SMAlow/undetectable pericytes differentiate into microglia- and macrophage-like cells in ischemic brain

Pericytes are multipotent perivascular cells that play important roles in CNS injury. However, controversial findings exist on how pericytes change and whether they differentiated into microglia-like cells after ischemic stroke. This discrepancy is mainly due to the lack of pericyte-specific markers: the “pericyte” population identified in previous studies contained vascular smooth muscle cells (vSMCs) and/or fibroblasts. Therefore, it remains unclear which cell type differentiates into microglia-like cells after stroke. In this study, lineage-tracing technique was used to mark α-smooth muscle actin (SMA)^{low/undetectable} pericytes, vSMCs, and fibroblasts, and their fates were analyzed after ischemic stroke. We found that SMA^{low/undetectable} pericytes and fibroblasts but not vSMCs substantially proliferated at the subacute phase after injury, and that SMA^{low/undetectable} pericyte but not vSMCs or fibroblasts differentiated into Iba1⁺ cells after ischemic stroke. Further imaging flow cytometry analysis revealed that SMA^{low/undetectable} pericytes differentiated into both microglia and macrophages at day 7 after stroke. These results demonstrate that SMA^{low/undetectable} pericytes rather than vSMCs or fibroblasts differentiate into both microglia-like and macrophage-like cells after stroke, suggesting that these pericytes may be targeted in the treatment of ischemic stroke.