The craftsmanship of mimicking embryogenesis in a dish – BioNews

The regulatory mechanisms governing organ development are, in general, poorly defined. To recreate the complex processes involved in organ growth and maturation, scientists have started fiddling with three-dimensional (3D) cell culture. The 3D self-organisation cell/tissue culture approach is conceptually quite different from standard tissue engineering, where cells are cultured in a flat 2D environment. The idea behind itis that realistic tissue formation is dictated both by the internal processes of the cells, and their interactions with the surrounding environment, including communication with neighbouring cells. Therefore, in vivo tissue development could be more accurately simulated by placing cells within an optimal 3D microenvironment.

A breakthrough happened in 2011, when a Japanese group from RIKEN Centre for Developmental Biology in Kobe reported that in a 3D culture of mouse embryonic stem cell aggregates, the cells self-organised to form organoid tissues including an eyecup-like structure and a functional frontal part of the pituitary gland (1, 2). Although mice are not men, in biological science a standard path is to be able to reproduce in human systems what was discovered first in mice. Indeed, a couple of years later, a team from Austria grew cerebral organoids with discrete brain regions by placing human pluripotent stem cells in a 3D culture system (3).

The next major game-changer in the field of organoids was a study reporting self-assembly of functional human liver 'buds'. Liver buds are functional units formed at the early stages of organ development (4). This time, the starting point was not 3D aggregates of one pluripotent stem cell line; instead, three different cell types liver cells derived from induced pluripotent stemcells, connective tissue stem cells, and blood vessel cells were mixed in a specific ratio, which led to the self-assembly of a functional liver bud. Such functional organoids, built from several distinct cell types, represent a new generation of organoids. By using advanced genome editing techniques, such as CRISPR, to interfere with a single gene expression or function in each of the participating cell types, we will be able to study the complex cell communication signals that govern organogenesis. We will be able to define which cell type is providing which signalling molecules and what their roles are establishing the different cell types that make up tissue.

The laboratory of Professor Magdalena Zernicka-Goetz from the University of Cambridge used a similar approach to generate structures highly resembling post-implantation mouse embryos (5). They combined a single mouse embryonic stem cell with a small clump of three trophoblast stem cells (stem cells that would form the placenta), and cultured them within Matrigel, a 3D extracellular matrix (ECM) scaffold, in a medium that allowed both cell types co-develop. To examine the cross-talk between the two cells types and the signalling pathways involved, the team used cell lines with specific mutations in one of the two cell types, and monitored how lack of a specific gene and/or signal affected the morphogenesis of an embryo-like structure.

I do not see why we would not be technically able to mimic human embryogenesis in a dish using a similar approach. However, I could see how that can be viewed with a touch of controversy even though, in my mind, there are no ethical issues or controversy at all. Although the embryo-like structures might resemble human embryos in vivo, they would have no potential to develop into a live organism. To those prophets who would see such development as a collapse of ethos and humanity, I want to say that I am pretty confident that in the future women will still be a part of our society. They will still be pregnant and they will still deliver babies. They will not be replaced with incubators nurturing endless copies of some future version of Kim Jong-un, Vladimir Putin or Donald Trump. Pregnancy and fetal development are too complex to be simulated.

The future of this work, as I see it, is not only as a 'powerful platform to dissect physical and molecular mechanisms that mediate critical crosstalk during natural embryogeneisis', as the Cambridge team say (5), but also as a sophisticated model for human embryotoxicity screening, to learn more about embryo development and the causes of infertility. Currently used in vitro testing protocols are based on animal embryos, not human embryos, and therefore lack specificity and predictability. This model has the potential to be used for large-scale throughput screening of the multiple stages of human embryo development. By studying and testing these stages, we can learn about the growth and differentiation processes of the embryo in great detail. Furthermore, we can test in vitro whether potential drug candidates affect any of these early embryo development stages. In such a way the embryotoxic or cancerous potential of an agent could be easily assessed in a human system, and many unexplained infertility cases classified as 'infertility of unknown etiology' could be resolved and appropriately addressed.

