Microglia control vascular architecture via a TGF?1 dependent paracrine mechanism linked to tissue mechanics.

ABSTRACT: Tissue microarchitecture and mechanics are important in development and pathologies of the Central Nervous System (CNS); however, their coordinating mechanisms are unclear. Here, we report that during colonization of the retina, microglia contacts the deep layer of high stiffness, which coincides with microglial bipolarization, reduction in TGF?1 signaling and termination of vascular growth. Likewise, stiff substrates induce microglial bipolarization and diminish TGF?1 expression in hydrogels. Both microglial bipolarization in vivo and the responses to stiff substrates in vitro require intracellular adaptor Kindlin3 but not microglial integrins. Lack of Kindlin3 causes high microglial contractility, dysregulation of ERK signaling, excessive TGF?1 expression and abnormally-patterned vasculature with severe malformations in the area of photoreceptors. Both excessive TGF?1 signaling and vascular defects caused by Kindlin3-deficient microglia are rescued by either microglial depletion or microglial knockout of TGF?1 in vivo. This mechanism underlies an interplay between microglia, vascular patterning and tissue mechanics within the CNS.

SUBMITTER: Dudiki T 

PROVIDER: S-EPMC7033106 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature