Where do stem cells come from? Expert answers

We often talk about stem cells but there are some pretty basic, important questions that often go unanswered like ‘where do stem cells come from?’

The Niche

It’s a more complicated and interesting question than you might think. Some of the answers point to novel ways in which stem cells may be used to treat human diseases. Note that if you are looking for information in a language other than English, check out my stem cell outreach pages. They have key facts about stem cells in dozens of languages. The website A Closer Look at Stem Cells is also a good resource.

As a stem cell biologist myself and professor of a research lab working on stem cells for 14+ years, stem cells are always on my mind. The origins and properties of stem cells are questions I’ve been thinking about for a few decades. I enjoy discussing these issues. This post is likely to be of special interest to patients interested in stem cells, other stem cell biologists, scientists more generally, and students who want to learn more. As to students, perhaps an upcoming test that will include questions on stem cells and their origins.

In a broad sense many stem cells can be found in what’s called ‘the niche’. It is kind of akin to their nest inside each particular tissue, but this post is more focused on their sourcing from different tissues.

Adult stem cells intro

Let’s start by discussing the adult sources of stem cells, which have great medical promise. In the old days people would widely classify stem cells as “adult” or “embryonic”. However, this arbitrary and binary way of thinking was in part driven more by antiquated views of “good” and “bad” stem cells than by science. For instance, since induced pluripotent stem cells or IPS cells (more on them below) were not made from embryos they were sometimes classified as adult stem cells. This doesn’t make sense to me.

Where can adult stem cells come from?

For today’s article, we’ll classify adult stem cells as stem cells that are from individuals who are already born but may still be children. In this sense, the term “adult” is a bit odd, but it seems like the best classification approach. So, for example, stem cells from the bone marrow of a six-year-old girl would be considered “adult” stem cells.

stem cell donor, where do stem cells come from?
A courageous stem cell donor who is having hematopoietic stem cells isolated from her blood.

In adults, where do stem cells come from?

  • Bone marrow. From a historical perspective, in a way bone marrow was the original source of some of the key concepts and data about stem cells. Bone marrow stem cells also arguably are the main success story of the stem cell or regenerative medicine field as well. They are the basis for bone marrow transplants, now sometimes called hematopoietic stem cell transplants. These therapies have saved hundreds of thousands of lives. For instance, bone marrow stem cells can regrow the entire immune system after chemotherapy is used to wipe out blood cancers. Bone marrow also contains so-called mesenchymal stem/stromal cells or MSCs. MSCs are now widely accepted to not necessarily be pure stem cells. Much depends on how they are produced. Still, they can be at least enriched for true stem cells along with other supportive cells like stromal cells. By stromal cells we mean those that are in the  tissue surrounding the actual stem cells.
  • Blood. Another source of hematopoietic stem cells is blood. At any one given time most of the hematopoietic stem cells are hanging out in the bone marrow, but some circulate through the blood. In addition, the number of stem cells in the blood can be increased greatly by treatment with certain mobilizing factors, like Neupogen, prior to donating such stem cells either for one’s own use or for another person. See a picture of a wonderful person donating stem cells above. Within the Blood category, we should also include umbilical cord blood, which is a somewhat unique source of stem cells. Umbilical cord blood stem cells seem to be more flexible in their functions as compared to typical stem cells found in regular blood.
  • Fat. Adipose or fat tissue is a good source of MSCs. Fat MSCs are being studied in many clinical trials for almost any disease you can think of, but they are also already being marketed as treatments for many conditions too despite there being little evidence to support such offerings. Usually those selling fat MSCs, which sometimes go by the name stromal vascular fraction or SVF, operate out of small “stem cell clinics”. Many of these have run into trouble with the FDA.

In addition to the examples above, one theory is that every adult tissue or organ has its own population of stem cells. In this sense, there may be stem cells right now in every part of your body including your brain, kidney, liver, lungs, etc. Scientists periodically debate whether certain organs have meaningful populations of stem cells and it seems like the topics of adult human brain stem cells and heart stem cells are particularly contentious. My own sense is that nearly every adult organ has stem cells, but in some cases like in the heart they may either be absent or present in such small numbers that they do not seem at this time to have much significance for health.

These adult stem cells are there for two main reasons. First, they help to maintain that particular tissue or organ. Every day some of the cells in our bodies randomly die even under normal conditions and the adult stem cells help replace those. Second, should a tissue or organ get damaged or become infected, the adult stem cells in it will help it heal.

Where do embryonic stem cells come from?

Knoepfler lab stem cells
Human embryonic stem cells grown in the Knoepfler lab.

As their name suggests, embryonic stem cells are largely generated using embryos. In the case of human embryonic stem cells, they are derived from human embryos left over from IVF procedures done to help infertile couples have babies.

These human embryos are at a very early stage of development 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.

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.

Still, some folks are opposed to making or using human embryonic stem cells.

Cloning stem cells

Embryonic stem cells can also be made 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 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 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, which could be very useful in medicine. For this reason, this process is sometimes called therapeutic cloning. It remains unclear whether SCNT-derived human embryonic stem cells are really needed given the innovation of IPS cells, which I’ll now discuss.

Reprogramming cells

IPS cells, induced pluripotent stem cells, Knoepfler lab, stained for TRA-1-60, an ES cell marker.
IPS cells, induced pluripotent stem cells, Knoepfler lab, stained for TRA-1-60, a human ES cell marker.

Induced pluripotent stem cells or IPS cells were first reported using mouse and human cells in 2006 and 2007, respectively. Where do IPS cells come from? They are made through a process called reprogramming, which in a nutshell means that adult cells are transformed into IPS cells using specific molecules that have the power to “convince” cells they are like embryonic stem cells.

One analogy is that cellular reprogramming is sort of like installing a new operating system on your computer to make it function differently, but in the case of cells this new “operating system” does physically changes the resulting cells as they make new proteins, RNAs, etc.

The bottom line is that the resulting IPS cells act just like embryonic stem cells, but no embryo is needed to make them. The IPS cells can be differentiated into just about any cell type for use as therapies including making adult stem cells.

An increasing number of clinical trials are ongoing using IPS cells across the globe including both here in the US and in Japan, just to name two hubs of IPS cell work.

A related method called direct reprogramming is also in the mix. Direct reprogramming (also called dedifferentiation) in a way skips the IPS cell step.

In this way, typical adult stem cells like from blood can be directly changed into totally different kinds of cells like brain cells without having to go through the IPS cell step.

axolotol, where do stem cells come from?
Where do stem cells come from? in creatures like the axolotol the answer is “all over” but in humans there are far fewer stem cells and only in certain places in specific tissues.

Where do stem cells come from in other animals?

Yes, us humans are amazing in some ways with our big brains and such, but when it comes to stem cells some other animals are way cooler than us. Certain species have far more stem cells than we do and even what seem like non-stem cells in these animals can convert to a stem cell-like state under stress. While some researchers believe that in humans some non-stem cells can change into stem cells under stress like disease, this remains a more controversial idea.

One of the more amazing creatures from a stem cell perspective is the type of amphibians called axolotls. You can see a picture of an axolotl above. If they are attacked by a predator deep within their habit like a pool in a cave in Mexico and lose an arm or a leg, they have so many stem cells that they can regrow a new arm or leg. They could also regrow a new part of their head or of a damaged organ in some cases. By doing research on such creatures the hope is that it will unlock the stem cell-based regenerative potential of humans too.

What’s a more important question than ‘where do stem cells come from?’

In a way, what’s more important than where particular stem cells come from is what those stem cells can do. A second important question goes hand-in-hand and that is what risks particular stem cells might pose. Overall, what biomedical scientists and patients should focus on is the ratio of potential benefit to potential risk. still, I understand that the source of stem cells is an important issue as well to many people.

2 thoughts on “Where do stem cells come from? Expert answers”

  1. Beautifully explained Paul. Your write up is simple to understand for any novice to the field. However, I am tempted to add to it. First is the concept of a niche (micro-environment). We have to think of the stem cells and their niche together since they are closely interlinked. Niche is a source of growth factors and cytokines crucial for stem cells to proliferate/differentiate.

    In adult tissues, two populations of stem cells exist including the pluripotent VSELs and lineage restricted & tissue committed progenitors which include the HSCs in the bone marrow. VSELs divide to self-renew and give rise to HSCs which in turn divide rapidly and differentiate into various types of blood and immune cells whereas the MSCs provide the niche. Similarly, besides VSELs – tissue specific progenitors exist in all adult tissues that maintain life-long tissue homeostasis and get activated to regenerate in response to any stress/ disease. Uncontrolled expansion (and blocked differentiation) of VSELs and their immediate descendants results in leukemia/ cancer. This is the reason why tumors in different body organs express embryonic markers including OCT-4 (PMID: 22126538).

    It has proved extremely difficult to isolate these adult stem cells as a physical entity. Even HSCs are present amongst the mononuclear cells obtained after density gradient centrifugation of bone marrow/ cord or peripheral blood samples. Thus it was proposed that stem cells need to be defined based on their function (PMID: 29494240) and are mitotic cells observed after any stress to an adult tissue (PMID: 31374197). Cancer stem cells are generally believed to be quiescent, survive oncotherapy and cause recurrence. But as it has proved difficult to enrich CSCs; it is being suggested that CSCs may not be necessarily be rare and quiescent in nature (PMID: 28985214). Adult stem cells may not exist and rather the somatic cells dedifferentiate to stem-like state when required. This reminds me of the story of the fox and the grapes. As we are not able to enrich the quiescent stem cells, we suggest that they may not exist.

    So where do VSELs come from? VSELs are developmentally linked to the primordial germ cells (PGCs) which migrate to all the organs during development, rather than the existing concept of only to the gonadal ridge (PMID: 30653438). Stella and Fragilis are PGC-specific transcripts and we have detected these transcripts in adult bone marrow, pancreas, uterus, prostate in addition to ovary and testis. Significance of this data needs to be discussed. There is a lack of consensus even on the presence of PGCs in adult ovary and testes as VSELs.

    To sum up, there is still no clarity on the true identity of adult stem cells and cancer stem cells and their origin. Everything revolves around the method to isolate them (VSELs) from adult tissues. I discussed this in your earlier post [https://ipscell.com/2020/12/stap-cell-deja-vu-28-vsel-papers-flagged-by-bik/]. Only after arriving at a consensus on these aspects will the field of ageing/ regenerative medicine/ cancer biology will evolve.

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