Jan. 23, 2014 Stem cells can turn into heart cells, skin cells can mutate to cancer cells; even cells of the same tissue type exhibit small heterogeneities. Scientists use single-cell analyses to investigate these heterogeneities. But the method is still laborious and considerable inaccuracies conceal smaller effects. Scientists at the Helmholtz Zentrum Muenchen, at the Technische Unitversitaet Muenchen and the University of Virginia (USA) have now found a way to simplify and improve the analysis by mathematical methods.

Each cell in our body is unique. Even cells of the same tissue type that look identical under the microscope differ slightly from each other. To understand how a heart cell can develop from a stem cell, why one beta-cell produces insulin and the other does not, or why a normal tissue cell suddenly mutates to a cancer cell, scientists have been targeting the activities of ribonucleic acid, RNA.

Proteins are constantly being assembled and disassembled in the cell. RNA molecules read blueprints for proteins from the DNA and initiate their production. In the last few years scientists around the world have developed sequencing methods that are capable of detecting all active RNA molecules within a single cell at a certain time.

At the end of December 2013 the journal Nature Methods declared single-cell sequencing the "Method of the Year." However, analysis of individual cells is extremely complex, and the handling of the cells generates errors and inaccuracies. Smaller differences in gene regulation can be overwhelmed by the statistical "noise."

Scientists led by Professor Fabian Theis, Chair of Mathematical modeling of biological systems at the Technische Universitaet Muenchen and director of the Institute of Computational Biology at the Helmholtz Zentrum Muenchen, have now found a way to considerably improve single-cell analysis by applying methods of mathematical statistics.

Instead of just one cell, they took 16-80 samples with ten cells each. "A sample of ten cells is much easier to handle," says Professor Theis. "With ten times the amount of cell material, the influences of ambient conditions can be markedly suppressed." However, cells with different properties are then distributed randomly on the samples. Therefore Theis's collaborator Christiane Fuchs developed statistical methods to still identify the single-cell properties in the mixture of signals.

On the basis of known biological data, Theis and Fuchs modeled the distribution for the case of genes that exhibit two well-defined regulatory states. Together with biologists Kevin Janes and Sameer Bajikar at the University of Virginia in Charlottesville (USA), they were able to prove experimentally that with the help of statistical methods samples containing ten cells deliver results of higher accuracy than can be achieved through analysis of the same number of single cell samples.

In many cases, several gene actions are triggered by the same factor. Even in such cases, the statistical method can be applied successfully. Fluorescent markers indicate the gene activities. The result is a mosaic, which again can be checked to spot whether different cells respond differently to the factor.

The method is so sensitive that it even shows one deviation in 40 otherwise identical cells. The fact that this difference actually is an effect and not a random outlier could be proven experimentally.

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Tracing unique cells with mathematics

8 hours ago Endodermal cells, they form organs such as lung, liver and pancreas. Credit: IDR, Helmholtz Zentrum Mnchen

The Wnt/-catenin signaling pathway and microRNA 335 are instrumental in helping form differentiated progenitor cells from stem cells. These are organized in germ layers and are thus the origin of different tissue types, including the pancreas and its insulin-producing beta cells. With these findings, Helmholtz Zentrum Mnchen scientists have discovered key molecular functions of stem cell differentiation which could be used for beta cell replacement therapy in diabetes. The results of the two studies were published in the renowned journal Development.

The findings of the scientists of the Institute of Diabetes and Regeneration Research (IDR) at Helmholtz Zentrum Mnchen (HMGU) provide new insights into the molecular regulation of stem cell differentiation. These results reveal important target structures for regenerative therapy approaches to chronic diseases such as diabetes.

During embryonic development, organ-specific cell types are formed from pluripotent stem cells, which can differentiate into all cell types of the human body. The pluripotent cells of the embryo organize themselves at an early stage in germ layers: the endoderm, mesoderm and ectoderm. From these three cell populations different functional tissue cells arise, such as skin cells, muscle cells, and specific organ cells.

Various signaling pathways are important for this germ layer organization, including the Wnt/-catenin signaling pathway. The cells of the pancreas, such as the beta cells, originate from the endoderm, the germ layer from which the gastrointestinal tract, the liver and the lungs also arise. Professor Heiko Lickert, director of the IDR, in collaboration with Professor Gunnar Schotta of LMU Mnchen, showed that the Wnt/-catenin signaling pathway regulates Sox17, which in turn regulates molecular programs that assign pluripotent cells to the endoderm, thus inducing an initial differentiation of the stem cells.

In another project Professor Lickert and his colleague Professor Fabian Theis, director of the Institute of Computational Biology (ICB) at Helmholtz Zentrum Mnchen, discovered an additional mechanism that influences the progenitor cells. miRNA-335, a messenger nucleic acid, regulates the endodermal transcription factors Sox17 and Foxa2 and is essential for the differentiation of cells within this germ layer and their demarcation from the adjacent mesoderm. The concentrations of the transcription factors determine here whether these cells develop into lung, liver or pancreas cells. To achieve these results, the scientists combined their expertise in experimental research with mathematical modeling.

"Our findings represent two key processes of stem cell differentiation," said Lickert. "With an improved understanding of cell formation we can succeed in generating functional specialized cells from stem cells. These could be used for a variety of therapeutic approaches. In diabetes, we may be able to replace the defective beta cells, but regenerative medicine also offers new therapeutic options for other organ defects and diseases."

