Spatial compartmentalization of signaling imparts source-specific functions on secreted factors
Elena Groppa,
Paolo Martini,
Nima Derakhshan,
Marine Theret,
Morten Ritso,
Lin Wei Tung,
Yu Xin Wang,
Hesham Soliman,
Mark Stephen Hamer,
Laura Stankiewicz,
Christine Eisner,
Le Nevé Erwan,
Chihkai Chang,
Lin Yi,
Jack H. Yuan,
Sunny Kong,
Curtis Weng,
Josephine Adams,
Lucas Chang,
Anne Peng,
Helen M. Blau,
Chiara Romualdi,
Fabio M.V. Rossi
Affiliations
Elena Groppa
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada; Borea Therapeutics, Scuola Internazionale Superiore di Studi Avanzati, Via Bonomea 265, Trieste, Italy
Paolo Martini
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Department of Biology, University of Padova, via U. Bassi 58B, Padova, Italy
Nima Derakhshan
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Marine Theret
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Morten Ritso
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Lin Wei Tung
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Yu Xin Wang
Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
Hesham Soliman
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada; Faculty of Pharmaceutical Sciences, Minia University, Minia, Egypt; Aspect Biosystems, 1781 W 75th Avenue, Vancouver, BC, Canada
Mark Stephen Hamer
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Laura Stankiewicz
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Christine Eisner
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Le Nevé Erwan
Department of Pediatrics, Université Laval, Laval, QC, Canada
Chihkai Chang
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Lin Yi
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Jack H. Yuan
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Sunny Kong
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Curtis Weng
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Josephine Adams
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Lucas Chang
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Anne Peng
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada
Helen M. Blau
Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA
Chiara Romualdi
Department of Biology, University of Padova, via U. Bassi 58B, Padova, Italy
Fabio M.V. Rossi
School of Biomedical Engineering, University of British Columbia, 2222 Health Sciences Mall, Vancouver, BC, Canada; Corresponding author
Summary: Efficient regeneration requires multiple cell types acting in coordination. To better understand the intercellular networks involved and how they change when regeneration fails, we profile the transcriptome of hematopoietic, stromal, myogenic, and endothelial cells over 14 days following acute muscle damage. We generate a time-resolved computational model of interactions and identify VEGFA-driven endothelial engagement as a key differentiating feature in models of successful and failed regeneration. In addition, the analysis highlights that the majority of secreted signals, including VEGFA, are simultaneously produced by multiple cell types. To test whether the cellular source of a factor determines its function, we delete VEGFA from two cell types residing in close proximity: stromal and myogenic progenitors. By comparing responses to different types of damage, we find that myogenic and stromal VEGFA have distinct functions in regeneration. This suggests that spatial compartmentalization of signaling plays a key role in intercellular communication networks.
