Bone Marrow Endosteal Mesenchymal Progenitors Depend on HIF Factors for Maintenance and Regulation of Hematopoiesis
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 maintena...
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doaj-808fae5bfcbd44fca8ddbe16bbbf80552020-11-24T20:52:39ZengElsevierStem Cell Reports2213-67112014-06-012679480910.1016/j.stemcr.2014.04.002Bone Marrow Endosteal Mesenchymal Progenitors Depend on HIF Factors for Maintenance and Regulation of HematopoiesisJlenia Guarnerio0Nadia Coltella1Ugo Ala2Giovanni Tonon3Pier Paolo Pandolfi4Rosa Bernardi5Division of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan 20132, ItalyDivision of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan 20132, ItalyUniversità degli Studi di Torino, Dipartimento di Scienze Cliniche e Biologiche, Turin 10124, ItalyDivision of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan 20132, ItalyCancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USADivision of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan 20132, ItalyMaintenance 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.http://www.sciencedirect.com/science/article/pii/S221367111400109X |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jlenia Guarnerio Nadia Coltella Ugo Ala Giovanni Tonon Pier Paolo Pandolfi Rosa Bernardi |
spellingShingle |
Jlenia Guarnerio Nadia Coltella Ugo Ala Giovanni Tonon Pier Paolo Pandolfi Rosa Bernardi Bone Marrow Endosteal Mesenchymal Progenitors Depend on HIF Factors for Maintenance and Regulation of Hematopoiesis Stem Cell Reports |
author_facet |
Jlenia Guarnerio Nadia Coltella Ugo Ala Giovanni Tonon Pier Paolo Pandolfi Rosa Bernardi |
author_sort |
Jlenia Guarnerio |
title |
Bone Marrow Endosteal Mesenchymal Progenitors Depend on HIF Factors for Maintenance and Regulation of Hematopoiesis |
title_short |
Bone Marrow Endosteal Mesenchymal Progenitors Depend on HIF Factors for Maintenance and Regulation of Hematopoiesis |
title_full |
Bone Marrow Endosteal Mesenchymal Progenitors Depend on HIF Factors for Maintenance and Regulation of Hematopoiesis |
title_fullStr |
Bone Marrow Endosteal Mesenchymal Progenitors Depend on HIF Factors for Maintenance and Regulation of Hematopoiesis |
title_full_unstemmed |
Bone Marrow Endosteal Mesenchymal Progenitors Depend on HIF Factors for Maintenance and Regulation of Hematopoiesis |
title_sort |
bone marrow endosteal mesenchymal progenitors depend on hif factors for maintenance and regulation of hematopoiesis |
publisher |
Elsevier |
series |
Stem Cell Reports |
issn |
2213-6711 |
publishDate |
2014-06-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S221367111400109X |
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