Restoring Vision with Stem Cells

Researchers have succeed in producing photoreceptors from human embryonic stem cells

Tuesday, 06 October 2015

Age-related macular degeneration (AMRD) could be treated by transplanting photoreceptors produced by the directed differentiation of stem cells, thanks to findings published today by Professor Gilbert Bernier of the University of Montreal and its affiliated Maisonneuve-Rosemont Hospital. ARMD is a common eye problem caused by the loss of cones. Bernier's team has developed a highly effective in vitro technique for producing light sensitive retina cells from human embryonic stem cells.

"Our method has the capacity to differentiate 80% of the stem cells into pure cones," Professor Gilbert explained.

"Within 45 days, the cones that we allowed to grow towards confluence spontaneously formed organised retinal tissue that was 150 microns thick. This has never been achieved before."

In order to verify the technique, Bernier injected clusters of retinal cells into the eyes of healthy mice. The transplanted photoreceptors migrated naturally within the retina of their host.

Age-related macular degeneration could be

treated by transplanting photoreceptors

produced by the directed differentiation of stem

cells, thanks to findings published today by

Professor Gilbert Bernier of the University of

Montreal and its affiliated Maisonneuve-

Rosemont Hospital. This image illustrates the 3D

reconstruction of the tissue that was produced in

vitro and labelled with antibodies against

photoreceptor-specific proteins. Credit: G.

Bernier, Université de Montréal.

"Cone transplant represents a therapeutic solution for retinal pathologies caused by the degeneration of photoreceptor cells," Bernier explained.

"To date, it has been difficult to obtain great quantities of human cones."

His discovery offers a way to overcome this problem, offering hope that treatments may be developed for currently non-curable degenerative diseases, like Stargardt disease and ARMD.

"Researchers have been trying to achieve this kind of trial for years," he said.

"Thanks to our simple and effective approach, any laboratory in the world will now be able to create masses of photoreceptors. Even if there's a long way to go before launching clinical trials, this means, in theory, that will be eventually be able to treat countless patients."

The findings are particularly significant in the light of improving life expectancies and the associated increase in cases of ARMD. ARMD is in fact the greatest cause of blindness amongst people over the age of 50 and affects millions of people worldwide. And as we age, it is more and more difficult to avoid - amongst people over 80, this accelerated aging of the retina affects nearly one in four. People with ARMD gradually lose their perception of colours and details to the point that they can no longer read, write, watch television or even recognize a face.

ARMD is due to the degeneration of the macula, which is the central part of the retina that enables the majority of eyesight. This degeneration is caused by the destruction of the cones and cells in the retinal pigment epithelium (RPE), a tissue that is responsible for the reparation of the visual cells in the retina and for the elimination of cells that are too worn out. However, there is only so much reparation that can be done as we are born with a fixed number of cones. They therefore cannot naturally be replaced. Moreover, as we age, the RPE's maintenance is less and less effective - waste accumulates, forming deposits.

"Differentiating RPE cells is quite easy. But in order to undertake a complete therapy, we need neuronal tissue that links all RPE cells to the cones. That is much more complex to develop," Bernier explains, noting nonetheless that he believes his research team is up to the challenge.

Bernier has been interested in the genes that code and enable the induction of the retina during embryonic development since completing his PhD in Molecular Biology in 1997.

"During my post-doc at the Max-Planck Institute in Germany, I developed the idea that there was a natural molecule that must exist and be capable of forcing embryonic stem cells into becoming cones," he said.

Indeed, bioinformatics analysis led him to predict the existence of a mysterious protein: COCO, a "recombinational" human molecule that is normally expressed within photoreceptors during their development.

In 2001, he launched his laboratory at Maisonneuve-Rosemont Hospital and immediately isolated the molecule. But it took several years of research to demystify the molecular pathways involved in the photoreceptors development mechanism. His latest research shows that in order to create cones, COCO can systematically block all the signalling pathways leading to the differentiation of the other retinal cells in the eye. It's by uncovering this molecular process that Bernier was able to produce photoreceptors. More specifically, he has produced S-cones, which are photoreceptor prototypes that are found in the most primitive organisms.