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The craftsmanship of mimicking embryogenesis in a dish - BioNews

For The First Time Ever, Scientists Have Successfully Created An … – Wall Street Pit

For The First Time Ever, Scientists Have Successfully Created An Artificial Embryo

It may soon become possible to grow artificial human life in a lab by using stem cells to create an actual embryo. While that might creep some people out because it sure sounds a lot like a precursor to designer babies or even clones, the scientists doing the research would like to make it clear that their intention is something totally different.

By growing embryos and replicating what happens during the early stages of reproduction, they are hoping that they will be able to understand why more than two out of three miscarriages happen, and use then this knowledge to prevent or at least minimize such unfortunate circumstances. In other words, the research is being done to help prevent the loss of lives, not create artificial ones.

Right now, scientists are only allowed to conduct experiments on embryos developed from egg cells donated through in vitro fertilization (IVF) clinics. There arent many of those, however. Plus, regulations (and ethics) dictate that they have to be destroyed after 14 days. But by being able to create their own unlimited supply of artificial embryos, research can be done faster and more extensively. As an added bonus, ethics will not be an issue.

To create the embryos, a research team from the University of Cambridge led by Professor Magdalena Zernicka-Goetz combined embryonic stem cells (ESCs) with extra-embryonic trophoblast stem cells or TSCs (the ones responsible for forming the placenta during a normal pregnancy).

Previous attempts to grow embryos didnt work because only embryonic stem cells were used and this prevented the cells from assembling in their correct positions. Adding the second type of placental stem cell solved this problem.

According to Professor Goetz, although they are aware that interaction between different types of stem cells is important for development, their experiment showed just how important that partnership was. After adding the extra-embryonic trophoblast stem cells, the two types of stem cells began communicating with each other, almost like guiding and telling each other where to go, what to do, and when to do it, until they were eventually able to form an embryo-like structure appearance-wise and behavior-wise, with separate clusters that will give rise to the different body organs, if development was allowed to continue.

The research team is quick to point out, however, that this is as far as they will allow it to progress. In other words, the artificial embryo will not continue to grow into a fetus because it will need a third type of stem cell for that one which forms the yolk sac that is responsible for providing nutrition.

So far, the technique has only been tested on mouse stem cells. Eventually, the team hopes to achieve the same results on human stem cells. And that might prove to be the key that can potentially help solve the problem of failed pregnancies in the future.

As Professor Goetz said in a statement she issued, the team is very optimistic that this will allow [them] to study key events of this critical stage of human development without actually having to work on embryos. Knowing how development normally occurs will allow us [noted Goetz] to understand why it so often goes wrong.

The research was recently published in the journal Science.

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For The First Time Ever, Scientists Have Successfully Created An ... - Wall Street Pit

Treating sickle cell disease with gene therapy – Jamaica Observer

After nearly two years of debate about its possible benefits and risks, the gene editing technique is now here to stay.

An article in the December 27, 2015 edition of the Sunday Observer told of the first recorded use of the inexpensive CASPR-Cas9 gene editing technology to cut and splice out bad genes and replace them with healthy genes.

INHERITED DISEASE

A gene is a unit of heredity that is passed down from parent to child, and which carries characteristics that become apparent in the child. Each cell of the human body has around 25,000 genes, and each of those genes carry information that determines the individual traits or features of the person. So there is a gene for eye colour, hair colour, skin colour, and so on.

However, when some genes are defective or they undergo changes or mutation, illnesses can occur. Illnesses may also occur when there are missing genes which should have played a particular role. Some of the problems with genes may also be inherited from a parent.

One such illness well known to us in Jamaica is sickle cell disease. This is a severe hereditary disease in which the haemoglobin protein that is present in red blood cells to carry oxygen around the body is mutated and abnormal. Red blood cells are customarily round and circular in shape to flow smoothly through our blood vessels, but when oxygen levels are low in the bloodstream, the abnormal haemoglobin that is present in people with sickle cell disease cause the red blood cells to bend into a sickle crescent shape, making it difficult for them to flow through the tiny blood vessels of the body, and consequently may cause severe joint pains and other complications.

GENE THERAPY

The concept behind gene therapy is to use the technology of genetic engineering to replace abnormal genes with healthy ones.