Diabetes is characterized by a dysfunction of the insulin-producing beta cells of the pancreas. Regenerative treatment approaches aim to renew or replace these cells. An EU-funded research project ('HumEn'), in which Lickert and his team are participating, shall provide further insights in the field of beta-cell replacement therapy.

The aim of research at Helmholtz Zentrum Mnchen, a partner in the German Center for Diabetes Research (DZD), is to develop new approaches for the diagnosis, treatment and prevention of major common diseases such as diabetes mellitus.

Explore further: Stem cells on the road to specialization

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Insulin-producing beta cells from stem cells: Scientists decipher early molecular mechanisms of differentiation

Jan. 23, 2014 The Wnt/-catenin signaling pathway and microRNA 335 are instrumental in helping form differentiated progenitor cells from stem cells. These are organized in germ layers and are thus the origin of different tissue types, including the pancreas and its insulin-producing beta cells. With these findings, Helmholtz Zentrum Mnchen scientists have discovered key molecular functions of stem cell differentiation which could be used for beta cell replacement therapy in diabetes. The results of the two studies were published in the journal Development.

The findings of the scientists of the Institute of Diabetes and Regeneration Research (IDR) at Helmholtz Zentrum Mnchen (HMGU) provide new insights into the molecular regulation of stem cell differentiation. These results reveal important target structures for regenerative therapy approaches to chronic diseases such as diabetes.

During embryonic development, organ-specific cell types are formed from pluripotent stem cells, which can differentiate into all cell types of the human body. The pluripotent cells of the embryo organize themselves at an early stage in germ layers: the endoderm, mesoderm and ectoderm. From these three cell populations different functional tissue cells arise, such as skin cells, muscle cells, and specific organ cells.

Various signaling pathways are important for this germ layer organization, including the Wnt/-catenin signaling pathway. The cells of the pancreas, such as the beta cells, originate from the endoderm, the germ layer from which the gastrointestinal tract, the liver and the lungs also arise. Professor Heiko Lickert, director of the IDR, in collaboration with Professor Gunnar Schotta of LMU Mnchen, showed that the Wnt/-catenin signaling pathway regulates Sox17, which in turn regulates molecular programs that assign pluripotent cells to the endoderm, thus inducing an initial differentiation of the stem cells. In another project Professor Lickert and his colleague Professor Fabian Theis, director of the Institute of Computational Biology (ICB) at Helmholtz Zentrum Mnchen, discovered an additional mechanism that influences the progenitor cells. miRNA-335, a messenger nucleic acid, regulates the endodermal transcription factors Sox17 and Foxa2 and is essential for the differentiation of cells within this germ layer and their demarcation from the adjacent mesoderm. The concentrations of the transcription factors determine here whether these cells develop into lung, liver or pancreas cells. To achieve these results, the scientists combined their expertise in experimental research with mathematical modeling.

"Our findings represent two key processes of stem cell differentiation," said Lickert. "With an improved understanding of cell formation we can succeed in generating functional specialized cells from stem cells. These could be used for a variety of therapeutic approaches. In diabetes, we may be able to replace the defective beta cells, but regenerative medicine also offers new therapeutic options for other organ defects and diseases."

Diabetes is characterized by a dysfunction of the insulin-producing beta cells of the pancreas. Regenerative treatment approaches aim to renew or replace these cells. An EU-funded research project ('HumEn'), in which Lickert and his team are participating, shall provide further insights in the field of beta-cell replacement therapy.

The aim of research at Helmholtz Zentrum Mnchen, a partner in the German Center for Diabetes Research (DZD), is to develop new approaches for the diagnosis, treatment and prevention of major common diseases such as diabetes mellitus.

Read more here:
Insulin-producing beta cells from stem cells

Stem cells can turn into heart cells, skin cells can mutate to cancer cells; even cells of the same tissue type exhibit small heterogeneities. Scientists use single-cell analyses to investigate these heterogeneities. But the method is still laborious and considerable inaccuracies conceal smaller effects. Scientists at the Technische Universitaet Muenchen (TUM), the Helmholtz Zentrum Muenchen and the University of Virginia (USA) have now found a way to simplify and improve the analysis by mathematical methods.

Each cell in our body is unique. Even cells of the same tissue type that look identical under the microscope differ slightly from each other. To understand how a heart cell can develop from a stem cell, why one beta-cell produces insulin and the other does not, or why a normal tissue cell suddenly mutates to a cancer cell, scientists have been targeting the activities of ribonucleic acid, RNA.

Proteins are constantly being assembled and disassembled in the cell. RNA molecules read blueprints for proteins from the DNA and initiate their production. In the last few years scientists around the world have developed sequencing methods that are capable of detecting all active RNA molecules within a single cell at a certain time.

At the end of December 2013 the journal Nature Methods declared single-cell sequencing the "Method of the Year." However, analysis of individual cells is extremely complex, and the handling of the cells generates errors and inaccuracies. Smaller differences in gene regulation can be overwhelmed by the statistical "noise."

Easier And More Accurate, Thanks To Statistics

Scientists led by Professor Fabian Theis, Chair of Mathematical modeling of biological systems at the Technische Universitaet Muenchen and director of the Institute of Computational Biology at the Helmholtz Zentrum Muenchen, have now found a way to considerably improve single-cell analysis by applying methods of mathematical statistics.

