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

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

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129 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2795-2806
Number of pages12
JournalJournal of Clinical Investigation
Volume119
Issue number9
DOIs
Publication statusPublished - 1 Sep 2009

Cite this

Paquet-Fifield, S., Schlüter, H., Li, A., Aitken, T., Gangatirkar, P., Blashki, D., ... Kaur, P. (2009). A role for pericytes as microenvironmental regulators of human skin tissue regeneration. Journal of Clinical Investigation, 119(9), 2795-2806. https://doi.org/10.1172/JCI38535
Paquet-Fifield, Sophie ; Schlüter, Holger ; Li, Amy ; Aitken, Tara ; Gangatirkar, Pradnya ; Blashki, Daniel ; Koelmeyer, Rachel ; Pouliot, Normand ; Palatsides, Manuela ; Ellis, Sarah Lynne ; Brouard, Nathalie ; Zannettino, Andrew C W ; Saunders, Nick ; Thompson, Natalie ; Li, Jason ; Kaur, Pritinder. / A role for pericytes as microenvironmental regulators of human skin tissue regeneration. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 9. pp. 2795-2806.
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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.",
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Paquet-Fifield, S, Schlüter, H, Li, A, Aitken, T, Gangatirkar, P, Blashki, D, Koelmeyer, R, Pouliot, N, Palatsides, M, Ellis, SL, Brouard, N, Zannettino, ACW, Saunders, N, Thompson, N, Li, J & Kaur, P 2009, 'A role for pericytes as microenvironmental regulators of human skin tissue regeneration', Journal of Clinical Investigation, vol. 119, no. 9, pp. 2795-2806. https://doi.org/10.1172/JCI38535

A role for pericytes as microenvironmental regulators of human skin tissue regeneration. / Paquet-Fifield, Sophie; Schlüter, Holger; Li, Amy; Aitken, Tara; Gangatirkar, Pradnya; Blashki, Daniel; Koelmeyer, Rachel; Pouliot, Normand; Palatsides, Manuela; Ellis, Sarah Lynne; Brouard, Nathalie; Zannettino, Andrew C W; Saunders, Nick; Thompson, Natalie; Li, Jason; Kaur, Pritinder.

In: Journal of Clinical Investigation, Vol. 119, No. 9, 01.09.2009, p. 2795-2806.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - A role for pericytes as microenvironmental regulators of human skin tissue regeneration

AU - Paquet-Fifield, Sophie

AU - Schlüter, Holger

AU - Li, Amy

AU - Aitken, Tara

AU - Gangatirkar, Pradnya

AU - Blashki, Daniel

AU - Koelmeyer, Rachel

AU - Pouliot, Normand

AU - Palatsides, Manuela

AU - Ellis, Sarah Lynne

AU - Brouard, Nathalie

AU - Zannettino, Andrew C W

AU - Saunders, Nick

AU - Thompson, Natalie

AU - Li, Jason

AU - Kaur, Pritinder

PY - 2009/9/1

Y1 - 2009/9/1

N2 - 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.

AB - 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.

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U2 - 10.1172/JCI38535

DO - 10.1172/JCI38535

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JF - Journal of Clinical Investigation

SN - 0021-9738

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Paquet-Fifield S, Schlüter H, Li A, Aitken T, Gangatirkar P, Blashki D et al. A role for pericytes as microenvironmental regulators of human skin tissue regeneration. Journal of Clinical Investigation. 2009 Sep 1;119(9):2795-2806. https://doi.org/10.1172/JCI38535