Whilst this concept has been around for 30 years, the process became much more accessible with the development of the inexpensive CASPR-Cas9 gene editing technology around two years ago.

In April 2015, scientists in China were able to use the technology to splice out bad genes that were present in human embryonic stem cells and replace them with healthy ones. The stem cells, however, were never implanted into women at the time for their development into humans.

In December 2015, a speaker at the annual symposium of the American Society of Hematology described possible work in which an infant with sickle cell disease would have his or her blood stem cells edited to repair the haemoglobin gene, thereby preventing the formation of blood cells that would have caused sickling. The specific work would involve harvesting the blood stem cells of the diseased infant, editing them outside the body with a normal DNA sequence, then returning them to the infant in a bone marrow transplant.

ETHICAL CONCERNS

As this technique involved editing the haemoglobin gene within the somatic stem cell rather than in the embryonic stem cell, this choice was deemed by many to be the more ethically acceptable approach. Many people are very concerned that the gene editing technique may be used to make long-lasting hereditable changes at the embryo stage or on germ cells (human sperm or eggs), and some find this unacceptable.

This notwithstanding, in February 2016, the United Kingdom Fertilisation and Embryology Authority, who are the UK regulators on fertility matters, granted permission for scientists in London to edit the genomes (the complete set of genetic instructions, which includes all genes) of human embryos for research purposes. The developmental biologists were allowed to use the gene editing technique in healthy embryos to alter genes that are active within the first few days after fertilisation of the egg.

The approved research would utilise healthy human embryos that had been left over from in vitro fertilisation procedures performed in fertility clinics. However, the caveat was that the researchers should stop the research after seven days of study, and the researched embryos destroyed. The study would illuminate how the modification of genes could assist in developing treatments for infertility.

MOST RECENT SUCCESS

A report in the most recent edition of the New England Journal of Medicine informed that a teenage boy with sickle cell disease appeared to have been cured using the gene therapy technique. The treatment had stopped the painful symptoms of the disease, and the teenager was doing well.

Success stories such as this are normally the first step in efforts to reproduce the benefits obtained in individual cases by conducting clinical trials of the treatment on large groups of affected people. Hopefully we will hear of such studies and their outcomes in the near future.

Until preliminary results are verified, however, scepticism will exist regarding whether the positive results obtained in one person will be translated to many more people. Time will tell.

Derrick Aarons MD, PhD is a consultant bioethicist/family physician, a specialist in ethical issues in medicine, the life sciences and research, and is the Ethicist at the Caribbean Public Health Agency CARPHA. (The views expressed here are not written on behalf of CARPHA)

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Treating sickle cell disease with gene therapy - Jamaica Observer

No egg? No sperm? No problem. First artificial embryo made from stem cells – Genetic Literacy Project

Using stem cells in grown-on 3D scaffolding in a laboratory petri dish, scientists have for the first time created an embryo made entirely from stem cells.

The artificial mouse embryois a major step toward creating synthetic embryos that closely resemble natural ones. It could shed light on early development and help improve fertility treatment procedures.

[W]ithout using an egg in some way, scientists have had difficulty getting cells to communicate with each other early in developmentThe Cambridge team got around this issue by taking embryonic stem cells (cells found in embryos that can mature into any type of body tissue) and growing them alongside trophoblast stem cells (the cells that produce the placenta).

The goal is not necessarily to create a real mouse from these cellsand the science is still a ways from that anywayBut being able to study the way the cells develop in the very early days of an embryos life could shed important light into early development. The Cambridge researchers, for example, engineered different cell types to glow different colors so that they might track how they behave as the embryo develops.

[The study can be found here.]

The GLP aggregated and excerpted this blog/article to reflect the diversity of news, opinion, and analysis. Read full, original post:Scientists Have Created the First Artificial Embryo Without Using an Egg or Sperm

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No egg? No sperm? No problem. First artificial embryo made from stem cells - Genetic Literacy Project

COMMENTARY: Saving a 10-year-old’s life but at what cost? – Globalnews.ca

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A researcher pulls a frozen vial of human embryonic stem cells at the University of Michigan Center for Human Embryonic Stem Cell Research Laboratory in Ann Arbor, Mich.

Im no Nostradamus. Neither was Nostradamus, come to think of it. But one doesnt need to be to see how ethically icky, in the professional vernacular, the future of medicine is going to be.

To paraphrase Captain Kirk, our medical tools are growing faster than our wisdom. The future isnt now, yet, but its closer than we realized. And almost certainly closer than were ready for.

Consider the case of the Al Sabbagh family. They recently arrived in Canada from Syria, with their children, including their son, Mohamad. Mohamad is 10 and suffers from idiopathic aplastic anemia, a rare condition. Mohamad has a severe case, and it would likely be fatal if untreated.

READ MORE:Could you save his life? Edmonton boy needs to find stem cell match

His illness has left his body incapable of producing blood cells necessary to remain healthy. According to a report in the CBC, he requires twice-weekly blood transfusions at the Hospital for Sick Children in Toronto. Even with those, his quality of life has absolutely been impacted.

Theres a chance for Mohamad to live a healthy, normal life. A bone marrow transplant could restore his ability to produce the blood cells he needs. But the donor must be a very, very close match. Mohamads parents are not optimal donors, neither are his siblings. Its also possible to seek a donor through public donor banks, but you want as close a genetic match as possible.

Canadas Arab population is relatively small, and the number of those Canadian-Arabs whove put their information into a donor registry is even smaller. The odds for young Mohamad are long.

READ MORE:Quebec family hopes to raise awareness for patients in need with stem cell registry drive

Thats led his parents to consider a remarkable step. New embryos could be created, using in vitro fertilization techniques, using the genetic material of his parents. The embryos can then be genetically screened, with only the best match implanted into Mohamads mother for gestation and delivery. That baby could then be used to provide a potentially life-saving transplant of stem cells into Mohamad.

If all went well, Mohamads bone marrow would regenerate, curing his illness. The infant would not be endangered (the donor cells would be collected from the umbilical cord blood, not the infants body).

There aretwo equally valid ways of looking at this. Indeed, they should go hand-in-hand. As a father of two young children myself, I cant fault the Al Sabbaghs for wanting to save their son, at any cost. If my children were suffering and this was the best chance to cure them, I wouldnt hesitate to sign on whatever dotted lines were required. Adding a third child to our family would be a blessing. I confess to not consulting with my wife before writing that, so dont blow my cover, but if thats what it took, I know wed be on board.

READ MORE:Calgary boy meets stem cell donor who saved his life: its a miracle

But on the other hand, how can it not send chills down your spine to think of creating a human being purely to benefit someone else?

This is not a criticism of the Al Sabbaghs, nor of any other family that has previously conceived a so-called saviour sibling. I 100 per cent understand the urge to save the child you have. Theres no moral blame here. But good Lord, what a strange path were embarking on.

A few decades ago, this wouldnt have been possible. The Al Sabbagh family would have had limited choices.

Bone marrow transplants have been around since the 1970s, but the ability to conceive multiple children, genetically screen them for compatibility and then bring specifically the best match to term, is much newer. Its a small peek into a future were just arriving at.

READ MORE:I need a man: Ethnic donors desperately needed for bone marrow registry

Medical technology is advancing rapidly, and stem cells are a particularly promising field. But as we push these technological envelopes, were going to encounter tough moral dilemmas that we are not ready for. Indeed, we probably havent even thought of them yet.

Im not a medical ethicist, nor an expert in the field of stem cells and transplantation. But one doesnt need to be to wonder about the morality of creating a person to save another. Even if the saviour sibling lives a long, healthy and happy life, cherished by its parents and the brother it saved, you cant help but wonder what psychological toll it would take knowing you were, at birth, essentially raw materials. And its also not too hard to envision a future where this treatment could be used more broadly, with new life being created simply to cure the injuries and illnesses of those already living.

After all, why not? Dont the needs of the sick and dying today take precedence over people who only exist in theory?

It seems wild now, like something out of science fiction. But our sci-fi daydreams have a habit of becoming reality. Are we ready for what this would mean? Are we prepared for a future where children can be conceived and harvested for parts? Would we feel better if the raw material babies were genetically tweaked in such a way that they never developed consciousness, and were therefore something less than human? Would it soothe our consciences to breed human tissue to serve just as spare parts if the bodies never grew a brain?