Instead of just one cell, they took 16-80 samples with ten cells each. "A sample of ten cells is much easier to handle," says Professor Theis. "With ten times the amount of cell material, the influences of ambient conditions can be markedly suppressed." However, cells with different properties are then distributed randomly on the samples. Therefore Theis's collaborator Christiane Fuchs developed statistical methods to still identify the single-cell properties in the mixture of signals.

Combining Model and Experiment

On the basis of known biological data, Theis and Fuchs modeled the distribution for the case of genes that exhibit two well-defined regulatory states. Together with biologists Kevin Janes and Sameer Bajikar at the University of Virginia in Charlottesville (USA), they were able to prove experimentally that with the help of statistical methods samples containing ten cells deliver results of higher accuracy than can be achieved through analysis of the same number of single cell samples.

In many cases, several gene actions are triggered by the same factor. Even in such cases, the statistical method can be applied successfully. Fluorescent markers indicate the gene activities. The result is a mosaic, which again can be checked to spot whether different cells respond differently to the factor.

Read the original:
Statistical Methods Improve Biological Single-Cell Analyses

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The bodys signals govern skin stem cells, controlling the decision to remain dormant, divide or differentiate (become normal, active tissue cells). Signals flow in path-ways and multiple paths funnel into the common Wnt signaling pathway. Signaling stimulatesskin stem cells to begin the process leading to fibroblasts, keratino-

cytesand other dermal/epidermalcells.

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Makucell - Best Anti Aging Skin Care

Jan. 19, 2014 Normally, tissue injury triggers a mechanism in cells that tries to repair damaged tissue and restore the skin to a normal, or homeostatic state. Errors in this process can give rise to various problems, such as chronic inflammation, which is a known cause of certain cancers.

"It has been noted that cancer resembles a state of chronic wound healing, in which the wound-healing program is erroneously activated and perpetuated," says Professor Adrian Krainer of Cold Spring Harbor Laboratory (CSHL). In a paper published today in Nature Structural & Molecular Biology, a team led by Dr. Krainer reports that a protein they show is normally involved in healing wounds and maintaining homeostasis in skin tissue is also, under certain conditions, a promoter of invasive and metastatic skin cancers.

The protein, called SRSF6, is what biologists call a splicing factor: it is one of many proteins involved in an essential cellular process called splicing. In splicing, an RNA "message" copied from a gene is edited so that it includes only the portions needed to instruct the cell how to produce a specific protein. The messages of most genes can be edited in multiple ways, using different splicing factors; thus, a single gene can give rise to multiple proteins, with distinct functions.

The SRSF6 protein, while normally contributing to wound healing in skin tissue, when overproduced can promote abnormal growth of skin cells and cancer, Krainer's team demonstrated in experiments in mice. Indeed, they determined the spot on a particular RNA message -- one that encodes the protein tenascin C -- where SRSF6 binds abnormally, giving rise to alternate versions of the tenascin C protein that are seen in invasive and metastatic cancers.

The CSHL team also found that overproduction of SRSF6 in mice results in the depletion of a type of stem cell called Lgr6+. These skin stem cells reside in the upper part of the hair follicle and participate in wound healing when tissue is damaged. Thus, aberrant alternative splicing by SRSF6 on the one hand increases cell proliferation, but on the other hand prevents the process by which proliferating cells mature. "The cells remain in an abnormal activation state that would otherwise be temporary during normal tissue repair. More studies are needed to understand this phenomenon in detail," says Mads Jensen, Ph.D., first author of the new paper who performed the experiments as a postdoctoral researcher in the Krainer lab.

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Overexpression of splicing protein in skin repair causes early changes seen in skin cancer

Durham, NC (PRWEB) January 17, 2014

A new assessment tool is helping scientists determine which treatments might benefit patients with a type of eye disorder called limbal stem cell deficiency (LSCD). The tool, developed by researchers at University College London and Moorfields Eye Hospital in London and funded by the UKs National Institute for Health Research Biomedical Research Centre at these institutions, has already shown that the majority of these patients can benefit in the short term from a stem cell transplantation and up to 30 percent are still experiencing better sight three years later, according to the study published in the current issue of STEM CELLS Translational Medicine.

LSCD is an eye disorder in which the stem cells responsible for forming the surface skin of the cornea are destroyed by injury or disease. This results in pain, loss of vision and a cosmetically unpleasant appearance. Many new treatments, including limbal stem cell transplants, are emerging for this condition but their effectiveness remains to be proven.

Assessing how well they perform has been severely hampered by the lack of biomarkers for LSCD and/or validated tools for determining its severity, said Alex Shortt, M.D., Ph.D., of University College Londons Institute of Ophthalmology and lead investigator in the study. In virtually all studies of limbal stem cell transplantation to date the clinical outcome has been assessed subjectively by the investigating clinician. This is clearly open to significant measurement and reporting bias.

His teams aims, then, were to design and test the reliability of a new tool for grading LSCD, to define a set of core outcome measures to use in evaluating treatments and to demonstrate the treatments impact on two common types of LSCD: a genetic disorder called aniridia and Stevens-Johnson syndrome (SJS), an inflammatory disorder.

They began developing an assessment tool by paring down a list of clinical signs taken from previously published studies to four key LSCD indicators: corneal epithelial haze, superficial corneal neovascularization, corneal epithelial irregularity and corneal epithelial defect. A standardized grading plate was then produced for each of these parameters, ranging from normal to severe. They named their assessment method the Clinical Outcome Assessment in Surgical Trials of Limbal stem cell deficiency [COASTL] tool and validated its performance in 26 patients with varying degrees of LSCD.

Once they had the COASTL tool in place, they used it to evaluate treatment outcomes in 14 patients with aniridia or SJS. All had undergone a limbal epithelial transplantation (allo-CLET), using cells taken from a deceased donor, cultivated in the lab before being transplanted into the recipient.

The COASTL tool showed that following allo-CLET there was a decrease in LSCD severity and an increase in visual acuity up to 12 months post-treatment, but thereafter LSCD severity and visual acuity progressively deteriorated, Dr. Shortt said. However, despite a recurrence of clinical signs, the visual benefit persisted in 30 percent of aniridic and 25 percent of SJS patients at 36 months.

A reliable method of obtaining objective outcome data for surgical trials of limbal stem cell deficiency will greatly contribute to the effective evaluation of current and new treatments, said Anthony Atala, M.D., editor of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine.

The full article, Three-Year Outcomes of Cultured Limbal Epithelial Allografts in Aniridia and Stevens-Johnson Syndrome Evaluated Using the Clinical Outcome Assessment in Surgical Trials Assessment Tool, can be accessed at http://www.stemcellstm.com.

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New Assessment Tool Shows Potential of Stem Cells in Restoring LSCD Patients’ Sight

Jan. 16, 2014 The human body is daily exposed to external assaults such as bacteria, ultraviolet light or chemical agents. Skin, the largest organ of the body, is the first line of defense against these agents. Skin performs this function thanks to the close connections established between its cells (e.g. adherens junctions). The loss of cell adhesion between these cells is related to inflammatory diseases and cancer, hence the special interest in this area of research over the past years.

A study by the Spanish National Cancer Research Centre (CNIO), featured on the cover of the Journal of Cell Biology, shows how interactions between skin stem cells -- the cells responsible for the constant renewal of skin -- maintain the architecture of this organ. "We knew that these junctions were important in skin stem cells but the cellular components involved in their structure and function were not yet understood," says Mirna Prez-Moreno, head of the Epithelial Cellular Biology Group that led the study.

Using skin cells derived from mice, researchers have discovered that one of the key elements in the formation and stabilisation of these junctions are microtubules, tubular structures that are part of all cells and that serve as pillars to maintain their form and function.

"We have seen for the first time that skin stem-cell microtubules connect with cell-cell junctions to form velcro-like structures that hold the cells together," says Marta Shahbazi, a researcher on Prez-Moreno's team and the first author of the study.

The connection between these two cellular components -- microtubules and cell-cell junctions -- occurs via the interaction between the CLASP2 and p120 catenin proteins, linked to microtubules and cell junctions respectively.

"We found that the abscence of CLASP2 or p120 catenin in epidermal stem cells caused a loss of their adhesion, and therefore the structure of these cells," says Shahbazi.

"Our results will open up new paths for exploring how these proteins regulate skin physiology," says Prez-Moreno, adding that this knowledge will be "important for the possible development of future regenerative or anti cancer therapies."

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'Molecular scaffolding' found that maintains skin structure, organization

Stem cells have made headlines in the scientific and medical realms for over a decade, and with good reason. Some can grow into any type of cell in the body. The therapeutic potential is staggering, and researchers are working towards using stem cells to treat everything from diabetes to spinal cord injuries.

More recently, stem cell has emerged as a cosmetics industry buzzword, cropping up in product names, claims and ingredient lists. Stem cells seem ideal for anti-aging skincare, and stem cell products allude to stimulating the skin to grow new, younger cells and reverse wrinkling.

Despite products with names such as Stem Cell Therapy and StemCellin, or ingredients that include stem cell extract and stem cell conditioned media, none of the beauty creams actually contain stem cells. And, none are proven to affect your own stem cells.

MORE: The First Anti-Wrinkle Pill?

So, whats going on here? Whats in these products, if not stem cells? YouBeauty explains whats inside, why it could be dangerous and how stem cell beauty companies are skimping on science.

Meet the Stem Cells

Before we delve into the beauty creams, a brief biology lesson. Stem cells come in several varieties: embryonic (ESC), adult (ASC), induced pluripotent (iPSC) and human parthenogenetic (hpSC). All can develop into other cell types, or differentiate, but not all are created equal. And, just two relate to stem cell beauty products.

In research, ESCs come from embryos that are made from an egg fertilized outside the body, in vitro. Embryos develop from just a small cluster of cells into an entire body, thus ESCs have the potential to differentiate into nearly all cell types, from brain to heart to liver. This quality, called pluriopotency, means they could potentially be used to treat any type of diseased or injured organ or tissue.

QUIZ: How Healthy is Your Skin?

ESCs, besides being difficult to grow, face an ethical quandary: using them destroys embryos, which is why theyve ignited in political debate. In the past few years, researchers introduced two methods that attempt to mimic ESCs pluripotency sans embryo, which could eventually avoid these thorny issues. One uses a cocktail of genes to reprogram differentiated cells back into an ESC-like state (iPSC). The other uses human parthenogenetic (translation: virgin birth) embryos, which come from non-fertilized eggs, but retain some characteristics of a normal embryo (hpSC). But, ongoing research must confirm the characteristics and safety of both cell types before they can replace ESC in research. Theres a long way to go.

