.uk.

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Plasticell And Kings College London To Collaborate In Trials Of Blood Platelet Substitute - Clinical Leader

IPS Cell Therapy Comments Off on Plasticell And Kings College London To Collaborate In Trials Of Blood Platelet Substitute – Clinical Leader | April 20th, 2017

MADISON, Wis.--(BUSINESS WIRE)--

Cellular Dynamics International (CDI), a FUJIFILM company and a leading developer and manufacturer of induced pluripotent stem cell-derived products, today announced it has signed a distribution agreement with STEMCELL Technologies, a world leader in iPS cell culture media.

This joint agreement with STEMCELL Technologies will make iPSC technology widely available to researchers worldwide, helping advance biological research leading to cellular therapies and drug discovery, said Dr. Bruce Novich, Division President-CNBD for FUJIFILM Holdings America Corporation and Executive Vice President and General Manager for CDI. We believe that STEMCELL Technologies, a leading developer, manufacturer and seller of stem cell related products, is an ideal partner for CDI, because their global sales and distribution infrastructure delivers to an established and an emerging customer base, which translates into faster access to and deeper penetration of CDIs leading edge technologies and products.

Under the terms of the agreement, STEMCELL Technologies will distribute CDIs iCell catalog of products in North America, Europe, and Singapore, with other countries under consideration. CDIs iCell products are differentiated human induced pluripotent stem cell (iPSC)-derived cells, which include cardiomyocytes, hepatocytes, and others, totaling up to 12 cell types.

STEMCELL Technologies is delighted for the opportunity to bring CDIs innovative products to the global research community. STEMCELL and CDI will work together on progressive solutions for the life science tools market. We look forward to a long and productive partnership with the shared goal of improving human health, said Dr. Allen Eaves, President and CEO of STEMCELL Technologies.

About Cellular Dynamics International:

Cellular Dynamics International (CDI), a FUJIFILM company, is a leading developer and supplier of human cells used in drug discovery, toxicity testing, and regenerative medicine applications. Leveraging technology that can be used to create induced pluripotent stem cells (iPSCs) and differentiated tissue-specific cells from any individual, CDI is committed to advancing life science research and transforming the therapeutic development process in order to fundamentally improve human health. The companys inventoried iCell products and donor-specific MyCell Products are available in the quantity, quality, purity, and reproducibility required for drug and cell therapy development. For more information please visit http://www.cellulardynamics.com.

About Fujifilm

FUJIFILM Holdings Corporation, Tokyo, Japan brings continuous innovation and leading-edge products to a broad spectrum of industries, including: healthcare, with medical systems, pharmaceuticals and cosmetics; graphic systems; highly functional materials, such as flat panel display materials; optical devices, such as broadcast and cinema lenses; digital imaging; and document products. These are based on a vast portfolio of chemical, mechanical, optical, electronic, software and production technologies. In the year ended March 31, 2016, the company had global revenues of $22.1 billion, at an exchange rate of 112.54 yen to the dollar. Fujifilm is committed to environmental stewardship and good corporate citizenship. For more information, please visit: http://www.fujifilmholdings.com.

About STEMCELL Technologies:

As Scientists Helping Scientists, STEMCELL Technologies is committed to providing high-quality cell culture media, cell isolation products, accessory tools and educational services for life science research. Driven by science and a passion for quality, STEMCELL provides over 2500 products to more than 90 countries worldwide. To learn more, visit http://www.stemcell.com.

All product and company names herein may be trademarks of their registered owners.

View source version on businesswire.com: http://www.businesswire.com/news/home/20170418005219/en/

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Cellular Dynamics International Signs Distribution Deal with STEMCELL Technologies - Yahoo Finance

IPS Cell Therapy Comments Off on Cellular Dynamics International Signs Distribution Deal with STEMCELL Technologies – Yahoo Finance | April 18th, 2017

TERT Identifiers Aliases TERT, CMM9, DKCA2, DKCB4, EST2, PFBMFT1, TCS1, TP2, TRT, hEST2, hTRT, telomerase reverse transcriptase External IDs OMIM: 187270 MGI: 1202709 HomoloGene: 31141 GeneCards: TERT Genetically Related Diseases breast cancer, interstitial lung disease, adenocarcinoma of the lung, prostate cancer, se atraganto con un caramelo, testicular germ cell cancer, idiopathic pulmonary fibrosis, malignant glioma[1] RNA expression pattern More reference expression data Orthologs Species Human Mouse Entrez Ensembl UniProt RefSeq (mRNA) RefSeq (protein) Location (UCSC) Chr 5: 1.25 1.3 Mb Chr 13: 73.63 73.65 Mb PubMed search [2] [3] Wikidata View/Edit Human View/Edit Mouse

Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.[4][5]

Telomerases are part of a distinct subgroup of RNA-dependent polymerases. Telomerase lengthens telomeres in DNA strands, thereby allowing senescent cells that would otherwise become postmitotic and undergo apoptosis to exceed the Hayflick limit and become potentially immortal, as is often the case with cancerous cells. To be specific, TERT is responsible for catalyzing the addition of nucleotides in a TTAGGG sequence to the ends of a chromosomes telomeres.[6] This addition of repetitive DNA sequences prevents degradation of the chromosomal ends following multiple rounds of replication.[7]

hTERT absence (usually as a result of a chromosomal mutation) is associated with the disorder Cri du chat.[8][9]

Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme consists of a protein component with reverse transcriptase activity, encoded by this gene, and an RNA component that serves as a template for the telomere repeat. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells, resulting in progressive shortening of telomeres. Studies in mice suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. Alternatively spliced variants encoding different isoforms of telomerase reverse transcriptase have been identified; the full-length sequence of some variants has not been determined. Alternative splicing at this locus is thought to be one mechanism of regulation of telomerase activity.[10]

The hTERT gene, located on chromosome 5, consists of 16 exons and 15 introns spanning 35 kb. The core promoter of hTERT includes 330 base pairs upstream of the translation start site (AUG since it's RNA by using the words "exons" and "introns"), as well as 37 base pairs of exon 2 of the hTERT gene.[11][12][13] The hTERT promoter is GC-rich and lacks TATA and CAAT boxes but contains many sites for several transcription factors giving indication of a high level of regulation by multiple factors in many cellular contexts.[11] Transcription factors that can activate hTERT include many oncogenes (cancer-causing genes) such as c-Myc, Sp1, HIF-1, AP2, and many more, while many cancer suppressing genes such as p53, WT1, and Menin produce factors that suppress hTERT activity .[13][14] Another form of up-regulation is through demethylation of histones proximal to the promoter region, imitating the low density of trimethylated histones seen in embryonic stem cells.[15] This allows for the recruitment of histone acetyltransferase (HAT) to unwind the sequence allowing for transcription of the gene.[14]

Telomere deficiency is often linked to aging, cancers and the conditions dyskeratosis congenita (DKC) and Cri du chat. Meanwhile, over-expression of hTERT is often associated with cancers and tumor formation.[8][16][17][18] The regulation of hTERT is extremely important to the maintenance of stem and cancer cells and can be used in multiple ways in the field of regenerative medicine.

hTERT is often up-regulated in cells that divide rapidly, including both embryonic stem cells and adult stem cells.[17] It elongates the telomeres of stem cells, which, as a consequence, increases the lifespan of the stem cells by allowing for indefinite division without shortening of telomeres. Therefore, it is responsible for the self-renewal properties of stem cells. Telomerase are found specifically to target shorter telomere over longer telomere, due to various regulatory mechanisms inside the cells that reduce the affinity of telomerase to longer telomeres. This preferential affinity maintains a balance within the cell such that the telomeres are of sufficient length for their function and yet, at the same time, not contribute to aberrant telomere elongation [19]