None of this matters much for Mohamad, a 10-year-old boy lucky enough to be born in a time and now live in a place where modern medical miracles make curing his brutal illness possible. And no one should judge the desperation of a mom and dad who just want their son to live a long, healthy, normal life.

But consider this a case study, a sample of the future. We are moving into new frontiers in leaps and bounds. I hope to hell were ready for the questions well face once were there.

Matt Gurney is host of The Morning Show on Torontos Talk Radio AM640 and a columnist for Global News.

2017Global News, a division of Corus Entertainment Inc.

Originally posted here:
COMMENTARY: Saving a 10-year-old's life but at what cost? - Globalnews.ca

Scientists Have Created the First Artificial Embryo Without Using an … – Gizmodo

An artificial mouse embryo after 48 hours (right) and 96 hours (left). Image: University of Cambridge

Using stem cells in grown-on 3D scaffolding in a laboratory petri dish, scientists have for the first time created an embryo made entirely from stem cells.

The artificial mouse embryo, detailed this month in the journal Science, is a major step toward creating synthetic embryos that closely resemble natural ones. It could shed light on early development and help improve fertility treatment procedures.

Cambridge biologist Magdalena Zernicka-Goetz, whose work focuses on the development of cell lineages, has long sought the development of an artificial embryo. But without using an egg in some way, scientists have had difficulty getting cells to communicate with each other early in development. Scientists managed to clone Dolly the sheep, for example, without requiring a rams sperm, but they still required an egg cell to fuse the cloned adult DNA with.

The Cambridge team got around this issue by taking embryonic stem cells (cells found in embryos that can mature into any type of body tissue) and growing them alongside trophoblast stem cells (the cells that produce the placenta). After growing the two types of cells separately, they combined them in a gel matrix. The two types of cells began to mix and develop together. After four days, the embryos began to resemble normal mouse embryos.

The goal is not necessarily to create a real mouse from these cellsand the science is still a ways from that anyway. Additional types of cells will likely needed to be added to the mix in order for the embryos to actually start developing organs. Even then, the cells may not develop past the very early stages shown in the Science paper.

But being able to study the way the cells develop in the very early days of an embryos life could shed important light into early development. The Cambridge researchers, for example, engineered different cell types to glow different colors so that they might track how they behave as the embryo develops. The work provided insight into how those two types of cells work together to form the blue print for the mouse body.

Heres a video of Zernicka-Goetz explaining the work:

[Science]

Excerpt from:
Scientists Have Created the First Artificial Embryo Without Using an ... - Gizmodo

Artificial Mouse ‘Embryo’ Created from Stem Cells for First Time – Laboratory Equipment

Scientists at the University of Cambridge have managed to create a structure resembling a mouse embryo in culture, using two types of stem cells - the body's 'master cells' - and a 3-D scaffold on which they can grow.

Understanding the very early stages of embryo development is of interest because this knowledge may help explain why more than two out of three human pregnancies fail at this time.

Once a mammalian egg has been fertilized by a sperm, it divides multiple times to generate a small, free-floating ball of stem cells. The particular stem cells that will eventually make the future body, the embryonic stem cells (ESCs) cluster together inside the embryo towards one end: this stage of development is known as the blastocyst. The other two types of stem cell in the blastocyst are the extra-embryonic trophoblast stem cells (TSCs), which will form the placenta; and primitive endoderm stem cells that will form the so-called yolk sac, ensuring that the fetus's organs develop properly and providing essential nutrients.

Previous attempts to grow embryo-like structures using only ESCs have had limited success. This is because early embryo development requires the different types of cell to coordinate closely with each other.

However, in a study published last week in the journal Science, Cambridge researchers describe how, using a combination of genetically-modified mouse ESCs and TSCs, together with a 3-D scaffold known as an extracellular matrix, they were able to grow a structure capable of assembling itself and whose development and architecture very closely resembled the natural embryo.

"Both the embryonic and extra-embryonic cells start to talk to each other and become organised into a structure that looks like and behaves like an embryo," explains Magdalena Zernicka-Goetz from the Department of Physiology, Development and Neuroscience, who led the research. "It has anatomically correct regions that develop in the right place and at the right time."