Beyond the clinical applications, Professor Bernier's findings could enable the modelling of human retinal degenerative diseases through the use of induced pluripotent stem cells, offering the possibility of directly testing potential avenues for therapy on the patient's own tissues.

Source: University of Montréal

Contact: William Raillant-Clark

Reference:

Differentiation of human embryonic stem cells into cone photoreceptors through simultaneous inhibition of BMP, TGFβ and Wnt signaling

Shufeng Zhou, Anthony Flamier, Mohamed Abdouh, Nicolas Tétreault, Andrea Barabino, Shashi Wadhwa and Gilbert Bernier

Development, 42, 3294-3306, October 1, 2015, doi: 10.1242/dev.125385

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Study Reveals the Genetic Start-up of a Human Embryo

Study Reveals the Genetic Start-up of a Human Embryo

Thursday, 03 September 2015

An international team of scientists led from Sweden’s Karolinska Institutet has for the first time mapped all the genes that are activated in the first few days of a fertilised human egg. The study, which is being published in the journal Nature Communications, provides an in-depth understanding of early embryonic development in human – and scientists now hope that the results will help finding for example new therapies against infertility.

At the start of an individual’s life there is a single fertilised egg cell. One day after fertilisation there are two cells, after two days four, after three days eight and so on, until there are billions of cells at birth. The order in which our genes are activated after fertilisation has remained one of the last uncharted territories of human development.

Juha Kere is a Professor of Molecular Genetics at

Karolinska Institutet. Credit: Ulf Sirborn.

There are approximately 23,000 human genes in total. In the current study, scientists found that only 32 of these genes are switched on two days after fertilization, and by day three there are 129 activated genes. Seven of the genes found and characterised had not been discovered previously.

“These genes are the ‘ignition key’ that is needed to turn on human embryonic development. It is like dropping a stone into water and then watching the waves spread across the surface”, says principal investigator Juha Kere, professor at theDepartment of Biosciences and Nutrition at Karolinska Institutet and also affiliated to the SciLifeLab facility in Stockholm.

The researchers had to develop a new way of analysing the results in order to find the new genes. Most genes code for proteins but there are a number of repeated DNA sequences that are often considered to be so-called ‘junk DNA’, but are in fact important in regulating gene expression.

Treatment of infertility

In the current study, the researchers show that the newly identified genes can interact with the ‘junk DNA’, and that this is essential to the start of development.

Outi Hovatta is a Professor of Obstetrics and

Gynaecology at Karolinska Institutet. Credit:

Ulf Sirborn.

“Our results provide novel insights into the regulation of early embryonic development in human. We identified novel factors that might be used in reprogramming cells into so-called pluripotent stem cells for possible treatment of a range of diseases, and potentially also in the treatment of infertility”, says Outi Hovatta, professor at Karolinska Institutet’s Department of Clinical Science, Intervention and Technology, and a senior author.

The study was a collaboration between three research groups from Sweden and Switzerland that each provided a unique set of skills and expertise. The work was supported by the Karolinska Institutet Distinguished Professor Award, the Swedish Research Council, the Strategic Research Program for Diabetes funding at Karolinska Institutet, Stockholm County, the Jane & Aatos Erkko Foundation, the Instrumentarium Science Foundation, and the Åke Wiberg and Magnus Bergvall foundations. The computations were performed on resources provided by SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX).

Source: Karolinska Institutet

Contact: KI Press Office

Reference:

Novel PRD-like homeodomain transcription factors and retrotransposon elements in early human development

Virpi Töhönen, Shintaro Katayama, Liselotte Vesterlund, Eeva-Mari Jouhilahti, Mona Sheikhi, Elo Madissoon, Giuditta Filippini-Cattaneo, Marisa Jaconi, Anna Johnsson, Thomas R. Bürglin, Sten Linnarsson, Outi Hovatta and Juha Kere

Nature Communications, 3 September 2015, doi: 10.1038/NCOMMS9207

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Most Complete Human Brain Model to Date Is a ‘Brain Changer’

Once licensed, model likely to accelerate study of Alzheimer’s, autism, more

Wednesday, 19 August 2015

Scientists at The Ohio State University have developed a nearly complete human brain in a dish that equals the brain maturity of a 5-week-old foetus.