High expression of hTERT is also often used as a landmark for pluripotency and multipotency state of embryonic and adult stem cells. Over-expression of hTERT was found to immortalize certain cell types as well as impart different interesting properties to different stem cells.[13][20]

hTERT immortalizes various normal cells in culture, thereby endowing the self-renewal properties of stem cells to non-stem cell cultures.[13][21] There are multiple ways in which immortalization of non-stem cells can be achieved, one of which being via the introduction of hTERT into the cells. Differentiated cells often express hTERC and TP1, a telomerase-associated protein that helps form the telomerase assembly, but does not express hTERT. Hence, hTERT acts as the limiting factor for telomerase activity in differentiated cells [13][22] However, with hTERT over-expression, active telomerase can be formed in differentiated cells. This method has been used to immortalize prostate epithelial and stromal-derived cells, which are typically difficult to culture in vitro. hTERT introduction allows in vitro culture of these cells and available for possible future research. hTERT introduction have an advantage over the use of viral protein for immortalization in that it does not involve the inactivation of tumor suppressor gene, which might lead to cancer formation.[21]

Over-expression of hTERT in stem cells changes the properties of the cells.[20][23][24] hTERT over-expression increases the stem cell properties of human mesenchymal stem cells. The expression profile of mesenchymal stem cells converges towards embryonic stem cells, suggesting that these cells may have embryonic stem cell-like properties. However, it has been observed that mesenchymal stem cells undergo decreased levels of spontaneous differentiation.[20] This suggests that the differentiation capacity of adult stem cells may be dependent on telomerase activities. Therefore, over-expression of hTERT, which is akin to increasing telomerase activities, may create adult stem cells with a larger capacity for differentiation and hence, a larger capacity for treatment.

Increasing the telomerase activities in stem cells gives different effects depending on the intrinsic nature of the different types of stem cells.[17] Hence, not all stem cells will have increased stem-cell properties. For example, research has shown that telomerase can be upregulated in CD34+ Umbilical Cord Blood Cells through hTERT over-expression. The survival of these stem cells was enhanced, although there was no increase in the amount of population doubling.[24]

Deregulation of telomerase expression in somatic cells may be involved in oncogenesis.[10]

Genome-wide association studies suggest TERT is a susceptibility gene for development of many cancers,[25] including lung cancer.[26]

Telomerase activity is associated with the number of times a cell can divide playing an important role in the immortality of cell lines, such as cancer cells. The enzyme complex acts through the addition of telomeric repeats to the ends of chromosomal DNA. This generates immortal cancer cells.[27] In fact, there is a strong correlation between telomerase activity and malignant tumors or cancerous cell lines.[28] Not all types of human cancer have increased telomerase activity. 90% of cancers are characterized by increased telomerase activity.[28]Lung cancer is the most well characterized type of cancer associated with telomerase.[29] There is a lack of substantial telomerase activity in some cell types such as primary human fibroblasts, which become senescent after about 3050 population doublings.[28] There is also evidence that telomerase activity is increased in tissues, such as germ cell lines, that are self-renewing. Normal somatic cells, on the other hand, do not have detectable telomerase activity.[30] Since the catalytic component of telomerase is its reverse transcriptase, hTERT, and the RNA component hTERC, hTERT is an important gene to investigate in terms of cancer and tumorigenesis.

The hTERT gene has been examined for mutations and their association with the risk of contracting cancer. Over two hundred combinations of hTERT polymorphisms and cancer development have been found.[29] There were several different types of cancer involved, and the strength of the correlation between the polymorphism and developing cancer varied from weak to strong.[29] The regulation of hTERT has also been researched to determine possible mechanisms of telomerase activation in cancer cells. Glycogen synthase kinase 3 (GSK3) seems to be over-expressed in most cancer cells.[27] GSK3 is involved in promoter activation through controlling a network of transcription factors.[27]Leptin is also involved in increasing mRNA expression of hTERT via signal transducer and activation of transcription 3 (STAT3), proposing a mechanism for increased cancer incidence in obese individuals.[27] There are several other regulatory mechanisms that are altered or aberrant in cancer cells, including the Ras signaling pathway and other transcriptional regulators.[27]Phosphorylation is also a key process of post-transcriptional modification that regulates mRNA expression and cellular localization.[27] Clearly, there are many regulatory mechanisms of activation and repression of hTERT and telomerase activity in the cell, providing methods of immortalization in cancer cells.

If increased telomerase activity is associated with malignancy, then possible cancer treatments could involve inhibiting its catalytic component, hTERT, to reduce the enzymes activity and cause cell death. Since normal somatic cells do not express TERT, telomerase inhibition in cancer cells can cause senescence and apoptosis without affecting normal human cells.[27] It has been found that dominant-negative mutants of hTERT could reduce telomerase activity within the cell.[28] This led to apoptosis and cell death in cells with short telomere lengths, a promising result for cancer treatment.[28] Although cells with long telomeres did not experience apoptosis, they developed mortal characteristics and underwent telomere shortening.[28] Telomerase activity has also been found to be inhibited by phytochemicals such as isoprenoids, genistein, curcumin, etc.[27] These chemicals play a role in inhibiting the mTOR pathway via down-regulation of phosphorylation.[27] The mTOR pathway is very important in regulating protein synthesis and it interacts with telomerase to increase its expression.[27] Several other chemicals have been found to inhibit telomerase activity and are currently being tested as potential clinical treatment options such as nucleoside analogues, retinoic acid derivatives, quinolone antibiotics, and catechin derivatives.[30] There are also other molecular genetic-based methods of inhibiting telomerase, such as antisense therapy and RNA interference.[30]

hTERT peptide fragments have been shown to induce a cytotoxic T-cell reaction against telomerase-positive tumor cells in vitro.[31] The response is mediated by dendritic cells, which can display hTERT-associated antigens on MHC class I and II receptors following adenoviral transduction of an hTERT plasmid into dendritic cells, which mediate T-cell responses.[32] Dendritic cells are then able to present telomerase-associated antigens even with undetectable amounts of telomerase activity, as long as the hTERT plasmid is present.[33]Immunotherapy against telomerase-positive tumor cells is a promising field in cancer research that has been shown to be effective in in vitro and mouse model studies.[34]

Induced pluripotent stem cells (iPS cells) are somatic cells that have been reprogrammed into a stem cell-like state by the introduction of four factors (Oct3/4, Sox2, Klf4, and c-Myc).[35] iPS cells have the ability to self-renew indefinitely and contribute to all three germ layers when implanted into a blastocyst or use in teratoma formation.[35]

Early development of iPS cell lines were not efficient, as they yielded up to 5% of somatic cells successfully reprogrammed into a stem cell-like state.[36] By using immortalized somatic cells (differentiated cells with hTERT upregulated), iPS cell reprogramming was increased by twentyfold compared to reprogramming using mortal cells.[36]

The reactivation of hTERT, and subsequently telomerase, in human iPS cells has been used as an indication of pluripotency and reprogramming to an ES (embryonic stem) cell-like state when using mortal cells.[35] Reprogrammed cells that do not express sufficient hTERT levels enter a quiescent state following a number of replications depending on the length of the telomeres while maintaining stem cell-like abilities to differentiate.[36] Reactivation of TERT activity can be achieved using only three of the four reprogramming factors described by Takahashi and Yamanaka: To be specific, Oct3/4, Sox2 and Klf4 are essential, whereas c-Myc is not.[15] However, this study was done with cells containing endogenous levels of c-Myc that may have been sufficient for reprogramming.

