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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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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From Pluripotency to Totipotency

Scientists discover mechanism that may lead to more efficient reprogramming of somatic cells

Wednesday, 05 August 2015

Human embryonic stem cells have the potential

to form in vitro neural tube-like structures of the

embryo. Credit: Inserm/Benchoua Alexandra.

While it is already possible to obtain in vitro pluripotent cells (i.e., cells capable of generating all tissues of an embryo) from any cell type, researchers from Maria-Elena Torres-Padilla's team from Institut de Génétique et de Biologie Moléculaire et Cellulaire, have pushed the limits of science even further. They managed to obtain totipotent cells with the same characteristics as those of the earliest embryonic stages and with even more interesting properties. Obtained in collaboration with Juanma Vaquerizas from the Max Planck Institute for Molecular Biomedicine (Münster, Germany), these results are published on 3rd of August in the journal Nature Structural & Molecular Biology.

Totipotency vs pluripotency

Just after fertilization, when the embryo is comprised of only 1 or 2 cells, cells are "totipotent", that is to say, capable of producing an entire embryo as well as the placenta and umbilical cord that accompany it. During the subsequent rounds of cell division, cells rapidly lose this plasticity and become "pluripotent". At the blastocyst stage (about thirty cells), the so-called "embryonic stem cells" can differentiate into any tissue, although they alone cannot give birth to a foetus anymore. Pluripotent cells then continue to specialise and form the various tissues of the body through a process called cellular differentiation.

For some years, it has been possible to re-programme differentiated cells into pluripotent ones, but not into totipotent cells. Now, the team of Maria-Elena Torres-Padilla has studied the characteristics of totipotent cells of the embryo and found factors capable of inducing a totipotent-like state.

“Totipotency is a much more flexible state than the pluripotent state and its potential applications are extraordinary”, says Maria-Elena Torres-Padilla, who led the study.

Looking for the keys of totipotency

When culturing pluripotent stem cells in vitro, a small amount of totipotent cells appear spontaneously; these are called "2C-like cells" (named after their resemblance to the 2-cell stage embryo). The researchers compared these cells to those present in early embryos in order to find their common characteristics and those that make them different from pluripotent cells. In particular, the teams found that the DNA was less condensed in totipotent cells and that the amount of the protein complex CAF1 was diminished. A closer look revealed that CAF1 – already known for its role in the assembly of chromatin (the organised state of DNA) – is responsible for maintaining the pluripotent state by ensuring that the DNA is wrapped around histones. Based on this hypothesis, the Torres-Padilla team was able to induce a totipotent state by inactivating the expression of the CAF1 complex, which led to chromatin reprogramming into a less condensed state.

A 2C-like cell (green) is different from an

embryonic stem cell (magenta). Credit:

IGBMC/Maria-Elena Torres-Padilla.

In order to carefully examine at a molecular level the similarities between 2-cell stage embryos, 2C-like cells and those induced by inactivating the CAF1 complex, the Torres-Padilla team then joined forces with the Vaquerizas laboratory to analyse, in a genome-wide fashion, the gene expression programmes of these cells. The scientists found that the induced, CAF1-depleted, totipotent cells overexpressed a significant amount of 2-cell stage embryo genes.

“One could imagine that if cells lose their ability to assemble chromatin, this would affect gene expression”, explains Cells-in-Motion PhD student Rocio Enriquez-Gasca of Juanma Vaquerizas’ lab, who performed the computational analyses of the work.

“So it was really exciting to realise that the resulting gene expression programme in fact significantly overlaps with that of early embryo, totipotent cells”.

Moreover, the teams found that specific classes of repetitive elements (repeated sequences of DNA that form around 50% of the mouse and human genomes) were also up-regulated in induced totipotent-like cells, a hallmark of the 2-cell embryo.

“The computational analysis of expression of repetitive elements is very challenging, since these are found many times in the genome”, says Juanma Vaquerizas.

“Now it is key to understand why these repetitive elements and gene expression programmes are both up-regulated in totipotent cells”.

These results provide new elements for the understanding of pluripotency and could increase the efficiency of reprogramming somatic cells to be used for applications in regenerative medicine.