The brain organoid, engineered from adult human skin cells, is the most complete human brain model yet developed, said Rene Anand, professor of biological chemistry and pharmacology at Ohio State.

The lab-grown brain, about the size of a pencil eraser, has an identifiable structure and contains 99 percent of the genes present in the human foetal brain. Such a system will enable ethical and more rapid and accurate testing of experimental drugs before the clinical trial stage and advance studies of genetic and environmental causes of central nervous system disorders.

“It not only looks like the developing brain, its diverse cell types express nearly all genes like a brain,” Anand said.

“We’ve struggled for a long time trying to solve complex brain disease problems that cause tremendous pain and suffering. The power of this brain model bodes very well for human health because it gives us better and more relevant options to test and develop therapeutics other than rodents.”

Anand reported on his lab-grown brain Tuesday (Aug. 18) at the 2015 Military Health System Research Symposium in Ft. Lauderdale, Florida.

This image of the lab-grown brain is labelled to

show identifiable structures: the cerebral

hemisphere, the optic stalk and the cephalic

flexure, a bend in the mid-brain region, all

characteristic of the human foetal brain. Credit:

courtesy of The Ohio State University.

Anand, who studies the association between nicotinic receptors and central nervous system disorders, was inspired to pursue a model of human neural biology after encountering disappointing results in a rodent study of an experimental autism drug. Taking a chance with a shoestring budget compared to other researchers doing similar projects, he added stem-cell engineering to his research program. Four years later, he had built himself a replica of the human brain.

The main thing missing in this model is a vascular system. What is there – a spinal cord, all major regions of the brain, multiple cell types, signalling circuitry and even a retina – has the potential to dramatically accelerate the pace of neuroscience research, said Anand, also a professor of neuroscience.

“In central nervous system diseases, this will enable studies of either underlying genetic susceptibility or purely environmental influences, or a combination,” he said.

“Genomic science infers there are up to 600 genes that give rise to autism, but we are stuck there. Mathematical correlations and statistical methods are insufficient to in themselves identify causation. You need an experimental system – you need a human brain.”

Converting adult skin cells into pluripotent cells – immature stem cells that can be programmed to become any tissue in the body – is a rapidly developing area of science that earned the researcher who discovered the technique, Shinya Yamanaka, a Nobel Prize in 2012.

“Once a cell is in that pluripotent state, it can become any organ – if you know what to do to support it to become that organ,” Anand said.

“The brain has been the holy grail because of its enormous complexity compared to any other organ. Other groups are attempting to do this as well.”

Anand’s method is proprietary and he has filed an invention disclosure with the university.

He said he used techniques to differentiate pluripotent stem cells into cells that are designed to become neural tissue, components of the central nervous system or other brain regions.

“We provide the best possible environment and conditions that replicate what’s going on in utero to support the brain,” he said of the work he completed with colleague Susan McKay, a research associate in biological chemistry and pharmacology.

High-resolution imaging of the organoid identifies functioning neurons and their signal-carrying extensions – axons and dendrites – as well as astrocytes, oligodendrocytes and microglia. The model also activates markers for cells that have the classic excitatory and inhibitory functions in the brain, and that enable chemical signals to travel throughout the structure.

It takes about 15 weeks to build a model system developed to match the 5-week-old foetal human brain. Anand and McKay have let the model continue to grow to the 12-week point, observing expected maturation changes along the way.

“If we let it go to 16 or 20 weeks, that might complete it, filling in that 1 percent of missing genes. We don’t know yet,” he said.

He and McKay have already used the platform to launch their own projects, creating brain organoid models of Alzheimer’s and Parkinson’s diseases and autism in a dish. They hope that with further development and the addition of a pumping blood supply, the model could be used for stroke therapy studies. For military purposes, the system offers a new platform for the study of Gulf War illness, traumatic brain injury and post-traumatic stress disorder.

Anand hopes his brain model could be incorporated into the Microphysiological Systems program, a platform the Defense Advanced Research Projects Agency is developing by using engineered human tissue to mimic human physiological systems.

Support for the work came from the Marci and Bill Ingram Research Fund for Autism Spectrum Disorders and the Ohio State University Wexner Medical Center Research Fund.

Anand and McKay are co-founders of a Columbus-based start-up company, NeurXstem, to commercialize the brain organoid platform, and have applied for funding from the federal Small Business Technology Transfer program to accelerate its drug discovery applications.