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Stem Cells in Skincare - YouBeauty.com

16 hours ago Mutant epidermal stem cells lose the connections to their neighbours (red, right) compared to normal stem cells (red, left). Credit: CNIO

The human body is daily exposed to external assaults such as bacteria, ultraviolet light or chemical agents. Skin, the largest organ of the body, is the first line of defense against these agents. Skin performs this function thanks to the close connections established between its cells (e.g. adherens junctions). The loss of cell adhesion between these cells is related to inflammatory diseases and cancer, hence the special interest in this area of research over the past years.

A study by the Spanish National Cancer Research Centre (CNIO), featured on the cover of the Journal of Cell Biology, shows how interactions between skin stem cellsthe cells responsible for the constant renewal of skinmaintain the architecture of this organ. "We knew that these junctions were important in skin stem cells but the cellular components involved in their structure and function were not yet understood", says Mirna Prez-Moreno, head of the Epithelial Cellular Biology Group that led the study.

Using skin cells derived from mice, researchers have discovered that one of the key elements in the formation and stabilisation of these junctions are microtubules, tubular structures that are part of all cells and that serve as pillars to maintain their form and function.

"We have seen for the first time that skin stem-cell microtubules connect with cell-cell junctions to form velcro-like structures that hold the cells together", says Marta Shahbazi, a researcher on Prez-Moreno's team and the first author of the study.

The connection between these two cellular componentsmicrotubules and cell-cell junctionsoccurs via the interaction between the CLASP2 and p120 catenin proteins, linked to microtubules and cell junctions respectively.

"We found that the abscence of CLASP2 or p120 catenin in epidermal stem cells caused a loss of their adhesion, and therefore the structure of these cells", says Shahbazi.

"Our results will open up new paths for exploring how these proteins regulate skin physiology", says Prez-Moreno, adding that this knowledge will be "important for the possible development of future regenerative or anti cancer therapies".

Explore further: Adult stem cells found to suppress cancer while dormant

Journal reference: Journal of Cell Biology

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Study finds a 'molecular scaffolding' that maintains skin structure and organisation

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Newswise While the ability of human embryonic stem cells (hESCs) to become any type of mature cell, from neuron to heart to skin and bone, is indisputably crucial to human development, no less important is the mechanism needed to maintain hESCs in their pluripotent state until such change is required.

In a paper published in this weeks Online Early Edition of PNAS, researchers from the University of California, San Diego School of Medicine identify a key gene receptor and signaling pathway essential to doing just that maintaining hESCs in an undifferentiated state.

The finding sheds new light upon the fundamental biology of hESCs with their huge potential as a diverse therapeutic tool but also suggests a new target for attacking cancer stem cells, which likely rely upon the same receptor and pathway to help spur their rampant, unwanted growth.

The research, led by principal investigator Karl Willert, PhD, assistant professor in the Department of Cellular and Molecular Medicine, focuses upon the role of the highly conserved WNT signaling pathway, a large family of genes long recognized as a critical regulator of stem cell self-renewal, and a particular encoded receptor known as frizzled family receptor 7 or FZD7.

WNT signaling through FZD7 is necessary to maintain hESCs in an undifferentiated state, said Willert. If we block FZD7 function, thus interfering with the WNT pathway, hESCs exit their undifferentiated and pluripotent state.

The researchers proved this by using an antibody-like protein that binds to FZD7, hindering its function. Once FZD7 function is blocked with this FZD7-specific compound, hESCs are no longer able to receive the WNT signal essential to maintaining their undifferentiated state.

FZD7 is a so-called onco-fetal protein, expressed only during embryonic development and by certain human tumors. Other studies have suggested that FZD7 may be a marker for cancer stem cells and play an important role in promoting tumor growth. If so, said Willert, disrupting FZD7 function in cancer cells is likely to interfere with their development and growth just as it does in hESCs.

Willert and colleagues, including co-author Dennis Carson, MD, of the Sanford Consortium for Regenerative Medicine and professor emeritus at UC San Diego, plan to further test their FZD7-blocking compound as a potential cancer treatment.

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Keeping Stem Cells Pluripotent

Abstract

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

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

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

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

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

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

Epidermal development and hair follicle morphogenesis. The surface of the early embryo is covered by a single layer of ectodermal cells that adheres to an underlying basement membrane of extracellular matrix. As development proceeds, the epidermis progressively ...

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

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

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Epidermal Stem Cells of the Skin

PUBLIC RELEASE DATE:

9-Jan-2014

Contact: Robert Miranda cogcomm@aol.com Cell Transplantation Center of Excellence for Aging and Brain Repair

Putnam Valley, NY. (Jan. 9, 2014) Using skin-derived stem cells (SDSCs) and a previously developed collagen tube designed to successfully bridge gaps in injured nerves in rat models, the research team in Milan, Italy that established and tested the procedure has successfully rescued peripheral nerves in the upper arms of a patient suffering peripheral nerve damage who would have otherwise had to undergo amputations.

The study will be published in a future issue of Cell Transplantation but is currently freely available on-line as an unedited early e-pub at: http://www.ingentaconnect.com/content/cog/ct/pre-prints/content-ct1096.

