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Stem Cell Reports. 2014 May 15;2(6):794-809. doi: 10.1016/j.stemcr.2014.04.002. eCollection 2014 Jun 3.

Bone marrow endosteal mesenchymal progenitors depend on HIF factors for maintenance and regulation of hematopoiesis.

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Division of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan 20132, Italy ; Università Vita-Salute San Raffaele, Milan 20132, Italy.
Division of Molecular Oncology, Leukemia Unit, San Raffaele Scientific Institute, Milan 20132, Italy.
Università degli Studi di Torino, Dipartimento di Scienze Cliniche e Biologiche, Turin 10124, Italy.
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.


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.

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