Stem Cell Clinic

Artificial embryo grown in a dish from two types of stem cells – New Scientist

By Andy Coghlan

Sarah Harrison and Gaelle Recher, Zernicka-Goetz Lab, University of Cambridge

Artificial mouse embryos grown from stem cells in a dish could help unlock secrets of early development and infertility that have until now evaded us.

Magdalena Zernicka-Goetz at the University of Cambridge and her team made the embryos using embryonic stem cells, the type of cells found in embryos that can mature into any type of tissue in the body.

The trick was to grow these alongside trophoblast stem cells, which normally produce the placenta. By growing these two types of cell separately and then combining them in a special gel matrix, the two mixed and started to develop together.

After around four-and-a-half days, the embryos resembled normal mouse embryos that were about to start differentiating into different body tissues and organs.

They are very similar to natural mouse embryos, says Zernicka-Goetz. We put the two types of stem cells together which has never been done before to allow them to speak to each other. We saw that the cells could self-organise themselves without our help.

This is the first time something resembling an embryo has been made from stem cells, without using an egg in some way. Techniques such as cloning, as done for Dolly the sheep and other animals, bypass the need for sperm, but still require an egg cell.

The artificial embryos are providing new insights into how embryos organise themselves and grow, says Zernicka-Goetz. The team engineered the artificial embryos so the cell types fluoresced in different colours, to reveal their movements and behaviour as the embryos go through crucial changes.

Mammal embryos were already known to start as a symmetrical ball, then elongate, form a central cavity and start developing a type of cell layer called mesoderm, which ultimately goes on to form bone and muscle.

We didnt know before how embryos form this cavity, but weve now found the mechanism for it and the sequential steps by which it forms, says Zernicka-Goetz. Its building up the foundations for the whole body plan.

The work is a great addition to the stem cell field and could be extended to human stem cell populations, says Leonard Zon at Boston Childrens Hospital, Massachusetts. Using the system, the factors that participate in embryo development could be better studied and this could help us understand early events of embryogenesis.

But Robin Lovell-Badge at the Francis Crick Institute in London says that the embryos lack two other types of cell layer required to develop the bodies organs: ectoderm, which forms skin and the central nervous system, and endoderm, which makes our internal organs.

Zernicka-Goetz hopes to see these types of cell layers develop in future experiments by adding stem cells that normally form the yolk sac, a third structure involved in embryonic development, to the mix.

If a similar feat can be achieved using human stem cells, this could tell us much about the earliest stages of our development. Current research is limited by the number of excess embryos that are donated from IVF procedures. But the new technique could produce a limitless supply, making it easier to conduct in-depth research. These artificial embryos may also be easier to tinker with, to see what effect different factors have in early embryogenesis.

Disrupting development in this way may provide new insights into the causes of abnormal embryo development and miscarriage. You would be able to understand the principles that govern each stage of development. These are not normally accessible, because they happen inside the mother, says Zernicka-Goetz.

But it is doubtful that this work could ever lead to fully grown babies in the lab. Lovell-Badge says the artificial embryos are unlikely to develop in vitro much further than shown in the study, as they would soon need the supply of nutrients and oxygen that a placenta normally channels from the mother.

Were not planning to make a mouse in the lab using stem cells, says Zernicka-Goetz. But she is hopeful that adding yolk sac stem cells will allow these artificial embryos to survive long enough to study the beginnings of organs like the heart.

Journal reference: Science, DOI: 10.1126/science.aal1810

Read more: Its time to relax the rules on growing human embryos in the lab

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Artificial embryo grown in a dish from two types of stem cells - New Scientist

Exclusive: CBMG CEO Talks Stem-Cell Therapies, Cancer Treatments, Financials & The Chinese Market – Benzinga

Cellular Biomedicine Group Inc (NASDAQ: CBMG) is a micro-cap biomedicine company focused on the development of treatments for cancerous and degenerative diseases through cell-based technologies.

Last week, Benzinga attended SCN Corporate Connects Family Office & Life Science Symposium at the NASDAQ and had the chance to talk with CBMG CEO Tony Liu who walked us through some of the companys products, management team, market potential, how they use stem cells and more.

CBMG has two leading technology platforms at the time, Liu began. One is an immune cell therapy aimed at the treatment of a broad range of cancers using Cancer Vaccines, Chimeric Antigen Receptor T cell (CAR-T) and anti-PD-1 Technologies. The other one uses stem cells for regenerative purposes; the key indication for this therapy is knee osteoarthritis.

Our focus is on these technologies and our market is China, because that is the largest -by far- in population for the indication, he pointed out.

Benzinga: How does the company use stem cells.

