Physiologic corticosterone oscillations regulate murine hematopoietic stem/progenitor cell proliferation and CXCL12 expression by bone marrow stromal progenitors

• Published in: Leukemia Vol. 27; no. 10; pp. 2006 - 2015
• Main Authors: Kollet, O, Vagima, Y, D'Uva, G, Golan, K, Canaani, J, Itkin, T, Gur-Cohen, S, Kalinkovich, A, Caglio, G, Medaglia, C, Ludin, A, Lapid, K, Shezen, E, Neufeld-Cohen, A, Varol, D, Chen, A, Lapidot, T
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.10.2013
• Subjects: Animals; Apoptosis; Blotting, Western; Bone marrow; Bone Marrow - drug effects; Bone Marrow - metabolism; Cell growth; Cell Movement; Cell proliferation; Cell Proliferation - drug effects; Cells (biology); Cells, Cultured; Chemokine CXCL12 - genetics; Chemokine CXCL12 - metabolism; Chemokines; Circadian rhythm; Circadian rhythms; Corticosterone; Corticosterone - metabolism; Corticotropin-releasing hormone; CXCL12 protein; Flow Cytometry; Gene expression; Genetic aspects; Health aspects; Hematopoiesis; Hematopoietic stem cells; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Immune system; Immunology; Jagged1 protein; Leukemia; Mice; Mice, Inbred C57BL; Mice, Knockout; Microenvironments; Mutants; Myeloid cells; Nervous system; Neurosciences; Notch1 protein; Oscillations; Osteoprogenitor cells; Phenotypes; Physiological aspects; Progenitor cells; Real-Time Polymerase Chain Reaction; Receptors, Corticotropin-Releasing Hormone - physiology; Repopulation; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal Transduction; Signaling; Stem cells; Stromal Cells - cytology; Stromal Cells - drug effects; Stromal Cells - metabolism; Supplements; Israel
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2013.154

The role of corticosterone (Cort), the immune system's major stress hormone, in the regulation of hematopoietic stem and progenitor cells (HSPCs) and their dynamic bone marrow (BM) microenvironment is currently unknown. We report that corticotropin-releasing factor receptor 1 (CRFR1) mutant mice with chronically low Cort levels showed aberrant HSPC regulation, having higher HSPC numbers and upregulation of the chemokine CXCL12, phenotypes that were restored by Cort supplementation. Expanded stromal progenitors known to support HSPCs were also observed in these low-Cort-containing mice. A similar phenotype was induced in wild-type (WT) mice by Metyrapone, a Cort synthesis inhibitor. Conversely, high Cort exposure induced HSPC apoptosis, reduced long-term BM repopulation and decreased stromal progenitor cell numbers. We documented circadian oscillations of Cort in WT BM but not in CRFR1 mutant mice, leading to diminished circadian BM CXCL12 fluctuations and increased number of circulating HSPCs in these mice. Finally, low Cort induced expansion of stromal progenitors, CXCL12 expression, HSPC proliferation and BM repopulation capacity, involving Notch1 signaling. This was associated with upregulation of the Notch ligand, Jagged1, in BM myeloid cells. Our results suggest that daily physiologic Cort oscillations are critical for balanced HSPC proliferation and function involving Notch1 signaling and their supportive BM microenvironment.