Source: INSERM

Contact: Maria-Elena Torres-Padilla 

Reference:

Early embryonic-like cells are induced by down-regulation of replication-dependent chromatin assembly

Takashi Ishiuchi, Rocio Enriquez-Gasca, Eiji Mizutani, Ana Boškovi, Celine Ziegler-Birling, Diego Rodriguez-Terrones, Teruhiko Wakayama, Juan M. Vaquerizas & Maria-Elena Torres-Padilla

Nature Structural & Molecular Biology, 3 Aug 2015, doi:10.1038/nsmb.3066

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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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Stem Cells Make Similar Decisions to Humans

Stem Cells Make Similar Decisions to Humans

Wednesday, 25 March 2015

Pancreas explant. 

Scientists at the University of Copenhagen have captured thousands of progenitor cells of the pancreas on video. They have filmed the cells making decisions to both divide and expand the organ or to specialize into the endocrine cells that regulate our blood sugar levels.

The new study reveals that stem cells behave as people in a society, making individual choices but with enough interactions to bring them to their end-goal. The results could eventually lead to a better control over the production of insulin-producing endocrine cells for diabetes therapy.

The research is published in the scientific journal PLOS Biology.

Why one cell matters

In a joint collaboration between the University of Copenhagen and University of Cambridge, Professor Anne Grapin- Botton and a team of researchers including Assistant Professor Yung Hae Kim from DanStem focused on marking the progenitor of the embryonic pancreas, commonly referred to as ‘mothers’, and their ‘daughters’ in different fluorescent colours and then captured them on video to analyse how they make decisions.

Prior to this work, there were methods to predict how specific types of pancreas cells would evolve as the embryo develops. However, by looking at individual cells, the scientists found that even within one group of cells presumed to be of the same type, some will divide many times to make the organ bigger while others will become specialized and will stop dividing.

The scientists witnessed interesting occurrences where the ‘mother’ of two ‘daughters’ made a decision and passed it on to the two ‘daughters’ who then acquired their specialization in synchrony. By observing enough cells, they were able to extract logic rules of decision-making, and with the help of Dr Pau Rué, a mathematician from the University of Cambridge, they developed a mathematical model to make long-term predictions over multiple generations of cells.

Stem cell movies

"It is the first time we have made movies of a quality that is high enough to follow thousands of individual cells in this organ, for periods of time that are long enough for us to follow the slow decision process. The task seemed daunting and technically challenging, but fascinating,” says Professor Grapin-Botton. 

"With these movies we can see and quantify the dynamics of decisions in each cell in the context of the organ, in a way that will inspire the study of many other organs," says Assistant Professor Yung Hae Kim.

"To complement the movies, which are done on isolated pancreas, we developed a method to visualize the family tree of cells in the untouched organ. We initially focused on one generation but now we are also observing their descendants over multiple generations," Kim elaborates.

Next steps in diabetes therapy

The project has been focused on basic research and is highly theoretical, but it now provides tools to control whether a cell should expand or specialize into an endocrine cell on its way to producing insulin.

“It is a worldwide quest to produce such insulin-producing cells from stem cells, for their transplantation in diabetic patients. In the future, this could be done by increasing the probability of specialization or by pushing ‘mother’ cells to pass on the decision to specialize to their two daughters”, Grapin-Botton concludes.

Source: University of Copenhagen

Contact: Yung Hae Kim

Reference:

Cell Cycle–Dependent Differentiation Dynamics Balances Growth and Endocrine Differentiation in the Pancreas

Yung Hae Kim , Hjalte List Larsen, Pau Rué, Laurence A. Lemaire, Jorge Ferrer and Anne Grapin-Botton 

PLOS Biology, March 18, 2015, DOI: 10.1371/journal.pbio.1002111

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NIH-Supported Researchers Map Epigenome of More Than 100 Tissue and Cell Types

NIH-Supported Researchers Map Epigenome of More Than 100 Tissue and Cell Types

Thursday, 19 February 2015

Much like mapping the human genome laid the foundations for understanding the genetic basis of human health, new maps of the human epigenome may further unravel the complex links between DNA and disease. The epigenome is part of the machinery that helps direct how genes are turned off and on in different types of cells.