Telomere length in healthy adult cells elongates and acquires epigenetic characteristics similar to those of ES cells when reprogrammed as iPS cells. Some epigenetic characteristics of ES cells include a low density of tri-methylated histones H3K9 and H4K20 at telomeres, as well as an increased detectable amount of TERT transcripts and protein activity.[15] Without the restoration of TERT and associated telomerase proteins, the efficiency of iPS cells would be drastically reduced. iPS cells would also lose the ability to self-renew and would eventually senesce.[15]

DKC (dyskeratosis congenita) patients are all characterized by the defective maintenance of telomeres leading to problems with stem cell regeneration.[16] iPS cells derived from DKC patients with a heterozygous mutation on the TERT gene display a 50% reduction in telomerase activity compared to wild type iPS cells.[37] Conversely, mutations on the TERC gene (RNA portion of telomerase complex) can be overcome by up-regulation due to reprogramming as long as the hTERT gene is intact and functional.[38] Lastly, iPS cells generated with DKC cells with a mutated dyskerin (DKC1) gene cannot assemble the hTERT/RNA complex and thus do not have functional telomerase.[37]

The functionality and efficiency of a reprogrammed iPS cell is determined by the ability of the cell to re-activate the telomerase complex and elongate its telomeres allowing for self-renewal. hTERT is a major limiting component of the telomerase complex and a deficiency of intact hTERT impedes the activity of telomerase, making iPS cells an unsuitable pathway towards therapy for telomere-deficient disorders.[37]

Although the mechanism is not fully understood, exposure of TERT-deficient hematopoietic cells to androgens resulted in an increased level of TERT activity.[39] Cells with a heterozygous TERT mutation, like those in DKC (dyskeratosis congenita) patients, which normally exhibit low baseline levels of TERT, could be restored to normal levels comparable to control cells. TERT mRNA levels are also increased with exposure to androgens.[39] Androgen therapy may become a suitable method for treating circulatory ailments such as bone marrow degeneration and low blood count linked with DKC and other telomerase-deficient conditions.[39]

As organisms age and cells proliferate, telomeres shorten with each round of replication. Cells restricted to a specific lineage are capable of division only a set number of times, set by the length of telomeres, before they senesce.[40] Depletion and uncapping of telomeres has been linked to organ degeneration, failure, and fibrosis due to progenitors' becoming quiescent and unable to differentiate.[19][40] Using an in vivo TERT deficient mouse model, reactivation of the TERT gene in quiescent populations in multiple organs reactivated telomerase and restored the cells abilities to differentiate.[41] Reactivation of TERT down-regulates DNA damage signals associated with cellular mitotic checkpoints allowing for proliferation and elimination of a degenerative phenotype.[41] In another study, introducing the TERT gene into healthy one-year-old mice using an engineered adeno-associated virus led to a 24% increase in lifespan, without any increase in cancer.[42]

The hTERT gene has become a main focus for gene therapy involving cancer due to its expression in tumor cells but not somatic adult cells.[43] One method is to prevent the translation of hTERT mRNA through the introduction of siRNA, which are complimentary sequences that bind to the mRNA preventing processing of the gene post transcription.[44] This method does not completely eliminate telomerase activity, but it does lower telomerase activity and levels of hTERT mRNA seen in the cytoplasm.[44] Higher success rates were seen in vitro when combining the use of antisense hTERT sequences with the introduction of a tumor-suppressing plasmid by adenovirus infection such as PTEN.[45]

Another method that has been studied is manipulating the hTERT promoter to induce apoptosis in tumor cells. Plasmid DNA sequences can be manufactured using the hTERT promoter followed by genes encoding for specific proteins. The protein can be a toxin, an apoptotic factor, or a viral protein. Toxins such as diphtheria toxin interfere with cellular processes and eventually induce apoptosis.[43] Apoptotic death factors like FADD (Fas-Associated protein with Death Domain) can be used to force cells expressing hTERT to undergo apoptosis.[46] Viral proteins like viral thymidine kinase can be used for specific targeting of a drug.[47] By introducing a prodrug only activated by the viral enzyme, specific targeting of cells expressing hTERT can be achieved.[47] By using the hTERT promoter, only cells expressing hTERT will be affected and allows for specific targeting of tumor cells.[43][46][47]

Aside from cancer therapies, the hTERT gene has been used to promote the growth of hair follicles.[48]

A schematic animation for gene therapy is shown as follows.

Telomerase reverse transcriptase has been shown to interact with:

Continued here:
Telomerase reverse transcriptase - Wikipedia

IPS Cell Therapy Comments Off on Telomerase reverse transcriptase – Wikipedia | April 16th, 2017

Sumitomo Dainippon Pharma Co Ltd has ordered cell culture technologies from Hitachi as part of its effort to develop a treatment for Parkinsons disease.

The order financial terms of which were not provided will see Hitachi supply automated cell culturing technologies designed for the manufacture of induced pluripotent stem cells (iPS).

Dainippon is developing a cell therapy for Parkinsons-related dopamine neuron loss and neurodegeneration in collaboration with both Hitachi and Center for iPS Cell Research and Application, Kyoto University (CiRA).

Part of the project which is funded by the Japanese Agency of Medical Research and Development (AMED) - involves the development of processing methods and technologies for the production of stem cells for regenerative therapies.

The Japanese drug firm has announced several regenerative medicine-based research projects in recent years, beginning in 2015 when it partnered with Sanbio to develop SB623, an allogenic cell therapy for ischemic stroke to improve motor abilities.

Regenerative meds

Regenerative medicine which engineers or replaces damaged cells within human patients has become a popular area of research in Japan sinceShinya Yamanaka won the 2012 Noel Prize for medicine for the discovery that mature cells can be reprogrammed to become pluripotent.

Regenerative medicine is also a big focus for the Japanese Government.

Laws introduced in November 2014 therevised pharmaceutical affairs law and newregenerative medicines legislation mean such products could be reviewed and approved in just two years, if deemed to be effective.

Japans Government further underlined its commitment to regenerative medicine in its budget in January 2015, allocating Y2.5bn ($20.8bn) to the industrialisation of regenerative medicine evaluation fundamental technology development business.

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Sumitomo Dainippon buys cell therapy processing tech from Hitachi - In-PharmaTechnologist.com

IPS Cell Therapy Comments Off on Sumitomo Dainippon buys cell therapy processing tech from Hitachi – In-PharmaTechnologist.com | April 15th, 2017

Distinct growth factors promote the survival of specific types of motor neurons in the spinal cord, according to a study led by Georg Haase, of Aix-Marseille University in Marseille, France. The results suggest that these factors may work together to provide trophic support to motor neurons in the CNS and therefore, a combination of them may be needed to protect motor neurons damaged by disease.

Growth factors have always been tantalizingly attractive in ALS, said Nicholas Boulis of Emory University Medical School, who was not involved in the study. But the problem is, there has been a failure of growth factors to perform [in the clinic]. This study provides tangible evidence that you may be able to get a bigger effect by combining growth factors.

The study appeared on March 16 in the Proceedings of the National Academy of Sciences.

Neurotrophic Factors in ALS: The power of two+

Sorting out ALS. George Haases team at Aix-Marseille University in France used a FACS-based method to identify NTFs needed to protect distinct classes of motor neurons in the developing lumbar spinal cord. Now, the researchers are adapting this method to determine which of these substances may be needed to protect adult motor neurons, including those affected by ALS. The results may help clinicians develop neuroprotective treatment strategies tailored for the disease. [Courtesy of Schaller et al., 2017, PNAS]

Researchers first turned to neurotrophic factors (NTFs) in the early 1990s as a potential therapy for ALS in hopes to promote the survival of motor neurons damaged by the disease. But initial therapies proved ineffective in part due to delivery challenges (see Rogers, 2014).

In more recent years, neuroscientists discovered that many of these growth factors may work together to provide trophic support for motor neurons and promote their survival at least in the developing spinal cord (see Gould and Enomoto, 2009). But how these substances orchestrate this process remains an open question.

A growing number of researchers suspect that there may be distinct classes of motor neurons that are protected by distinct NTFs during development. To test this hypothesis, Haases team at Aix-Marseille University in France isolated motor neurons from the developing lumbar spinal cord in the mouse and determined which growth factors supported them.

To carry out this analysis, first author Sbastien Schaller and colleagues dissected out lumbar spinal cords at day E12 and suspended the tissue. Then, they used fluorescence-activated cell sorting (FACS) to isolate the motor neurons, cultured them and exposed them to combinations of neurotrophic substances.

