Stem Cells: A Primer

Many of the questions I receive after a pitch or talking to prospective customers revolve around the ubiquitous but somewhat mysterious “stem cell”. Even though I was a bioengineer and not a developmental biologist, stem cell biology is actually one of my favorite areas of scientific study, and the advent of stem cell technology in the late 90s and early 00s was one of the motivating factors for me to go into Biomedical Engineering as an undergrad and into my PhD studies. Nearly 20 years after the first human embryonic stem cell lines were isolated by Dr. James Thomson, we’ve made incredible progress in the stem cell field. Unfortunately, us scientists aren’t usually great at disseminating this information widely and in an easy to understand format. In this primer, I’ll try to hit the main points of stem cell biology without going too deep into the weeds — I’ll remain as technically accurate (maybe with disclaimers) as possible but may generalize. If you’re a stem cell scientist or just an enthusiast and find issues with my generalizations — please comment! Otherwise, read on for a stem cell primer.

What are stem cells and what do they do?

The basics of stem cell biology start with the definition of what a stem cell is. Broadly, a stem cell is a cell that has two important functions: 1) self-renewal and 2) differentiation, or turning into another cell. Self-renewal means that the cell is able to divide (mitosis) and proliferate, or increase in number. Differentiation is the process by which a stem cell turns into another, more specialized cell. An example of this would be a hematopoeitic stem cell, or blood stem cell that resides in the bone marrow, dividing to increase its numbers (self-renewal), then differentiating into white blood cells for an immune response (author’s caveat: I know the technical lineage is through a progenitor population and then into a terminally differentiated cell).

Since stem cells can both self-renew as well as turn into other cell types, they’re often the mechanism by which tissues and organs can repair or replenish themselves. Many tissues have resident stem cell populations, usually referred to as “adult stem cells”, that are responsible for downstream repair or replenishment of damaged or old tissues. Why is this necessary? Most cells in the body (somatic cells, or basically specialized, differentiated cells, or basically non-stem cells) have limited self-renewal capabilities. After a number of cell divisions, our cells will become “senescent”, or stop dividing (due to shortening of their telomeres) (read more about senescence in the appendix). Other times, our cells will undergo “apoptosis”, or programmed cell death (or necrosis, which is a more traumatic form of cell death). Either way, a cell population will need to be replaced, either due to the lack of cell function (senescence) or death of the cell (apoptosis, necrosis), which is where stem cells come in. They’ll divide and differentiate and replace lost cells. Our bodies are very yin and yang, and a lot of biology is a balance.

So take home message: stem cells are cells that self-renew and differentiate into specialized cells (like skin cells, muscle cells, blood cells). Most tissues have resident stem cells to replace lost, damaged, or aged tissues, but these are typically referred to as “adult stem cells”.

Not all stem cells are equal

Now that we’ve defined what stem cells are and their function, another important concept is that not all stem cells are equal. Stem cells, broadly, can be grouped into different levels of “potency”, or differentiation potential. This concept was modeled beautiful by CH Waddington and Waddington’s Hill. Imagine stem cell potency like a marble at the top of a hill, with the marble representing the cell and the hill representing different levels of potency. If you’re a physics nerd, you can relate this fuzzily to potential energy.

 

Waddington’s Hill. Waddington, C. H. (1956). Principles of Embryology

At the top of the hill, our cells are the least differentiated and have the most potency, or the ability to turn into the most cell types. This level of potency — the ability to differentiate into all 3 germ layers and extra-embryonic (placental) tissue — is called totipotent. An example of a totipotent cell is a zygote, or basically a fertilized egg cell. Once the cell begins to divide and differentiate, or starts to go down Waddington’s Hill, it loses potency — it cannot go back up the hill without outside intervention (think of this like a marble rolling down a hill — its not going to go back up that hill without an external force). The next level of potency is called pluripotent, or the ability to turn into all 3 germ layers (or basically, any cell or tissue in the adult body). An example of a pluripotent cell is an embryonic stem cell. As a pluripotent cell begins to differentiate and roll down Waddington’s Hill, the cell loses potency and becomes multipotent, or the ability to turn into more than one cell type, but not all 3 germ layers. An example of a multipotent stem cell is the aforementioned blood (hematopoeitic) stem cell, which can turn into all 5 types of white blood cells. Further down the hill, and more specialized, come progenitor cells, or oligopotent (although I don’t see this term used that much). Progenitor cells typically can only differentiate into a few cell types that are closely related — an example of this would be a lymphoid progenitor cell, which can only turn into lymphocytes (T cells, B cells, Natural killer cells), which is 1 of the types of white blood cells. Finally, some people believe in the existence of unipotent stem cells, which can self renew but are only able to turn into 1 cell type. An example of a unipotent cell would be a hepatoblast, or liver cell precursor, that can self renew but can only turn into a hepatocyte (this happens during development), but there is not much focus on unipotent stem cells (if they exist, again, I believe there’s debate around this).

