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

Area of Science:

• Neuroscience
• Developmental Biology
• Biophysics

Background:

• Tissue mechanics and microarchitecture are critical for Central Nervous System (CNS) development and pathology.
• The precise mechanisms coordinating tissue mechanics with CNS cellular behavior, particularly microglia, remain largely undefined.

Purpose of the Study:

• To elucidate the role of tissue mechanics in regulating microglial behavior during CNS development.
• To identify the molecular players involved in mechanotransduction by microglia and their impact on vascular patterning.

Main Methods:

• In vivo studies of retinal microglia colonization during development.
• In vitro experiments using hydrogels to mimic varying tissue stiffness.
• Genetic manipulation including microglial depletion and knockout of specific genes (Kindlin3, TGFβ1).
• Analysis of microglial morphology, signaling pathways (TGFβ1, ERK), and vascular development.

Main Results:

• Microglia contact stiff retinal layers, leading to bipolarization, reduced TGFβ1 signaling, and cessation of vascular growth.
• Stiff substrates in vitro induce microglial bipolarization and decrease TGFβ1 expression.
• Microglial bipolarization and mechanosensitivity require intracellular adaptor Kindlin3, independent of microglial integrins.
• Kindlin3 deficiency results in increased microglial contractility, ERK signaling dysregulation, elevated TGFβ1, and severe vascular malformations.
• Loss of TGFβ1 or microglial depletion rescues vascular defects in Kindlin3-deficient models.

Conclusions:

• Tissue stiffness regulates microglial behavior and function through Kindlin3-dependent mechanotransduction.
• This mechanism highlights a critical interplay between microglia, tissue mechanics, and vascular patterning in the CNS.
• Dysregulation of this interplay can lead to severe developmental defects and pathologies within the CNS.