Reserve stem cells: Differentiated cells reprogram to fuel repair, metaplasia, and neoplasia in the adult gastrointestinal tract

Abstract

It has long been known that differentiated cells can switch fates, especially in vitro, but only recently has there been a critical mass of publications describing the mechanisms adult, post-mitotic cells use in vivo to reverse their differentiation state. We propose that this sort of cellular reprogramming is a fundamental cellular process akin to apoptosis or mitosis. Because reprogramming can invoke regenerative cells from mature cells, it is critical to the longterm maintenance of tissues like the pancreas, which encounter large insults during adulthood but lack constitutively active adult stem cells to repair the damage. However, even in tissues with adult stem cells, like stomach and intestine, reprogramming may allow mature cells to serve as reserve (“quiescent”) stem cells when normal stem cells are compromised. We propose that the potential downside to reprogramming is that it increases risk for cancers that occur late in adulthood. Mature, long-lived cells may have years of exposure to mutagens. Mutations that affect the physiological function of differentiated, post-mitotic cells may lead to apoptosis, but mutations in genes that govern proliferation might not be selected against. Hence, reprogramming with reentry into the cell cycle might unmask those mutations, causing an irreversible progenitor-like, proliferative state. We review recent evidence showing that reprogramming fuels irreversible metaplastic and precancerous proliferations in stomach and pancreas. Finally, we illustrate how we think reprogrammed differentiated cells are likely candidates as cells of origin for cancers of the intestine.

Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis

“…Dclk1+ cells were significantly more efficient in forming mPanINs than the majority of adult Mist1+ acinar cells. This remarkable susceptibility of quiescent Dclk1+ cells to the combination of an oncogenic hit and cellular stress can be explained by their remarkable proliferative potential, demonstrated in sphere cultures and during regeneration, a possible prerequisite for PDAC development (Mills and Sansom, 2015; Puri et al, 2015). While adult acinar cells are relatively resistant to malignant transformation in the absence of a secondary hit (Guerra et al, 2007), the longevity of such a mutant cell population has not been addressed.…”

“…It has not been determined whether all acinar cells have the same ability to dedifferentiate, or if there is a specific subset with greater plasticity (Bailey et al, 2015; Kong et al, 2011; Puri et al, 2015; Reichert et al, 2013; Yanger and Stanger, 2011; Yanger et al, 2013; Ziv et al, 2013). While some investigators support the notion of committed progenitors, others propose that during injury, acinar cells dedifferentiate to act as facultative progenitor cells (Kong et al, 2011; Mills and Sansom, 2015). In theory, such facultative progenitors should demonstrate considerable plasticity in response to stress (Valdez et al, 2015).…”

Murine Models of Gastric Corpus Preneoplasia

“…Work in mouse models and human beings suggests that the loss of mature chief cells may not simply be because they all die similar to parietal cells, but rather that chief cells, in response to loss of parietal cells, change their differentiation state. Specifically, they reprogram into metaplastic mucous cells 7, 8, 9, 10, 11. Such a reprogramming of cell fate also is known as transdifferentiation.…”

Defining key concepts of intestinal and epithelial cancer biology through the use of mouse models

“…These papers demonstrate that the CBC is not the exclusive cell of origin for all subtypes of colorectal cancer, and that the top-down model is also valid. However it should be remembered that in human cancer it would be very rare that 3 alleles would be lost simultaneously, so the top down model would require the first APC mutation in a stem cell to repopulate the crypt (for a more thorough review of this area see (166). It is possible that multiple mutations could occur in the same cell at the same time, in situations of high cellular stress such as inflammation or during massive chromosomal rearrangements (133).…”