Converting Adult Human Cells to Hair-follicle Generating Stem Cells

Implications for hair regeneration

Tuesday, 28 January 2014

If the content of many a situation comedy, not to mention late-night TV advertisements, is to be believed, there's an epidemic of balding men, and an intense desire to fix their follicular deficiencies.

This shows hair shafts (arrows) formed by

induced pluripotent stem cell-derived epithelial

stem cells. Credit: Ruifeng Yang, Perelman

School of Medicine, University of

Pennsylvania. 

One potential approach to reversing hair loss is to use stem cells to regenerate the missing or dying hair follicles. But it hasn't been possible to generate sufficient number of hair-follicle-generating stem cells – until now.

Xiaowei "George" Xu, MD, PhD, associate professor of Pathology and Laboratory Medicine and Dermatology at the Perelman School of Medicine, University of Pennsylvania, and colleagues published in Nature Communications a method for converting adult cells into epithelial stem cells (EpSCs), the first time anyone has achieved this in either humans or mice.

The epithelial stem cells, when implanted into immunocompromised mice, regenerated the different cell types of human skin and hair follicles, and even produced structurally recognizable hair shaft, raising the possibility that they may eventually enable hair regeneration in people.

Xu and his team, which includes researchers from Penn's departments of Dermatology and Biology, as well as the New Jersey Institute of Technology, started with human skin cells called dermal fibroblasts. By adding three genes, they converted those cells into induced pluripotent stem cells (iPSCs), which have the capability to differentiate into any cell types in the body. They then converted the iPS cells into epithelial stem cells, normally found at the bulge of hair follicles.

Starting with procedures other research teams had previously worked out to convert iPSCs into keratinocytes, Xu's team demonstrated that by carefully controlling the timing of the growth factors the cells received, they could force the iPSCs to generate large numbers of epithelial stem cells. In the Xu study, the team's protocol succeeded in turning over 25% of the iPSCs into epithelial stem cells in 18 days. Those cells were then purified using the proteins they expressed on their surfaces.

Comparison of the gene expression patterns of the human iPSC-derived epithelial stem cells with epithelial stem cells obtained from human hair follicles showed that the team had succeeded in producing the cells they set out to make in the first place. When they mixed those cells with mouse follicular inductive dermal cells and grafted them onto the skin of immunodeficient mice, they produced functional human epidermis (the outermost layers of skin cells) and follicles structurally similar to human hair follicles.

"This is the first time anyone has made scalable amounts of epithelial stem cells that are capable of generating the epithelial component of hair follicles," Xu says.

And those cells have many potential applications, he adds, including wound healing, cosmetics, and hair regeneration.

That said, iPSC-derived epithelial stem cells are not yet ready for use in human subjects, Xu adds. First, a hair follicle contains epithelial cells – a cell type that lines the body's vessels and cavities – as well as a specific kind of adult stem cell called dermal papillae. Xu and his team mixed iPSC-derived EpSCs and mouse dermal cells to generate hair follicles to achieve the growth of the follicles.

"When a person loses hair, they lose both types of cells." Xu explains.

"We have solved one major problem, the epithelial component of the hair follicle. We need to figure out a way to also make new dermal papillae cells, and no one has figured that part out yet."

What's more, the process Xu used to create iPSCs involves genetic modification of human cells with genes encoding oncogenic proteins and so needs more refinement. Still, he notes that stem-cell researchers are developing more workarounds, including strategies using only chemical agents.

Source: University of Pennsylvania School of Medicine 

Contact: Karen Kreeger

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Successful Regeneration of Human Skeletal Muscle in Mice Enables Accelerated Research in Muscular Dystrophy

Kennedy Krieger researchers develop valid and accurate model for FSHD

Tuesday, 28 January 2014

Researchers at the Kennedy Krieger Institute recently announced study findings showing the successful development of a humanized preclinical model for facioscapulohumeral muscular dystrophy (FSHD), providing scientists with a much needed tool to accelerate novel therapeutic research and development.

Published in Human Molecular Genetics, the study outlines the validity of a unique model that, for the first time, mirrors the gene expression and biomarker profile of human FSHD tissue. Previously, there has been no accepted preclinical model for FSHD, a complex and rare neuromuscular disorder that affects approximately 4 - 7 per 100,000 individuals. As a result, therapeutic development for the disorder has been stymied.

