title: Bone marrow endosteal mesenchymal progenitors depend on HIF factors for maintenance and regulation of hematopoiesis.
abstract: Maintenance and differentiation of hematopoietic stem cells (HSCs) is regulated through cell-autonomous and non-cell-autonomous mechanisms within specialized bone marrow microenvironments. Recent evidence demonstrates that signaling by HIF-1α contributes to cell-autonomous regulation of HSC maintenance. By investigating the role of HIF factors in bone marrow mesenchymal progenitors, we found that murine endosteal mesenchymal progenitors express high levels of HIF-1α and HIF-2α and proliferate preferentially in hypoxic conditions ex vivo. Inactivation of either HIF-1α or HIF-2α dramatically affects their phenotype, propagation, and differentiation. Also, downregulation of HIF factors provokes an increase in interferon-responsive genes and triggers expansion and differentiation of hematopoietic progenitors by a STAT1-mediated mechanism. Interestingly, in conditions of demand-driven hematopoiesis HIF factors are specifically downregulated in mesenchymal progenitors in vivo. In conclusion, our findings indicate that HIF factors also regulate hematopoiesis non-cell-autonomously by preventing activation of a latent program in mesenchymal progenitors that promotes hematopoiesis.
authors.affiliation: Division of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan 20132, Italy ; Università Vita-Salute San Raffaele, Milan 20132, Italy.
authors.forename: Jlenia
authors.initials: J
authors.lastname: Guarnerio
authors.affiliation: Division of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Coltella
authors.affiliation: Università degli Studi di Torino, Dipartimento di Scienze Cliniche e Biologiche, Turin 10124, Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Ala
authors.affiliation: Division of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.affiliation: Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.affiliation: Division of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan 20132, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Bernardi
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D015398:Signal Transduction / Q000502:physiology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse