Opposing roles for TGFβ- and BMP-signaling during nascent alveolar differentiation in the developing human lung

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

doi:10.1038/s41536-023-00325-z

Opposing roles for TGFβ- and BMP-signaling during nascent alveolar differentiation in the developing human lung

NPJ Regen Med. 2023 Sep 9;8(1):48. doi: 10.1038/s41536-023-00325-z.

Authors

Tristan Frum¹, Peggy P Hsu^{1

2}, Renee F C Hein³, Ansley S Conchola⁴, Charles J Zhang⁵, Olivia R Utter¹, Abhinav Anand¹, Yi Zhang¹, Sydney G Clark⁴, Ian Glass⁶, Jonathan Z Sexton^{1

5

7

8}, Jason R Spence^{9

10

11}

Affiliations

¹ Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
² Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
³ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
⁴ Program in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
⁵ Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA.
⁶ Department of Pediatrics, Genetic Medicine, University of Washington, Seattle, WA, 98195, USA.
⁷ Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA.
⁸ Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, MI, 48109, USA.
⁹ Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. spencejr@umich.edu.
¹⁰ Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA. spencejr@umich.edu.
¹¹ Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, 48109, USA. spencejr@umich.edu.

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.

Abstract

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