Brain PDGFR β + Cells Exhibit Diverse Reactive Phenotypes After Stroke Without Requiring KLF4

ABSTRACT The pathobiology of ischemic stroke is associated with the activation of brain platelet‐derived growth factor receptor (PDGFR) β + perivascular cells. While Krüppel‐like factor (KLF)4 is a well‐established mediator of peripheral PDGFR β + cell activation, its role in brain PDGFR β + cells remains elusive. Herein, we aimed to characterize the spatiotemporal reactivity of brain PDGFR β + cells, while assessing KLF4 contribution upon experimental ischemic stroke using transgenic mice that enable tracking PDGFR β + cells or conditionally depleting KLF4 in PDGFR β + cells. Moving beyond the qualitative descriptors, we sought to develop point pattern analysis (PPA) and topological data analysis (TDA) workflows to generate robust and reusable mathematical models to assess spatial cell responses and tissue scar topological changes. First, we report the emergence of phenotypically distinct reactive parenchymal PDGFR β + cells, which cannot be causally and exclusively linked, as it is currently proposed, to local cell proliferation or adjacent vascular detachment. Furthermore, we show that KLF4 is barely expressed in brain PDGFR β + cells under normal conditions and that it is only marginally induced in reactive PDGFR β + cells at the injured brain. Notably, the conditional attenuation of KLF4 expression specifically in reactive PDGFR β + cells does not alter spatial cellular distribution nor scar organization. This suggests that, in contrast to peripheral PDGFR β + cells upon ischemic insults, KLF4 is not a main regulator of the reactivity of brain cells in response to ischemic stroke. Ultimately, our findings supported by open‐source spatiotemporal models indicate that the reactivity of brain PDGFR β + perivascular cells is highly heterogeneous and fundamentally distinct from peripheral PDGFR β + cells.