“The inability to mimic the FSHD’s genetic mechanism in preclinical models has been an ongoing challenge for the research community. Without an accurate model, making the leap to clinical research commonly fails,” said Kathryn Wagner MD, PhD, director of the Center for Genetic Muscle Disorders at the Kennedy Krieger Institute in Baltimore, MD.

“We believe this unique model will open the door to studying muscle regeneration over time and help better predict clinical response to therapeutic drugs.”

Inspired by cancer preclinical models developed with human tumour tissue, Dr. Wagner and her research team leveraged both basic science and clinical research resources available at Kennedy Krieger to successfully regenerate grafted muscle within the models. Human bicep muscle biopsies transplanted into models survived for over 41 weeks and retained features of normal and diseased tissue.

“This model is not only applicable to genetic muscle diseases for which we lack appropriate research models, but for other acquired muscle conditions,” said Wagner.

“Now there will be more research possibilities related to the overall impact of age and disease on the regenerative and growth capacity of human skeletal muscle.”

Source: Kennedy Krieger Institute 

Contact: Jennifer Burke

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New Method Increases Supply of Embryonic Stem Cells

New Method Increases Supply of Embryonic Stem Cells

Monday, 27 January 2014

Single cell removal from an embryo.

A new method allows for large-scale generation of human embryonic stem cells of high clinical quality. It also allows for production of such cells without destroying any human embryos. The discovery is a big step forward for stem cell research and for the high hopes for replacing damaged cells and thereby curing serious illnesses such as diabetes and Parkinson's disease.

Currently human embryonic stem cells are made from surplus in vitro fertilized (IVF) embryos that are not used for the generation of pregnancies. The embryos do not survive the procedure. Therefore it has been illegal in the USA to use this method for deriving embryonic stem cell lines. Sweden's legislation has been more permissive. It has been possible to generate embryonic stem cells from excess, early IVF embryos with the permission of the persons donating their eggs and sperm.

Prof. Karl Tryggvason, KI.

An international research team led by Karl Tryggvason, Professor of Medical Chemistry at Karolinska Institute in Sweden and Professor at Duke-NUS Graduate Medical School in Singapore has, together with Professor Outi Hovatta at Karolinska Institute, developed a method that makes it possible to use a single cell from an embryo of eight cells. This embryo can then be re-frozen and, theoretically, be placed in a woman's uterus. The method is already used in Pre-implantation Genetic Diagnosis (PGD) analyses, where a genetic test is carried out on a single cell of an IVF embryo in order to detect potential hereditary diseases. If mutations are not detected, the embryo is inserted in the woman's uterus, where it can grow into a healthy child.

"We know that an embryo can survive the removal of a single cell. This makes a great ethical difference," says Karl Tryggvason.

The single stem cell is then cultivated on a bed of a human laminin protein known as LN-521 that is normally associated with pluripotent stem cells in the embryo. This allows the stem cell to duplicate and multiply without being contaminated. Previously the cultivation of stem cells has been done on proteins from animals or on human cells, which have contaminated the stem cells through uninhibited production of thousands of proteins.

"We can cultivate the stem cells in a chemically defined, clinical quality environment. This means that one can produce stem cells on a large scale, with the precision required for pharmaceutical production," says Karl Tryggvason.

Embryonic stem cells are pluripotent and can develop into any kind of cell. This means that they can become dopamine producing cells, insulin producing cells, heart muscle cells or eye cells, to name but a few of the hopes placed on cell therapy using stem cells.

"Using this technology the supply of human embryonic stem cells is no longer a problem. It will be possible to establish a bank where stem cells can be matched by tissue type, which is important for avoiding transplants being rejected," says Karl Tryggvason.

Source: Karolinska Institute

Contact: Press Office

Reference:

Clonal culturing of human embryonic stem cells on laminin-521/E-cadherin matrix in defined and xeno-free environment

Sergey Rodin, Liselotte Antonsson, Colin Niaudet, Oscar E. Simonson, Elina Salmela, Emil M. Hansson, Anna Domogatskaya, Zhijie Xiao, Pauliina Damdimopoulou, Mona Sheikhi, José Inzunza, Ann-Sofie Nilsson, Duncan Baker, Raoul Kuiper, Yi Sun, Elisabeth Blennow, Magnus Nordenskjöld, Karl-Henrik Grinnemo, Juha Kere, Christer Betsholtz, Outi Hovatta and Karl Tryggvason. 

