Brain pericytes serve as microglia-generating multipotent vascular stem cells following ischemic stroke

Abstract

BackgroundMicroglia are the resident macrophage population of the central nervous system (CNS) and play essential roles, particularly in inflammation-mediated pathological conditions such as ischemic stroke. Increasing evidence shows that the population of vascular cells located around the blood vessels, rather than circulating cells, harbor stem cells and that these resident vascular stem cells (VSCs) are the likely source of some microglia. However, the precise traits and origins of these cells under pathological CNS conditions remain unclear.MethodsIn this study, we used a mouse model of cerebral infarction to investigate whether reactive pericytes (PCs) acquire microglia-producing VSC activity following ischemia.ResultsWe demonstrated the localization of ionized calcium-binding adaptor molecule 1 (Iba1)-expressing microglia to perivascular regions within ischemic areas. These cells expressed platelet-derived growth factor receptor-β (PDGFRβ), a hallmark of vascular PCs. PDGFRβ+ PCs isolated from ischemic, but not non-ischemic, areas expressed stem/undifferentiated cell markers and subsequently differentiated into various cell types, including microglia-like cells with phagocytic capacity.ConclusionsThe study results suggest that vascular PCs acquire multipotent VSC activity under pathological conditions and may thus be a novel source of microglia.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0523-9) contains supplementary material, which is available to authorized users.

Leptomeninges: a novel stem cell niche with neurogenic potential

“…However, reprogramming has been reported to cause adult brain pericytes to become non-pericytic lineages, such as neuronal lineages (10). In support of this notion, we showed that adult brain pericytes, which do not possess stem cell activity under normal conditions, reacquired stemness in response to ischemia, presumably through cellular reprogramming by mesenchymal-epithelial transition (11,12). We also showed that PDGFRβ + cells isolated from ischemic areas, including the leptomeninges, have a multipotent stem cell activity that gives rise to neuronal cells (11,12).…”

“…In support of this notion, we showed that adult brain pericytes, which do not possess stem cell activity under normal conditions, reacquired stemness in response to ischemia, presumably through cellular reprogramming by mesenchymal-epithelial transition (11,12). We also showed that PDGFRβ + cells isolated from ischemic areas, including the leptomeninges, have a multipotent stem cell activity that gives rise to neuronal cells (11,12). Therefore, we proposed that brain pericytes localized along the leptomeninges to cortical parenchyma are likely the origin of leptomeningeal stem cells.…”

“…O f n o t e , u s i n g s i n g l e -c e l l transcriptomics, they also showed that leptomeningeal PDGFRβ + cells generate various types of clusters that exhibited features of pericytic/fibroblastic, endothelial, and microglial lineages in addition to radial glia-like lineages. However, we recently showed that PDGFRβ + pericytes isolated from post-stroke areas, including the leptomeninges, exhibited multipotent stem cell activity and that they give rise to not only neural (e.g., neurons) but also vascular lineages (e.g., endothelial cells and microglia) (11,12 (5,6,19,20). Thus, the leptomeninges should become a new target for treating CNS developmental disorders and diseases.…”

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.…”