Researchers supported by the National Institutes of Health Common Fund's Roadmap Epigenomics Program have mapped the epigenomes of more than 100 types of cells and tissues, providing new insight into which parts of the genome are used to make a particular type of cell. The data, available to the biomedical research community, can be found at the National Center for Biotechnology Information website.

Reference epigenomes are available for more than 100 cell and tissue types.
Credit: Image courtesy of Nature and Roadmap Epigenomics Consortium. 

"This represents a major advance in the ongoing effort to understand how the 3 billion letters of an individual's DNA instruction book are able to instruct vastly different molecular activities, depending on the cellular context," said NIH Director Francis Collins, M.D., Ph.D.

"This outpouring of data-rich publications, produced by a remarkable team of creative scientists, provides powerful momentum for the rapidly growing field of epigenomics."

Researchers from the NIH Common Fund's Roadmap Epigenomics Program published a description of the epigenome maps in the journal Nature. More than 20 additional papers, published in Nature and Nature-associated journals, show how these maps can be used to study human biology.

"What the Roadmap Epigenomics Program has delivered is a way to look at the human genome in its living, breathing nature from cell type to cell type," said Manolis Kellis, Ph.D., professor of computer science at the Massachusetts Institute of Technology, Cambridge, and senior author of the paper.

Understanding epigenomics

Almost all human cells have identical genomes that contain instructions on how to make the many different cells and tissues in the body. During the development of different types of cells, regulatory proteins turn genes on and off and, in doing so, establish a layer of chemical signatures that make up the epigenome of each cell. In the Roadmap Epigenomics Program, researchers compared these epigenomic signatures and established their differences across a variety of cell types. The resulting information can help us understand how changes to the genome and epigenome can lead to conditions such as Alzheimer's disease, cancer, asthma, and foetal growth abnormalities.

An epigenomic signature can be made on the

genome in two ways, both of which play a role in

turning genes off or on. The first occurs when

chemical tags called methyl groups are attached

to a DNA molecule directly (DNA methylation).

The second occurs when a variety of chemical

tags attach to the tails of histone proteins that

package DNA (histone modifications). Credit:

Image courtesy of John Stamatoyannopoulos

and Rae Senarighi. 

The value of epigenomic data

Researchers can now take data from different cell types and directly compare them.

"Today, sequencing the human genome can be done rapidly and cheaply, but interpreting the genome remains a challenge," said Bing Ren, Ph.D., professor of cellular and molecular medicine at the University of California, San Diego, and co-author of the Nature paper and several of the associated papers.

"These 111 reference epigenome maps are essentially a vocabulary book that helps us decipher each DNA segment in distinct cell and tissue types. These maps are like snapshots of the human genome in action."

"This is the most comprehensive catalogue of epigenomic data from primary human cells and tissues to date," said Lisa Helbling Chadwick, Ph.D., project team leader and a program director at the National Institute of Environmental Health Sciences (NIEHS), part of NIH.

"This coordinated effort, along with uniform data processing, makes it much easier for researchers to make direct comparisons across the entire data set."

"Researchers from the 88 projects supported by the program, including those from this recent series of papers, have propelled the development of new epigenomic technologies," said John Satterlee, Ph.D., co-coordinator of the Roadmap Epigenomics Program, and program director at the National Institute on Drug Abuse (NIDA), part of NIH. Satterlee added that the work of this program has served as a foundation for continued exploration of the human epigenome through the International Human Epigenome Consortium.

"With this increased understanding of the full epigenome, and the datasets available to the entire scientific community, the NIH Common Fund is striving to catalyse future research, to aid the understanding of how epigenomics plays a role in human diseases, with the expectation that further studies will identify early indications of disease and targets for therapeutics," said James Anderson, M.D., Ph.D., director of NIH Division of Program Coordination, Planning, and Strategic Initiatives that oversees the NIH Common Fund.

NIDA, NIEHS, and the National Institute on Deafness and Other Communication Disorders are co-administrators of the NIH Common Fund's Epigenomics Program.

Source: National Institute of Environmental Health Sciences

Contact: Robin Mackar

Reference:

Integrative analysis of 111 reference human epigenomes

Roadmap Epigenomics Consortium

Nature, (2015); doi: 10.1038/nature14248

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