The technique enabled motor neurons to be specifically captured from embryos by using Hb9:GFP mice, originally developed by Columbia Universitys Thomas Jessell in New York, which express GFP in motor neurons in the developing central nervous system.

100% of the cells expressed the motor neuronal markers ChAT and SMI 32, and none expressed interneuronal markers, indicating the exquisite purity of the isolated cells, said Haase. That, combined with the methods speed and degree of automation, make FACS-derived motor neurons a promising platform for future studies, he said, including screening for potential ALS therapies.

A combinatorial approach? Beginning in the early 1990s, researchers developed potential neuroprotective therapies for ALS that delivered single neurotrophic substances. But according to a new study, multiple NTFs may be needed to promote the survival of motor neurons affected by the disease. [Courtesy of Schaller et al., 2017, PNAS]

Next, the team exposed motor neurons to 12 different neurotrophic factors (BDNF, NT3, GDNF, neurturin, artemin, persephin, CNTF, CT1, LIF, HGF, IGF1, and VEGF), alone or in combination. Individually, all NTFs promoted neuronal survival after 3 days in culture, with GDNF being the most effective (43%). HGF, however, protected only about 20% of motor neurons in culture. But when HGF, CNTF and artemin were combined, motor neuron survival reached nearly 50%.

The effects were additive, explained Haase. That suggested to us that each [of these growth factors] were supporting a subset of motor neurons.

To test that hypothesis, the researchers used subtype cell surface-specific antibodies to label three major subsets of motor neurons from the lumbar spinal cordthe medial motor column, which innervate axial muscles, the lateral motor column, which innervate limb muscles, and preganglionic, which synapse with downstream neurons of the autonomic motor system. They then used FACS to separate each subtype, and exposed them to HGF, CNTF or artemin.

They found that each of these NTFs promoted the survival of distinct classes of motor neurons in the lumbar spinal cord. For example, HGF preferentially supported survival of motor neurons in the lateral motor column neurons, key motor neurons affected by ALS.

The effects were mediated by distinct neurotrophic factor receptors decorating the surface of each type of motor neuron, explained Haase. When we blocked the HGF receptor, we completely blocked the survival effect of HGF. That means these motor neurons depend on this particular factor for their survival.

Additional analysis indicated that CNTF and artemin protected other types of motor neurons located elsewhere in the spinal cord.

Lateral thinking. HGF promotes the survival of motor neurons that innervate the limbs through a c-Met-mediated mechanism at least in the developing spinal cord (Schaller et al., 2017). The neurotrophic substance is the basis of Viromeds VM202, a gene therapy-based strategy now being evaluated at the phase 1/2 stage (Sufit et al., 2017). [Image: Emw, Wikimedia Commons.]

Together, the findings suggest that these substances provide trophic support and promote the survival of specific types of motor neurons in the developing spinal cord.

This is a very high-quality paper that helps clarify the field, said Clive Svendsen of Cedars-Sinai in Los Angeles, California. Until now, it was not clear that distinct subsets of motor neurons may respond to their own subsets of growth factors.

Motor neurons that could potentially include those that descend from the brainstem, and those involved in breathing, also affected by the disease.

The results suggest that combining growth factors may offer more therapeutic benefit than single factors in ALS according to Nicholas Boulis.

Svendsen agreed. This is suggesting that for therapies, if you want to protect motor neurons, you may have to expand to include multiple growth factors, Svendsen said. However, he noted, and as confirmed in this study, GDNF by itself is still perhaps the most powerful all-around survival factor for motor neurons.

Svendsen is now developing a potential therapy for ALS that uses genetically engineered neural stem cells to deliver GDNF to the spinal cord. The Phase 1 clinical trial is soon to be launched (see October 2016 news).

Neuroprotective therapies: the next generation?

The next big question, which this paper leaves open, according to Svendsen is whether the growth factors identified in this study protect motor neurons in the adult nervous system.

Haase agreed. This is a critical question, and we are adapting our method to look at this now.

A stem cell-based approach? Haases team previously developed a FACS-based technique to isolate reprogrammed motor neurons generated from human iPS cells (Toli et al., 2015). The approach could be used to identify key neurotrophic substances that promote the survival of patient-derived motor neurons. [Image: Reprogrammed sALS motor neuron, Alves et al., 2015. CC BY 4.0].

Some neural circuits change drastically during adulthood, while others stay pretty much the same, so weve got to do the experiments to find out, explained Svendsen. But I will probably be trying HGF soon in my own experiments.

In the meantime, said Haase, it is important to keep in mind that the growth factors found to be less effective in this study should not be ruled out as potential therapies. They may act sequentially during development, or may require co-factors to exert their effect which were not present in our growth medium, he said.

It is also important to keep in mind that this study did not evaluate the ability of any of these substances to regenerate axons, a key goal in terms of developing therapies for ALS and other motor neuron diseases including SMA.

The challenges of delivery, which have stymied the field to date, remain paramount, Haase also noted. Gene delivery approaches with adeno-associated vectors have been studied for single growth factors, but if several are needed, a larger-capacity vector, such as lentivirus, may be required, according to Boulis. Multiple rounds of ex vivo gene therapy to equip stem cells with multiple growth factor genes, would be another option, followed by surgical implantation of the modified cells.

Further exploration in in vivo models and patient-derived iPS cells are an important next step to determine which combination of these substances could be of the most benefit, added Boulis.

But despite these challenges, Boulis agrees this approach is worth considering. As a surgeon who does translational work on the application of growth factors to ALS, this may be an Aha! moment.

Reference

Schaller S, Buttigieg D, Alory A, Jacquier A, Barad M, Merchant M, Gentien D, de la Grange P, Haase G. Novel combinatorial screening identifies neurotrophic factors for selective classes of motor neurons. Proc Natl Acad Sci U S A. 2017 Mar 21;114(12):E2486-E2493. [PubMed].

Toli D, Buttigieg D, Blanchard S, Lemonnier T, Lamotte dIncamps B, Bellouze S, Baillat G, Bohl D, Haase G.Modeling amyotrophic lateral sclerosis in pure human iPSc-derived motor neurons isolated by a novel FACS double selection technique. Neurobiol Dis. 2015 Oct;82:269-80. [PubMed].

Further Reading

Rogers, ML. Neurotrophic Therapy for ALS/MND. New York: Springer New York; c2014. p. 1755-85. (Kostrzewa RM, editor. Handbook of Neurotoxicity.)

Gould TW, Enomoto H. Neurotrophic modulation of motor neuron development. Neuroscientist. 2009 Feb;15(1):105-16. [PubMed].

disease-als gdnf HGF neuroprotection neurotrophic factor topic-clinical topic-randd VEGF

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Neurotrophic factors in ALS: a winning combination? - ALS Research Forum

IPS Cell Therapy Comments Off on Neurotrophic factors in ALS: a winning combination? – ALS Research Forum | April 8th, 2017

The global stem cells market is expected to grow at an incredible CAGR of 25.5% from 2015 to 2022 and reach a market value of US$297 billion by 2022.

Florida, April 06: Market Research Engine adds a new research study on the report, titled Global Stem Cells Market Analysis by Therapy, Application and Geography Trends and Forecast, 2015 2022.

The global stem cells market is expected to grow at an incredible CAGR of 25.5% from 2015 to 2022 and reach a market value of US$297 billion by 2022.

Browse Full Report from here: http://www.marketresearchengine.com/reportdetails/global-stem-ce

The emergence of Induced Pluripotent Stem (iPS) cells as an alternative to ESCs (embryonic stem cells), growth of developing markets, and evolution of new stem cell therapies represent promising growth opportunities for leading players in this sector.

Due to the increased funding from Government and Private sector and rising global awareness about stem cell therapies and research are the main factors which are driving this market. A surge in therapeutic research activities funded by governments across the world has immensely propelled the global stem cells market. However, the high cost of stem cell treatment and stringent government regulations against the harvesting of stem cells are expected to restrain the growth of the global stem cells market.

This report will definitely help you make well informed decisions related to the stem cell market.

