Inferring Gene Networks in Bone Marrow Hematopoietic Stem Cell-Supporting Stromal Niche Populations
Christophe Desterke,
Laurence Petit,
Nadir Sella,
Nathalie Chevallier,
Vincent Cabeli,
Laura Coquelin,
Charles Durand,
Robert A.J. Oostendorp,
Hervé Isambert,
Thierry Jaffredo,
Pierre Charbord
Affiliations
Christophe Desterke
Université Paris Sud, Hôpital Paul Brousse, Villejuif, France
Laurence Petit
Sorbonne Université, UPMC Université Paris 06, IBPS, CNRS UMR7622, Inserm U 1156, Laboratoire de Biologie du Développement; Paris 75005, France
Nadir Sella
Institut Curie, PSL Research University, CNRS UMR168, Paris, France
Nathalie Chevallier
IMRB U955-E10, INSERM, Unité d'Ingenierie et de Thérapie Cellulaire- EFS, Université Paris-EST, Créteil, France
Vincent Cabeli
Institut Curie, PSL Research University, CNRS UMR168, Paris, France
Laura Coquelin
IMRB U955-E10, INSERM, Unité d'Ingenierie et de Thérapie Cellulaire- EFS, Université Paris-EST, Créteil, France
Charles Durand
Sorbonne Université, UPMC Université Paris 06, IBPS, CNRS UMR7622, Inserm U 1156, Laboratoire de Biologie du Développement; Paris 75005, France
Robert A.J. Oostendorp
Clinic and Polyclinic for Internal Medicine III, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany
Hervé Isambert
Institut Curie, PSL Research University, CNRS UMR168, Paris, France
Thierry Jaffredo
Sorbonne Université, UPMC Université Paris 06, IBPS, CNRS UMR7622, Inserm U 1156, Laboratoire de Biologie du Développement; Paris 75005, France
Pierre Charbord
Sorbonne Université, UPMC Université Paris 06, IBPS, CNRS UMR7622, Inserm U 1156, Laboratoire de Biologie du Développement; Paris 75005, France; Corresponding author
Summary: The cardinal property of bone marrow (BM) stromal cells is their capacity to contribute to hematopoietic stem cell (HSC) niches by providing mediators assisting HSC functions. In this study we first contrasted transcriptomes of stromal cells at different developmental stages and then included large number of HSC-supportive and non-supportive samples. Application of a combination of algorithms, comprising one identifying reliable paths and potential causative relationships in complex systems, revealed gene networks characteristic of the BM stromal HSC-supportive capacity and of defined niche populations of perivascular cells, osteoblasts, and mesenchymal stromal cells. Inclusion of single-cell transcriptomes enabled establishing for the perivascular cell subset a partially oriented graph of direct gene-to-gene interactions. As proof of concept we showed that R-spondin-2, expressed by the perivascular subset, synergized with Kit ligand to amplify ex vivo hematopoietic precursors. This study by identifying classifiers and hubs constitutes a resource to unravel candidate BM stromal mediators.
