[R01] Molecular Mechanisms Controlling Lung Capillary Speciation, Plasticity and Function During Early Postnatal Development
Ente: National Heart Lung and Blood Institute
Scadenza: 2030-02-28
Importo max: 778.504 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
During early postnatal life, septation of distal lung saccules into millions of alveoli and rapid expansion of lung
capillaries markedly increases gas exchange surface area. Angiocrine signals from lung endothelial cells (EC)
help promote alveolar formation and repair after injury. The lung capillary network is comprised of two distinct
subtypes. Capillary 1 EC (Cap1) are smaller and more proliferative, and highly express Kit. In contrast, Cap2
are larger, highly specialized EC with multiple filopodia (reminiscent of tip cells), that closely associate with
alveolar epithelial cells and highly express Tbx2. However, the separate roles of these distinct capillary EC on
informing the alveolar niche, their sensitivity to injury, and their regenerative capacity remain unclear. Cap2
rapidly expand after birth and progress toward terminal differentiation across early postnatal life. Postnatal
hyperoxia, an injury that suppresses Cap1 proliferation, further expands Cap2. Using genetic lineage tracing, we
showed that the majority of expanded Cap2 in hyperoxia are derived from Tbx2+ EC present at birth. This exciting
finding contrasts with the adult lung where Cap1 EC appear to serve as the main progenitors for new Cap2.
Additional data identified the unique presence of capillary EC that co-express Kit and Tbx2 in the immature lung.
These intermediate capillary EC (CapINT) were abundant at P3 but rare by P7 and comprised a significant portion
of proliferating EC in the late saccular lung. Hyperoxia increased CapINT abundance and persistence, suggesting
that this cell state precedes Cap2 expansion and terminal differentiation. Hyperoxia also increased chromatin
accessibility for activator protein-1 (AP-1) transcription factors, a pathway that promotes tip cell phenotype in EC
of other organs. Although it is known that VEGFR2 signaling is required for Cap2 differentiation, the VEGFR2
mediated downstream mechanisms that regulate Cap2 differentiation are not known. Further, embryonic loss of
epithelial-derived VEGF blocks Cap2 differentiation and disrupts alveolarization, however, how Cap2 inform the
alveolar niche has not been studied. Using a novel mouse model, we show that inducible abrogation of VEGFR2
in Tbx2+ EC after birth: (i) blocked the hyperoxia-induced expansion of Cap2 EC; (ii) prevented Cap2 terminal
differentiation; (iii) increased CapINT EC; and (iv) heightened expression of fibrotic mediators in the alveolus.
Taken together, our data suggest the overall hypothesis that postnatal expansion of Cap2 is preceded by entry
of Cap1 progenitors into an intermediate cell state; and requires VGFR2-mediated activation of AP-1 to promote
Cap2 terminal differentiation to maintain a homeostatic alveolar capillary niche, which will be tested through three
specific aims. Aim 1 will employ hyperoxia, in vivo EdU labeling, genetic lineage tracing and paired single cell
RNA- and ATAC-seq to identify the molecular regulation of the CapINT
Istituzione: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
PI: Cristina Maria Alvira
Progetto: 1R01HL177070-01A1
Settori: National Heart Lung and Blood Institute
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.