The Adult Stem Cell Revolution: How Regenerative Medicine Rediscovered Old Science
If you’ve read this blog on a regular basis, you’ll note that we have brought up the topic of “adult stem cells” when discussing aging or regeneration (see our blog on how stem cells age). This is because a lot of current research focuses on how adult stem cells maintain health and proper functioning of our tissues and organs. But knowledge of adult stem cells and their importance to aging wasn’t appreciated until fairly recently.
So why the current interest in stem cells? After all, stem cells have been well known to developmental biologists and medical scientists for over 100 years, since early embryos are basically made entirely of stem cells. The notion of stem cells playing an important role in adults is slightly more recent. As early as the 1850s, German physician Rudolf Virchow proposed that cancer arises from embryonic-like cells, and further work by Julius Cohnheim showed that these “embryonic remnants” were still present in adult tissue. By the 1930s, medical pathologists began to understand that adult stem cells (bone marrow “hematopoietic stem cells”, HSCs) formed the basis for our continually regenerating blood supply and immune system. By the 1960s, scientists had discovered that these stem cells had a wider use than expected, even being able to produceskin and bone cell types. But for a long time, stem cells were really only discussed among hematologists and other scientists who study blood.
Why then did it take until the 2000s for people to start getting excited about stem cells, particularly adult stem cells? Well, it turns out that there were a few hurdles, some having to do with understanding and some having to do with technical difficulties.
1) “Mitotic” vs “Post-mitotic” tissues
First, most regeneration within the body doesn’t happen directly via stem cells but rather through mitosis (cellular division), and many tissues in our body are not capable of this. Your skin and gut lining are examples of tissues that continually regenerate by mitosis of existing adult cells; hence they are referred to as “mitotic” tissues. Your muscles (including your heart) and brain are examples of tissues that don’t continually regenerate by mitosis; they’re “post-mitotic”. As such, it’s a common misinterpretation that the brain and muscle *don’t* regenerate—you see a lot of internet commentary even today saying that “the number of muscle cells one is born with is all they will ever have” (the same misinterpretation also happens regarding the brain). While scientists know better, the fact that *most* regeneration doesn’t occur directly via stem cells probably led to ignoring their contribution.
2) Difficulty of detecting stem cells and their “daughter cells”
Stem cells are rare and sometimes difficult to detect in tissues, and it’s also difficult to detect new cells (“daughter cells”) that arise from them. A major advancement in this area came in 2005 by scientists at the Karolinska Institute. They discovered that naturally occurring radioactive isotopes like carbon-14 (14C, which dramatically built up in the earth after nuclear testing, and has since gradually decreased by decay after nuclear testing bans) could be used to determine the “birth date” of different tissues in our body. By measuring the levels of 14C in different tissues, researchers could determine how recently new cells were produced (newer tissues have less 14C, older tissues have more). These studies allowed scientists to see that, for example, rib muscle cells in 30-year olds had an average age of 15 years—suggesting that either the post-mitotic muscle cells divide (less likely) or that stem cells were adding new muscle cells to the mix (more likely). These results fit in with earlier studies using DNA labeling in mice to show that “new” cells appear in many different tissues throughout a mouse’s lifetime.
At about the same time, improved techniques allowed detection of adult stem cells in many different “post-mitotic” tissues (muscle, fat, liver, joints, brain) in the late 1990s/2000s, including some that were not believed to regenerate at all (heart). These stem cells were capable of producing the full range of cell types found in the each tissue and were very long-lived, which are the main criteria for considering a cell type a “stem cell”.
3) Evidence of use and replacement of stem cells
Lastly, if adult stem cells really are playing an important role in tissue regeneration, we should see evidence of their being used, replicated, and replaced by the body. Evidence for this came with a series of studies in the early 2000s showing that patients who underwent bone marrow transplants and organ transplants developed “new” cells thatappeared to “colonize” organs and develop into replacement tissue cells. Because receiving a bone marrow or organ transplant causes a patient to have two different types of DNA, scientists were able to detect new cells with “foreign” DNA in the patient’s organs as evidence this colonization was going on.
The result of discoveries of type (2) and (3) was that, by the mid-2000s, scientists realized that stem cells are present in virtually all tissues and can regenerate or repair them in certain situations. The fact that stem cells are present and seem to contribute to even “post-mitotic” tissues like muscle (heart and skeletal muscle) and brain suggests that they may be especially important for preventing age-related damage to these tissues. The exciting research that remains to be done is determining how to stimulate them to do so, and how to maintain their health throughout a lifetime.
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