Zernicka-Goetz and colleagues found a remarkable degree of communication between the two types of stem cell: in a sense, the cells are telling each other where in the embryo to place themselves.

"We knew that interactions between the different types of stem cell are important for development, but the striking thing that our new work illustrates is that this is a real partnership - these cells truly guide each other," she says. "Without this partnership, the correct development of shape and form and the timely activity of key biological mechanisms doesn't take place properly."

Comparing their artificial 'embryo' to a normally-developing embryo, the team was able to show that its development followed the same pattern of development. The stem cells organise themselves, with ESCs at one end and TSCs at the other. A cavity opens then up within each cluster before joining together, eventually to become the large, so-called pro-amniotic cavity in which the embryo will develop.

While this artificial embryo closely resembles the real thing, it is unlikely that it would develop further into a healthy fetus, say the researchers. To do so, it would likely need the third form of stem cell, which would allow the development of the yolk sac, which provides nourishment for the embryo and within which a network of blood vessel develops. In addition, the system has not been optimized for the correct development of the placenta.

Zernicka-Goetz recently developed a technique that allows blastocysts to develop in vitro beyond the implantation stage, enabling researchers to analyze for the first time key stages of human embryo development up to 13 days after fertilization. She believes that this latest development could help them overcome one of the main barriers to human embryo research: a shortage of embryos. Currently, embryos are developed from eggs donated through IVF clinics.

"We think that it will be possible to mimic a lot of the developmental events occurring before 14 days using human embryonic and extra-embryonic stem cells using a similar approach to our technique using mouse stem cells," she says. "We are very optimistic that this will allow us to study key events of this critical stage of human development without actually having to work on embryos. Knowing how development normally occurs will allow us to understand why it so often goes wrong."

The research was largely funded by the Wellcome Trust and the European Research Council.

"This is an elegant study creating a mouse embryo in culture that gives us a glimpse into the very earliest stages of mammalian development. Professor Zernicka-Goetz's work really shows the importance of basic research in helping us to solve difficult problems for which we don't have enough evidence for yet. In theory, similar approaches could one day be used to explore early human development, shedding light on the role of the maternal environment in birth defects and health," said Andrew Chisholm, head of Cellular and Developmental Science at Wellcome.

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Artificial Mouse 'Embryo' Created from Stem Cells for First Time - Laboratory Equipment

Role of Stem Cell Reprogramming Factor Uncovered – Technology Networks

A little over 10 years ago, the first reprogramming of adult cells into undifferentiated stem cells was achieved. These induced pluripotent stem cells (iPSCs) have the ability to become almost any cell type and can divide indefinitely, so share many features with embryonic stem cells. Such characteristics enable iPSCs to be used in several applications of regenerative medicine, particularly because they can be derived from an individuals own cells so tissue rejection problems are not encountered. They can also be programmed to develop into rare or inaccessible cell types, used to screen novel drugs, and studied to understand the cellular basis of disease or reprogramming.

However, while the genetic factors responsible for reprogramming are well known, the mechanisms underlying the responses to induced gene expression changes are not as clear.

Now, research led by the University of Tsukuba has solved the mystery surrounding one of the reprogramming factors, KLF4.

KLF4 together with other reprogramming transcription factors is used in the lab to force the expression of genes in somatic cells (adult non-germline cells) in the development of iPSCs. Somatic cells generate their energy in an oxygen-fueled process called oxidative phosphorylation, which takes place in the mitochondria, also known as cellular powerhouses.

In contrast, stem cells have small mitochondria and use glycolysis as an alternative biochemical pathway to generate energy. This series of reactions can be anaerobic, so more suited to their typically low-oxygen environment, but also provides the supply of metabolic intermediates necessary for rapid growth and division.

University of Tsukuba researchers developed a gene transfer system that allowed iPSC reprogramming to only occur in the presence of KLF4, thus focusing exclusively on its role in the process. They then used genome-wide analysis to search for genes switched on by KLF4 at a late stage of reprogramming.

"We found that the Tcl1 gene was upregulated by KLF4 binding to its enhancer and promoter regions," study co-first author Ken Nishimura says. "KLF4 also caused the binding of another reprogramming factor, OCT4, to the Tcl1 promoter."

