Pericytes: A newly recognized player in wound healing

Abstract

Pericytes have generally been considered in the context of stabilizing vessels, ensuring the blood barriers, and regulating the flow through capillaries. However, new reports suggest that pericytes may function at critical times to either drive healing with minimal scarring or, perversely, contribute to fibrosis and ongoing scar formation. Beneficially, pericytes probably drive much of the vascular involution that occurs during the transition from the regenerative to the resolution phases of healing. Pathologically, pericytes can assume a fibrotic phenotype and promote scarring. This perspective will discuss pericyte involvement in wound repair and the relationship pericytes form with the parenchymal cells of the skin. We will further evaluate the role pericytes may have in disease progression in relation to chronic wounds and fibrosis.

Figure 1

CXCR3 signaling leading to anoikis in endothelial cells. The ligands for CXCR3 (CXCL4/PF4, CXCL9/Mig, CXCL10/IP-10, and CXCL11/IP-9/I-TAC), derived from pericytes and other cells, lead to calcium influx. In the calcium sparks at the membrane, the calcium concentration can be sufficient to activate μ-calpain which then cleaves the β3 integrin. As β3 integrin is the main isoform in endothelial cells, this leads to anoikis and endothelial cell death.

Figure 2

Pericytes regulate the angiogenic response during wound healing. As the tissue replacement phase initiates, the wound bed is largely anoxic, with the VEGF response driving angiogenic sprouting; the pericytes are driven to express TGFβ1 being both angiogenic and pro-fibrotic. These immature endothelial cells express high levels of CXCR3. Upon establishing functional vascular conduits, the endothelial cells mature, concomitantly downregulating CXCR3 expression but producing CXCR3 ligands that attract pericytes. The pericytes also express CXCR3 ligands, with these ligands driving anoikis of nearby immature endothelial cells resulting in vascular involution. Late in wound healing the pericytes coat and stabilize the remaining, CXCR3-negative endothelial cell tubes.