Luteinizing hormone signaling restricts hematopoietic stem cell expansion during puberty

The number and self‐renewal capacity of hematopoietic stem cells (HSCs) are tightly regulated at different developmental stages. Many pathways have been implicated in regulating HSC development in cell autonomous manners; however, it remains unclear how HSCs sense and integrate developmental cues. In this study, we identified an extrinsic mechanism by which HSC number and functions are regulated during mouse puberty. We found that the HSC number in postnatal bone marrow reached homeostasis at 4 weeks after birth. Luteinizing hormone, but not downstream sex hormones, was involved in regulating HSC homeostasis during this period. Expression of luteinizing hormone receptor (Lhcgr) is highly restricted in HSCs and multipotent progenitor cells in the hematopoietic hierarchy. When Lhcgr was deleted, HSCs continued to expand even after 4 weeks after birth, leading to abnormally elevated hematopoiesis and leukocytosis. In a murine acute myeloid leukemia model, leukemia development was significantly accelerated upon Lhcgr deletion. Together, our work reveals an extrinsic counting mechanism that restricts HSC expansion during development and is physiologically important for maintaining normal hematopoiesis and inhibiting leukemogenesis.

[1]  R. Jenq,et al.  Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury , 2018, Nature Medicine.

[2]  A. Bergman,et al.  Fetal liver hematopoietic stem cell niches associate with portal vessels , 2016, Science.

[3]  M. Ratajczak,et al.  Hematopoietic stem/progenitor cells express several functional sex hormone receptors-novel evidence for a potential developmental link between hematopoiesis and primordial germ cells. , 2015, Stem cells and development.

[4]  M. V. D. van den Brink,et al.  Enhanced Hematopoietic Stem Cell Function Mediates Immune Regeneration following Sex Steroid Blockade , 2015, Stem cell reports.

[5]  I. Mårtensson,et al.  Androgens regulate bone marrow B lymphopoiesis in male mice by targeting osteoblast-lineage cells. , 2015, Endocrinology.

[6]  A. Sánchez-Aguilera,et al.  Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis. , 2014, Cell stem cell.

[7]  Xi C. He,et al.  Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells , 2014, Nature Medicine.

[8]  S. Morrison,et al.  The bone marrow niche for haematopoietic stem cells , 2014, Nature.

[9]  B. Levi,et al.  Estrogen increases haematopoietic stem cell self-renewal in females and during pregnancy , 2014, Nature.

[10]  Jun Yeon Jo,et al.  Leukocytes and systemic inflammatory response syndrome as prognostic factors in pulmonary embolism patients , 2013, BMC Pulmonary Medicine.

[11]  A. Bergman,et al.  Megakaryocytes regulate hematopoietic stem cell quiescence via Cxcl4 secretion , 2013, Nature Medicine.

[12]  C. Eaves,et al.  Developmental changes in hematopoietic stem cell properties , 2013, Experimental & Molecular Medicine.

[13]  L. Calvi,et al.  Ovariectomy expands murine short-term hemopoietic stem cell function through T cell expressed CD40L and Wnt10B. , 2013, Blood.

[14]  D. Tenen,et al.  C/EBPa controls acquisition and maintenance of adult hematopoietic stem cell quiescence , 2013, Nature Cell Biology.

[15]  S. Morrison,et al.  Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches , 2013, Nature.

[16]  D. Link,et al.  CXCL12 Production by Early Mesenchymal Progenitors is Required for Hematopoietic Stem Cell Maintenance , 2012, Nature.

[17]  Lei Ding,et al.  Endothelial and perivascular cells maintain haematopoietic stem cells , 2011, Nature.

[18]  S. Morrison,et al.  Sox17 expression confers self-renewal potential and fetal stem cell characteristics upon adult hematopoietic progenitors. , 2011, Genes & development.

[19]  M. Merad,et al.  Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche , 2011, The Journal of experimental medicine.

[20]  T. Barbui,et al.  Leukocytosis is a risk factor for recurrent arterial thrombosis in young patients with polycythemia vera and essential thrombocythemia , 2009, American journal of hematology.

[21]  Christopher G. King,et al.  Luteinizing Hormone-Releasing Hormone Enhances T Cell Recovery following Allogeneic Bone Marrow Transplantation1 , 2009, The Journal of Immunology.

[22]  Andreas Trumpp,et al.  IFNα activates dormant haematopoietic stem cells in vivo , 2009, Nature.

[23]  S. Morrison,et al.  Sox17 Dependence Distinguishes the Transcriptional Regulation of Fetal from Adult Hematopoietic Stem Cells , 2007, Cell.

[24]  D. Kent,et al.  Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties , 2007, Proceedings of the National Academy of Sciences.

[25]  T. Barbui,et al.  Leukocytosis is a risk factor for thrombosis in essential thrombocythemia: interaction with treatment, standard risk factors, and Jak2 mutation status. , 2007, Blood.

[26]  David G Kent,et al.  Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. , 2006, The Journal of clinical investigation.

[27]  M. Cleary,et al.  Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. , 2006, Cancer cell.

[28]  S. Orkin,et al.  The journey of developing hematopoietic stem cells , 2006, Development.

[29]  T. Golub,et al.  Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9 , 2006, Nature.

[30]  A. Trumpp,et al.  Bone-marrow haematopoietic-stem-cell niches , 2006, Nature Reviews Immunology.

[31]  G. Lip,et al.  White blood cell count and hypertension , 2006, Journal of Human Hypertension.

[32]  S. Orkin,et al.  Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells , 2004, Nature.

[33]  S. Orkin,et al.  Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. , 2004, Genes & development.

[34]  G. Sauvageau,et al.  Genetic programs regulating HSC specification, maintenance and expansion , 2004, Oncogene.

[35]  D. Scadden,et al.  Osteoblastic cells regulate the haematopoietic stem cell niche , 2003, Nature.

[36]  Haiyang Huang,et al.  Identification of the haematopoietic stem cell niche and control of the niche size , 2003, Nature.

[37]  N. Powe,et al.  Leukocytosis, hypoalbuminemia, and the risk for chronic kidney disease in US adults. , 2003, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[38]  I. Huhtaniemi,et al.  Luteinizing Hormone Receptor Knockout (LuRKO) Mice and Transgenic Human Chorionic Gonadotropin (hCG)-Overexpressing Mice (hCG αβ+) Have Bone Phenotypes , 2003 .

[39]  Irving L. Weissman,et al.  Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells , 2003, Nature.

[40]  M. Poutanen,et al.  Transgenic and knockout mouse models for the study of luteinizing hormone and luteinizing hormone receptor function , 2002, Molecular and Cellular Endocrinology.

[41]  K. Garrett,et al.  Identification of very early lymphoid precursors in bone marrow and their regulation by estrogen , 2001, Nature Immunology.

[42]  J. Gustafsson,et al.  Role of oestrogen receptors α and β in immune organ development and in oestrogen‐mediated effects on thymus , 2001 .

[43]  M. T. Moser,et al.  Alterations in peripheral B cells and B cell progenitors following androgen ablation in mice. , 2001, International immunology.

[44]  K. Korach,et al.  Role of Estrogen Receptor α in Hematopoietic Stem Cell Development and B Lymphocyte Maturation in the Male Mouse. , 2000, Endocrinology.

[45]  I. Weissman,et al.  A clonogenic common myeloid progenitor that gives rise to all myeloid lineages , 2000, Nature.

[46]  R. Erben,et al.  Ovariectomy augments B lymphopoiesis and generation of monocyte-macrophage precursors in rat bone marrow. , 1998, American journal of physiology. Endocrinology and metabolism.

[47]  I. Weissman,et al.  Identification of Clonogenic Common Lymphoid Progenitors in Mouse Bone Marrow , 1997, Cell.

[48]  C. Wilson,et al.  Enhanced production of B lymphocytes after castration. , 1995, Blood.

[49]  H. McClure,et al.  Neonatal treatment with luteinizing hormone-releasing hormone analogs alters peripheral lymphocyte subsets and cellular and humorally mediated immune responses in juvenile and adult male monkeys. , 1994, The Journal of clinical endocrinology and metabolism.

[50]  M. Mauricas,et al.  Leukocytosis as a prognostic marker in the development of fetal inflammatory response syndrome. , 2013, The Libyan journal of medicine.

[51]  I. Huhtaniemi,et al.  Luteinizing hormone receptor knockout (LuRKO) mice and transgenic human chorionic gonadotropin (hCG)-overexpressing mice (hCG alphabeta+) have bone phenotypes. , 2003, Endocrinology.

[52]  M. Poutanen,et al.  Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice. , 2001, Molecular endocrinology.

[53]  C. Rao,et al.  Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene. , 2001, Molecular endocrinology.

[54]  K. Korach,et al.  Role of estrogen receptor alpha in hematopoietic stem cell development and B lymphocyte maturation in the male mouse. , 2000, Endocrinology.

[55]  S. Morrison,et al.  Supplemental Experimental Procedures , 2022 .

[56]  Abbreviations used: G-CSFR, , 2022 .