Category Archives: Stem Cells

Javascript is currently disabled in your web browser. For full site functionality, it is necessary to enable Javascript. In order to enable it, please see these instructions. 22 hours ago A detailed analysis of the methylation patterns of histone H3 revealed a nuanced picture of the epigenetic rules governing expression of developmental genes in mouse embryonic stem cells. The image shows a ChIP-seq track file example of H3K4me3 at mouse Homeobox (Hox) gene clusters. Credit: Study's authors and Nature Structure & Molecular Biology.

A decade ago, gene expression seemed so straightforward: genes were either switched on or off. Not both. Then in 2006, a blockbuster finding reported that developmentally regulated genes in mouse embryonic stem cells can have marks associated with both active and repressed genes, and that such genes, which were referred to as "bivalently marked genes", can be committed to one way or another during development and differentiation.

This paradoxical stateakin to figuring out how to navigate a red and green traffic signalhas since undergone scrutiny by labs worldwide. What has been postulated is that the control regions (or promoters) of some genes, particularly those critical for development during the undifferentiated state, stay "poised" for plasticity by communicating with both activating and repressive histones, a state biologists term "bivalency."

A study by researchers at the Stowers Institute for Medical Research now revisits that notion. In this week's advance online edition of the journal Nature Structural and Molecular Biology, a team led by Investigator Ali Shilatifard, Ph.D., identifies the protein complex that implements the activating histone mark specifically at "poised" genes in mouse embryonic stem (ES) cells, but reports that its loss has little effect on developmental gene activation during differentiation. This suggests that there is more to learn about interpreting histone modification patterns in embryonic and even cancer cells.

"There has been a lot of excitement over the idea that promoters of developmentally regulated genes exhibit both the stop and go signals," explains Shilatifard. "That work supports the idea that histone modifications could constitute a code that regulates gene expression. However, we have argued that the code is not absolute and is context dependent."

Shilatifard has a historic interest in gene regulation governing development and cancer. In 2001, his laboratory was the first to characterize a complex of yeast proteins called COMPASS, which enzymatically methylates histones in a way that favors gene expression. Later, he discovered that mammals have six COMPASS look-alikestwo SET proteins (1A and 1B) and four MLL (Mixed-Lineage Leukemia) proteins, the latter so named because they are mutant in some leukemias. The group has since focused on understanding functional differences among the COMPASS methylases. The role of mouse Mll2 in establishing bivalency was the topic of the latest study.

Comprehending the results of the paper requires a brief primer defining three potential methylation states of histone H3. If the 4th amino acid, lysine (K), displays three methyl groups (designated H3K4me3), then this mark is a sign of active transcription from that region of the chromosome. If the 27th residue of histone H3 (also a lysine) is trimethylated (H3K27me3), this mark is associated with the silencing of that region of the chromosome. But if both histone H3 residues are marked by methylation (H3K4me3 and H3K27me3 marks), that gene is deemed poised for activation in the undifferentiated cell state.

The team already knew that an enzyme complex called PRC2 implemented the repressive H3K27me3 mark. To identify which COMPASS family member is involved in this process, the group genetically eliminated all possibilities and came up with Mll2 as the responsible factor. Mll2-deficient cells indeed show H3K4me3 loss, not at all genes, but at the promoters of developmentally regulated genes, such as the Hox genes.

The revelation came when the researchers evaluated behaviors of Mll2-deficient mouse embryonic stem cells. First, the cells continued to display the defining property of a stem cell, the ability to "self-renew," meaning that genes that permit stem cell versatility were undisturbed by Mll2 loss. But remarkably, when cultured with a factor that induces their maturation, Mll2-deficient mouse ES cells showed no apparent abnormalities in gene expression. In fact, expression of the very Hox genes that normally exhibit bivalent histone marks was as timely in Mll2-deficient cells as it was in non-mutant cells.

"This means that Mll2-deficient mouse ES cells that receive a differentiation signal can still activate genes required for maturation, even though they have lost the H3K4me3 mark on bivalent regions" says Deqing Hu, Ph.D., the postdoctoral fellow who led the study. "This work paves the way for understanding what the real function of bivalency is in pluripotent cells and development."

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Rules governing expression of developmental genes in mouse embryonic stem cells are more nuanced than anticipated

Aug. 11, 2013 A decade ago, gene expression seemed so straightforward: genes were either switched on or off. Not both. Then in 2006, a blockbuster finding reported that developmentally regulated genes in mouse embryonic stem cells can have marks associated with both active and repressed genes, and that such genes, which were referred to as "bivalently marked genes," can be committed to one way or another during development and differentiation.

This paradoxical state -- akin to figuring out how to navigate a red and green traffic signal -- has since undergone scrutiny by labs worldwide. What has been postulated is that the control regions (or promoters) of some genes, particularly those critical for development during the undifferentiated state, stay "poised" for plasticity by communicating with both activating and repressive histones, a state biologists term "bivalency."

A study by researchers at the Stowers Institute for Medical Research now revisits that notion. In this week's advance online edition of the journal Nature Structural and Molecular Biology, a team led by Investigator Ali Shilatifard, Ph.D., identifies the protein complex that implements the activating histone mark specifically at "poised" genes in mouse embryonic stem (ES) cells, but reports that its loss has little effect on developmental gene activation during differentiation. This suggests that there is more to learn about interpreting histone modification patterns in embryonic and even cancer cells.

"There has been a lot of excitement over the idea that promoters of developmentally regulated genes exhibit both the stop and go signals," explains Shilatifard. "That work supports the idea that histone modifications could constitute a code that regulates gene expression. However, we have argued that the code is not absolute and is context dependent."

Shilatifard has a historic interest in gene regulation governing development and cancer. In 2001, his laboratory was the first to characterize a complex of yeast proteins called COMPASS, which enzymatically methylates histones in a way that favors gene expression. Later, he discovered that mammals have six COMPASS look-alikes -- two SET proteins (1A and 1B) and four MLL (Mixed-Lineage Leukemia) proteins, the latter so named because they are mutant in some leukemias. The group has since focused on understanding functional differences among the COMPASS methylases. The role of mouse Mll2 in establishing bivalency was the topic of the latest study.

Comprehending the results of the paper requires a brief primer defining three potential methylation states of histone H3. If the 4th amino acid, lysine (K), displays three methyl groups (designated H3K4me3), then this mark is a sign of active transcription from that region of the chromosome. If the 27th residue of histone H3 (also a lysine) is trimethylated (H3K27me3), this mark is associated with the silencing of that region of the chromosome. But if both histone H3 residues are marked by methylation (H3K4me3 and H3K27me3 marks), that gene is deemed poised for activation in the undifferentiated cell state.

The team already knew that an enzyme complex called PRC2 implemented the repressive H3K27me3 mark. To identify which COMPASS family member is involved in this process, the group genetically eliminated all possibilities and came up with Mll2 as the responsible factor. Mll2-deficient cells indeed show H3K4me3 loss, not at all genes, but at the promoters of developmentally regulated genes, such as the Hox genes.

The revelation came when the researchers evaluated behaviors of Mll2-deficient mouse embryonic stem cells. First, the cells continued to display the defining property of a stem cell, the ability to "self-renew," meaning that genes that permit stem cell versatility were undisturbed by Mll2 loss. But remarkably, when cultured with a factor that induces their maturation, Mll2-deficient mouse ES cells showed no apparent abnormalities in gene expression. In fact, expression of the very Hox genes that normally exhibit bivalent histone marks was as timely in Mll2-deficient cells as it was in non-mutant cells.

"This means that Mll2-deficient mouse ES cells that receive a differentiation signal can still activate genes required for maturation, even though they have lost the H3K4me3 mark on bivalent regions" says Deqing Hu, Ph.D., the postdoctoral fellow who led the study. "This work paves the way for understanding what the real function of bivalency is in pluripotent cells and development."

The study's findings also potentially impact oncogenesis, as tumor-initiating "cancer stem cells" exhibit bivalent histone marks at some genes. "Cancer stem cells are resistant to chemotherapy, making them difficult to eradicate," says Hu. "Our work could shed light on how cancer stem cells form a tumor or suggest a way to shut these genes down."

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A more nuanced genetic code: Rules governing expression of developmental genes in embryonic stem cells

WINSTON-SALEM, N.C. A daily bodily function urinating may become another option for collecting stem cells that can be transformed into regenerated tissue and organs.

Researchers with the Wake Forest Institute of Regenerative Medicine have identified stem cells in urine that can become multiple cell types. Their report is available on the website of the journal Stem Cells.

In a separate study released July 30, a group of researchers from the Guangzhou Institutes of Biomedicine and Health said they have been able to generate in mice tooth-like structures from urine-induced pluripotent stem cells.

Dr. Anthony Atala, director of the Wake Forest institute, said the use of urine-derived stem cells to regenerate human tissue and organs remains several years away.

Weve been looking at urine as a stem cell option since 2006, Atala said. Research has been so far, so good in rodents.

Being able to use a patients own stem cells for therapy is considered advantageous because they do not induce immune responses or rejection.

However, because tissue-specific cells are a very small subpopulation of cells, they can be difficult to isolate from organs and tissues.

The challenge has been getting the right cells and the right results every time, Atala said. This study reflects the promise of achieving those goals with samples that most people get rid of six times a day.

Atala and Dr. Yuanyuan Zhang, senior Wake Forest researcher on the study, said one advantage of collecting stem cells through urine is that it is a non-invasive, low-cost approach that avoids surgical procedures. Other post-birth options can require drilling into bone marrow.

