January 17, 2021

The Niche

Trusted stem cell blog & resources

Sometimes patients or my students ask me, “What are the best stem cells?” what information are they looking for?

I think they often are looking for the most powerful stem cells so perhaps they should be asking, “What are totipotent stem cells?”

Other times it seems what patients specifically want to know is what might be the best stem cells for their particular condition. The answer to that is, of course, going to depend on many factors. I’m a long-time stem cell biologist so I can give them that perspective, but this should be something they discuss primarily with their physician

Today’s post focuses on the question of what totipotent cells are all about and addresses more specific questions about them, including why so far there seem to be fewer clinical applications for them as compared to most other stem cell types.

very early human embryos, totipotent stem cells
Photomicrograph of early human embryo development. An arrow in the inset higher magnification view of the hatched blastocyst (breaking out of the zona pellucida) indicates the inner cell mass (ICM) that can produce embryonic stem cells when cultured. Photos courtesy of Meri Firpo. Image and caption from Stem Cells: An Insider’s Guide by Paul Knoepfler.

What are totipotent stem cells?

Every year I give a lecture here at UC Davis School of Medicine for my medical students about stem cells. Some students seem especially fascinated by totipotent stem cells. Their interest probably is piqued because these are the most powerful cells. For example, recently a student asked me, “Professor Knoepfler, are there any types of cells that totipotent stem cells cannot make?”

As their name implies, totipotent stem cells are entirely potent or all-powerful from a cellular perspective. What that means is that these cells can make any other cells in the developing body in utero as well as the special cells and tissues needed during development. Those latter structures include placenta and umbilical cord.

For example, the classic kind of totipotent cell is the fertilized egg, also called a zygote. In the animal world, a newly pregnant bear has a zygote that will develop in its uterus that is totipotent. That bear’s zygote can make the actual new eventual baby bear including all of the several hundred kinds of bear cells and also the placenta and umbilical cord that the fetal bear will need in utero. The same goes for a totipotent human zygote. Also the zygote of a dog, cat, and so on.

You can see examples of real human totipotent stem cells in the image above of early human embryos at the 2- and 4-cell stages at the top of the figure. This material is excerpted from my book on stem cells, Stem Cells: An Insider’s Guide.

Totipotency and twins

Interestingly, as normal early embryo development proceeds and the fertilized egg/zygote goes from just being that one cell to divide to make 2 cells and 4 cells and then 8 cells, it is thought that all of the cells are still totipotent. What this means is that if, for example, an 8-cell human embryo for whatever reason breaks into 2 pieces of 3 and 5 cells or 1 and 7 cells, in many cases those separate totipotent cells will go on to make 2 separate embryos and ultimately babies. Congrats, you have twins. Each twin in that case can also develop their own umbilical cord and placenta too, although they sometimes share. This is all possible because these very early embryonic cells are totipotent.

After the 8-cell stage or so, the embryonic cells start to lose their totipotency and become either multipotent (can make only a few types of cells) or pluripotent stem cells. The latter are the second most powerful stem cells so let’s briefly talk about them next.

Totipotent vs pluripotent

Pluripotent stem cells are almost as flexible as those with totipotency, but not quite. See video above. The pluripotent cells inside a developing early embryo of a specific species can make all the cells that will become the actual body of a person, a bear, or many other animals, again depending on which animal is involved. These pluripotent cells cannot, however, make the placenta or umbilical cord. This one thing that they cannot do is what makes them different than totipotent cells.

Pluripotent stem cells include some of the most well known kinds of stem cells out there including embryonic stem cells (ES cells) and induced pluripotent stem cells, also known as IPS cells

Pluripotent stem cells are often grown in labs and differentiated into a wide variety of other types of more specialized cells such as neurons, muscle cells including beating heart muscle (see video below), lung cells and more. Some have claimed that certain IPS cells can be totipotent but that is still being debated.

Both ES cells and IPS cells can also be made into what are called organoids, which are miniature versions of normal organs. For instance, my lab makes brain organoids regularly from IPS cells. Organoids are a very powerful technology in many ways so as being a way to find new drugs for specific diseases.

Future clinical potential of totipotent stem cells?

I have not heard yet of specific clinical applications for these most powerful stem cells.  On the global clinical trial database Clinicaltrials.gov I found just a single trial that mentions the word “totipotent” and it isn’t related to using such cells as a treatment.

Most of the clinical potential seems to be focused on adult stem cells as well as IPS cells and ES cells. One could imagine that totipotent stem cells will be useful for research on human development and potentially infertility.

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