Microglia control vascular architecture via a TGFβ1 dependent paracrine mechanism linked to tissue mechanics.
Actomyosin
/ physiology
Animals
Biomechanical Phenomena
Cell Movement
/ physiology
Cytoskeletal Proteins
/ deficiency
Female
Hydrogels
Integrins
/ physiology
MAP Kinase Signaling System
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia
/ cytology
Paracrine Communication
Retina
/ growth & development
Retinal Vessels
/ cytology
Transforming Growth Factor beta1
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
20 02 2020
20 02 2020
Historique:
received:
11
02
2019
accepted:
01
02
2020
entrez:
22
2
2020
pubmed:
23
2
2020
medline:
6
5
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32080187
doi: 10.1038/s41467-020-14787-y
pii: 10.1038/s41467-020-14787-y
pmc: PMC7033106
doi:
Substances chimiques
Cytoskeletal Proteins
0
Hydrogels
0
Integrins
0
Tgfb1 protein, mouse
0
Transforming Growth Factor beta1
0
kindlin-3 protein, mouse
0
Actomyosin
9013-26-7
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
986Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL071625
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL077213
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL145536
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR026820
Pays : United States
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