The stem cell therapy market includes large number of players that are involved in development of stem cell therapies of the treatment of various diseases. Mesoblast Ltd. (Australia), Aastrom Biosciences, Inc. (U.S.), Celgene Corporation (U.S.), and StemCells, Inc. (U.S.) are the key players involved in the development of stem cell therapies across the globe.

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Scope of the Report

This market research report categorizes the stem cell therapy market into the following segments and sub-segments:

By Mode of Therapy

Allogeneic Stem Cell Therapy Market o CVS Diseases o CNS Diseases o GIT diseases o Eye Diseases o Musculoskeletal Disorders o Metabolic Diseases o Immune System Diseases o Wounds and Injuries o Others

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Stem Cells Market is Expected to Cross US$ 297 Billion by 2022 - MilTech

IPS Cell Therapy Comments Off on Stem Cells Market is Expected to Cross US$ 297 Billion by 2022 – MilTech | April 8th, 2017

In Brief A Japanese man has become the first recipient of donated, reprogrammed stem cells as a treatment for macular degeneration. If the treatment proves effective against the age-related eye condition, it could halt or prevent the vision loss of the 10 million people in the U.S. who have macular degeneration. A New Treatment for Macular Degeneration

Macular degeneration is the leading cause of progressive vision loss with almost 10million Americans affected by the disease. Currently, there are no known cures for the conditionalthough stem cells might change that entirely.

Macular degeneration occurs when the central portion, the macula, of the retina is deteriorated. This is where our eyes record images and send them to the brain through the optic nerve. The macula is known for focusing our vision, controlling our ability to read, recognize faces, and see objects clearly.

A Japaneseman in his sixties is the worlds first person to receive induced pluripotent stem (iPS) cells donated by a different individual. Rather than tip-toeing around the ethics of embryonic stem cells, scientists were able to remove mature cells from a donor and reprogram them into an embryonic state, which then could be developed into a specific cell-type to treat the disease. Physicians cultivated donated skin cells that were transplanted onto the mans retina to halt the progression of his age-related macular degeneration.

While the mans first surgery was a success, the doctors have said they will make no more announcements about his progress until they have completed all five of the planned procedures. While the effectiveness of this technique cannot be evaluated until the fate of the donated cells and the progression of the patientsmacular degenerationhave been fully monitored, there is increasing interest inusing iPScells for theraputic purposes.

A similar therapy was performed at the Kobe City Medical Center General Hospital in Japan in September 2014, but with a slight difference. In this case, the patient received her own skin cells reprogrammed into retinal cells. As hoped, a year after the surgery her vision had no decline, seemingly halting the macular degeneration. Four more patients in the clinical trial are expected to receive donor cells as well.

The donor-cell procedure, if successful, could help pave the way for the iPS cell bank thatShinya Yamanaka is establishing. An iPS cell bank would allow physicians find theperfect iPS donor per each patients biological signatures. Yamanaka is a Nobel-prizewinning scientist at Kyoto University who pioneered the iPS cells.

Yamanakas idea of a iPS cell bank has the potential torevolutionize modern medicine. It would provide patients with ready-made cells immediately, givinga widespread population access to more treatment options bylower all-around costs. While the risk of genetic defects or a poor donor match still remains, the new procedurecould offer enormous advantagescompared toother alternatives.

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March 29, 2017 (A) Bio-imaging analysis to evaluate the therapeutic effect of iPS-ML producing IFN- on metastatic liver cancer. (B) Quantification of the image data shown in A. (C) Histological data indicating migration of iPS-ML (PKH26, red) into intrahepatic tumor tissues (GFP, green). Adapted from M. Sakisaka, M. Haruta, Y. Komohara, S. Umemoto, K. Matsumura, T. Ikeda, M. Takeya, Y. Inomata, Y. Nishimura, and S. Senju, "Therapy of primary and metastatic liver cancer by human iPS cell-derived myeloid cells producing interferon-," Journal of Hepato-Biliary-Pancreatic Sciences, vol. 24, pp. 109-119, Feb. 2017. DOI: 10.1002/jhbp.422

Causes of the most common form of liver cancer, hepatocellular carcinoma (HCC), include hepatitis B or C, cirrhosis, obesity, diabetes, a buildup of iron in the liver, or a family of toxins called aflatoxins produced by fungi on some types of food. Typical treatments for HCC include radiation, chemotherapy, cryo- or radiofrequency ablation, resection, and liver transplant. Unfortunately, the mortality rate is still quite high; the American Cancer Society estimates the five-year survival rate for localized liver cancer is 31 percent.

Hoping to improve primary liver cancer outcomes, including HCC and metastatic liver cancer, researchers from Japan began studying induced pluripotent stem (iPS) cell-derived immune cells that produce the protein interferon- (IFN-). IFN- has antiviral effects related to immune response, and exhibits two antitumor activities, the JAK-STAT signaling pathway and p53 protein expression. IFN- has been used for some forms of cancer, but problems like rapid inactivation, poor tissue penetration, and toxicity prevent widespread use. To overcome that hurdle, Kumamoto University researchers used iPS cell-derived proliferating myelomonocytic (iPS-ML) cells, which they developed in a previous research project. These cells were found to mimic the behavior of tumor-associated macrophages (TAMS), which inspired the researchers to develop them as a drug delivery system for IFN- and evaluate the therapeutic effect on liver cancer in a murine model in vivo.

The researchers selected two cancer cell lines that were sensitive to IFN- treatmentone that easily metastasized to the liver after injection into the spleen, and another that produced a viable model after being directly injected into the liver. After injection, mice that tested positive for cancer (~80 percent) were separated into test and control groups. iPS-ML/IFN- cells were injected two to three times a week for three weeks into the abdomens of the test group subjects.

Livers with tumors were found to have higher levels of IFN- than those without. This was likely due to iPS-ML/IFN- cells penetrating the fibrous connective tissue capsule surrounding the liver and migrating toward intrahepatic cancer sites. The iPS-ML/IFN- cells did not penetrate non-tumorous livers, but rather stayed on the surface of the organ. Furthermore, concentrations of IFN- from 24 to 72 hours after iPS-ML/IFN- injections were found to be high enough to inhibit proliferation or even cause the death of the tumor cells.

Due to differences between species, mouse cells are not adversely affected by human IFN-, meaning that side effects of this treatment are not visible in this model. Thus, the researchers are working on a new model with the mouse equivalent of human iPS-ML/IFN, and testing its therapeutic abilities.

"Our recent research into iPS-cell derived, IFN- expressing myeloid cells should be beneficial for many cancer patients," says research leader Dr. Satoru Senju. "If it is determined to be safe for human use, this technology has the potential to slow cancer progression and increase survival rates. At this point, however, we still have much work ahead."

This research may be found in the Journal of Hepato-Biliary-Pancreatic Sciences.

Explore further: Scientists stimulate immune system, stop cancer growth

More information: Masataka Sakisaka et al, Therapy of primary and metastatic liver cancer by human iPS cell-derived myeloid cells producing interferon-, Journal of Hepato-Biliary-Pancreatic Sciences (2017). DOI: 10.1002/jhbp.422

A chemical found in tumors may help stop tumor growth, according to a new study.

Scientists at EPFL have found a way to starve liver cancer cells by blocking a protein that is required for glutamine breakdownwhile leaving normal cells intact. The discovery opens new ways to treat liver cancer.

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Liver cancer remains among the leading causes of cancer-related death worldwide.

Researchers at University of California San Diego School of Medicine and Sanford Burnham Prebys Medical Discovery Institute have discovered that high levels of the protein p62 in human liver samples are strongly associated ...

Immunotherapydeveloping treatments by boosting natural immune system responsesholds much potential in the fight against serious diseases. Now, A*STAR researchers have determined how one group of immune cells called ...

Detailed analysis of two brain tumor subtypes has revealed that they may originate from the same type of neural progenitor cells and be distinguished by gene mutation patterns and by the composition of their microenvironments. ...

