When you hear the word “stem cell,” I imagine this conjures up the image of cells that are special. Unlike most cells, stem cells can differentiate into other cell types. They hold the promise of curing many diseases, and thus they are continually the source of hype in mainstream and social media.
Yet the above isn’t really true, is it? With the development of induced pluripotent stem (iPS) cell technology, we have, ironically, come to a situation where any cell can theoretically be a stem cell. A wide variety of somatic cell sources have been shown to successfully reprogram to a pluripotent state, and, while they may differ in their ease of reprogramming or their subsequent differentiation, this suggests that a stem cell is more of an epigenetic state than an innate and unattainable cell phenotype.
Indeed, since being introduced, iPS cell technology has led to a massive effort towards better understanding the epigenetic modifications (e.g. DNA methylation, histone modifications) that characterize undifferentiated vs. specifically differentiated cells.
Along with this greater understanding of gene regulation has come greater ambition. If all cells have the same genome but differ in gene regulation, can we convert one mature cell type to another without creating iPS cells as an intermediate step?
Some investigators certainly think so. Particularly since this process, also known as transdifferentiation, has been shown to occur naturally in some species.
In the last few years, there have been several studies published in high impact journals covering “direct reprogramming” of cells across germ layer barriers. A few examples include the reprogramming of liver cells to neurons (endoderm à ectoderm) or fibroblasts to neural cells (mesoderm à ectoderm). As with the induction of pluripotency, direct reprogramming is often achieved by overexpression of specific transcription factors that, in this case, are instructive for a certain lineage. However, it is not always clear how closely such cells resemble their in vivo counterparts, and as with iPS cell induction, there may be some residual epigenetic modifications and mRNA expression that is more characteristic of their original cell type.
Another approach being explored, which is sort of a merge between first forming iPS cells and direct differentiation, is a process known as cell-activation and signaling-directed (CASD) transdifferentiation (or lineage conversion). Here, the cells are briefly exposed to reprogramming factors followed by soluble differentiation cues. The reprogramming stage is shorter and less complete than what would be used for full iPS cell line development, but it serves to prime the cells (erasing some epigenetic signatures) in a manner that makes them more susceptible to differentiation (like partially erasing a blackboard before writing a new set of notes).
It is unclear whether direct reprogramming or CASD will become a more popular alternative to iPS cell lines in the years to come. However, regardless of the specific strategy, it is clear that iPS cell technology has inspired us to pursue and achieve something previously thought impossible – interconversion of mature cell types. With progress in this area, all of our cells may hold curative potential.
My blog is just one of many covering this topic as part of the iPSC anniversary blog carnival. Please click here to read what other bloggers think about this.
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