What are embryonic stem cells & where do they come from?

What are embryonic stem cells and how are they obtained? My lab has been doing research on embryonic stem cells for more than 14 years. You’ve come to the right place for expert answers on these very intriguing cells.

What’s in this article

Where do embryonic stem cells come from?SCNT or cloning stem cells |single-blastomere ES cells |ES cell history including Nobels | Is embryonic stem cell research legal? |Uses of ES cells in research | TeratomaClinical trials involving ES cells | References

Where do embryonic stem cells come from?

Knoepfler lab stem cells
Human embryonic stem cells grown in the Knoepfler lab. Shown is one round colony of several hundred ES cells packed together, growing on top of feeder cells.

As their name suggests, embryonic stem cells are largely generated using embryos. Note that there are a few exceptions to this that I discuss later in the post.

In the case of human embryonic stem cells, they are most often derived from human embryos left over from IVF procedures. These procedures are done to help infertile couples have babies. Usually fertility clinics make too many embryos so there are some left in liquid nitrogen. Sometimes these unneeded embryos are then used for research.

The human embryos used to make stem cells are at a very early stage of development. They are only a few days after fertilization and have around 100 cells.

They have no specific tissues or organs yet, as those will come much later. Instead they are essentially a ball of mostly uniform cells.

Human embryonic stem cells or ES cells are pluripotent stem cells. This means they can make any other kind of cell, although this has not been formally tested in every case.

While years ago human embryonic stem cells were the source of quite a bit of debate, today they are much more widely accepted by the public including in the U.S. Gallup polling has found a dramatic increase in the percentage of Americans who are OK with these sometimes so-called “ES cells.” The latest poll shows 2/3 of Americans feel it is morally acceptable research.

My own lab, as mentioned earlier, does some research on human ES cells, but we do not make new ES cell lines ourselves. We have, however, made iPS cells (more on those below).

I’ve also made a YouTube video outlining the main points of this post.

More rarely part 1: SCNT or cloning stem cells

Embryonic stem cells can also be made another way, but it’s extremely difficult in humans.  It is through a process called somatic cell nuclear transfer or SCNT. In this process, the nucleus of an adult cell is transferred into an egg (or one-cell embryo) that has had its own nucleus removed. Sometimes if this all goes right the hybrid cell will go on with development normally. It can do this even though it has the nucleus from another cell.

Such cloning is widely used to make more farm animals. To my knowledge it has never been used to make a living human clone, but the topic often comes up.

If the SCNT procedure is done with human cells, instead of trying to make a cloned person those early embryos can instead be used to make human embryonic stem cells. Such cells could be very useful in medicine. For this reason, this process is sometimes called “therapeutic cloning”.

More rarely part 2: single-blastomere embryonic stem cells

embryo-human
Human early embryo with about 8 cells. At this stage the cells can be referred to as “blastomeres.”

Dr. Robert Lanza led a team at an old biotech firm called Advanced Cell Technology or ACT that made ES cells yet another way.

After just the first few divisions, early human embryos are made of functionally equivalent cells, sometimes referred to as “blastomeres”.  See image at left.

Bob’s team determined that if you pluck off just one of these cells, you can make a human ES cell line from it.

The rest of the embryo can be frozen. Technically, this method then does not destroy a human embryo, an important point given restrictions on federal funding in the US.

They reported this discovery in Nature in 2006.

It remains unclear whether single-blastomere or SCNT-derived human embryonic stem cells are needed given the innovation of IPS cells, which I’ll now discuss.

ES cell history including Nobels

Researchers figured out early in the mouse how to isolate embryonic stem cells from blastocyst embryos. Mario Capecchi, Martin Evans and Oliver Smithies were involved in this area and shared the Nobel Prize in 2007 “for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells.”

Gail Martins deserved major credit here too. I think she should have also won a Nobel Prize for her work. She not only isolated these cells, but also named them “embryonic stem cells.” Unfortunately, Nobel Prizes in the sciences have a long history of sexism.

In 1998 James “Jamie” Thomson was the first to successfully produce human ES cells. This opened the door for the first time to the possibility of clinical impact of human pluripotent stem cells.

Is embryonic stem cell research legal?

At a federal level in the US, human ES cell research is legal. While federal funding of the derivation of entirely new human ES cells is a more complicated area of law, there are a wide variety of human ES cell lines already available and private funding can be used to derive new lines. The NIH currently lists 485 lines available for research. Laws related to human ES cell research vary greatly by country around the globe.

ES cell research using cells from other animals is legal and hasn’t really generated debate.

A variety of states in the US have laws about human ES cell research within their boundaries. This makes for a more complicated landscape for researchers in certain states.

Uses of ES cells in research

ES cells have a vast array of uses in biomedical research and have potential in medicine too. As to the research, ES cells aid studies of early human development. Since issues that arise during development often lead to disease, this modeling is quite useful.

You can see a video above from my lab of human embryonic stem cells that have differentiated into beating human heart muscle above.

More recently induced pluripotent stem cells or iPS cells have come onto the scene. iPS cells behave almost identically to ES cells, but no embryo is needed to make them. This makes iPS cells more widely accepted than ES cells, but every batch of iPS cells needs to be validated. Some iPS cells may be much less like ES cells than others. In addition, some iPS cells, if not properly validated, may contain mutations or other changes. Still, for many applications, iPS cells work just fine. iPS cells have the additional benefit of being made from the same patient who gets a therapy back. In a sense it is a self-transplant.

What is a teratoma? human stem cell teratoma knoepfler lab
Human stem cell derived teratoma. Knoepfler lab research image.

Teratoma

A defining feature of pluripotent stem cells including ES cells is that they can form a tumor called a teratoma. This embryonic cell tumor is generally benign. In rare cases teratoma can be malignant in which case they are called teratocarcinoma. Even benign teratoma can cause tissue destruction as they grow. For these reasons, clinical researchers are not planning to use ES cells themselves in trials. In fact, they are taking every step possible to differentiate ES cells so fully that no teratoma causing cells are left. New methods are being developed to remove or kill off residual pluripotent cells in cell production methods for clinical trials. You can see an image from an experimental teratoma generated in our lab above.

Clinical trials involving ES cells

Several biotechs are working to develop therapies based on human ES cells. Since human ES cells can in theory make any kind of human cells or tissues, there is broad potential here. A recent publication covered human pluripotent stem cell-related clinical trials more generally. It’s a useful resource. I particularly have found their Table listing of details of each kind of pluripotent stem cell trial to be useful and you can find the human ES cell-related ones there easily.

NIH currently lists 45 trials on Clinicaltrials.gov at least mentioning these cells. There is exciting work ongoing for vision loss including macular degeneration. Work by ViaCyte for diabetes brings real hope there. A firm called Lineage Cell Therapeutics is studying an embryonic stem cell-derived oligodendrocyte product for spinal cord injury.

Overall, these are important cells for both research and medicine.

References

  1. The New Federalism: State Policies Regarding Embryonic Stem Cell Research, J Law Med Ethics, Nefi D. Acosta and Sidney H. Golub, 2015.
  2. Embryonic and Fetal Research Laws, NCSL, 2016.
  3. Embryonic stem cell lines derived from human blastocysts, Science, 1998.
  4. NIH Human Embryonic Stem Cell Registry, NIH Registry of human ES cell lines, updated 2/25/2021
  5. Human embryonic stem cell lines derived from single blastomeres, Nature, 2006.
  6. Global trends in clinical trials involving pluripotent stem cells: a systematic multi-database analysis. Julia Deinsberger, David Reisinger & Benedikt Weber npj Regenerative Medicine volume 5, Article number: 15 (2020).
  7. Clinicaltrials.gov search for embryonic stem cell trials. Source NIH. February 25, 2021.

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