Microglia control vascular architecture via a TGFβ1 dependent paracrine mechanism linked to tissue mechanics

Tejasvi Dudiki, Julia Meller, Gautam Mahajan, Huan Liu, Irina Zhevlakova, Samantha Stefl, Conner Witherow, Eugene Podrez, Chandrasekhar R. Kothapalli and Tatiana V. Byzova ()
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Tejasvi Dudiki: Lerner Research Institute, Cleveland Clinic
Julia Meller: Lerner Research Institute, Cleveland Clinic
Gautam Mahajan: Washkewicz College of Engineering, Cleveland State University
Huan Liu: Lerner Research Institute, Cleveland Clinic
Irina Zhevlakova: Lerner Research Institute, Cleveland Clinic
Samantha Stefl: Lerner Research Institute, Cleveland Clinic
Conner Witherow: Lerner Research Institute, Cleveland Clinic
Eugene Podrez: Lerner Research Institute, Cleveland Clinic
Chandrasekhar R. Kothapalli: Washkewicz College of Engineering, Cleveland State University
Tatiana V. Byzova: Lerner Research Institute, Cleveland Clinic

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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 TGFβ1 signaling and termination of vascular growth. Likewise, stiff substrates induce microglial bipolarization and diminish TGFβ1 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 TGFβ1 expression and abnormally-patterned vasculature with severe malformations in the area of photoreceptors. Both excessive TGFβ1 signaling and vascular defects caused by Kindlin3-deficient microglia are rescued by either microglial depletion or microglial knockout of TGFβ1 in vivo. This mechanism underlies an interplay between microglia, vascular patterning and tissue mechanics within the CNS.

Date: 2020
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DOI: 10.1038/s41467-020-14787-y

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