Brain pericytes acquire a microglial phenotype after stroke

Abstract

Pericytes are located on the abluminal side of endothelial cells lining the microvasculature in all organs. They have been identified as multipotent progenitor cells in several tissues of the body including the human brain. New evidence suggests that pericytes contribute to tissue repair, but their role in the injured brain is largely unknown. Here, we investigate the role of pericytes in ischemic stroke. Using a pericyte-reporter mouse model, we provide unique evidence that regulator of G-protein signaling 5 expressing cells are activated pericytes that leave the blood vessel wall, proliferate and give rise to microglial cells after ischemic brain injury. Consistently, we show that activated pericytes express microglial markers in human stroke brain tissue. We demonstrate that human brain-derived pericytes adopt a microglial phenotype and upregulate mRNA specific for activated microglial cells under hypoxic conditions in vitro. Our study indicates that the vasculature is a novel source of inflammatory cells with a microglial phenotype in brain ischemia and hence identifies pericytes as an important new target for the development of future stroke therapies.

Pericytes, mesenchymal stem cells and their contributions to tissue repair

“…A recent paper by Ozen et al showed that in mice subjected to focal brain ischaemia GFP+ pericytes (driven by the RGS5 promoter) migrate into the ischaemic brain parenchyma, adopt an active morphology and express microglial markers IBA-1, CD11b and GAL-1 at one week postischaemia. Consistent with this, human pericytes exposed to hypoxic conditions in vitro similarly upregulate several microglial genes (CD11b, GAL-2, IBA1, TNF-α and MHC11), demonstrating the ability of pericytes to acquire a microglial phenotype (Ozen et al, 2014). Further work has shown that Type 2 pericytes form oligodendrocytes under in vitro culture conditions and differentiate into mature oligodendrocytes and Schwann cells (Birbrair et al, 2013b), indicating that pericytes may constitute a previously unknown vascular source of microglial cells in stroke and may therefore play a role in the pathogenesis of tissue damage after injury (Ozen et al, 2014).…”

“…Consistent with this, human pericytes exposed to hypoxic conditions in vitro similarly upregulate several microglial genes (CD11b, GAL-2, IBA1, TNF-α and MHC11), demonstrating the ability of pericytes to acquire a microglial phenotype (Ozen et al, 2014). Further work has shown that Type 2 pericytes form oligodendrocytes under in vitro culture conditions and differentiate into mature oligodendrocytes and Schwann cells (Birbrair et al, 2013b), indicating that pericytes may constitute a previously unknown vascular source of microglial cells in stroke and may therefore play a role in the pathogenesis of tissue damage after injury (Ozen et al, 2014). Again, fate mapping looking at both pericytes and satellite cells after skeletal muscle denervation would be helpful to identify whether pericytes form peri-/endoneural cells and Schwann cells or whether satellite cells are the ones that differentiate into Schwann cells, neural cells or even pericytes, ECs and smooth muscle cells to replenish the damaged peripheral nerve niche.…”

Microglia and Monocyte-Derived Macrophages in Stroke

“…The activated microglia peak at 2 to 3 days poststroke and remain sustained for several weeks [8]. Recent evidence suggests that activated pericytes, located on the abluminal side of endothelial cells lining the microvasculature, leave the vessel wall, and give rise to activated microglia following stroke [45,46]. However, this requires further investigation.…”

Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/Reperfusion Damage in Diabetic Stroke

“…During the hypoxic phase of stroke, pericyte migration from their usual microvascular location can directly or indirectly induce BBB disruption 32. Following ischemic stroke, pericytes acquire multipotent stem cell activity, leave the vessel wall, proliferate, and exhibit microglial cell phenotype 36, 37. Pericyte‐derived vascular endothelial growth factor (VEGF) may promote BBB disruption after stroke in mice 38.…”