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 4

Human dermal pericytes synthesize and secrete LAMA5 in the skin.

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Human dermal pericytes synthesize and secrete LAMA5 in the skin. (A) Qua...
(A) Quantification of LAMA5 mRNA expression by RT-PCR in freshly sorted epidermal cell populations from human neonatal foreskin. LAMA5 mRNA was highly expressed in unfractionated human foreskin keratinocytes (HFK), KSCs, and TA keratinocytes; and downregulated in early differentiating keratinocytes (ED). LAMA5 was undetectable in HFFs. (B) LAMA5 mRNA expression by RT-PCR in HD-1bri cells, HD-1dim cells, and HFFs, illustrating overexpression in the HD-1bri pericytes. In A and B, data represent results from 3 independent sorting experiments; mean ± SEM is shown. (C–I) Immunogold electron microscopic localization of human LAMA5 with mAb 4C7 in skin sections. LAMA5 was detected in the basement membrane between the endothelial cells (En) of blood vessels and the surrounding pericytes (P) (C and F); in the basement membrane region between the epidermis (E) and dermis (D) (G); and at hemidesmosomes (HD) (I). In addition, immunogold particles were also localized abluminally, i.e., secreted into the dermal space at the periphery of pericytes (D). Labeling with isotype-matched negative control mAb 1D4.5 showed the absence of staining in skin sections, as shown for blood vessels (E) and the epidermal-dermal junction (H). (D and F) Higher-magnification views of regions indicated in C. Scale bars in C–F: 10 μm; G and H: 0.5 μm; I: 0.1 μm.