Scientists at EPFL and NTU have discovered that combining an anticancer drug with an antirheumatic produces improved effects against tumors. The discovery opens a new path for drug-drug synergy.

Clinical trials found that it is safe to regularly infuse brain and lung cancer patients with 8001000 times the daily recommended amount of vitamin C as a potential strategy to improve outcomes of standard cancer treatments. ...

Hepatocellular carcinoma (HCC), a cancer associated with underlying liver disease and cirrhosis that often only becomes symptomatic when it is very advanced, is the second leading cause of cancer deaths around the world, ...

The chemical bisphenol A, or BPA, appears to aid the survival of inflammatory breast cancer cells, revealing a potential mechanism for how the disease grows, according to a study led by researchers in the Department of Surgery ...

One reason pancreatic cancer has a particularly low survival rate is the difficulty in getting drugs to the tumour, but new knowledge of how pancreatic cancer cells invade neighbouring cells could change that.

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March 28, 2017 by Layne Cameron Kristin Parent mapped the structure of the giant Samba virus with MSUs cryo-EM microscope, which is featured on the cover of the journal Viruses. Credit: Michigan State University

In a laboratory at Michigan State University, scientists took a DIY approach to build a retrofitted cryo-electron microscope that allowed them to map a giant Samba virus one of the worlds largest viruses.

If the common cold virus is scaled to the size of a ladder, then the giant Samba virus is bigger than the Washington Monument, said Kristin Parent, assistant professor of biochemistry and molecular biology and co-author of the paper featured on the cover of the journal Viruses. Cryo-EM allowed us to map this virus structure and observe the proteins it uses to enter, or attack, cells.

It seems counterintuitive that bigger organisms are harder to see, but they are when using cryo-electron microscopy. Thats because these microscopes usually are used to look at thin specimens and cant decipher larger organisms to reveal their biological mechanisms. For thick samples, scientists see only dark gray or black blobs instead of seeing the molecular framework.

Cryo-EM allowed Parents team to image the giant Samba virus and understand the structures that allow it to enter an amoeba. Once inside, Samba opens one of its capsid layers and releases its nucleocapsid which carries the genetic cargo that sparks an infection. While Samba isnt known to cause any diseases in humans, its cousin, the mimivirus, may be a culprit for causing some respiratory ailments in humans.

If you scoop up a handful of water from Lake Michigan, you are literally holding more viruses than there are people on the planet, said Parent, who published the paper with Jason Schrad and Eric Young, MSU biochemistry and molecular biology graduate students. While scientists cant study every virus on Earth, the insights we glean from viruses like the giant Samba can help us understand the mechanisms of other viruses in its family, how they thrive and how we can attack them.

As bacteria become more resistant to antibiotics, looking for new ways to fight diseases will continue to grow in importance. Parents lab also studies how bacteria-infecting viruses enter cells using this method, which could potentially lead to new antibacterial treatments. Yet the worlds best cryo-EM microscope costs more than $5 million. Limited by funds but not drive, Parent was able to upgrade an existing microscope at MSU to do cryo-EM one that is a tinkerers dream.

This traditional transmission electron microscope was retrofitted with a cryostage, which keeps viruses frozen in liquid nitrogen while theyre being studied. Parent and her team then added a Direct Electron DE-20 detector, a powerful camera the mighty microscopes piece de resistance.

Parent didnt invent cryo-EM, but establishing it on campus serves as a viable proof-of-concept for MSU, opening the door for many interdisciplinary partnerships. This cutting-edge microscopy has applications across many fields, from those addressing a single protein to others studying entire cells. Virtually anyone studying complex molecular machines can advance their work with this tool, Parent added.

Parent has earned an AAAS Marion Milligan Mason Award for Women in the Chemical Sciences. This award, her paper in Viruses and being the co-author who performed cryo-EM work in a recent Nature Communications paper, lays the groundwork to some day have a more advanced cryo-EM microscope housed at MSU to be able to perform high-resolution structural studies.

Weve done quite a bit with our limited resources, but were primed to do more, Parent said. I think MSU could serve as a cryo-EM center and to increase the prevalence of this technology in the Midwest and beyond.

As one example, scientists from Universidade Federal de Minas Gerais (Brazil) and Universidade Federal do Rio de Janeiro (Brazil) also contributed to this study and benefitted from the technology MSU has to offer.

Explore further: Cryo-electron microscopy achieves unprecedented resolution using new computational methods

Cryo-electron microscopy (cryo-EM)which enables the visualization of viruses, proteins, and other biological structures at the molecular levelis a critical tool used to advance biochemical knowledge. Now Lawrence Berkeley

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Scientist maps giant virus Phys.org Phys.Org IPS ...

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Stem cells are undifferentiated biological cells that can differentiate into specialized cells and can divide (through mitosis) to produce more stem cells. They are found in multicellular organisms. In mammals, there are two broad types of stem cells: embryonic stem cells, which are isolated from the inner cell mass of blastocysts, and adult stem cells, which are found in various tissues. In adult organisms, stem cells and progenitor cells act as a repair system for the body, replenishing adult tissues. In a developing embryo, stem cells can differentiate into all the specialized cellsectoderm, endoderm and mesoderm (see induced pluripotent stem cells)but also maintain the normal turnover of regenerative organs, such as blood, skin, or intestinal tissues.

There are three known accessible sources of autologous adult stem cells in humans:

Stem cells can also be taken from umbilical cord blood just after birth. Of all stem cell types, autologous harvesting involves the least risk. By definition, autologous cells are obtained from ones own body, just as one may bank his or her own blood for elective surgical procedures.

Adult stem cells are frequently used in medical therapies, for example in bone marrow transplantation. Stem cells can now be artificially grown and transformed (differentiated) into specialized cell types with characteristics consistent with cells of various tissues such as muscles or nerves. Embryonic cell lines and autologous embryonic stem cells generated through Somatic-cell nuclear transfer or dedifferentiation have also been proposed as promising candidates for future therapies.[1] Research into stem cells grew out of findings by Ernest A. McCulloch and James E. Till at the University of Toronto in the 1960s.[2][3]

The classical definition of a stem cell requires that it possess two properties:

Two mechanisms exist to ensure that a stem cell population is maintained:

Potency specifies the differentiation potential (the potential to differentiate into different cell types) of the stem cell.[4]

In practice, stem cells are identified by whether they can regenerate tissue. For example, the defining test for bone marrow or hematopoietic stem cells (HSCs) is the ability to transplant the cells and save an individual without HSCs. This demonstrates that the cells can produce new blood cells over a long term. It should also be possible to isolate stem cells from the transplanted individual, which can themselves be transplanted into another individual without HSCs, demonstrating that the stem cell was able to self-renew.

Properties of stem cells can be illustrated in vitro, using methods such as clonogenic assays, in which single cells are assessed for their ability to differentiate and self-renew.[7][8] Stem cells can also be isolated by their possession of a distinctive set of cell surface markers. However, in vitro culture conditions can alter the behavior of cells, making it unclear whether the cells will behave in a similar manner in vivo. There is considerable debate as to whether some proposed adult cell populations are truly stem cells.

Embryonic stem (ES) cells are stem cells derived from the inner cell mass of a blastocyst, an early-stage embryo.[9] Human embryos reach the blastocyst stage 45 days post fertilization, at which time they consist of 50150 cells. ES cells are pluripotent and give rise during development to all derivatives of the three primary germ layers: ectoderm, endoderm and mesoderm. In other words, they can develop into each of the more than 200 cell types of the adult body when given sufficient and necessary stimulation for a specific cell type. They do not contribute to the extra-embryonic membranes or the placenta.

