Researchers Reconstruct Early Stages of Embryo Development

Researchers Reconstruct Early Stages of Embryo Development

Tuesday, 04 November 2014

Researchers at the University of Cambridge have managed to reconstruct the early stage of mammalian development using embryonic stem cells, showing that a critical mass of cells – not too few, but not too many – is needed for the cells to being self-organising into the correct structure for an embryo to form.

All organisms develop from embryos: a cell divides generating many cells. In the early stages of this process, all cells look alike and tend to aggregate into a featureless structure, more often than not a ball. Then, the cells begin to 'specialise' into different types of cell and space out asymmetrically, forming an axis which begins to provide a structure for the embryo to develop along.

In animal embryos this stage is followed by a process known as gastrulation: a choreographed movement of the cells that, using the initial axis as a reference, positions the head and the tail, the front and the back. During the process, the cells begin to form three distinct layers: the endoderm, mesoderm and ectoderm, determining which tissues or organs the cells will then develop into.

Professor Alfonso Martinez-Arias from the Department of Genetics at the University of Cambridge, who led the research, says:

"Gastrulation was described by biologist Professor Lewis Wolpert as being 'truly the most important event in your life' because it creates the blueprint of an organism. Axis formation and gastrulation are the two central processes that initiate the development of an organism and are inextricably associated with the embryo. We have managed to recreate this for the first time in the lab."

Professor Martinez-Arias and colleagues, supported by the European Research Council and the Wellcome Trust, have reconstructed these early stages of development using mouse embryonic stem cells. Embryonic stem cells, discovered in the Department of Genetics in the 1980s (for which Sir Martin Evans was awarded the Nobel Prize in Physiology or Medicine 2007), have become an important tool for developmental biology, understanding disease, and in regenerative medicine due to the ability to give rise to all cell types in culture. Over the last few years, they have been used to 'grow' organs including the eye and the cerebral cortex; surprisingly, these structures develop without an axis.

In research published today in the journal Development, the researchers report a way to coax cells to reorganize in the manner that they do in an embryo, creating an axis and undergoing movements and organisations that mimic the process of gastrulation. Over the years researchers have been making aggregates of embryonic stem cells to obtain certain cell types, for example red blood cells. However, these aggregates lack structure and the different cell types emerge in a disorganised fashion. This is the first time that researchers have been able to elicit axis formation, spatial organisation and gastrulation-like movements from aggregates of embryonic stem cells.

The researchers show that if the number of cells aggregated initially is similar to that of a mouse embryo, the cells generate a single axis and this serves as a template for a sequence of events that mimics those of the early embryo. By manipulating the signals that the cells see at a particular time, the researchers were able to influence what type of cell they become and how they are organised. In one of the experiments, for example, activation of a particular signal at the correct time elicits the appearance of the mesoderm, endoderm and ectoderm – the precursors of all cell types – with a spatial organization similar to that of an embryo.

Using this experimental system, the researchers were able to generate the early stages of a spinal cord, which they showed forms as part of the process of gastrulation. This finding complements previous research from the University of Edinburgh and the National Institute for Medical Research which showed that embryonic stem cells can be coaxed into this spinal cord cells; however, the Cambridge researchers showed that in the embryo-like aggregates, the structural organization is more robust and allows for the polarised growth of the tissue.

Professor Martinez-Arias adds:

"It is early days but this system promises insights into the early stages of development and what determines the specification of the different cell types. This will allow more robust protocols for differentiation with cues that mimic those that the cells are subject to in embryos.”

"Most significantly, the system will provide a means to test, experimentally, how a homogeneous group of cells organizes itself in space, a central process in the development of any organism, and the ability to recreate in culture the niches that adult stem cells create during embryogenesis and which have remained elusive experimentally."

