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Organ Boundary Circuits Regulate Sox9+ Alveolar Tuft Cells During Post-Pneumonectomy Lung Regeneration.
Obata, Tomohiro; Mizoguchi, Satoshi; Greaney, Allison M; Adams, Taylor; Yuan, Yifan; Edelstein, Sophie; Leiby, Katherine L; Rivero, Rachel; Wang, Nuoya; Kim, Haram; Yang, Junchen; Schupp, Jonas C; Stitelman, David; Tsuchiya, Tomoshi; Levchenko, Andre; Kaminski, Naftali; Niklason, Laura E; Brickman Raredon, Micha Sam.
Afiliação
  • Obata T; Department of Anesthesiology, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Mizoguchi S; Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
  • Greaney AM; Vascular Biology & Therapeutics, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Adams T; Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
  • Yuan Y; Department of Anesthesiology, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Edelstein S; Vascular Biology & Therapeutics, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Leiby KL; Department of Immunobiology, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Rivero R; Koch Institute for Integrative Cancer Research, Massachusetts Institute of technology, Cambridge, MA, 02139.
  • Wang N; Pulmonary, Critical Care, & Sleep Medicine, Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Kim H; Department of Anesthesiology, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Yang J; Vascular Biology & Therapeutics, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Schupp JC; Pulmonary, Critical Care, & Sleep Medicine, Internal Medicine, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Stitelman D; Department of Anesthesiology, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Tsuchiya T; Vascular Biology & Therapeutics, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Levchenko A; Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
  • Kaminski N; Vascular Biology & Therapeutics, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Niklason LE; Vascular Biology & Therapeutics, Yale School of Medicine, New Haven, CT, 06511, USA.
  • Brickman Raredon MS; Department of Surgery, Yale School of Medicine, New Haven, CT, 06511, USA.
bioRxiv ; 2024 Jan 08.
Article em En | MEDLINE | ID: mdl-38260691
ABSTRACT
Tissue homeostasis is controlled by cellular circuits governing cell growth, organization, and differentation. In this study we identify previously undescribed cell-to-cell communication that mediates information flow from mechanosensitive pleural mesothelial cells to alveolar-resident stem-like tuft cells in the lung. We find mesothelial cells to express a combination of mechanotransduction genes and lineage-restricted ligands which makes them uniquely capable of responding to tissue tension and producing paracrine cues acting on parenchymal populations. In parallel, we describe a large population of stem-like alveolar tuft cells that express the endodermal stem cell markers Sox9 and Lgr5 and a receptor profile making them uniquely sensitive to cues produced by pleural Mesothelium. We hypothesized that crosstalk from mesothelial cells to alveolar tuft cells might be central to the regulation of post-penumonectomy lung regeneration. Following pneumonectomy, we find that mesothelial cells display radically altered phenotype and ligand expression, in a pattern that closely tracks with parenchymal epithelial proliferation and alveolar tissue growth. During an initial pro-inflammatory stage of tissue regeneration, Mesothelium promotes epithelial proliferation via WNT ligand secretion, orchestrates an increase in microvascular permeability, and encourages immune extravasation via chemokine secretion. This stage is followed first by a tissue remodeling period, characterized by angiogenesis and BMP pathway sensitization, and then a stable return to homeostasis. Coupled with key changes in parenchymal structure and matrix production, the cumulative effect is a now larger organ including newly-grown, fully-functional tissue parenchyma. This study paints Mesothelial cells as a key orchestrating cell type that defines the boundary of the lung and exerts critical influence over the tissue-level signaling state regulating resident stem cell populations. The cellular circuits unearthed here suggest that human lung regeneration might be inducible through well-engineered approaches targeting the induction of tissue regeneration and safe return to homeostasis.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos