Pericyte-Mediated Molecular Mechanisms Underlying Tissue Repair and Functional Recovery after Ischemic Stroke

Abstract

There are still many patients suffering from ischemic stroke and related disabilities worldwide. To develop a treatment that promotes functional recovery after acute ischemic stroke, we need to elucidate endogenous tissue repair mechanisms. The concept of a neurovascular unit (NVU) indicates the importance of a complex orchestration of cell-cell interactions and their microenvironment in the physiology and pathophysiology of various central nervous system diseases, particularly ischemic stroke. In this concept, microvascular pericytes play a crucial role in regulating the blood-brain barrier integrity, cerebral blood flow (CBF), and vascular stability. Recent evidence suggests that pericytes are also involved in the tissue repair leading to functional recovery following acute ischemic stroke through the interaction with other cell types constituting the NVU; pericytes may organize CBF recovery, macrophage-mediated clearance of myelin debris, intrainfarct fibrosis, and periinfarct astrogliosis and remyelination. In this review, we will discuss the physiological and pathophysiological functions of pericytes, their involvement in the molecular mechanisms underlying tissue repair and functional recovery after ischemic stroke, and a therapeutic strategy to promote endogenous regeneration.

Keywords: Acute ischemic stroke; Blood–brain barrier; Extracellular matrix; Functional recovery; Pericytes.

Fig. 1. Schematic diagram showing the NVU

The NVU is a concept in which neurons, cerebrovascular endothelial cells, pericytes, astrocytes, oligodendrocytes, microglia, and ECM are considered one structural unit. BM surrounds blood vessels with two layers of endothelial BM and parenchymal BM and regulates barrier function and interactions between cells.

Fig. 2. Interaction of NVU components in tissue repair and functional recovery after ischemic stroke (modified from Shibahara et al. )

After cerebral ischemia, pericytes accumulate around the infarct lesions, differentiate into fibroblast-like cells, and produce ECM proteins such as fibronectin (fibrotic scar formation). Pericytes promote macrophage-mediated clearance of myelin debris within the infarct, periinfarct astrogliosis, and remyelination and thereby contribute to functional recovery by interacting with astrocytes and OPCs.