Source: University of Cambridge

Contact: Craig Brierley

References:

Symmetry breaking, germ layer specification and axial organisation in aggregates of mouse ES cells

Susanne C. van den Brink, Peter Baillie-Johnson, Tina Balayo, Anna-Katerina Hadjantonakis, Sonja Nowotschin, David A. Turner, and Alfonso Martinez Arias

Development 2014 141:4231-4242; doi:10.1242/dev.113001

Wnt/β-catenin and FGF signalling direct the specification and maintenance of a neuromesodermal axial progenitor in ensembles of mouse ES cells

David A. Turner, Penelope C. Hayward, Peter Baillie-Johnson, Pau Rué, Rebecca Broome, Fernando Faunes, and Alfonso Martinez Arias

Development; 2014 141:4243-4253; doi:10.1242/dev.112979

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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

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Human Skin Cells Reprogrammed Directly into Brain Cells

Human Skin Cells Reprogrammed Directly into Brain Cells

Wednesday, 22 October 2014

Scientists have described a way to convert human skin cells directly into a specific type of brain cell affected by Huntington's disease, an ultimately fatal neurodegenerative disorder. Unlike other techniques that turn one cell type into another, this new process does not pass through a stem cell phase, avoiding the production of multiple cell types, the study's authors report.

Scientists have described a way to convert

human skin cells directly into a specific type of

brain cell affected by Huntington's disease, an

ultimately fatal neurodegenerative disorder.

Unlike other techniques that turn one cell type

into another, this new process does not pass

through a stem cell phase, avoiding the

production of multiple cell types, the study's

authors report. The researchers, at Washington

University School of Medicine in St. Louis,

demonstrated that these converted cells survived

at least six months after injection into the brains

of mice and behaved similarly to native cells in

the brain. Human skin cells (top) can be

converted into medium spiny neurons (bottom)

with exposure to the right combination of

microRNAs and transcription factors, according

to work by Andrew Yoo and his research team. 

Credit: Yoo lab.

The researchers, at Washington University School of Medicine in St. Louis, demonstrated that these converted cells survived at least six months after injection into the brains of mice and behaved similarly to native cells in the brain.

"Not only did these transplanted cells survive in the mouse brain, they showed functional properties similar to those of native cells," said senior author Andrew S. Yoo, PhD, assistant professor of developmental biology.

"These cells are known to extend projections into certain brain regions. And we found the human transplanted cells also connected to these distant targets in the mouse brain. That's a landmark point about this paper."

The work appears Oct. 22 in the journal Neuron.

The investigators produced a specific type of brain cell called medium spiny neurons, which are important for controlling movement. They are the primary cells affected in Huntington's disease, an inherited genetic disorder that causes involuntary muscle movements and cognitive decline usually beginning in middle-adulthood. Patients with the condition live about 20 years following the onset of symptoms, which steadily worsen over time.

The research involved adult human skin cells, rather than more commonly studied mouse cells or even human cells at an earlier stage of development. In regard to potential future therapies, the ability to convert adult human cells presents the possibility of using a patient's own skin cells, which are easily accessible and won't be rejected by the immune system.

Scientists have described a way to convert

human skin cells directly into a specific type of

brain cell affected by Huntington's disease, an

ultimately fatal neurodegenerative disorder.

Unlike other techniques that turn one cell type

into another, this new process does not pass

through a stem cell phase, avoiding the

production of multiple cell types, report

researchers at Washington University School of

Medicine in St. Louis. The investigators,

including Andrew Yoo, PhD, (from left) Michelle

Richner and Matheus Victor, demonstrated that

these converted cells survived at least six months

after injection into the brains of mice and

behaved similarly to native cells in the brain. 

Credit: Daniel Abernathy.

To reprogram these cells, Yoo and his colleagues put the skin cells in an environment that closely mimics the environment of brain cells. They knew from past work that exposure to two small molecules of RNA, a close chemical cousin of DNA, could turn skin cells into a mix of different types of neurons.

In a skin cell, the DNA instructions for how to be a brain cell, or any other type of cell, are neatly packed away, unused. In past research published in Nature, Yoo and his colleagues showed that exposure to two microRNAs called miR-9 and miR-124 altered the machinery that governs packaging of DNA. Though the investigators still are unravelling the details of this complex process, these microRNAs appear to be opening up the tightly packaged sections of DNA important for brain cells, allowing expression of genes governing development and function of neurons.