The team discovered that the TCL1 protein played a key role in increasing glycolysis by activating a different metabolic pathway that is important for the self-renewal of stem cells.

"We also showed that TCL1 inhibits a mitochondrial enzyme required for in oxidative phosphorylation, leading to a reduction in oxygen consumption of the cells", co-first author Shiho Aizawa explains. "This was matched by increased glucose uptake for glycolysis, revealing that TCL1 promotes the metabolic switch in energy generation necessary for cells to acquire pluripotency."

Reference:

Nishimura, K., Aizawa, S., Nugroho, F. L., Shiomitsu, E., Tran, Y. T., Bui, P. L., . . . Hisatake, K. (2017). A Role for KLF4 in Promoting the Metabolic Shift via TCL1 during Induced Pluripotent Stem Cell Generation. Stem Cell Reports. doi:10.1016/j.stemcr.2017.01.026

This article has been republished frommaterialsprovided byUniversity of Tsukuba. Note: material may have been edited for length and content. For further information, please contact the cited source.

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Role of Stem Cell Reprogramming Factor Uncovered - Technology Networks

Artificial mouse embryo created out of stem cells – BioNews

Stem cells from an adult mouse have been used to grow a structure resembling a mouse embryo in vitro for the first time.

The ability to study the early stages of embryo development outside the womb may one day help explain why a significant number of human pregnancies fail. This breakthrough in developmental research originated from the same team at University of Cambridge which recently developed a technique that allows human embryos to develop in the lab up to the legal limit of 14 days in the UK.

'We are very optimistic that this will allow us to study key events of this critical stage of human development without actually having to work on (IVF) embryos,'said lead researcher Professor Magdalena Zernicka-Goetzof the University of Cambridge.

The development of a fertilised egg into a fetus is a complex and poorly understood process of self-assembly and intricate cell-to-cell interaction. In a few days a small ball of undifferentiated cells develops into a blastocyst consisting of three different types of embryonic stem cell. Previous attempts to grow embryos using only one kind of stem cell proved unsuccessful because the cells would not assemble into their correct positions.

The researchers placed both placental andembryonic stem cellsinto a three-dimensional scaffold and discovered that within 96 hoursthe cells had begun to communicate, forming two distinct clusters of cells at each end and a cavity in the middle.

'We knew that interactions between the different types of stem cell are important for development, but the striking thing that our new work illustrates is that this is a real partnership these cells truly guide each other,' said Professor Zernicka-Goetz.

The scientists' goal was not to grow mice outside of the womb, but to open a new window on embryonic development just prior to implantation the so-called 'black box' of embryonic development,later than human embryos can be studiedin vitrobut earlier than ultrasound imaging can be used to view the embryo in the womb. About two-thirds of pregnancies are thought to fail during this stage, but because it is so difficult to study, the reasons are poorly understood.

Professor Robin Lovell-Badge of The Crick Institute, who was not involved in the research,lauded the findings as 'permitting study of events that normally take place within the uterus and are therefore difficult to observe, but in this case with an essentially unlimited supply of starting material'.

If used in human embryology, this methodology could make scientists less dependent on fertilised eggs;using artificial embryos could speed up research and potentially sidestep some ethical concerns.

Some critics fear that the technique could be used irresponsibly however. Dr David King, director of Human Genetics Alert,told the Telegraph: 'What concerns me about the possibility of artificial embryos is that this may become a route to creating GM or even cloned babies.'

The research was published in the journal Science.

Read more here:
Artificial mouse embryo created out of stem cells - BioNews

Artificial Mouse Embryo Created in Culture – Technology Networks

Stem cell-modelled embryo at 96 hours (left); Embryo cultured in vitro for 48 hours from the blastocyst stage (right) Credit: Sarah Harrison and Gaelle Recher, Zernicka-Goetz Lab, University of Cambridge

Scientists at the University of Cambridge have managed to create a structure resembling a mouse embryo in culture, using two types of stem cells the bodys master cells and a 3D scaffold on which they can grow.

Understanding the very early stages of embryo development is of interest because this knowledge may help explain why more than two out of three human pregnancies fail at this time.

