Homeostasis

 
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Epithelial nuclei marked by K14-H2BGFP showing proliferation events in a hair follicle during anagen.

Tissue regeneration is an extremely dynamic process, requiring coordination of many cellular behaviors, including self-renewal and differentiation, to maintain normal tissue function. In an organ like the skin, tissues in close proximity have to coordinate their actions to maintain distinct identities. By investigating homeostatic principles that maintain different tissue types within an organ we can begin to elucidate sufficiency and requirements of specific tissues towards maintaining overall organ function.

Utilizing our novel live imaging approach we have begun to understand what factors dictate stem cell behavior, including that: 1) location dictates stem cell fate (Rompolas, Nature 2013), 2) stem cell decisions are balanced through extrinsic regulation via TGF-β signaling from the niche (Mesa 2015), 3) β-catenin activation induces stem cell autonomous survival as well as non-autonomous growth of neighboring stem cells (Mesa 2015; Deschene*, Myung* 2014), and 4) epidermal stem cells are equipotent for self-renewal and differentiation behaviors (Rompolas*, Mesa* 2016).

 

More recently, we discovered that stem cells in the hair follicle have incredible plasticity during homeostasis (Xin, 2018). Importantly, this plasticity is not an emerging property of a pathological or injury state but an embedded property of the tissue, allowing it to remain flexible to dynamic environmental demands.

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Left: optical section of basal layer cells (K14-H2BCerulean). Right: result of whole cell population tracking. Colors represent clones from the initial timepoint, and the regions of colors represent the voronoi diagram calculated from the position of the cells.

In the epidermis, we have found that direct stem cell neighbors coordinate their fate decisions to support tissue regeneration, with self-renewal always following the differentiation of a neighboring cell (Mesa*, Kawaguchi*, Cockburn*, 2018). This work showed for the first time that stem cell self-renewal is not the constitutive driver of epidermal homeostasis but instead a direct response to demand for neighboring cells.

Timelapse movie of a single membrane-GFP labeled fibroblast in undamaged live mouse paw skin upper dermis.

As the skin contains multiple cell types it is paramount to understand how each maintain themselves over time, as well as how they coordinate their own homeostatic behaviors with those of the epidermal stem cell neighbors. By broadening our investigation of the epithelium to include mesenchymal fibroblasts, we found that fibroblasts in the dermis are stably positioned during homeostasis, even upon the spontaneous loss of neighboring cells that occurs during aging (Marsh, 2018). In contrast, fibroblast membranes are highly dynamic and extend to fill the void left by the lost neighbors, revealing that these membrane extensions enable fibroblasts to sustain organ homeostasis in the absence of proliferation.

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