The researchers say they have taken stem cells from urine and transformed them into bladder-type cells, such as smooth muscle and urothelial, the cells that line the bladder.

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Wake Forest researchers study urine as source for stem cells

SAN DIEGO, Aug. 12, 2013 /PRNewswire/ -- Cardium Therapeutics (NYSE MKT: CXM) today reported on a research collaboration with researchers at Boston Children's Hospital, to assess the medical utility of Excellagen as a delivery scaffold to seed autologous mesenchymal fetal stem cells for ex-vivo engineering of tissue grafts for transplantation into infants to repair prenatally diagnosed birth defects.

(Logo: http://photos.prnewswire.com/prnh/20051018/CARDIUMLOGO)

Autologous mesenchymal fetal stem cells are derived prenatally from infants with a medical defect requiring life-saving tissue repairs. These stem cells are sourced from amniotic fluid, the placenta or umbilical cord blood. The stem cells are then seeded into a scaffold to promote the growth of an engineered tissue graft. These grafts will potentially be used to surgically repair, either in the fetus or immediately following birth, certain prenatally diagnosed birth defects that could include congenital diaphragmatic hernia, tracheal and chest wall defects, bladder extrophy and various cardiac anomalies. Preliminary pre-clinical research has confirmed that Excellagen collagen homogenate maintains mesenchymal fetal stem cell viability. Additional proof of concept studies are currently underway.

"Boston Children's team has made remarkable progress in the field of tissue regeneration and surgical repair of prenatally diagnosed congenital defects. We believe that Excellagen has an opportunity serve as a delivery platform in the field of stem cell therapy and we look forward to continuing to work with the Boston Children's team to help make their innovative therapeutic vision a new standard of care, and potentially advance stem cell therapies toward commercialization," stated Christopher J. Reinhard, Chairman and Chief Executive Officer of Cardium. "Excellagen was specifically designed to support advanced biologics and this new application further highlights its potential versatility as an important delivery agent for a variety of innovative therapeutic applications."

Cardium's FDA-cleared Excellagen is an aseptically-manufactured, quaternary fibrillar Type I bovine collagen homogenate that is configured into a staggered array of three-dimensional, triple helical, telopeptide-deleted, tropocollagen molecules. This linear array forms a flowable, biocompatible and bioactive structural matrix that can promote chemotaxis, cellular adhesion, migration and proliferation to stimulate tissue formation. The Excellagen homogenate represents a new product delivery platform that allows for the potential development of a portfolio of advanced tissue regeneration therapeutic opportunities that could include anti-infectives, antibiotics, peptides, proteins, small molecules, DNA, stem cells, differentiated cells and conditioned cell media.

About Excellagen

Excellagen is a syringe-based, professional-use, pharmaceutically-formulated 2.6% fibrillar Type I bovine collagen homogenate that functions as an acellular biological modulator to activate the wound healing process and significantly accelerate the growth of granulation tissue. Excellagen's FDA clearance provides for very broad labeling including partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/graft, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds (abrasions, lacerations, second-degree burns and skin tears) and draining wounds. Excellagen is intended for professional use following standard debridement procedures in the presence of blood cells and platelets, which are involved with the release of endogenous growth factors. Excellagen's unique fibrillar Type I bovine collagen homogenate formulation is topically applied through easy-to-control, pre-filled, sterile, single-use syringes and is designed for application at only one-week intervals.

There have been important, positive findings reported by physicians using Excellagen as part of Cardium's physician sampling, patient outreach and market "seeding" programs. In several case studies, physicians reported a rapid onset of the growth of granulation tissue in a wide array of wounds, including non-healing diabetic foot ulcers (consistent with the results of Cardium's Matrix clinical study), as well as pressure ulcers, venous ulcers and Mohs surgical wounds. In certain cases, rapid granulation tissue growth and wound closure have been achieved with Excellagen following unsuccessful treatment with other advanced wound care approaches. From a dermatology perspective, a previously unexplored vertical market, remarkable healing responses have been observed following Mohs surgery for patients diagnosed with squamous and basal cell carcinomas, including deep surgical wounds extending to the periosteum (a membrane that lines the outer surface of bones). Additionally, because of the easy-use and platelet activating capacity, physicians have been employing Excellagen in severe non-healing wounds at near-amputation status, in combination with autologous platelet-rich plasma therapy and collagen sheet products. These case studies and positive physician feedback provide additional support of Excellagen's potential utility as an important new tool to help promote the wound healing process. Excellagen case studies are available at http://www.excellagen.com/surgical-wounds.html.