Knowing exposure to these microRNAs alone could change skin cells into a mix of neurons, the researchers then started to fine tune the chemical signals, exposing the cells to additional molecules called transcription factors that they knew were present in the part of the brain where medium spiny neurons are common.

"We think that the microRNAs are really doing the heavy lifting," said co-first author Matheus B. Victor, a graduate student in neuroscience.

"They are priming the skin cells to become neurons. The transcription factors we add then guide the skin cells to become a specific subtype, in this case medium spiny neurons. We think we could produce different types of neurons by switching out different transcription factors."

Yoo also explained that the microRNAs, but not the transcription factors, are important components for the general reprogramming of human skin cells directly to neurons. His team, including co-first author Michelle C. Richner, senior research technician, showed that when the skin cells were exposed to the transcription factors alone, without the microRNAs, the conversion into neurons wasn't successful.

The researchers performed extensive tests to demonstrate that these newly converted brain cells did indeed look and behave like native medium spiny neurons. The converted cells expressed genes specific to native human medium spiny neurons and did not express genes for other types of neurons. When transplanted into the mouse brain, the converted cells showed morphological and functional properties similar to native neurons.

To study the cellular properties associated with the disease, the investigators now are taking skin cells from patients with Huntington's disease and reprogramming them into medium spiny neurons using the approach described in the new paper. They also plan to inject healthy reprogrammed human cells into mice with a model of Huntington's disease to see if this has any effect on the symptoms.

Source: Washington University School of Medicine

Contact: Julia Evangelou Strait

Reference:

Generation of human striatal neurons by microRNA-dependent direct conversion of fibroblasts

Victor MB, Richner M, Hermanstyne TO, Ransdell JL, Sobieski C, Deng PY, Klyachko VA, Nerbonne JM, Yoo AS

Neuron. Oct. 22, 2014, Volume 84, Issue 2, p311–323

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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

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Shopping for an Egg Donor

Is beauty, brains, or health most important?

Tuesday, 21 October 2014

Human egg cell. 

When it comes to picking an egg donor, until recent years, recipients tended to prefer someone with a similar appearance. Donor trait choices are changing, though, and which traits are now more preferable and why is the focus of "Beauty, Brains or Health: Trends in Ovum Recipient Preferences," an article published in Journal of Women's Health, a peer-reviewed publication from Mary Ann Liebert, Inc., publishers. The article is available free on the Journal of Women's Health website at http://online.liebertpub.com/doi/full/10.1089/jwh.2014.4792 until November 20, 2014.

Homero Flores, MD and coauthors from Reproductive Medicine Associates of New York and Icahn School of Medicine at Mount Sinai (New York, NY) reviewed the requests of ovum donor recipients over a 5-year period and assessed their preferences for donor traits, categorizing them by appearance, ethnicity, intellect, ability, and mental health. The authors documented statistically significant increases and decreases in the different categories over the years, with more "practical traits" that would improve offspring's overall quality of life tending to increase compared to "self-reflective" traits.

"As social acceptance of ovum donation has increased, and donor selection has become more sophisticated, couples are changing their preferences for what donor characteristics they value most for their future offspring," says Susan G. Kornstein, MD, Editor-in-Chief of Journal of Women's Health, Executive Director of the Virginia Commonwealth University Institute for Women's Health, Richmond, VA, and President of the Academy of Women's Health.

Source: Mary Ann Liebert, Inc./Genetic Engineering News

Contact: Kathryn Ryan

Reference:

Beauty, Brains or Health: Trends in Ovum Recipient Preferences

Flores Homero, Lee Joseph, Rodriguez-Purata Jorge, Witkin Georgia, Sandler Benjamin, and Copperman Alan B.

Journal of Women's Health. October 2014, 23(10): 830-833. doi:10.1089/jwh.2014.4792

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ZenMaster

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For more on stem cells and cloning, go to CellNEWS at

http://cellnews-blog.blogspot.com/

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