A role for pericytes as microenvironmental regulators of human skin tissue regeneration
Sophie Paquet-Fifield, … , Jason Li, Pritinder Kaur
Sophie Paquet-Fifield, … , Jason Li, Pritinder Kaur
Published August 3, 2009
Citation Information: J Clin Invest. 2009;119(9):2795-2806. https://doi.org/10.1172/JCI38535.
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Research Article Dermatology

A role for pericytes as microenvironmental regulators of human skin tissue regeneration

Abstract

The cellular and molecular microenvironment of epithelial stem and progenitor cells is poorly characterized despite well-documented roles in homeostatic tissue renewal, wound healing, and cancer progression. Here, we demonstrate that, in organotypic cocultures, dermal pericytes substantially enhanced the intrinsically low tissue-regenerative capacity of human epidermal cells that have committed to differentiate and that this enhancement was independent of angiogenesis. We used microarray analysis to identify genes expressed by human dermal pericytes that could potentially promote epidermal regeneration. Using this approach, we identified as a candidate the gene LAMA5, which encodes laminin α5, a subunit of the ECM component laminin-511/521 (LM-511/521). LAMA5 was of particular interest as we had previously shown that it promotes skin regeneration both in vitro and in vivo. Analysis using immunogold localization revealed that pericytes synthesized and secreted LAMA5 in human skin. Consistent with this observation, coculture with pericytes enhanced LM-511/521 deposition in the dermal-epidermal junction of organotypic cultures. We further showed that skin pericytes could also act as mesenchymal stem cells, exhibiting the capacity to differentiate into bone, fat, and cartilage lineages in vitro. This study suggests that pericytes represent a potent stem cell population in the skin that is capable of modifying the ECM microenvironment and promoting epidermal tissue renewal from non-stem cells, a previously unsuspected role for pericytes.

Authors

Sophie Paquet-Fifield, Holger Schlüter, Amy Li, Tara Aitken, Pradnya Gangatirkar, Daniel Blashki, Rachel Koelmeyer, Normand Pouliot, Manuela Palatsides, Sarah Ellis, Nathalie Brouard, Andrew Zannettino, Nick Saunders, Natalie Thompson, Jason Li, Pritinder Kaur

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Figure 3

The inclusion of HD-1bri pericytes in the dermal equivalent of OCs reconstituted with P7 HFFs stimulates epidermal regeneration capacity of α6dim differentiating keratinocytes.

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The inclusion of HD-1bri pericytes in the dermal equivalent of OCs recon...
Sections of OCs stained with H&E showing reconstituted skin tissue from α6bri (stem and TA) keratinocytes (A–C) or α6dim early differentiating keratinocytes (D–F) grown on dermal equivalents containing either P7 HFFs alone (A and D), P7 HFFs plus 10% HD-1bri cells (B and E), or fresh HFFs depleted of HD-1bri cells (C and F). The intrinsically low epidermal tissue-regenerative capacity of α6dim keratinocytes is substantially enhanced by coculture with dermal equivalents containing HD-1bri cells (E; n = 3), while depletion of HD-1bri cells diminishes their tissue-regenerative capacity (F; n = 2). Notably, the α6bri stem and TA–containing fraction exhibits excellent tissue regeneration irrespective of the presence of pericytes (A–C; n = 3). (G–I) Ki67 staining of OCs of α6bri (stem and TA) keratinocytes (G) or α6dim early differentiating keratinocytes (H and I) grown on dermal equivalents containing either P7 HFFs alone (G and H) or P7 HFFs plus 10% HD-1bri cells (I). Note the increase in cellularity and number of Ki67-positive cells in the α6dim epithelium upon coculture with the HD-1bri cells compared with P7 HFFs alone (I versus H), restoring epithelial regeneration to levels comparable to those obtained with the α6bri stem and TA compartment (G). Scale bars: 100 μm.