About Cardium

Cardium is an asset-based health sciences and regenerative medicine company focused on the acquisition and strategic development of innovative products and businesses with the potential to address significant unmet medical needs and having definable pathways to commercialization, partnering or other economic monetizations. Cardium's current portfolio includes LifeAgain medical data analytics, Tissue Repair Company, Cardium Biologics, and the Company's To Go Brands nutraceutical business. The Company's lead commercial product, Excellagen topical gel for wound care management, has received FDA clearance for marketing and sale in the United States. Cardium's lead clinical development product candidate Generx is a DNA-based angiogenic biologic intended for the treatment of patients with myocardial ischemia due to coronary artery disease. To Go Brands develops, markets and sells dietary supplements through established regional and national retailers. In addition, consistent with its capital-efficient business model, Cardium continues to actively evaluate new technologies and business opportunities. For more information, visit http://www.cardiumthx.com.

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Cardium Reports On Potential Use Of Excellagen To Repair Prenatally Diagnosed Birth Defects Using Mesenchymal Stem Cells

Stem cells to mass-produce cancer-killing treatment

Monday, August 12, 2013

Stem cell technology can be used to mass-produce cancer-killing immune cells designed to target different kinds of tumour, scientists have shown.

By John von Radowitz

But in practice, T-cells that target and kill cancer cells while ignoring healthy cells are very rare, and progress towards immune-based cancer treatments has been limited.

The new approach provides a way to reprogramme T-cells and create large numbers of them off the shelf primed to attack specific cancers.

A small number of healthy human T-cells were first reprogrammed into malleable stem cells with embryonic properties, US scientists reported in the journal Nature Biotechnology.

These induced pluripotent stem cells were then engineered to produce a tumour-specific receptor molecule on their surfaces.

Finally, the stem cells were coaxed to reacquire their original T-cell properties while expanding to large numbers.

Each of the T-cells now had the all-important receptor that allowed it to target a particular cancer antigen or protein, in this case lymphoma.

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Stem cells to mass-produce cancer-killing treatment

People suffering from cancer have been given fresh hope after scientists revealed that stem cell technology can be used to mass-produce cancer-killing immune cells.

The research shows that it could treat all kinds of tumours, and opens up the prospect of immunotherapy treatments helping many more cancer patients in the future.

In theory cancer can be tackled by elements of the body's own immune defences, especially white blood cells called T-cells.

But in practice, T-cells that target and kill cancer cells while ignoring healthy cells are very rare, and progress towards immune-based cancer treatments has been limited.

The new approach provides a way to reprogramme T-cells and create large numbers of them "off the shelf" primed to attack specific cancers.

A small number of healthy human T-cells were first reprogrammed into malleable stem cells with embryonic properties, US scientists reported in the journal Nature Biotechnology.

These induced pluripotent stem cells (iPScs) were then engineered to produce a tumour-specific receptor molecule on their surfaces.

Finally, the stem cells were coaxed to re-acquire their original T-cell properties while expanding to large numbers.

Kody Grode, 24, told her best friend of nine years and colleagues at a local daycare that she had stage-three ovarian cancer. Grode allegedly grifted over $2,000 before being caught. Grode has been sentenced to 90 days in jail. Read the full story here.

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How Stem Cells Can Be Used To Fight Cancer

Medical science has progressed by leaps and bounds with the advent of stem cell therapy. Stem cell is a generic cell that has the potential to become many types of specialised cells for the treatment of a wide range of diseases.

In stem cell treatment, the damaged tissues of the diseased part are replaced by new adult cells. Stem cells have the potential to divide and grow into multiple tissues and regenerate natural organs.

Stem cell therapy is the new realm of regenerative medicine for Diabetes Type 1, wound healing, Parkinson's, spinal cord injury, MI, MS, and many other terminal conditions.

Who can become a Stem Cell Therapist?

From a chief scientific officer to a lab assistant, opportunities are many for medical and non-medical students. There is a prevalent misconception that only medical professionals can become a stem cell therapist. In fact, stem cells cover a lot of ground, from molecular biology and biotechnology to cell transplantation and therapy. It means that people can come into stem cell biology from more or less any field. Candidates skilled in imaging are also eligible to become stem cells researchers or therapists.

As there is always need for more tools, an electrical engineer with knowledge of biology could also develop tools for in vitro or in vivo analysis of stem cells. But he should also have a complete understanding of cellular and molecular biology.

This emerging branch of biomedicine needs quality and trained manpower. Therefore, there is plenty of room for trained scientists.

Despite the specialisation, stem cell research requires the basics, as well. Therefore a stem cell therapist needs to have core knowledge of cellular and molecular biology understanding the lab techniques and the analytical approaches.

Multiple career option

Students have the option of pursuing courses such as M.Sc. in biotechnology, biochemistry, genetics, zoology, biophysics, microbiology and life sciences and M.Sc. regenerative. After completing the degree course, they have various options of quality check, research and development, production, clinical research, supply chain and human resources besides finance and other administrative functions.

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Looking for a cure with stem cells