Ischemic brains regenerate vascular mural pericytes by recycling detached endothelial cells, depending on TGFβ signaling

Abstract Ischemic stroke, one of the leading causes of death in the world, is accompanied by the dysfunction of the blood-brain barrier (BBB), which aggravates neuron damage. However, the mechanisms underlying the restoration of BBB in the chronic stage after stroke remain unclear. Here, we investigated the changes in the pericyte pool and their effects on BBB function and brain self-repair after stroke. Using lineage tracing, RNA-seq and immunofluorescence staining, we detected endothelial cells (ECs) transdifferentiated into pericytes (E-pericytes) after stroke in the MCAO model. E-pericytes depletion by diphtheria toxin A (DTA) aggravated BBB leakage and exacerbated neurological deficits in the MCAO model. The myeloid cell-driven transdifferentiation of ECs into pericytes accelerated BBB restoration and brain self-repair after stroke via endothelial-mesenchymal transformation (EndoMT). Decreasing the number of E-pericytes by specific knockout of the Tgfbr2 gene in ECs also aggravated BBB leakage and exacerbated neurological deficits. Specific-ECs overexpression of the Tgfbr2 gene promoting E-pericytes transdifferentiation reduced BBB leakage and exerted neuroprotective effects. Our findings solve a key question about how changes in the pericyte pool after stroke affect the restoration of BBB function and brain self-repair and may offer a new approach to therapy.