Skin and Its Regenerative Powers: An Alliance between Stem Cells and Their Niche

Gonzales, Kevin Andrew Uy; Fuchs, Elaine

doi:10.1016/j.devcel.2017.10.001

Our review of epithelial stem cell dynamics in the skin culminates toward a single moral: during homeostasis, epithelial stem cell populations govern only their specific tissue territory, but they possess a plasticity that is unleashed during wound repair. If this versatility is intrinsic to stem cell identity, what prevents stem cell potency from going rogue? As discussed in this review, the answers all point to the niche microenvironment in which the stem cell finds itself. Thus, when skin epithelial stem cells are ablated, their neighbors happily adopt each other's responsibility and move into vacated niches. How neighbors sense these vacancies is still not clear. However, the signals appear to be local, as the closest neighbors nearly if not always seem to win in these resettlements. Moreover, the new squatters appear to gain all rights of their bona fide prior residents, underscoring the domineering role of the niche in instructing stem cell behavior. Indeed, if niche cells are ablated or otherwise irrevocably damaged, the stem cells cannot exert their tissue regenerating potential. In the many engraftment studies described in this review, epithelial stem cell plasticity was only displayed through the addition or existing presence of the appropriate mesenchymal niche cells. These two facets—the more rapid response of neighboring SCs to injury and the need for the requisite niche components—explain why de novo HFs are such a rare occurrence in regenerated skin from full-thickness wounds, and why SwG myoepithelial SCs are refractory to shallow wounds and will only make glands when placed in a glandular permissive environment.

Indeed, the research over the past decade has illuminated the resilient ability of the body to rapidly restore the skin's barrier following injury and to return to normal tissue homeostasis following re-epithelialization. In these processes, the interactions between epithelial stem cells and their microenvironment are critical. In fact, simply viewed, the field is converging on the view that the progenitors of the epidermis and its appendages may be intrinsically equivalent, sharing certain core structural features, including expression of KRT5 and KRT14, and integrins α6β4 and α3β1, and residing on a basement membrane that demarcates the dermo-epidermal border. According to this model, their differences in behavior emanate from their cross-talk with their local niche environment. Although there are still some findings that are inconsistent with this notion, the evidence is increasingly beginning to point in this direction. In this view, the versatility of a stem cell in a wound response may then simply be a reflection of changes in this environment.

When stem cells are removed from their native context, either in a wound response or in culture, they then must adjust their chromatin dynamics and change their program of gene expression in order to survive in their new environment (Adam et al., 2015; Ge et al., 2017). Given that not all epigenetic adjustments are rapid, this could account for why aging keratinocytes in vitro are initially readily distinguishable from their younger counterparts, but with time and passage in culture, these differences wane (Keyes et al., 2013).

The famed British philosopher John Locke (1632–1704) suggested that the individual is strongly influenced by social and cultural factors rather than by innate mechanisms. Similarly, the research shows that tissue stem cells are malleable, responding to their niche microenvironment rather than exhibiting a predetermined, innate behavior. If this model is correct, as seems increasingly likely, it prompts us to reconsider the steps necessary to make strides in regenerative medicine and wound repair. For under this view, it will not be sufficient merely to identify and culture stem cells. Rather, in addition, it will be essential either to recreate the stem cell niches or to recreate the environment that is needed to generate the desired stem cell behavior.

This concept provides a clear explanation for why a spray harboring millions of tiny skin fragments—each replete with stem cells in their native niches—has replaced passaged cultured epidermal keratinocytes as the favored method of burn therapy (Zielins et al., 2014). However, the importance of the niche microenvironment need not necessarily require that all niche components are present, as long as the necessary factors they produce are provided. In organotypic cultures, ranging from human epidermal equivalents to mammary and intestinal epithelia, this is in fact what is being done.

The challenge now is to exploit this newfound knowledge to harness the natural potential of stem cells for the desired task at hand. For homeostasis, the future challenge is squarely placed in the arena of unearthing a better understanding of SC niches. Will this knowledge be sufficient to regenerate skin appendages from scratch, or are there features of development that impose irreversible restrictions on fate options? The challenges are as great in the field of wound repair, where further characterization of wound-stimulated alterations to the microenvironment is needed, as is a deeper understanding of the relative contributions of different stem cell populations to the re-epithelialization process. The solutions to these unresolved biological problems will occupy researchers for the coming decade, but will provide the molecular soil that will nurture new and improved clinical applications for wound healing and regenerative medicine.

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