Nature Communications, January 27, 2014, doi: 10.1038/ncomms4195

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Insulin-producing Beta Cells from Stem Cells

Scientists decipher early molecular mechanisms of differentiation

Thursday, 23 January 2014

Endodermal cells, they form organs such as lung,

liver and pancreas. Credit: IDR, Helmholtz

Zentrum München.

The Wnt/β-catenin signalling 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 München 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 München (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 signalling pathways are important for this germ layer organization, including the Wnt/β-catenin signalling 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 München, showed that the Wnt/β-catenin signalling 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 München, 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 modelling.

"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 München, 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.

Source: Helmholtz Zentrum München

Contact: Heiko Lickert

References:

Wnt/β-catenin signalling regulates Sox17 expression and is essential for organizer and endoderm formation in the mouse 

Silvia Engert, Ingo Burtscher, W. Perry Liao, Stanimir Dulev, Gunnar Schotta and Heiko Lickert

Development, 2013, 140:3128-3138, doi:10.1242/dev.088765

miR-335 promotes mesendodermal lineage segregation and shapes a transcription factor gradient in the endoderm

Dapeng Yang, Dominik Lutter, Ingo Burtscher, Lena Uetzmann, Fabian J. Theis, and Heiko Lickert

Development, 2014, 141, 514-525, doi:10.1242/dev.104232

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Keeping Stem Cells Pluripotent

By blocking key signal, researchers maintain embryonic stem cells in vital, undifferentiated state

Tuesday, 14 January 2014

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 week’s Online Early Edition of PNAS, researchers from the University of California, San Diego School of Medicine identify a key gene receptor and signalling 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 signalling 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 signalling 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 tumours. Other studies have suggested that FZD7 may be a marker for cancer stem cells and play an important role in promoting tumour 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.

Source: University of California - San Diego 

Contact: Scott LaFee

Reference:

The WNT receptor FZD7 is required for maintenance of the pluripotent state in human embryonic stem cells

Antonio Fernandez, Ian J. Huggins, Luca Perna, David Brafman, Desheng Lu, Shiyin Yao,Terry Gaasterland, Dennis A. Carson, and Karl Willert

PNAS, January 13, 2014, doi:10.1073/pnas.1323697111

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Rewiring Stem Cells

Rewiring Stem Cells

Friday, 10 January 2014

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."

Source: University of Cambridge 

Contact: Sarah Collins

Reference:

Genetic Exploration of the Exit from Self-Renewal Using Haploid Embryonic Stem Cells

Martin Leeb, Sabine Dietmann, Maike Paramor, Hitoshi Niwa, Austin Smith

Cell Stem Cell, 09 January 2014, 10.1016/j.stem.2013.12.008

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Stem Cells Injected into Nerve Guide Tubes Repair Injured Peripheral Nerve

Stem Cells Injected into Nerve Guide Tubes Repair Injured Peripheral Nerve

Friday, 10 January 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. 

"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 monofilaments along with electrophysiological and MRI examinations.

"Our three-year follow up has witnessed nerve regeneration with suitable functional recovery in the patient and the salvage of upper arms from amputation," said the researchers.

"This finding opens an alternative avenue for patients who are at-risk of amputation after the injury to important nerves."

"This single case study provides the first step towards a proof-of-principle for a new treatment for peripheral nerve injury" said Dr. Camillo Ricordi, coeditor-in-chief of Cell Transplantation, Stacy Joy Goodman Professor of Surgery and Director of the Cell Transplant Center at the University of Miami.

"Further studies will be necessary to determine whether the work in this report could be validated, introducing a novel therapeutic strategy for peripheral nerve injury".

Source: Cell Transplantation Center of Excellence for Aging and Brain Repair

Contact: Robert Miranda

Reference:

Stem Cell Salvage of injured peripheral nerve

Grimoldi, N.; Colleoni, F.; Tiberio, F.; Vetrano, I. G.; Cappellar, A.; Costa, A.; Belicchi, M.; Razini, P.; Giordano, R.; Spagnoli, D.; Pluderi, M.; Gatti, S.; Morbin, M.; Gaini, S. M.; Rebulla, P.; Bresolin, N.; Torrente, Y.

