Luteinizing hormone signaling restricts hematopoietic stem cell expansion during puberty

Abstract

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.

Cellular Heterogeneity of the Luteinizing Hormone Receptor and Its Significance for Cyclic GMP Signaling in Mouse Preovulatory Follicles

“…Outside of the ovary, the LHR is expressed in the uterus and oviduct (58), although LHR expression in these tissues is not required for reproduction (59). Outside of the reproductive system, recent evidence indicates that the LHR functions in hematopoietic stem cells (60). Likewise the NPR2 guanylyl cyclase functions in the skeletal, cardiovascular, and nervous systems ( 61), but its localization is not well characterized.…”

dcHiC: differential compartment analysis of Hi-C datasets

“…We found the luteinizing hormone/choriogonadotropin receptor gene ( Lhcgr ) as part of the hormone regulatory process and that exclusively overlaps with differential A compartments in LT and ST-HSCs ( Supplementary Figure 3D ). A previous study [61] identified the Lhcgr gene as highly critical in regulating the HSC homeostasis and showed that its loss leads to abnormally elevated hematopoiesis and leukocytosis.…”

Variation of the apparent diffusion coefficient of skull bone marrow by age group, pubertal status, and gender in a pediatric population

“…Although there is extensive evidence linking fat replacement in the marrow of adults to steroid therapy, there are no data linking the increase in marrow fat to the surge of sex steroid hormones at puberty. A recent study in a preclinical mouse model has elegantly demonstrated that leutinizing hormone is involved in hematopoietic stem-cell homeostasis (22); it may well be that the expression of this receptor particularly at sites within long bones and where hematopoietic function is no longer needed after puberty is one molecular mechanism driving the replacement of this functionally active tissue with fat.…”