A century ago, we didn’t even know they existed. Now we know their function is essential to nearly every regenerative process in our body, and for creating life itself. But despite decades of research on these ubiquitous cells, it is still worth exploring the question:
What is a stem cell?
In fact, most researchers do have an answer prepared. “Stem cells are cells that self-renew and differentiate.” It sounds like a simple definition, one exemplified by the standard model of stem cell division—asymmetric mitosis, where one of the two resulting daughter cells is a photocopy of the original stem cell (self-renewal) and the other is an altered progenitor cell that can give rise to a variety of cell types (differentiation). But what about cells that in some contexts do self-renew and differentiate, and in other cases do not? Are they stem cells too? For example, researchers from Genentech described a certain type of cell in the intestine that, in most contexts, remained quiescent (non-dividing), but if the other resident stem cell population in the intestinal crypt was destroyed, these originally quiescent cells suddenly came to life, dividing both to rebuild the entire intestinal crypt (differentiation) and to replenish its own cell type (self-renewal).(1) Clearly these intestinal cells are stem cells, even if they do not always exhibit stem cell behaviors. Perhaps we should expand our definition to include not only cells that constantly self-renew and differentiate, but also those that have the capacity to self-renew and differentiate, regardless of their behavior at any one moment.
Expanded definition of a stem cell: a cell that can self-renew and differentiate (2)
If we define a stem cell as any cell that has the capacity to self-renew and differentiate, this begs a follow-up question—where do we draw the line? Do all cells with this capacity count as stem cells? The answer is obvious in the case of cells like the quiescent intestinal cells, which merely need a small nudge from environmental cues in order to behave like stem cells. But what about when the nudge needs to be stronger? Scientists have now discovered a method to produce induced pluripotent stem cells (iPSCs), which are essentially fully differentiated cells that exhibit stem cell behaviors (including self-renewal and differentiation). With our new expanded definition, centered around a cell’s capacity to self-renew and differentiate, this implies that every single cell in our body can be considered a stem cell. In other words, the iPSC protocol merely “unlocks” the capacity for stem-ness that any cell possesses. So why shouldn’t those original fully differentiated cells also be considered stem cells? Clearly this stem cell definition needs more work.
“Digging a little deeper unravels that first black-and-white definition into shades of grey.” (3)
The question of stem cell identity sounds simple, but digging a little deeper unravels that first black-and-white definition into shades of grey. All cells in the body cannot be stem cells; if our definition says every cell is a stem cell, then that definition is meaningless. Aside from the fact that conflating these two cell types goes against common sense, there are significant gene expression differences between those fully differentiated cells and the iPSCs they become. In fact, scientists have identified gene expression patterns that they believe are expressed solely by stem cells. On the other hand, genetics alone do not define stem cells either (e.g. intestinal stem cells can have the same genetic makeup, but still behave differently in different environmental contexts). The definition of a stem cell is likely somewhere in between, a combination of both a cell’s genetic expression and its current environmental cues. Or perhaps there may be no concrete solution to this question of stem cell identity. In some ways, defining a stem cell is like trying to pin down the identity of a person—are you the same personality in different contexts, around supervisors or friends or family? Do you feel like a completely different person than you were 5 years ago, or after a major life event? Defining identity is a complex, tangled question with no clear answer. But maybe we don’t need an answer. Maybe, just maybe, the fun part is actually asking the question.
Since 2012, Antara Rao has worked with SSSCR to raise awareness about stem cell science and encourage students to get involved in research. She has served as president of SSSCR’s UC Berkeley chapter and is now the Communications and Sponsorship Coordinator for SSSCR-International’s Executive Committee. Antara’s past research has included 3D differentiation of human Embryonic Stem Cells (hESCs) for potential therapeutic application to Parkinson’s and Huntington’s Disease, and she plans to continue working on clinically relevant stem cell research as a PhD candidate at the University of California, San Francisco, studying Developmental and Stem Cell Biology. Outside of lab, she keeps herself sane with some of her other interests: baking, board games, Kathak dance, and historical literature.