Cell Transplant. Appeared online: November 21, 2013

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Study Dispels Theories of Human Y Chromosome's Demise

Stripped-down chromosome retains key genes for fertility

Friday, 10 January 2014

A comparison of Y chromosomes in eight African and eight European men dispels the common notion that the Y's genes are mostly unimportant and that the chromosome is destined to dwindle and disappear.

"The Y chromosome has lost 90 percent of the genes it once shared with the X chromosome, and some scientists have speculated that the Y chromosome will disappear in less than 5 million years," said evolutionary biologist Melissa A. Wilson Sayres, a Miller Postdoctoral Fellow in the Department of Integrative Biology at the University of California, Berkeley, and lead author of the new analysis.

Some mammals have already lost their Y chromosome, though they still have males and females and reproduce normally. And last month, researchers reported shuffling some genes in mice to create Y-less males that could produce normal offspring, leading some commentators to wonder whether the chromosome is superfluous.

"Our study demonstrates that the genes that have been maintained, and those that migrated from the X to the Y, are important, and the human Y is going to stick around for a long while," she said.

Wilson Sayres and co-author Rasmus Nielsen, UC Berkeley professor of integrative biology, show in a paper published online today (Jan. 9, 2014) in PLOS Genetics that patterns of variation on the Y chromosome among the 16 men are consistent with natural selection acting to maintain the gene content there, much of which has been shown to play a role in male fertility. The Y chromosome's puny size – it contains 27 unique genes versus thousands on the other chromosomes – is a sign it is lean and stripped down to essentials.

"Melissa's results are quite stunning. They show that because there is so much natural selection working on the Y chromosome, there has to be a lot more function on the chromosome than people previously thought," Nielsen said.

Variations in Y chromosomes are used to track how human populations moved around the globe, and according to Nielsen, the new research will help improve estimates of humans' evolutionary history.

"Melissa has shown that this strong negative selection – natural selection to remove deleterious genes – tends to make us think the dates are older than they actually are, which gives quite different estimates of our ancestors' history," Nielsen said.

Y has degraded over past 200 million

Before about 200 million years ago, when mammals were relatively new on Earth, early versions of the sex chromosomes, X and Y, were just like other pairs of chromosomes: with each generation, they swapped a few genes so that offspring were a mix of their parents' genes. Fertilized eggs that got two proto-Xs became females and eggs with a proto-X and proto-Y became males.

But for some reason, Wilson Sayres said, the gene that triggers the cascade of events that result in male features became fixed on the Y chromosome and attracted other male-specific genes, such as those that control development of the testes, sperm and semen. Many of these turned out to be harmful for females, so the X and Y stopped swapping genes and the two chromosomes began to evolve separately.

"Now the X and Y do not swap DNA over most of their lengths, which means that the Y cannot efficiently fix mistakes, so it has degraded over time," she said.

"In XX females, the X still has a partner to swap with and fix mistakes, which is why we think the X hasn't also degraded."

Wilson Sayres was fascinated by the strange history of the sex chromosomes and in particular the lack of genetic variation worldwide on the Y chromosome compared to the variety seen in DNA on the non-sex chromosomes. This variation, though used to chart human history, was poorly characterized across the entire Y chromosome.

"Y chromosomes are more similar to each other than we expect," said Wilson Sayres.

"There has been some debate about whether this is because there are fewer males contributing to the next generation, or whether natural selection is acting to remove variation."

Did fewer males contribute genes to Y chromosome?

The UC Berkeley researchers demonstrated that if fewer males were the only cause of the low variability, it would mean that fewer than 1 in 4 males throughout history had passed on their Y chromosome each generation. Variations in other human chromosomes, including the X chromosome, make this an unlikely scenario. Instead, they showed that the low variation can be explained by intense natural selection, that is, a strong evolutionary pressure to weed out bad mutations that ended up trimming the chromosome down to its essentials.

"We show that a model of purifying selection acting on the Y chromosome to remove harmful mutations, in combination with a moderate reduction in the number of males that are passing on their Y chromosomes, can explain low Y diversity," Wilson Sayres said.

The researchers also found that all 27 genes on the Y chromosome – the 17 that humans retain after 200 million years, and 10 more recently acquired but poorly understood genes – are likely affected by natural selection. Most of the newer genes, called ampliconic genes, are present in multiple copies on the chromosome and loss of one or more copies has been linked to male infertility.