Once a mammalian egg has been fertilised by a sperm, it divides multiple times to generate a small, free-floating ball of stem cells. The particular stem cells that will eventually make the future body, the embryonic stem cells (ESCs) cluster together inside the embryo towards one end: this stage of development is known as the blastocyst. The other two types of stem cell in the blastocyst are the extra-embryonic trophoblast stem cells (TSCs), which will form the placenta, and primitive endoderm stem cells that will form the so-called yolk sac, ensuring that the foetuss organs develop properly and providing essential nutrients.

Previous attempts to grow embryo-like structures using only ESCs have had limited success. This is because early embryo development requires the different types of cell to coordinate closely with each other.

However, in a study published in the journal Science, Cambridge researchers describe how, using a combination of genetically-modified mouse ESCs and TSCs, together with a 3D scaffold known as an extracellular matrix, they were able to grow a structure capable of assembling itself and whose development and architecture very closely resembled the natural embryo.

Both the embryonic and extra-embryonic cells start to talk to each other and become organised into a structure that looks like and behaves like an embryo, explains Professor Magdalena Zernicka-Goetz from the Department of Physiology, Development and Neuroscience, who led the research. It has anatomically correct regions that develop in the right place and at the right time.

Image: Stem cell-modelled embryo at 96 hours (embryonic (magenta) and extra-embryonic (blue) tissue with surrounding extracellular matrix (cyan)). Credit: Berna Sozen, Zernicka-Goetz Lab, University of Cambridge

Professor Zernicka-Goetz and colleagues found a remarkable degree of communication between the two types of stem cell: in a sense, the cells are telling each other where in the embryo to place themselves.

We knew that interactions between the different types of stem cell are important for development, but the striking thing that our new work illustrates is that this is a real partnership these cells truly guide each other, she says. Without this partnership, the correct development of shape and form and the timely activity of key biological mechanisms doesnt take place properly.

Comparing their artificial embryo to a normally-developing embryo, the team was able to show that its development followed the same pattern of development. The stem cells organise themselves, with ESCs at one end and TSCs at the other. A cavity opens then up within each cluster before joining together, eventually to become the large, so-called pro-amniotic cavity in which the embryo will develop.

While this artificial embryo closely resembles the real thing, it is unlikely that it would develop further into a healthy foetus, say the researchers. To do so, it would likely need the third form of stem cell, which would allow the development of the yolk sac, which provides nourishment for the embryo and within which a network of blood vessel develops. In addition, the system has not been optimised for the correct development of the placenta.

Professor Zernicka-Goetz recently developed a technique that allows blastocysts to develop in vitro beyond the implantation stage, enabling researchers to analyse for the first time key stages of human embryo development up to 13 days after fertilisation. She believes that this latest development could help them overcome one of the main barriers to human embryo research: a shortage of embryos. Currently, embryos are developed from eggs donated through IVF clinics.

We think that it will be possible to mimic a lot of the developmental events occurring before 14 days using human embryonic and extra-embryonic stem cells using a similar approach to our technique using mouse stem cells, she says. We are very optimistic that this will allow us to study key events of this critical stage of human development without actually having to work on embryos. Knowing how development normally occurs will allow us to understand why it so often goes wrong.

The research was largely funded by the Wellcome Trust and the European Research Council.

Dr Andrew Chisholm, Head of Cellular and Developmental Science at Wellcome, said: This is an elegant study creating a mouse embryo in culture that gives us a glimpse into the very earliest stages of mammalian development. Professor Zernicka-Goetzs work really shows the importance of basic research in helping us to solve difficult problems for which we dont have enough evidence for yet. In theory, similar approaches could one day be used to explore early human development, shedding light on the role of the maternal environment in birth defects and health.

Reference:

Harrison, S. E., Sozen, B., Christodoulou, N., Kyprianou, C., & Zernicka-Goetz, M. (2017). Assembly of embryonic and extra-embryonic stem cells to mimic embryogenesis in vitro. Science. doi:10.1126/science.aal1810

This article has been republished frommaterialsprovided by the University of Cambridge. Note: material may have been edited for length and content. For further information, please contact the cited source.

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