Megakaryocyte and platelet thrombospondin-1 regulates matrix remodeling by stabilizing basement membrane COL6A1 in lung injury
An early event after lung injury is extracellular matrix (ECM) remodeling and the formation of a provisional matrix. While megakaryocytes and platelets (Mgk/plt) play important roles in hemostasis, their impact on the matrix in lung injury is not fully understood. Using lung intravital microscopy, 3D large area scanning with multiphoton confocal hybrid imaging, and label-free quantitative proteomics, the matricellular protein thrombospondin-1 (TSP1) arising from Mgk/plt protects the lung from alveolar injury. Mgk/plt cell-specific Thbs1 knockout (cKO) mice show increased alveolar barrier disruption with exaggerated neutrophil-mediated injury. The cKO mice exhibit striking extracellular matrix re-organization with reduction in basement membrane matrix protein COL6A1 after injury. Moreover, cKO mice increase Mgk numbers to regions of fibrillar collagen deposition and alveolar leak. Our findings indicate Mgk/plt-derived TSP1 represents a key mechanism of matrix stabilization by protecting the basement membrane from neutrophil-mediated proteolytic damage, regulating injury severity and Mgk numbers at the alveolar interface.
Authors
- Hernán F. Peñaloza (ORCID: https://orcid.org/0000-0002-1593-678X)
- Rick van der Geest (ORCID: https://orcid.org/0000-0002-1973-5934)
- Tomasz Waldemar Kaminski (ORCID: https://orcid.org/0000-0002-8688-4171)
- Mélia Magnen (ORCID: https://orcid.org/0000-0001-5189-0072)
- Claudette M. St. Croix (ORCID: https://orcid.org/0000-0003-0794-4939)
- Matthew R. Rosengart (ORCID: https://orcid.org/0000-0001-9203-5478)
- Mark R. Looney (ORCID: https://orcid.org/0000-0003-0241-9190)
- Gregory A. Gibson (ORCID: https://orcid.org/0000-0002-7421-9334)
- Donovan Watza (ORCID: https://orcid.org/0000-0002-6882-065X)
- Shekina Gonzalez-Ferrer (ORCID: https://orcid.org/0000-0002-0188-8844)
- Sébastien Gingras (ORCID: https://orcid.org/0000-0003-2607-8642)
- Mohammadreza Tabary (ORCID: https://orcid.org/0000-0002-3746-7371)
- Prithu Sundd (ORCID: https://orcid.org/0000-0001-7568-5719)
- Pooja Bhojraj (ORCID: https://orcid.org/0000-0002-4565-1574)
- Bo‐Ram Jin
- Anupam Kumari
- Xingan Wang
- Ananya Gupta
- Jaehyung Cho
- Janet S. Lee
- Kyunghee Choi
- Zeyu Xiong
- Rama K. Mallampalli
- Liwen Zhang
- Prabir Ray
- William G. Bain
- Jonathan K. Alder
- Arpad Somogy
- Jae-Sung Kim
- Atish Gheware
- Anuradha Ray
Institutions
- Pontificia Universidad Católica de Chile (CL)
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- Medical College of Wisconsin (US)
- Washington University in St. Louis (US)
- Versiti Blood Center of Wisconsin (US)
- Millennium Institute on Immunology and Immunotherapy (CL)
- The Ohio State University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-12
- DOI
- https://doi.org/10.1038/s41467-026-70489-x
- Primary Topic
- Cell Adhesion Molecules Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00