Stem cell diversity and disease: A new wrinkle to a very old story

Message from the Director, May 2021

Part of studying stem cells is the realization that the stem cell pattern of tissue formation, maintenance, repair, and role in diseases, has a long evolutionary history. Single cell organisms ((essentially stem cells)) eventually coalesced together with other cells to form organisms made up of many cells, and eventually many different types of cells. These multicellular (metazoan) species arose long before modern times.

Stem cells self-renew to make more stem cells, and also give rise to the functional cells in the tissue or organ in which they reside. Different stem cells make different tissues, and there is not interconversion between different kinds of stem cells that happen naturally. The general properties–but not the exact genes­–shared between different stem cells (say, between blood forming stem cells and skin forming stem cells) are the conserved suites of genes that must be turned on or off for each stem cell type. In general, stem cells self-renew to maintain the number needed for tissue or organ maintenance. Blood stem cells have the ability, at the single stem cell level, to self renew and differentiate. Through differentiation, they make all of the blood cell types for all blood functions, such as carrying oxygen, fighting dangerous microbial and parasitic invaders, clotting blood after an injury, hollowing out bone to make room for blood formation, etc. Skin stem cells express genes to allow their differentiation to all of the skin structures (whether hairy, hairless, pigmented, thick in palms and soles, or covered with fluids that keep skin functioning, and so on). These outcomes change through life, and these changes are also properties of skin stem cells.

 This may seem simple, but we now know that the blood stem cells we have during development before birth differ from those that dominate in youth and through the reproductive period, which in turn differ from those that dominate as we age. The same could be said about how our skin stem cells differ over time (what happened to my hair?  What causes wrinkles? Why do I have bags under my eyes?). 

Since stem cells are likely born from pre-stem cells only during the embryo to fetal stage of development, the potential for the diversity of stem cells must be intrinsic in the numbers and types of stem cells first formed. For all systems, the changing diversity of stem cells may derive by precise instructions of how and when the stem cells of youth turn into the stem cells of aging…..and/or…..diverse stem cells are there from the beginning, but undergo competition and natural selection so that one type eventually wins over another. The changes from one type to the other, or the competition between the two types likely result from the accumulation of changes in the body with aging and exposure to damaging element—the changing soil in which the seeds—stem cells—find themselves.

Blood stem cells or skin stem cells didn’t start with humans. So over millions and millions of years, single cells gave rise to organizations of cells for each creature. As different species arose and won their own competitions and natural selection, they slowly traveled from their place of origin to nearby geographies, encountering the challenges from other species, including disease-causing microbes. All of these stem cell varieties arose and diversified in animals for hundreds of millions of years before humans, in just a few thousand years, changed everything in the world around them. Modern humans, nevertheless, still have stem cells much like ancient humans. The same could be said of all species.

 As recently as 5-10,000 years ago, human lifespan extended not much longer than their reproductive lifespan. But with social organization and communication that could be remembered (oral histories) or written down(books), humans learned to develop safer environments, realized the value of sanitation, and developed a scientific approach to medicine, so that humans now live much longer than their reproductive lifespan. It is unclear if there has been positive natural selection to account for aging after reproduction cannot occur.

 And even more problematic, humans invented transportation: boats, trains, planes and cars allowed geographically-limited species to travel. Environments formerly commonly used by large numbers of geographically stable populations became available to highly itinerant people. The disease-causing microbes limited to the geography of your ancestors were also limited to the geographies they inhabit, until mass transportation developed

All vertebrates are protected by immediate activated innate immune cells such as macrophages and neutrophils that rapidly get rid of microbes by eating them; and also adaptive immune system cells responsible for immunological memory—immune cells (memory lymphocytes) that live as long as we do, each precommitted to a single agent. The encounter with microbes or vaccines triggers the massive expansion of the lymphocytes responding to those microbes, creating a large pool of specific lymphocytes that can quickly act upon a second infection by the same microbe, thus giving rise to faster and more powerful immune responses. This is immunological memory. The innate cells don’t expand every time they re-encounter the same microbe, and they lack immune memory. But both come from blood-forming stem cells.

All of these innate and adaptive immune cells worked fine for the young, and for old folks who did not travel beyond a geography with a limited diversity of microbes. They could live on their immunological memory, just as other functions also shifted from activity to memory. But recently, stem cell scientists in the institute and their trainees around the world found that as all vertebrates age, blood stem cell competitions in post-reproductive, aging individuals result in a few innate immunity-biased blood stem cells becoming the dominant pool of blood stem cells that mainly make scavenger macrophages and bacteria-fighting), which are incapable of expanding and keeping immune memory cells. These blood stem cells make few new lymphocytes, because in the pre-modern era the long-lived memory lymphocytes protected individuals from the microbes they grew up with. 

But now trains, planes and cars bring new microbes to which individuals cannot readily make new immune responses, because the old folks’ blood stem cells make precious few new lymphocytes to combat them, and immune memory can’t be developed. Infected individuals arriving via modern global transportation have brought disastrous pandemics, such as HIV-AIDS, Zika, Ebola, Bolivian Hemorrhagic Fever, and of course, SARS-2 covid-19. More of us old folks get dangerous infections, and our degree of illness and mortality is much greater, even under the best of care. We need much higer doses of vaccines to make sure the few new lymphocytes we do make have time to encounter the vaccine and make new memory cells against these pathogens.

This isn’t just a property of blood. It also works for brain stem cells, skin and hair stem cells, and even the wound repair fibroblasts, including those just under the skin. 

Back in olden times four-legged vertebrates were preyed upon by larger vertebrates and birds that attacked from above, opening wounds mainly in the back skin. Escapees from these attacks had skin-healing stem cells and wound-healing fibroblast stem cells that rapidly made large, thick, and (to some nowadays) ugly scars. But cuts on the gums in the mouth healed without scars. It happens over and over again, and most of us don’t even think about it. But a young surgeon in training nearly 30 years ago started to operate on animal fetuses to prepare to try to save human fetuses with dangerous anomalies and malformations that could compromise birth itself, or could be fatal just after birth. That young surgeon was Mike Longaker, now a co-director of the Institute, who noticed that the animal fetuses that he operated on before birth  didn’t have scars after they were born.  

Nearly 10 years ago Mike and his trainees had the idea that there may be a diversity of fibroblasts, including some that had intrinsic gene-expression properties that made masses of collagen, and others that made not so much. He discovered that the fibroblasts on the back of mice that made big scars came from a genetic pathway called engrailed, and these dorsal-dermal fibroblasts made much more collagen per cell than those on the soft underside covering the belly.  That discovery led him and colleague Geoff Gurtner to search for how engrailed gene function could give rise to these strong, but ugly scars—the extreme of which are keloid scars that are disfiguring and cannot be healed by cutting out the scar. You can read about this discovery in this issue.

Fibroblasts can cause a number of diseases and a number of non-healing scars. So discovering the mechanisms by which these dorsal-dermal, engrailed-derived fibroblasts and their stem cell precursors work and could be made to heal without scarring, could also be the basis for preventing scarring after surgery in the abdomen or pelvis or chest. These surgical adhesions that form in some people after surgery are more likely to cause disease than heal. This new understanding could also be the basis for ameliorating scarring with fibroblasts in scleroderma, lung fibrosis, and liver fibrosis—a field led by pathologist and stem cell faculty member Gerlinde Wernig. 

This story of discovery and translating discovery is a theme in our institute. The fact that we are confronted by stem cell variations that came from olden times is just a new ‘wrinkle’.