Source: Ohio State University

Contact: Rene Anand

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Chemical-only Cell Reprogramming Transforms Human and Mouse Skin Cells into Neurons

Chemical-only Cell Reprogramming Transforms Human and Mouse Skin Cells into Neurons

Friday, 07 August 2015

Two labs in China have independently succeeded in transforming skin cells into neurons using only a cocktail of chemicals, with one group using human cells from healthy individuals and Alzheimer's patients, and the other group using cells from mice. The two studies reinforce the idea that a purely chemical approach is a promising way to scale up cell reprogramming research that may avoid the technical challenges and safety concerns associated with the more popular method of using transcription factors. Both papers appear on August 6 in the journal Cell Stem Cell.

One of the challenges of forcing cells to change identity is that the cells you end up with may look normal but have different internal activities than their naturally forming counterparts. The two papers provide evidence that similar gene expression, action potentials, and synapse formation can be detected in transcription-factor-induced neurons as those generated from the chemical cocktails. (Both groups used mixtures of seven small molecules, but different recipes – outlined in detail in the supplemental information section of each paper – because they focused on different species.)

This is an image of mouse chemical-induced

neurons. Credit: Courtesy of Hongkui Deng.

"We found that the conversion process induced by our chemical strategy is accompanied by the down-regulation of [skin-cell] specific genes and the increased expression of neuronal transcription factors," said human study co-author Jian Zhao, of the Shanghai Institutes for Biological Sciences and Tongji University.

"By coordinating multiple signalling pathways, these small molecules modulate neuronal transcription factor gene expression and thereby promote the neuronal cell transition."

The authors add that the direct conversion bypasses a proliferative intermediate progenitor stage, which circumvents safety issues posed by other reprogramming methods.

This is an image of human chemical induced

neurons. Credit: Courtesy of Gang Pei and

Jian Zhao.

Zhao's paper, co-led with cell biologist Gang Pei, also shows that the pure chemical protocol can be used to make neurons from the skins cells of Alzheimer's patients. Most of the work using patient stem cells has been done by using transcription factors – molecules that affect which genes are expressed in a cell – to create induced pluripotent stem cells. Chemical cell reprogramming is seen as an alternative for disease modelling or even potential cell replacement therapy of neurological disorders, but the "proof-of-concept" is still emerging.

"In comparison with using transgenic reprogramming factors, the small molecules that are used in this chemical approach are cell permeable; cost-effective; and easy to synthesize, preserve, and standardize; and their effects can be reversible," says mouse study co-author Hongkui Deng of the Peking University Stem Cell Research Center.

"In addition, the use of small molecules can be fine-tuned by adjusting their concentrations and duration, and the approach bypasses the technical challenges and safety concerns of genetic manipulations, which may be promising in their future applications."

Deng worked for four years with Zhen Chai and Yang Zhao, also of Peking University, to identify the small molecules that could create chemically induced mouse neurons. Researchers had been close for years, but a transcription factor was always necessary to complete the transformation. Through many chemical screens they identified the key ingredient, I-BET151, which works to suppress transcription in skin cells. They then found the right steps and conditions to mature the neurons post-transformation.

The authors of both papers aim to learn more about the biology behind chemically induced reprogramming and to make the protocols more efficient. While their success is promising, there are still a number of hurdles to overcome.

"We hope in the future that the chemical approaches would be more robust in inducing functional mature neurons," Deng says.

"In addition, we are attempting to generate specific neuronal subtypes and patient-specific functional neurons for translational medicine by using pure chemicals."

Jian Zhao, of the human study, says:

"It should be possible to generate different subtypes of neurons with a similar chemical approach but using slightly modified chemical cocktails."

"It also needs to be explored whether functional neurons could be induced by chemical cocktails in living organisms with neurological diseases or injury," she adds.

