What are totipotent stem cells & what can they do?

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.

3 thoughts on “What are totipotent stem cells & what can they do?”

  1. people trying to understand the science of regenerative medicine ……it is not about believing or not , stem cells , they exist ….
    What are stem cells, and what do they do?

    Cells in the body have specific purposes, but stem cells are cells that do not yet have a specific role and can become almost any cell that is required. Stem cells are undifferentiated cells that can turn into specific cells, as the body needs them. Scientists and doctors are interested in stem cells as they help to explain how some functions of the body work, and how they sometimes go wrong. Stem cells also show promise for treating some diseases that currently have no cure.
    Sources of stem cells
    Stem cells originate from two main sources: adult body tissues and embryos. Scientists are also working on ways to develop stem cells from other cells, using genetic “reprogramming” techniques.
    Adult stem cells
    Stem cells can turn into any type of cell before they become differentiated. A person’s body contains stem cells throughout their life. The body can use these stem cells whenever it needs them. Also called tissue-specific or somatic stem cells, adult stem cells exist throughout the body from the time an embryo develops. The cells are in a non-specific state, but they are more specialized than embryonic stem cells. They remain in this state until the body needs them for a specific purpose, say, as skin or muscle cells. Day-to-day living means the body is constantly renewing its tissues. In some parts of the body, such as the gut and bone marrow, stem cells regularly divide to produce new body tissues for maintenance and repair.

    Stem cells are present inside different types of tissue. Scientists have found stem cells in tissues, including:
    the brain
    bone marrow
    blood and blood vessels
    skeletal muscles
    the liver

    However, adult stem cells can be difficult to find. They can stay non-dividing and non-specific for years until the body summons them to repair or grow new tissue. Adult stem cells can divide or self-renew indefinitely. This means they can generate various cell types from the originating organ or even regenerate the original organ, entirely. This division and regeneration are how a skin wound heals, or how an organ such as the liver, for example, can repair itself after damage. In the past, scientists believed adult stem cells could only differentiate based on their tissue of origin. However, some evidence now suggests that they can differentiate to become other cell types, as well.

    Embryonic stem cells,
    Human Embryonic Stem Cell Lines Generated without Embryo Destruction

    From the very earliest stage of pregnancy, after the sperm fertilizes the egg, zygote is form to blastomere to blastocytes in an embryo form. Around 3–5 days after a sperm fertilizes an egg, the embryo takes the form of a blastocyst or ball of cells. The blastocyst contains stem cells and will later implant in the womb. Embryonic stem cells come from a blastocyst that is 4–5 days old. It has been demonstrated that hESCs can be generated from single blastomeres (Klimanskaya et al., 2006 https://www.sciencedirect.com/…/pii/S193459090700330X). In that “proof-of-principle” study, multiple cells can be removed from an embryo and the embryos can continue to develop. No death of embryo in harvesting cells …..The derivation of hESC lines using a non-embryo destruction (NED) technique , including one without hESC coculture. Single blastomeres are removed from the embryos by using a technique similar to preimplantation genetic diagnosis (PGD). The biopsied embryos were shown to grown to the blastocyst stage and frozen. The blastomeres were cultured by using a modified approach aimed at recreating the ICM niche, which substantially improved the efficiency of the hESC derivation to rates comparable to whole embryo derivations. When scientists take stem cells from embryos, these are usually extra embryos that result from in vitro fertilization (IVF). In IVF clinics, the doctors fertilize several eggs in a test tube, to ensure that at least one survives. They will then implant a limited number of eggs to start a pregnancy.

    Mesenchymal stem cells (MSCs)

    MSCs come from the connective tissue or stroma that surrounds the body’s organs and other tissues.
    Scientists have used MSCs to create new body tissues, such as bone, cartilage, and fat cells. They may one day play a role in solving a wide range of health problems.

    Induced pluripotent stem cells (iPS)

    Scientists create these in a lab, using skin cells and other tissue-specific cells. These cells behave in a similar way to embryonic stem cells, so they could be useful for developing a range of therapies.
    However, more research and development is necessary.
    To grow stem cells, scientists first extract samples from adult tissue or an embryo. They then place these cells in a controlled culture where they will divide and reproduce but not specialize further. Stem cells that are dividing and reproducing in a controlled culture are called a stem-cell line. Researchers manage and share stem-cell lines for different purposes. They can stimulate the stem cells to specialize in a particular way. This process is known as directed differentiation. Until now, it has been easier to grow large numbers of embryonic stem cells than adult stem cells. However, scientists are making progress with both cell types.

    Types of stem cells
    Researchers categorize stem cells, according to their potential to differentiate into other types of cells.
    Embryonic stem cells are the most potent, as their job is to become every type of cell in the body.

    The full classification includes:
    Totipotent: These stem cells can differentiate into all possible cell types. The first few cells that appear as the zygote starts to divide are totipotent.

    Pluripotent: These cells can turn into almost any cell. Cells from the early embryo are pluripotent.

    Multipotent: These cells can differentiate into a closely related family of cells. Adult hematopoietic stem cells, for example, can become red and white blood cells or platelets.

    Oligopotent: These can differentiate into a few different cell types. Adult lymphoid or myeloid stem cells can do this.
    Unipotent: These can only produce cells of one kind, which is their own type. However, they are still stem cells because they can renew themselves. Examples include adult muscle stem cells.

    Embryonic stem cells are considered pluripotent instead of totipotent because they cannot become part of the extra-embryonic membranes or the placenta.

  2. I have knee and some vascular issues in the left leg my knee is grinding down and as this is happening the choice of knee replacement is the a choice I have I have no blood vessels that can be transferred from my right leg to my left leg and without any vessels I need stem cells if I don’t or can’t my knee will get to the point it will get to the point that the ground up knee will cut the arteries and I will not let them take my leg off I will DIE approximately in one year

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