"Peripheral nerve repair with satisfactory functional recovery remains a great surgical challenge, especially for severe nerve injuries resulting in extended nerve defects," said study corresponding author Dr. Yvan Torrente, of the Department of Pathophysiology and Transplantation at the University of Milan. "However, we hypothesized that the combination of autologous (self-donated) SDSCs placed in collagen tubes to bridge gaps in the damaged nerves would restore the continuity of injured nerves and save from amputation the upper arms of a patient with poly-injury to motor and sensory nerves."

Although autologous nerve grafting has been the 'gold standard' for reconstructive surgeries, these researchers felt that there were several drawbacks to that approach, including graft availability, donor site morbidity, and neuropathic pain.

According to the researchers, autologous SDSCs have advantages over other stem cells as they are an accessible source of stem cells rapidly expandable in culture, and capable of survival and integration within host tissues.

While the technique of using the collagen tubes - NeuraGen, an FDA-approved device - to guide the transplanted cells over gaps in the injured nerve had been previously developed and tested by the same researchers with the original research successfully saving damaged sciatic nerves on rats, the present case, utilizing the procedure they developed employing SDSCs and a nerve guide, is the first to be carried out on a human.

Over three years, the researchers followed up on the patient, assessing functional recovery of injured median and ulnar nerves by pinch gauge test and static two-point discrimination and touch test with monofiliments along with electrophysiological and MRI examinations.

Originally posted here:
Stem cells injected into nerve guide tubes repair injured peripheral nerve

18 hours ago This is a set of chromosomes in haploid mouse embryonic stem cells. Credit: Martin Leeb

A fast and comprehensive method for determining the function of genes could greatly improve our understanding of a wide range of diseases and conditions, such as heart disease, liver disease and cancer.

The method uses stem cells with a single set of chromosomes, instead of the two sets found in most cells, to reveal what causes the "circuitry" of stem cells to be rewired as they begin the process of conversion into other cell types. The same method could also be used to understand a range of biological processes.

Embryonic stem cells rely on a particular gene circuitry to retain their original, undifferentiated state, making them self-renewing. The dismantling of this circuitry is what allows stem cells to start converting into other types of cells - a process known as cell differentiation - but how this happens is poorly understood.

Researchers from the University of Cambridge Wellcome Trust-MRC Stem Cell Institute have developed a technique which can pinpoint the factors which drive cell differentiation, including many that were previously unidentified. The method, outlined in the Thursday (9 January) edition of the journal Cell Stem Cell, uses stem cells with a single set of chromosomes to uncover how cell differentiation works.

Cells in mammals contain two sets of chromosomes one set inherited from the mother and one from the father. This can present a challenge when studying the function of genes, however: as each cell contains two copies of each gene, determining the link between a genetic change and its physical effect, or phenotype, is immensely complex.

"The conventional approach is to work gene by gene, and in the past people would have spent most of their careers looking at one mutation or one gene," said Dr Martin Leeb, who led the research, in collaboration with Professor Austin Smith. "Today, the process is a bit faster, but it's still a methodical gene by gene approach because when you have an organism with two sets of chromosomes that's really the only way you can go."

Dr Leeb used unfertilised mouse eggs to generate embryonic stem cells with a single set of chromosomes, known as haploid stem cells. These haploid cells show all of the same characteristics as stem cells with two sets of chromosomes, and retain the same full developmental potential, making them a powerful tool for determining how the genetic circuitry of mammalian development functions.

The researchers used transposons "jumping genes" to make mutations in nearly all genes. The effect of a mutation can be seen immediately in haploid cells because there is no second gene copy. Additionally, since embryonic stem cells can convert into almost any cell type, the haploid stem cells can be used to investigate any number of conditions in any number of cell types. Mutations with important biological effects can then rapidly be traced to individual genes by next generation DNA sequencing.

"This is a powerful and revolutionary new tool for discovering how gene circuits operate," said Dr Leeb. "The cells and the methodology we've developed could be applied to a huge range of biological questions."

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Rewiring stem cells

Stem cell technology in skin care is relativity new to most skin care consumers, while consumers are keen to have new technology as part of their skin care regime, cosmeceutical companies have taken a very in-depth approach to educating their clients on everything stem cell.

Dermelect who are based in New York, have a complete line of skincare stem cell technology whereby each product links and connects to the next, covering all the aspects of skincare a client asks for. Key ingredients across the three products are Alpine Rose, AHA, Mushroom Extract, Algisium C, Ecoskin and Vitamin C.

Reconstruction, regeneration and firmness to begin with the first product in this series in Dermelect Resurface Stem Cell Reconstructing Serum, this serum utilizes the extracted stem cells of the Swiss Alpine Rose, this stem cell works well when the skin is subject to high oxidative, UV stress and environment aggressors. Consider your living and working environment where unseen free radicals are roaming in the atmosphere, reconstruction serum will boost the facial skin stem activity to stimulate the skins protein production.

Post Dermelect Resurface Stem Cell Reconstructing Serum, there is a rich treatment cream Dermelect Resilient Stem Cell Regenerating Treatment that works on the providing a barrier against damaging factors that attack the skins cells ,that try to break down the stem cell production. This luxurious cream has the potential to reverse skin damage as it works to stimulate new skin from the stem cell reservoirs.