Source: Cell Press

Contact: Joseph Caputo

References:

Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons

Xiang Li, Xiaohan Zuo, Junzhan Jing, Yantao Ma, Jiaming Wang, Defang Liu, Jialiang Zhu, Xiaomin Du, Liang Xiong, Yuanyuan Du, Jun Xu, Xiong Xiao, Jinlin Wang, Zhen Chai, Yang Zhao, Hongkui Deng

Cell Stem Cell Volume 17, Issue 2, p195–203, 6 August 2015

Direct Conversion of Normal and Alzheimer's Disease Human Fibroblasts into Neuronal Cells by Small Molecules

Wenxiang Hu, Binlong Qiu, Wuqiang Guan, Qinying Wang, Min Wang, Wei Li, Longfei Gao, Lu Shen, Yin Huang, Gangcai Xie, Hanzhi Zhao, Ying Jin, Beisha Tang, Yongchun Yu, Jian Zhao, Gang Pei

Cell Stem Cell Volume 17, Issue 2, p204–212, 6 August 2015

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Recovery of Sensory Function by Stem Cell Transplants

Recovery of Sensory Function by Stem Cell Transplants

Monday, 08 June 2015

New research from Uppsala University shows promising progress in the use of stem cells for treatment of spinal cord injury. The results, which are published in the scientific journal Scientific Reports, show that human stem cells that are transplanted to the injured spinal cord contribute to restoration of some sensory functions.

Traffic accidents and severe falls can cause ruptures of nerve fibres that enter/exit the spinal cord. Most commonly, these avulsion injuries affect the innervation of the arm and hand, and lead to paralysis, loss of sensation and cause chronic pain. Surgical interventions can help the patient regain some muscle function, but there is currently no treatment able to restore sensory functions. The reason for this is the emergence of a "barrier" at the junction between the ruptured nerve fibres and the spinal cord which prevents them from growing into the spinal cord and restore lost nerve connections.

In a new study the PhD students Jan Hoeber, Niclas König and Carl Trolle, working in Dr.Elena Kozlova's research group transplanted human stem cells to an avulsion injury in mice with the aim to restore a functional route for sensory information from peripheral tissues into the spinal cord.

The results show that the transplanted stem cells act as a "bridge" which allows injured sensory nerve fibres to grow into the spinal cord, rebuilds functional nerve connections, and thereby achieve long term restoration of major parts of the lost sensory functions. The transplanted stem cells differentiated to different types of cells with variable level of maturation, specific for the nervous system. No signs of tumour development or any functional abnormalities from the transplants were observed in the study, outcomes which are important in view of potential risks with transplantation of embryonic stem cells.

The results encourage further research on the use of stem cells for treatment of injury and disease in the spinal cord, and may contribute to the development of novel treatment strategies in these disorders.

Source: Uppsala University

Contact: Elena Kozlova

Reference:

Human embryonic stem cell-derived progenitors assist functional sensory regeneration after dorsal root avulsion injury

Hoeber J, Trolle C, König N, Du Z, Gallo A, Hermans E, Aldskogius H, Shortland P, Zheng, S-C, Deumens R, Kozlova EN. 

Scientific Reports 5, 08 June 2015, Article number: 10666, doi:10.1038/srep10666

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New Stem Cell May Overcome Hurdles for Regenerative Medicine

Salk Institute scientists discover new type of stem cell that could potentially generate mature, functional tissues

Thursday, 07 May 2015

In this image, a novel type of human stem cell is

shown in green integrating and developing into

the surrounding cells of a nonviable mouse

embryo. Red indicates cells of endoderm lineage.

Endoderm cells can give rise to tissue that covers

organs from the digestive and respiratory

systems. The new stem cell, developed at the

Salk Institute, holds promise for one day growing

replacement functional cells and tissues. Credit:

Courtesy of the Salk Institute for Biological

Studies.

Scientists at the Salk Institute have discovered a novel type of pluripotent stem cell – cells capable of developing into any type of tissue – whose identity is tied to their location in a developing embryo. This contrasts with stem cells traditionally used in scientific study, which are characterized by their time-related stage of development.

In the paper, published May 6, 2015 in Nature, the scientists report using these new stem cells to develop the first reliable method for integrating human stem cells into nonviable mouse embryos in a laboratory dish in such a way that the human cells began to differentiate into early-stage tissues.

“The region-specific cells we found could provide tremendous advantages in the laboratory to study development, evolution and disease, and may offer avenues for generating novel therapies,” says Salk Professor Juan Carlos Izpisua Belmonte, senior author of the paper and holder of Salk’s Roger Guillemin Chair.