Nearly all research to date has made use of mouse embryonic stem cells (mES) or human embryonic stem cells (hES). Both have the essential stem cell characteristics, yet they require very different environments in order to maintain an undifferentiated state. Mouse ES cells are grown on a layer of gelatin as an extracellular matrix (for support) and require the presence of leukemia inhibitory factor (LIF). Human ES cells are grown on a feeder layer of mouse embryonic fibroblasts (MEFs) and require the presence of basic fibroblast growth factor (bFGF or FGF-2).[10] Without optimal culture conditions or genetic manipulation,[11] embryonic stem cells will rapidly differentiate.

A human embryonic stem cell is also defined by the expression of several transcription factors and cell surface proteins. The transcription factors Oct-4, Nanog, and Sox2 form the core regulatory network that ensures the suppression of genes that lead to differentiation and the maintenance of pluripotency.[12] The cell surface antigens most commonly used to identify hES cells are the glycolipids stage specific embryonic antigen 3 and 4 and the keratan sulfate antigens Tra-1-60 and Tra-1-81. The molecular definition of a stem cell includes many more proteins and continues to be a topic of research.[13]

There are currently no approved treatments using embryonic stem cells. The first human trial was approved by the US Food and Drug Administration in January 2009.[14] However, the human trial was not initiated until October 13, 2010 in Atlanta for spinal injury victims. On November 14, 2011 the company conducting the trial announced that it will discontinue further development of its stem cell programs.[15] ES cells, being pluripotent cells, require specific signals for correct differentiationif injected directly into another body, ES cells will differentiate into many different types of cells, causing a teratoma. Differentiating ES cells into usable cells while avoiding transplant rejection are just a few of the hurdles that embryonic stem cell researchers still face.[16] Many nations currently have moratoria on either ES cell research or the production of new ES cell lines. Because of their combined abilities of unlimited expansion and pluripotency, embryonic stem cells remain a theoretically potential source for regenerative medicine and tissue replacement after injury or disease.

Human embryonic stem cell colony on mouse embryonic fibroblast feeder layer

The primitive stem cells located in the organs of fetuses are referred to as fetal stem cells.[17] There are two types of fetal stem cells:

Adult stem cells, also called somatic (from Greek , of the body) stem cells, are stem cells which maintain and repair the tissue in which they are found.[19] They can be found in children, as well as adults.[20]

Pluripotent adult stem cells are rare and generally small in number, but they can be found in umbilical cord blood and other tissues.[21] Bone marrow is a rich source of adult stem cells,[22] which have been used in treating several conditions including spinal cord injury,[23] liver cirrhosis,[24] chronic limb ischemia [25] and endstage heart failure.[26] The quantity of bone marrow stem cells declines with age and is greater in males than females during reproductive years.[27] Much adult stem cell research to date has aimed to characterize their potency and self-renewal capabilities.[28] DNA damage accumulates with age in both stem cells and the cells that comprise the stem cell environment. This accumulation is considered to be responsible, at least in part, for increasing stem cell dysfunction with aging (see DNA damage theory of aging).[29]

Most adult stem cells are lineage-restricted (multipotent) and are generally referred to by their tissue origin (mesenchymal stem cell, adipose-derived stem cell, endothelial stem cell, dental pulp stem cell, etc.).[30][31]

Adult stem cell treatments have been successfully used for many years to treat leukemia and related bone/blood cancers through bone marrow transplants.[32] Adult stem cells are also used in veterinary medicine to treat tendon and ligament injuries in horses.[33]

The use of adult stem cells in research and therapy is not as controversial as the use of embryonic stem cells, because the production of adult stem cells does not require the destruction of an embryo. Additionally, in instances where adult stem cells are obtained from the intended recipient (an autograft), the risk of rejection is essentially non-existent. Consequently, more US government funding is being provided for adult stem cell research.[34]

Multipotent stem cells are also found in amniotic fluid. These stem cells are very active, expand extensively without feeders and are not tumorigenic. Amniotic stem cells are multipotent and can differentiate in cells of adipogenic, osteogenic, myogenic, endothelial, hepatic and also neuronal lines.[35] Amniotic stem cells are a topic of active research.

Use of stem cells from amniotic fluid overcomes the ethical objections to using human embryos as a source of cells. Roman Catholic teaching forbids the use of embryonic stem cells in experimentation; accordingly, the Vatican newspaper Osservatore Romano called amniotic stem cells the future of medicine.[36]

It is possible to collect amniotic stem cells for donors or for autologuous use: the first US amniotic stem cells bank [37][38] was opened in 2009 in Medford, MA, by Biocell Center Corporation[39][40][41] and collaborates with various hospitals and universities all over the world.[42]

These are not adult stem cells, but rather adult cells (e.g. epithelial cells) reprogrammed to give rise to pluripotent capabilities. Using genetic reprogramming with protein transcription factors, pluripotent stem cells equivalent to embryonic stem cells have been derived from human adult skin tissue.[43][44][45]Shinya Yamanaka and his colleagues at Kyoto University used the transcription factors Oct3/4, Sox2, c-Myc, and Klf4[43] in their experiments on cells from human faces. Junying Yu, James Thomson, and their colleagues at the University of WisconsinMadison used a different set of factors, Oct4, Sox2, Nanog and Lin28,[43] and carried out their experiments using cells from human foreskin.

As a result of the success of these experiments, Ian Wilmut, who helped create the first cloned animal Dolly the Sheep, has announced that he will abandon somatic cell nuclear transfer as an avenue of research.[46]

Frozen blood samples can be used as a source of induced pluripotent stem cells, opening a new avenue for obtaining the valued cells.[47]

To ensure self-renewal, stem cells undergo two types of cell division (see Stem cell division and differentiation diagram). Symmetric division gives rise to two identical daughter cells both endowed with stem cell properties. Asymmetric division, on the other hand, produces only one stem cell and a progenitor cell with limited self-renewal potential. Progenitors can go through several rounds of cell division before terminally differentiating into a mature cell. It is possible that the molecular distinction between symmetric and asymmetric divisions lies in differential segregation of cell membrane proteins (such as receptors) between the daughter cells.[48]

An alternative theory is that stem cells remain undifferentiated due to environmental cues in their particular niche. Stem cells differentiate when they leave that niche or no longer receive those signals. Studies in Drosophila germarium have identified the signals decapentaplegic and adherens junctions that prevent germarium stem cells from differentiating.[49][50]

Diseases and conditions where stem cell treatment is being investigated include:

Stem cell therapy is the use of stem cells to treat or prevent a disease or condition. Bone marrow transplant is a crude form of stem cell therapy that has been used clinically for many years without controversy. No stem cell therapies other than bone marrow transplant are widely used.[64][65]

Research is underway to develop various sources for stem cells, and to apply stem cell treatments for neurodegenerative diseases and conditions, diabetes, heart disease, and other conditions.[66]

In more recent years, with the ability of scientists to isolate and culture embryonic stem cells, and with scientists growing ability to create stem cells using somatic cell nuclear transfer and techniques to created induced pluripotent stem cells, controversy has crept in, both related to abortion politics and to human cloning.

Stem cell treatments may require immunosuppression because of a requirement for radiation before the transplant to remove the patients previous cells, or because the patients immune system may target the stem cells. One approach to avoid the second possibility is to use stem cells from the same patient who is being treated.