At this point in the treatment the stem cells increase their potency to promote cell regenerating, so that tissue is reconstructed to a denser quality and a more elastic skin. In the anti aging skin care lines gaining a better skin density can bring back a more youthful look.

Post Dermelect Resilient Stem Cell Regenerating Treatment, is followed by Dermelect Resurgent Stem Cell Firming Activator this acts as a finishing application to promote stem cell protection, while the activator continues to prevent further free radical damage. Each layer that is easily absorbed into the skin is applied in the gentle circular motion in the morning and evening, each product in the series is light to the touch, but packed with active ingredients.

The founder of Dermelect Cosmeceuticals, Amos Lavian considered the exaggerated claims and prices in skincare when he put together the Dermelect line, Lavian comments We do not exaggerate about benefits nor do we make outrageous claims. We give you an honest approach to skincare with cutting edge ingredients, excellent delivery systems and innovative treatments that focus on targeted solutions of key areas of concern. We empower you with the tools to be more confident in your appearance and to elevate your self-esteem.

The Dermelect line can be experienced in New York at C.O Bigelow 414 6 Avenue New York, NY 10011-8495. It s worth reviewing the Dermelect web site to see the depth of research and knowledge they offer their clients on stem cell skincare.

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Dermelect cosmeceuticals stem cells to reconstruct, regenerate ...

Researchers have developed a new way to study bone disorders and bone growth, using stem cells from patients afflicted with a rare, genetic bone disease. The approach, based on Nobel-Prize winning techniques, could illuminate the illness, in which muscles and tendons progressively turn into bone, and addresses the similar destructive process that afflicts a growing number of veterans who have suffered blast injuries including traumatic amputations or injuries to the brain and nervous system. This insidious hardening of tissues also grips some patients following joint replacement or severe bone injuries.

The disease model, described in a new study by a UC San Francisco-led team, involves taking skin cells from patients with the bone disease, reprogramming them in a lab dish to their embryonic state, and deriving stem cells from them.

Edward Hsiao, MD, PhD

Once the team derived the stem cells, they identified a cellular mechanism that drives abnormal bone growth in the thus-far untreatable bone disease, calledfibrodysplasiaossificansprogressiva(FOP). Furthermore, they found that certain chemicals could slow abnormal bone growth in the stem cells, a discovery that might help guide future drug development.

Clinically, the genetic and trauma-caused conditions are very similar, with bone formation in muscle leading to pain and restricted movement, according to the leader of the new study, Edward Hsiao, MD, PhD, an endocrinologist who cares for patients with rare and unusual bone diseases at the UCSF Metabolic Bone Clinic in the Division of Endocrinology and Metabolism.

The human cell-based disease model is expected to lead to a better understanding of these disorders and other illnesses, Hsiao said.

The new FOP model already has shed light on the disease process in FOP by showing that the mutated gene can affect different steps of bone formation, Hsiao said. These different stages represent potential targets for limiting or stopping the progression of the disease, and may also be useful for blocking abnormal bone formation in other conditions besides FOP. The human stem-cell lines we developed will be useful for identifying drugs that target the bone-formation process in humans."

The teams development of, and experimentation with, the human stem-cell disease model for FOP, published in the December issue of theOrphanetJournal of Rare Diseases, is a realization of the promise of research using stem cells of the type known as induced pluripotent stem (iPS) cells, immortal cells of nearly limitless potential, derived not from embryos, but from adult tissues.

Shinya Yamanaka, MD, PhD, a UCSF professor of anatomy and a senior investigator with the UCSF-affiliated Gladstone Institutes, as well as the director of the Center foriPSCell Research and Application (CiRA) and a principal investigator at Kyoto University, shared the Nobel Prize in 2012 for discovering how to makeiPScells from skin cells using a handful of protein factors. These factors guide a reprogramming process that reverts the cells to an embryonic state, in which they have the potential to become virtually any type of cell.

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Stem Cells Used to Model Disease that Causes Abnormal Bone Growth

PUBLIC RELEASE DATE:

7-Jan-2014

Contact: David McKeon DMckeon@nyscf.org 212-365-7440 New York Stem Cell Foundation

NEW YORK, NY (January 7, 2014) Scientists at The New York Stem Cell Foundation (NYSCF) Research Institute, working in collaboration with scientists from Columbia University Medical Center (CUMC), for the first time generated induced pluripotent stem (iPS) cells lines from non-cryoprotected brain tissue of patients with Alzheimer's disease.

These new stem cell lines will allow researchers to "turn back the clock" and observe how Alzheimer's develops in the brain, potentially revealing the onset of the disease at a cellular level long before any symptoms associated with Alzheimer's are displayed. These reconstituted Alzheimer's cells will also provide a platform for drug testing on cells from patients that were definitively diagnosed with the disease. Until now, the only available method to definitively diagnose Alzheimer's disease that has been available to researchers is examining the brain of deceased patients. This discovery will permit scientists for the first time to compare "live" brain cells from Alzheimer's patients to the brain cells of other non-Alzheimer's patients.

NYSCF scientists successfully produced the iPS cells from frozen tissue samples stored for up to eleven years at the New York Brain Bank at Columbia University.