The researchers dubbed this new class of cells “region-selective pluripotent stem cells,” or rsPSCs for short. The rsPSCs were easier to grow in the laboratory than conventional human pluripotent stem cells and offered advantages for large-scale production and gene editing (altering a cell’s DNA), both desirable features for cell replacement therapies.

Juan Carlos Izpisua Belmonte and Jun Wu

Credit: Courtesy of the Salk Institute for

Biological Studies.

To produce the cells, the Salk scientists developed a combination of chemical signals that directed human stem cells in a laboratory dish to become spatially oriented.

They then inserted the spatially oriented human stem cells (human rsPSCs) into specific regions of partially dissected mouse embryos and cultured them in a dish for 36 hours. Separately, they also inserted human stem cells cultured using conventional methods, so that they could compare existing techniques to their new technique.

While the human stem cells derived through conventional methods failed to integrate into the modified embryos, the human rsPSCs began to develop into early stage tissues. The cells in this region of an early embryo undergo dynamic changes to give rise to all cells, tissues and organs of the body. Indeed the human rsPSCs began the process of differentiating into the three major cell layers in early development, known as ectoderm, mesoderm and endoderm. The Salk researchers stopped the cells from differentiating further, but each germ layer was theoretically capable of giving rise to specific tissues and organs.

The new stem cell (green), developed at the Salk

Institute, holds promise for one day growing

replacement functional cells and tissues. Credit:

Courtesy of the Salk Institute for Biological

Studies.

Collaborating with the labs of Salk Professors Joseph Ecker and Alan Saghatelian, the Izpisua Belmonte team performed extensive characterization of the new cells and found rsPSCs showed distinct molecular and metabolic characteristics as well as novel epigenetic signatures – that is, patterns of chemical modifications to DNA that control which genes are turned on or off without changing the DNA sequence.

“The region selective-state of these stem cells is entirely novel for laboratory-cultured stem cells and offers important insight into how human stem cells might be differentiated into derivatives that give rise to a wide range of tissues and organs,” says Jun Wu, a postdoctoral researcher in Izpisua Belmonte’s lab and first author of the new paper.

“Not only do we need to consider the timing, but also the spatial characteristics of the stem cells. Understanding both aspects of a stem cell’s identity could be crucial to generate functional and mature cell types for regenerative medicine.”

Source: Salk Institute

Contact: Salk Communications

Reference:

An alternative pluripotent state confers interspecies chimaeric competency

Authors: Jun Wu, Daiji Okamura, Mo Li, Keiichiro Suzuki, Chongyuan Luo,Li Ma, Yupeng He, Zhongwei Li, Chris Benner, Isao Tamura, Marie N. Krause, Joseph R. Nery, Tingting Du, Zhuzhu Zhang, Tomoaki Hishida, Yuta Takahashi, Emi Aizawa, Na Young Kim, Jeronimo Lajara, Pedro Guillen, Josep M. Campistol, Concepcion Rodriguez Esteban, Pablo J. Ross, Alan Saghatelian, Bing Ren, Joseph R. Ecker and Juan Carlos Izpisua Belmonte

Nature, 06 May 2015, doi:10.1038/nature14413

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New Clues into How Stem Cells Get Their Identity

New Clues into How Stem Cells Get Their Identity

Wednesday, 06 May 2015

Scientists at the University of Copenhagen have identified one mechanism that explains how some stem cells choose to become a given cell type: the cells combine specific sets of proteins at precise positions along the DNA. When these particular groups of proteins are combined, the gates are opened so that certain groups of genes can now be used, giving the cells a new identity.

Scientists have now identified one of these combinations, which drive the cells along the path that allow them to become organs such as liver and pancreas. This latest research could lead scientists to a better understanding on how to generate insulin-producing cells in the laboratory to use as therapy for Type I diabetes. The work has just been published in the journal Cell Stem Cell.

Specificity – choosing the combinations

Scientists working under the leadership of Henrik Semb from the DanStem Center at the University of Copenhagen have explained how the acquisition of a new cell identity is achieved; cells respond to information from their surroundings, in turn activating a specific combination of proteins at certain places on the DNA, to turn on a genetic programme.

Stem cells. 