"These ampliconic regions that we haven't really understood until now are evidently very important and probably should be investigated and studied for fertility," she said.

Wilson Sayres was able to precisely measure Y variability because for the first time she compared variation on a person's Y chromosome with variation on that person's other 22 chromosomes (called autosomes), the X chromosome and the mitochondrial DNA. She used whole genome data from 16 men whose DNA had been sequenced by the Mountain View-based company Complete Genomics Inc., which has the most accurate sequences of the Y chromosome. The company was recently acquired by BGI, the Beijing Genome Institute.

Cross-population studies of variation in the Y chromosome are in their infancy, she said, noting that of the more than 36 mammalian genomes sequenced to date, complete Y chromosomes are only available for three. Most of the 1,000+ human genomes already sequenced do not have sufficiently accurate coverage of the Y to make this type of comparison among individuals, but advances in technology to better characterize DNA will facilitate future analyses of the Y chromosome, she said.

Source: University of California - Berkeley 

Contact: Robert Sanders

Reference:

Natural Selection Reduced Diversity on Human Y Chromosomes

Melissa A. Wilson Sayres, Kirk E. Lohmueller and Rasmus Nielsen

PLOS Genetics, January 09, 2014, DOI: 10.1371/journal.pgen.1004064

See also:

Why is Y Disappearing?

Male sex chromosome losing genes by rapid evolution
CellNEWS - Friday, 17 July 2009 

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Scientists Make Living Brain Cells from Alzheimer's Patients Biobanked Brain Tissue

New study shows ability to make living human cells from biobanked brain tissue

Tuesday, 07 January 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.

Source: New York Stem Cell Foundation 

Contact: David McKeon

Reference:

Generation of iPSC lines from archived non-cryoprotected biobanked dura mater

Andrew A Sproul, Lauren B Vensand, Carmen R Dusenberry, Samson Jacob, Jean Paul Vonsattel, Daniel J Paull, Michael L Shelanski, John F Crary and Scott A Noggle

Acta Neuropathologica Communications 2014, (7 January 2014), 2:4

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Stem Cells on the Road to Specialization

Stem Cells on the Road to Specialization

Tuesday, 07 January 2014

Extracellular matrix. 

Scientists at the University of Copenhagen have gained new insight into how both early embryonic cells and embryonic stem cells are directed into becoming specialised cell types, like pancreatic and liver cells. The results have just been published in the scientific journal eLife.

This latest research from the Danish Stem Cell Center (Danstem) at the University of Copenhagen, helps identify how stem cells create so called pathways and roads supporting their own specialization. This understanding is an important step towards stem cell-based cell therapies for conditions like diabetes and liver diseases.

"The new insight that we have gained into the impact of the physical environment on cell development is highly valuable," says Professor Joshua Brickman from DanStem,

"It enables us to create the optimal physical environment in the laboratory for stem cells and progenitor cells to develop into specific, mature cells."

On the road

Developing cells constantly move and while moving around, they organise and build a physical environment very much like a small city with pathways and roads. The new research published in the scientific journal eLife shows two important things. Firstly the embryonic cells receive signals from other cells that actually instruct them in how to organise and build the road leading the cells towards early stages of pancreas and liver cells.

Professor Brickman and his team also found that they could isolate these roads from the developing stem cells and literally freeze them. The saved roads were then used in a separate experiment which showed that in the absence of an important cell signal, the road alone can be used to improve the cells' development and differentiation towards mature cells.

"Apart from gaining new important insight into cell development, our work also suggests that some of the current approaches to human embryonic stem cells specialization towards both pancreatic and liver cells may not have been effective, because the important role of these roads, the so called extra-cellular matrix, was ignored," says Joshua Brickman.

Source: University of Copenhagen

Contact: Joshua Brickmann

Reference:

PI3K/Akt1 signalling specifies foregut precursors by generating regionalized extra-cellular matrix

S Nahuel Villegas, Michaela Rothová, Martin E Barrios-Llerena, Maria Pulina, Anna-Katerina Hadjantonakis, Thierry Le Bihan, Sophie Astrof, Joshua M Brickman

eLife 2013;2:e00806, DOI: http://dx.doi.org/10.7554/eLife.00806

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ZenMaster

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