Hematopoietic Stem/Progenitor Cells Express Several Functional Sex Hormone Receptors—Novel Evidence for a Potential Developmental Link Between Hematopoiesis and Primordial Germ Cells

Abstract

Evidence has accumulated that hematopoietic stem progenitor cells (HSPCs) share several markers with the germline, a connection supported by reports that prolactin, androgens, and estrogens stimulate hematopoiesis. To address this issue more directly, we tested the expression of receptors for pituitary-derived hormones, such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH), on purified murine bone marrow (BM) cells enriched for HSPCs and tested the functionality of these receptors in ex vivo signal transduction studies and in vitro clonogenic assays. We also tested whether administration of pituitary-and gonad-derived sex hormones (SexHs) increases incorporation of bromodeoxyuridine (BrdU) into HSPCs and expansion of hematopoietic clonogenic progenitors in mice and promotes recovery of blood counts in sublethally irradiated animals. We report for the first time that HSPCs express functional FSH and LH receptors and that both proliferate in vivo and in vitro in response to stimulation by pituitary SexHs. Furthermore, based on our observations that at least some of CD45 -very small embryonic-like stem cells (VSELs) may become specified into CD45+ HSPCs, we also evaluated the expression of pituitary and gonadal SexHs receptors on these cells and tested whether these quiescent cells may expand in vivo in response to SexHs administration. We found that VSELs express SexHs receptors and respond in vivo to SexHs stimulation, as evidenced by BrdU accumulation. Since at least some VSELs share several markers characteristic of migrating primordial germ cells and can be specified into HSPCs, this observation sheds new light on the BM stem cell hierarchy.

Pituitary sex hormones enhance the pro-metastatic potential of human lung cancer cells by downregulating the intracellular expression of heme oxygenase-1

“…Namely, since pituitary SexH receptors are expressed by cells from the germ lineage beginning at the very early stages of embryogenesis (35,36), and, as demonstrated in this study, lung cancer cells also express pituitary SexH rec eptors, there may be a developmental link between these cells, as suggested at the beginning of this section. Interestingly, 150 years ago Virchow (37) and Cohnheim (38) proposed that some malignancies develop from dormant embryonic or germ cells residing in adult tissues.…”

“…One can speculate that these or closely related cells could theoretically be the source of some tumors. In support of this possibility, VSELs express several SexH receptors as well as genes involved in primordial germ cell development (35,36,39,41). This working hypothesis, however, requires more experimental evidence.…”

Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury

“…2e,f). Although Lhcgr expression has previously been demonstrated in a crude fraction of Lin − CD45 + Sca1 + cells 3 , this is the first evidence to our knowledge of its enriched expression in the most primitive HSCs.…”

“…In addition to their role in promoting sexual dimorphisms, increasing evidence suggests that sex hormones regulate HSC self-renewal, differentiation, and proliferation 3–5 . We and others previously reported that sex steroid ablation promotes bone marrow (BM) lymphopoiesis and HSC recovery in aged and immunodepleted mice 5–7 .…”

Evaluation of the Effects of Tetrapleura tetraptera Extract and Clomiphene Citrate to Determine Influence of Reproductive Hormones and Estrous Cycle on Leukocyte Counts: Novel Evidence for a Potential Developmental Link Between Luteinizing Hormone and MID Cells

“…However, data have shown that leuprolide acetate, a luteinizing hormone-releasing hormone agonist increases the myeloid progenitor cells in the bone marrow [38]. The first studies on LH and hematopoietic stem/progenitor cell found that hematopoietic stem/progenitor cell express functional FSH and LH receptors that proliferate in vivo and in vitro in response to FSH and LH [39]. Abdelbaset-Ismail and colleagues further affirmed that LH stimulates growth of human hematopoietic/ progenitor cells and mesenchymal cells in vivo and in vitro [40].…”