“We added one particular chemical compound to the culture media to promote the generation of new cell types. The information transmitted by this compound is deciphered only by a small number of proteins. We then looked all along the cell’s DNA to find the positions of the proteins that were activated by the compound. We repeated the experiment using additional compounds, to get an idea of how specific the responses were and to categorize the genes that the cells decided to use when being directed toward different cellular fates,” says Assistant Professor Karen Schachter.

Getting the identity right

The work in the field of human pluripotent stem cell research has concentrated on finding the correct combination of drugs or chemical compounds that can be used to drive the cells into specific cell types in the culture dish.

“There is however a lack of understanding of how these compounds activates the genes that give the cells unique identities, which has resulted in a lack of reproducibility of the methods used by different labs. As a comparison; if you use a pre-mixed powder to bake a cake you will face problems if you run out on an important ingredient and do not know how to replace its action. We believe that our study provides useful information that will help us to understand the recipe better, so that we can generate functional cells in a more controlled manner,” adds Post doc Nina Funa.

There is already a lot of focus in the stem cell community to generate cells in the laboratory to use as therapy, so the scientists at DanStem want to emphasize the importance of continuing doing this important basic research work.

“Our ultimate aim is to understand how stem cells make choices, which will also help improve the quality of the work that will put stem cells into therapeutic use,” concludes Funa.

Source: University of Copenhagen

Contact: Assistant Professor Karen Schachter

Reference:

β-Catenin Regulates Primitive Streak Induction through Collaborative Interactions with SMAD2/SMAD3 and OCT4

Nina S. Funa, Karen A. Schachter, Mads Lerdrup, Jenny Ekberg, Katja Hess, Nikolaj Dietrich, Christian Honoré, Klaus Hansen, Henrik Semb

Cell Stem Cell, April 23, 2015, DOI: http://dx.doi.org/10.1016/j.stem.2015.03.008

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Researchers Grow Cardiac Tissue on 'Spider Silk' Substrate

Researchers Grow Cardiac Tissue on 'Spider Silk' Substrate

Saturday, 11 April 2015

Genetically engineered fibres of the protein spidroin, which is the construction material for spider webs, has proven to be a perfect substrate for cultivating heart tissue cells, Moscow Institute of Physics and Technology researchers found. They discuss their findings in an article that has recently come out in the journal PLOS ONE.

These are heart tissue cells grown on a matrix,

stained with fluorescent markers. Credit: ©

Alexander Teplenin et al./PLOS ONE.

The cultivation of organs and tissues from a patient's cells is the leading edge of medical research - regenerative methods can solve the problem of transplant rejection. However, it’s quite a challenge to find a suitable frame, or substrate, to grow cells on. The material should be non-toxic and elastic and should not be rejected by the body or impede cell growth. A group of researchers led by Professor Konstantin Agladze, who heads the Laboratory of the Biophysics of Excitable Systems at MIPT, works on cardiac tissue engineering. The group has been cultivating fully functional cardiac tissues, able to contract and conduct excitation waves, from cells called cardiomyocytes. Previously, the group used synthetic polymeric nano-fibres but recently decided to assay another material – electro-spun fibres of spidroin, the cobweb protein. Cobweb strands are incredibly light and durable. They're five times stronger than steel, twice more elastic than nylon, and are capable of stretching a third of their length. The structure of spidroin molecules that make up cobweb drag lines is similar to that of the silk protein, fibroin, but is much more durable.

This is a spidroin fibre matrix captured with a

microscope. Credit: Alexander Teplenin et al./

PLOS ONE.

Researchers would normally use artificial spidroin fibre matrices as a substrate to grow implants like bones, tendons and cartilages, as well as dressings. Professor Agladze's team decided to find out whether a spidroin substrate derived from genetically modified yeast cells can serve to grow cardiac cells.

For this purpose, they seeded isolated neonatal rat cardiomyocytes on fibre matrices. During the experiment, the researchers monitored the growth of the cells and tested their contractibility and the ability to conduct electric impulses, which are the main features of normal cardiac tissue.

The monitoring, carried out with the help of a microscope and fluorescent markers, showed that within three to five days a layer of cells formed on the substrate that were able to contract synchronously and conduct electrical impulses just like the tissue of a living heart would.