This advance, published today in Acta Neuropathologica Communications , shows that disease-specific iPS cells can be generated from readily available biobanked tissue that has not been cryoprotected, even after they have been frozen for many years. This allows for the generation of iPS cells from brains with confirmed disease pathology as well as allows access to rare patient variants that have been banked. In addition, findings made using iPS cellular models can be cross-validated in the original brain tissue used to generate the cells. The stem cell lines generated for this study included samples from patients with confirmed Alzheimer's disease and four other neurodegenerative diseases.

This important advance opens up critical new avenues of research to study cells affected by disease from patients with definitive diagnoses. This success will leverage existing biobanks to support research in a powerful new way.

iPS cells are typically generated from a skin or blood sample of a patient by turning back the clock of adult cells into pluripotent stem cells, cells that can become any cell type in the body. While valuable, iPS cells are often generated from patients without a clear diagnosis of disease and many neurodegenerative diseases, such as Alzheimer's disease, often lack specific and robust disease classification and severity grading. These diseases and their extent can only be definitively diagnosed by post-mortem brain examinations. For the first time we will now be able to compare cells from living people to cells of patients with definitive diagnoses generated from their banked brain tissue.

Brain bank networks, which combined contain tens of thousands of samples, provide a large and immediate source of tissue including rare disease samples and a conclusive spectrum of disease severity among samples. The challenge to this approach is that the majority of biobanked brain tissue was not meant for growing live cells, and thus was not frozen in the presence of cryoprotectants normally used to protect cells while frozen. NYSCF scientists in collaboration with CUMC scientists have shown that these thousands of samples can now be used to make living human cells for use in disease studies and to develop new drugs or preventative treatments for future patients.

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NYSCF scientists make living brain cells from Alzheimer's patients biobanked brain tissue

Despite some ethical concerns, most patients are now broadly endorsing stem cell research.

In the case of induced pluripotent stem cells (iPSCs), which are stem cells made from skin or other tissues, researchers at the Johns Hopkins University found patients were largely in favour of participating in iPSC research even if personal benefit was unlikely.

The patients, however, raised concerns about consent, privacy and transparency.

"Bioethicists as well as stem cell researchers and policy-makers have discussed ethical issues at length but till date, we didn't have any systematic information about what patients think about these issues," said Jeremy Sugarman, the Harvey M. Meyerhoff professor of bioethics and medicine at Johns Hopkins Berman Institute of Bioethics.

Unlike human embryonic stem cells, iPSCs are derived without destroying a human embryo. Research with human iPSCs is valuable for developing new drugs, studying disease, and perhaps developing medical treatments, said the study published in the journal Cell Stem Cell.

According to the study, consent was highly important for patients. Some patients even suggested that proper informed consent could compensate for other concerns they had about privacy, the "immortalisation" of cells and the commercialisation of stem cells.

There was a "strong desire among participants to have full disclosure of the anticipated uses, with some participants wanting to be able to veto certain uses of their cells", the study added.

"The idea that donated cells would potentially live forever was unnerving to some participants," the report stated.

"This study is a first step in getting crucial information about what values are factored into a decision to participate in iPSC research, and what those participants expect from the experience," said Sugarman.

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Patients endorse key stem cell research

MADISON--After Susan Derse Phillips had chemotherapy for leukemia, she received a stem cell transplant, getting blood-forming cells from a donor to restore her immune system and attack any remaining leukemia cells.

The procedure apparently cured her leukemia, a type of blood cancer. But her skin turned red, her mouth and eyes became dry and she developed diarrhea, fatigue, bronchitis and pneumonia.

She had graft-versus-host disease, or GVHD, a life-threatening complication of the transplant. Her donors cells the graft werent attacking just her leukemia. They were attacking her skin, her gut, her lungs and other organs essentially, her body, the host.

It got pretty scary pretty quickly, said Phillips, 66, of Madison, who continues to struggle with the condition two years after the transplant.

More than half of patients who get donor stem cell transplants develop GVHD, and at least 20 percent of them die from it, said Dr. Mark Juckett, a hematologist at UW Health. But the complication, which likely is under-reported, receives relatively little attention.

Phillips, former president and CEO of Agrace HospiceCare in Fitchburg, set out to change that in Wisconsin. With $500,000 from two donors as seed money, she persuaded UW Health to launch a program to focus on the condition.

UW Carbone Cancer Centers new GVHD program aims to provide better treatment for the 250 or so UW Health patients with the condition and up to 1,000 such patients in Wisconsin and parts of neighboring states, said Juckett, one of the programs two leaders. The program will also study ways to prevent GVHD.

Too often, when doctors give donor stem cell transplants, were trading one disease for another, said Juckett, Phillips doctor. Theres been a lot of focus on how best to do the transplant ... but theres never been a real recognition of dealing with GHVD as a real problem.

Nationwide, about 18,500 stem cell or bone marrow transplants were performed in 2011, according to the Center for International Blood and Marrow Transplant Research in Milwaukee.

At UW Hospital, about 150 patients receive the transplants each year. Roughly 100 of them get infusions of their own stem cells, after high-dose chemotherapy or radiation, for conditions such as multiple myeloma and non-Hodgkins lymphoma. They are not at risk for GVHD.

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Stem cell transplant complication gains attention at UW Health

Cellogica
Cellogica is a non-greasy formula that uses revolutionary stem cell technology to regenerate new skin stem cells, prevent the loss of existing skin stem cell...

By: Jordan Kaleb

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Cellogica - Video