Opposing Roles for TGFβ- and BMP-signaling During Nascent Alveolar Differentiation in the Developing Human Lung

Overview

Journal NPJ Regen Med

Date 2023 Sep 9

PMID 37689780

Authors

Tristan Frum

Peggy P Hsu

Renee F C Hein

Ansley S Conchola

Charles J Zhang

Olivia R Utter

Abhinav Anand

Yi Zhang

Sydney G Clark

Ian Glass

Jonathan Z Sexton

Jason R Spence

Affiliations

Soon will be listed here.

Abstract

Alveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in repair after injury. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development. Using lung explant and organoid models, we identified opposing effects of TGFβ- and BMP-signaling, where inhibition of TGFβ- and activation of BMP-signaling in the context of high WNT- and FGF-signaling efficiently differentiated early lung progenitors into AT2-like cells in vitro. AT2-like cells differentiated in this manner exhibit surfactant processing and secretion capabilities, and long-term commitment to a mature AT2 phenotype when expanded in media optimized for primary AT2 culture. Comparing AT2-like cells differentiated with TGFβ-inhibition and BMP-activation to alternative differentiation approaches revealed improved specificity to the AT2 lineage and reduced off-target cell types. These findings reveal opposing roles for TGFβ- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell type in vitro.

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