"We can answer positively all questions we put at the beginning of this research project," Professor Agladze says.

"Cardiac tissue cells successfully adhere to the substrate of recombinant spidroin; they grow forming layers and are fully functional, which means they can contract co-ordinately."

Source: Moscow Institute of Physics and Technology

Contact: Stanislav Goryachev

Reference:

Functional Analysis of the Engineered Cardiac Tissue Grown on Recombinant Spidroin Fiber Meshes

Alexander Teplenin, Anna Krasheninnikova, Nadezhda Agladze, Konstantin Sidoruk, Olga Agapova, Igor Agapov, Vladimir Bogush, Konstantin Agladze

PLOS ONE, March 23, 2015, DOI:10.1371/journal.pone.0121155

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“Open” Stem Cell Chromosomes Reveal New Possibilities for Diabetes

Researchers map chromosomal changes that must take place before stem cells can be used to produce pancreatic and liver cells 

Thursday, 02 April 2015

These are pancreatic cells derived from

embryonic stem cells. Credit: UC San Diego

School of Medicine. 

Stem cells hold great promise for treating a number of diseases, in part because they have the unique ability to differentiate, specializing into any one of the hundreds of cell types that comprise the human body. Harnessing this potential, though, is difficult. In some cases, it takes up to seven carefully orchestrated steps of adding certain growth factors at specific times to coax stem cells into the desired cell type. Even then, cells of the intestine, liver and pancreas are notoriously difficult to produce from stem cells. Writing in Cell Stem Cell April 2, researchers at University of California, San Diego School of Medicine have discovered why.

It turns out that the chromosomes in laboratory stem cells open slowly over time, in the same sequence that occurs during embryonic development. It isn’t until certain chromosomal regions have acquired the “open” state that they are able to respond to added growth factors and become liver or pancreatic cells. This new understanding, say researchers, will help spur advancements in stem cell research and the development of new cell therapies for diseases of the liver and pancreas, such as type 1 diabetes.

“Our ability to generate liver and pancreatic cells from stem cells has fallen behind the advances we’ve made for other cell types,” said Maike Sander, MD, professor of paediatrics and cellular and molecular medicine and director of the Pediatric Diabetes Research Center at UC San Diego.

“So we haven’t yet been able to do things like test new drugs on stem cell-derived liver and pancreatic cells. What we have learned is that if we want to make specific cells from stem cells, we need ways to predict how those cells and their chromosomes will respond to the growth factors.”

Sander led the study, together with co-senior author Bing Ren, PhD, professor of cellular and molecular medicine at UC San Diego and Ludwig Cancer Research member.

Chromosomes are the structures formed by tightly wound and packed DNA. Humans have 46 chromosomes – 23 inherited from each parent. Sander, Ren and their teams first made maps of chromosomal modifications over time, as embryonic stem cells differentiated through several different developmental intermediates on their way to becoming pancreatic and liver cells. Then, in analysing these maps, they discovered links between the accessibility (openness) of certain regions of the chromosome and what they call developmental competence – the ability of the cell to respond to triggers like added growth factors.

“We’re also finding that these chromosomal regions that need to open before a stem cell can fully differentiate are linked to regions where there are variations in certain disease states,” Sander says.

In other words, if a person were to inherit a genetic variation in one of these chromosomal regions and his or her chromosome didn’t open up at exactly the right time, he or she could hypothetically be more susceptible to a disease affecting that cell type. Sander’s team is now working to further investigate what role, if any, these chromosomal regions and their variations play in diabetes.

Source: UCSD

Contact: Heather Buschman

Reference:

Epigenetic Priming of Enhancers Predicts Developmental Competence of hESC-Derived Endodermal Lineage Intermediates

Allen Wang, Feng Yue, Yan Li, Ruiyu Xie, Thomas Harper, Nisha A. Patel, Kayla Muth, Jeffrey Palmer, Yunjiang Qiu, Jinzhao Wang, Dieter K. Lam, Jeffrey C. Raum, Doris A. Stoffers, Bing Ren, Maike Sander

Cell Stem Cell, Volume 16, Issue 4, p386–399, 2 April 2015, DOI: http://dx.doi.org/10.1016/j.stem.2015.02.013

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