So in summary
totipotent: stem cells that can turn into all 3 germ layers and placental tissue. Not found in the adult human body
pluripotent: stem cells that can turn into all 3 germ layers. Not found in the adult human body
multipotent: stem cells that can turn into multiple other cell types
progenitor/oligopotent: stem cells that can turn into a few, related cell types

The specific stem cell is important

Putting this together, stem cells are cells that self-renew and turn into other cells. Our bodies have stem cells that are able to replenish old or damaged tissues. However, not all stem cells are created equal — some stem cells have the ability to turn into more cell types than others. Now, thinking of the concept of Waddington’s Hill, since certain stem cells have lost potency because they have fallen down Waddington’s Hill (or differentiated into a more specialized cell type), they cannot replace lost or damaged tissue of cells that they cannot turn into. For instance, a blood stem cell (hematopoeitic) can turn into red and white blood cells, but cannot turn into heart cells, as they’re too far removed from the heart lineage. For researchers and scientists, looking at developmental biology and plotting out stem cell lineage charts or maps like this one, it’s relatively easy to determine which stem cell types can yield specific cells of interest. For instance, being a heart researcher, I know that hematopoietic, or blood, stem cells do not differentiate into heart cells. There is a bit of debate sometimes on whether or not certain multipotent stem cells can turn into specific cells — like a mesenchymal stem cell turning into a heart cell (my take: they can’t) — but as this field continues to develop, most of these pathways and potentials will be well mapped out.

 

Map of stem cell differentiation. Credit: philschatz.com

The importance of this? When reading studies or about interventions using stem cells, it’s important for me to look at A) the stem cell being used, and B) the tissue type being repaired. For instance, as we just noted above, blood stem cells do not turn into heart cells. Therefore, a study using blood stem cells injected into the heart after a heart attacked aimed at regenerating heart tissue raises some red flags to me. Since the blood stem cells cannot turn into heart cells, that means regeneration is unlikely to come from the injected stem cells. Instead, if there is any regeneration, it would have to come from the heart cells interacting with the blood stem cells (like the heart cells start dividing and growing) — but this would be extremely atypical of heart cells. So instead, it would make sense that if any improvements were seen with injecting blood stem cells into the heart after a heart attack, it would be temporary — it is unlikely that either the stem cells or the existing heart cells regenerated heart tissue. There’s even an additional level of complexity here — even if a stem cell can turn into a specific cell type, some cells are easier for the stem cell to turn into than others. For instance, mesenchymal stem cells can turn into muscle cells, but will more easily turn into fat or bone without additional manipulation, and we’re finding that simply putting the stem cell into the tissue of interest isn’t enough of a cue to turn them into that cell type. It usually takes a lot of external (in vitro) manipulation of stem cells to turn them into a cell of interest.

Take home message here: based on which stem cell we’re using, that can affect the cell types that the stem cell can differentiate into. Therefore, we (scientists and doctors) should plan well-reasoned studies using the appropriate stem cell for the appropriate tissue.

Reprogramming cells — induced pluripotency

One special stem cell worth mentioning is an induced Pluripotent Stem cell, or iPS cell. I’ll write more about this special cell type at a later date, but essentially in 2006, a Japanese medical scientist by the name of Shinya Yamanaka was able to reprogram a skin cell into a pluripotent stem cell. If you recall from the previous section, an example of a pluripotent stem cell is an embryonic stem cell, so essentially Dr. Yamanaka was able to reprogram a skin cell into an embryonic stem cell. If we refer back to the Waddington Hill analogy, this means basically that now we have the ability to take a cell that’s fallen to the bottom of Waddington’s Hill, and move it back near the top to an pluripotent state by reprogramming or manipulating the cell. As you can imagine, this opens up the door to a number of exciting possibilities — now any cell in our bodies can be reprogrammed to a pluripotent state. Since the reprogrammed iPS cells are pluripotent, they can then be turned into any other cell type in our body. So instead of injecting blood stem cells into the heart to repair damaged heart tissue (with little to no long-term effects as analyzed above), we can reprogram that blood stem cell into an iPS cell, turn those iPS cells into heart cells, and then inject those heart cells back into the heart to regenerate heart muscle. Of course, you could also do this with embryonic stem cells, and in fact, research from the University of Washington (and by a former professor of mine) has shown that injection of pluripotent stem cell-derived heart cells was able to successfully regenerate damaged monkey hearts. However, the ability to reprogram your own cells into iPS cells could lead to more personalized therapies, but this field is still very new.

Basically “new” technology allows us to reprogram cells back into a pluripotent, or embryonic-like state. But one advantage of this technology is now we can generate our own pluripotent stem cells, which otherwise do not exist in the adult human body.

Summary

Hopefully that clarifies a lot of the ambiguity of stem cells. Stem cells are an important innate part of repairing our bodies already but can also serve as an additional, powerful tool as a therapy. However, given how popular stem cell medicine is now, there is a lot of noise with certain doctors or scientists broadly using stem cells to treat every disease possible without a sound fundamental hypothesis. It’s still good to be cautiously optimistic about the field — we’re very early — but we must also be very discerning as to what studies are being done with which type of cells and why.

-Alex

Appendix

Some theorize that this process of cellular senescence evolved to reduce cancer risk — whenever cells divide, or through daily processes, a number of mutations accumulate in their DNA, which could possibly give rise to cancer. These senescent cells can be cleared by our immune system, but an accumulation of senescent cells is a hallmark of aging. Going back to that yin yang analogy, our bodies might be balancing between reducing cancer risk with losing cell and tissue function.

*Slight programming note about the existence of pluripotent stem cells in the adult body: I’m not really sure if it’s a change in the use of terminology, however some stem cells have been found in the adult human body which have been referred to as pluripotent in publications, e.g. intestinal crypt stem cells or dental pulp stem cells. Personally, I don’t think these cells are pluripotent and I don’t believe any of these studies have demonstrated true pluripotency of the cells — they may express certain pluripotent markers but I don’t believe we’ve seen definitive 3 germ layer lineage differentiation of these cells, like ES or iPS cells. Moreover, I think the publications that refer to these cells as pluripotent actually mean multipotent — again, maybe the definition of pluripotent has gotten more specific over the years.