Liu: In simple terms, a stem cell is basically regenerative. So a stem cell has the enormous power of expanding, continue from the embryonic stem cell to the baby stem cell and ultimately to the adult stem cell, so it has a great ability to continue to expand and grow.

From the medical perspective, an adult stem cell can regenerate, it can repair [tissue]. So, in our lead product, we use fat tissue from the stomach and we all have a few ounces of extra fat. We take the stem cell out from the fat tissue culture, expand it, and then we inject back in the kneecap for patients with a knee osteoarthritis problem.

Benzinga: Are there any other indications you will be targeting in the near-future?

Liu: Were targeting lymphoma, leukemia, solid tumors and many other areas.

Benzinga moved on to ask about the size of the market.

Liu: Every year we look at 4.5 million to 5 million new cancer patients. That is, every minute we are talking about eight or nine new cancer patients. That is why it is a huge social issue. That is one of the reasons why I choose to stay in the business after I spent 19 years with Microsoft Corporation (NASDAQ: MSFT) and four years with Alibaba Group Holding Ltd (NYSE: BABA). I think this area socially, you want to make impactful, and economically I think there is a huge business from that side.

Because our focus is on the Chinese market there are many investors in the U.S. who do not know us well. However, I believe investors should look at the company: we have a huge market, great scientists, manufacturing space

Then, for our stem cell therapies in China, 57 million people have a knee issue; in the U.S., 27 million [people] have a knee issue. Stem cells can help knees regenerate by doing two things. First, by helping with the pain, providing symptom relief and functional improvements. Secondly, they regenerate the cartilage, which originally caused the knee problem. Nowadays, patients can only opt between pain pills or a knee replacement.

Today, if you do a knee replacement, you are looking at tens of thousands [of dollars]. So, any way you look at it, [its a] multi-billion [market] for knee treatments.

Benzinga: When you say stem cells, people imagine It is a slightly controversial subject; it has some political implications. So, what is the Chinese governments stance regarding stem cells? Are there any risks? Is it accepted? What is the view of stem cells in China?

Liu: Chinas government has been extremely supportive of using stem cells. I think the controversy comes in where people use embryonic stem cells, when you create a new life, that is where the controversy is. But, we use what we call adult stem cells to improve peoples lives, improve their life experiences

On adult stem cells, there is little controversy. The policy of Chinas government is very clear. In fact, in the U.S. it is very clear as well. CBMG has been graced to work with the California Stem Cell Institute. Potentially, we are going to ask the U.S. for large-scale clinical trials.

Our management team was educated in the U.S., and has experience managing large businesses, Liu commented. Our Chief Scientific Officer is a former MedImmune/AstraZeneca plc (ADR) (NYSE: AZN) director. Some of our oncology scientists are from there as well. We also have scientists from the National Cancer Institute. We also have a person who is leading our manufacturing capabilities who worked for Harvard for 30 years and a top German company, leading research for seven years total.

So, we have this kind of people with skills come to China. Our company has 130 people with PhDs, and more than 30 with post-doctorate studies, so there is a lot of brain power, I believe, and we have a common vision that is to create the best, first in class, biotech business in China.

Benzinga: Whats one objective you have as a CEO for 2017?

Liu: In 2017 is about clinical, clinical, clinical. We now have moved our first two indications into the clinical trial stage. We have a lot of patients lined up for clinical trials.

So, as CEO Ill make sure we mobilize all the resources around the clinical trials and make sure we have the lead PI, lead hospitals, and we have resources waiting in the company to make sure we have successful clinical trials. Those are key elements, and we are confident that we should be able to move forward, given the number of patients we have, move schedule, look at the indications

Benzinga: Are you comfortable with your cash and debt position? Do you have any plans to raise capital this year or any time soon?

Liu: One of the benefits we have, CBMG has been regarded as the leader in Chinas cell therapy space, so we have investors who have given us money for the last three years, always at a premium to the market. They know who we are; they know the space we are in. I feel as we move forward, we will be getting more investment needs from trials, and I feel confident investors will look at CBMG as a way for them to both put money into the research, but also, as an investment that could reap great returns.

Benzinga: Your stock had been performing pretty well, but experienced a tumble between mid-November and late-February. What happened there?

Liu: CBMGs stock is really thinly traded. Much of the stock is owned by those who have been with the company for a long time; so, they dont sell. Having said this, there are many reasons that drive stocks: the U.S. election, the pricing discussion Many investors dont discriminate, and just punish biotech as a whole. However, CBMG is not really subject to most of these pricing pressures. In fact, because we have a different cost structure, I expect CBMG to do extremely well.

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Exclusive: CBMG CEO Talks Stem-Cell Therapies, Cancer Treatments, Financials & The Chinese Market - Benzinga

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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Artificial Mouse Embryo Created in Culture - Technology Networks