Pluripotency in certain stem cells could also make it difficult to obtain a specific cell type. It is also difficult to obtain the exact cell type needed, because not all cells in a population differentiate uniformly. Undifferentiated cells can create tissues other than desired types.[67]

Some stem cells form tumors after transplantation; pluripotency is linked to tumor formation especially in embryonic stem cells, fetal proper stem cells, induced pluripotent stem cells. Fetal proper stem cells form tumors despite multipotency.[citation needed]

Hepatotoxicity and drug-induced liver injury account for a substantial number of failures of new drugs in development and market withdrawal, highlighting the need for screening assays such as stem cell-derived hepatocyte-like cells, that are capable of detecting toxicity early in the drug development process.[68]

Some of the fundamental patents covering human embryonic stem cells are owned by the Wisconsin Alumni Research Foundation (WARF) they are patents 5,843,780, 6,200,806, and 7,029,913 invented by James A. Thomson. WARF does not enforce these patents against academic scientists, but does enforce them against companies.[69]

In 2006, a request for the US Patent and Trademark Office (USPTO) to re-examine the three patents was filed by the Public Patent Foundation on behalf of its client, the non-profit patent-watchdog group Consumer Watchdog (formerly the Foundation for Taxpayer and Consumer Rights).[69] In the re-examination process, which involves several rounds of discussion between the USTPO and the parties, the USPTO initially agreed with Consumer Watchdog and rejected all the claims in all three patents,[70] however in response, WARF amended the claims of all three patents to make them more narrow, and in 2008 the USPTO found the amended claims in all three patents to be patentable. The decision on one of the patents (7,029,913) was appealable, while the decisions on the other two were not.[71][72] Consumer Watchdog appealed the granting of the 913 patent to the USTPOs Board of Patent Appeals and Interferences (BPAI) which granted the appeal, and in 2010 the BPAI decided that the amended claims of the 913 patent were not patentable.[73] However, WARF was able to re-open prosecution of the case and did so, amending the claims of the 913 patent again to make them more narrow, and in January 2013 the amended claims were allowed.[74]

In July 2013, Consumer Watchdog announced that it would appeal the decision to allow the claims of the 913 patent to the US Court of Appeals for the Federal Circuit (CAFC), the federal appeals court that hears patent cases.[75] At a hearing in December 2013, the CAFC raised the question of whether Consumer Watchdog had legal standing to appeal; the case could not proceed until that issue was resolved.[76]

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All causes of the most common form of liver cancer, hepatocellular carcinoma (HCC), are not yet known, but the risk of getting it is increased by hepatitis B or C, cirrhosis, obesity, diabetes, a buildup of iron in the liver, or a family of toxins called aflatoxins produced by fungi on some types of food. Typical treatments for HCC include radiation, chemotherapy, cryo- or radiofrequency ablation, resection, and liver transplant. Unfortunately, the mortality rate is still quite high, with the American Cancer Society giving a 5-year survival rate for localized liver cancer at 31%.

Hoping to improve primary liver cancer including HCC and metastatic liver cancer therapies, researchers from Japan began studying induced pluripotent stem (iPS) cell-derived immune cells that produced the protein interferon-? (IFN-). IFN- exhibits antiviral effects related to immune response, and two different antitumor activities, the JAK-STAT signaling pathway and p53 protein expression. IFN- has been used for some forms of cancer but problems like rapid inactivation, poor tissue penetration, and toxicity have kept it from being used extensively. To get over that hurdle, Kumamoto University researchers used iPS cell-derived proliferating myelomonocytic (iPS-ML) cells, which they developed in a previous research project. These cells were found to mimic the behavior of tumor associated macrophages (TAMS), which inspired the researchers to develop them as a drug delivery system for IFN- and evaluate the therapeutic effect on liver cancer in a murine model in vivo.

The researchers selected two cancer cell lines that were sensitive to IFN- treatment, one that easily metastasized to the liver after injection into the spleen and the other that produced a viable model after being directly injected into the liver. After injection, mice that tested positive for cancer (~80%) were separated into test and control groups. iPS-ML/IFN- cells were injected two to three times a week for three weeks into the abdomen of the test groups.

Livers with tumors were found to have higher levels of IFN- than those without. This was likely due to iPS-ML/IFN- cells penetrating the fibrous connective tissue capsule surrounding the liver ?serous membrane?and migrating toward intrahepatic cancer sites. The iPS-ML/IFN- cells did not penetrate non-tumorous livers, but rather stayed on the surface of the organ. Furthermore, concentrations of IFN- from 24 to 72 hours after iPS-ML/IFN- injections were found to be high enough to inhibit proliferation or even cause the death of the tumor cells.

Due to differences between species, mouse cells are not adversely affected by human IFN-, meaning that side effects of this treatment are not visible in this model. Fortunately, the researchers are working on a new model with the mouse equivalent of human iPS-ML/IFN, and testing its therapeutic abilities.

"Our recent research into iPS-cell derived, IFN- expressing myeloid cells should be beneficial for many cancer patients," says research leader Dr. Satoru Senju. "If it is determined to be safe for human use, this technology has the potential to slow cancer progression and increase survival rates. At this point, however, we still have much work ahead."

This research may be found in the Journal of Hepato-Biliary-Pancreatic Sciences online.

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But its always been clear that they could be risky too, especially if theyre not used carefully. The LCSB team has published its results in the scientific journal PLOS Biology.

This study shows that for the first time, targeting the proliferating tumor mass and dormant cancer stem cells with combination therapy effectively inhibited tumor growth and prevented metastasis compared to monotherapy in mice, said Wang, who is a member of the UCLA Jonsson Comprehensive Cancer Center and of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. However, as of April 2016, new rules on human cells and tissue require FDA oversight and approval for such procedures.

Although the women had moderate vision loss prior to the stem cell treatments, a year later their vision ranged from total blindness to 20/200, which is considered legally blind.

NPR contacted the FDA, and was told by a spokeswoman that the agency is now finalizing a series of new guidelines regulating how clinics could use stem cells for treatment purposes. So far, however, scientists only partially understand how the body controls the fate of these all-rounders, and what factors decide whether a stem cell will differentiate, for example, into a blood, liver or nerve cell. He wrote an editorial accompanying the two papers.

As reported Wednesday in the New England Journal of Medicine, one of the women, a 72-year-old, went completely blind after doctors injected stem cells into her eye in an attempt to cure the disease.

But within a week of starting the off-the-charts dangerous therapy at an American clinic, the patients suffered complications.

Two of the patients sought treatment at the universitys hospital for the complications they suffered. The agency also noted that it had previously issued a warning to patients. She said that they were treating patients with their own stem cells.

In addition to charging a fee for treatment, there were several other red flags in the Florida cases that consumers should watch for when considering participation in a clinical trial, Goldberg said. They sought treatment at a Florida clinic that had announced a study to treat the condition on clinicaltrials.gov, a federal database of research studies.

Within days of the stem cell injections she was almost blind and ultimately progressed to complete blindness. Their attorney, Andrew Yaffa of Coral Gables, said that the case was resolved to the mutual satisfaction of the parties but that neither he nor his clients could comment beyond that.

She acknowledged, however, that the clinic had been performing the stem cell procedures.

Shoddy preparation of the stem cells may have led to some of the complications, said the study authors. We feel very confident about the procedures that we do, and weve had great success in many different indications. We believe that regenerative medicine / cellular therapeutics will play a large role in positively changing the natural history of diseases ultimately, we contend, lessening patient burdens, as well as reducing the associated economic impact disease imposes upon modern society.

The body produces a variety of stem cells. It is also costly, at almost $900,000 to develop and test the iPS cells for the first trial, Takahashi adds.

Whatever happened, experts said there was no evidence to suggest the procedure would have helped restore vision, since so little study has been done on whether adipose-derived stem cells can mature into the kinds of retinal cells that are involved in macular degeneration.

This represents a landmark, says Daley. But it proved too slow and expensive, says Shinya Yamanaka of Kyoto University in Japan, who first discovered how to create iPS cells and is a co-author of the NEJM paper. The registry may be useful as a starting point, but patients should then discuss potential trials with qualified physicians, an academic medical center.

A second patient was supposed to be treated, but transplantation was called off after the cells were found to have potential genetic problems. The cells were extracted their from fat, mixed with blood plasma and injected into their eyes.

Even though the safety and effectiveness of this procedure is unknown, all three patients received injections in both eyes. Dr. Thomas Albini of the University of Miami examined the women after they were treated at a clinic in Florida.

Before the procedure, all three women still had at least some vision. Medical experts said the episode raises questions about whether the government and doctors are doing enough to protect patients from the dangers of unapproved therapies.

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Three women blinded after clinical trial went wrong - Normangee Star

IPS Cell Therapy Comments Off on Three women blinded after clinical trial went wrong – Normangee Star | March 27th, 2017