Novel Evidence That Murine and Human Mesenchymal Stromal Cells Express Functional Gonadotropic Hormone Receptors, Demonstrating the Involvement of the Pituitary gonadotropin–bone Marrow Axis in Hematopoiesis

Background: Mesenchymal stromal cells (MSCs) play an important role in bone marrow (BM) by providing a supportive microenvironment for hematopoietic stem/progenitor cells (HSPCs). MSCs are also employed in organ regeneration as a rich source of several paracrine signals that inhibit apoptosis and promote angiogenesis in damaged tissues. As reported in the literature, several mediators, including a growth factor (HGF), a chemokine (SDF-1), bioactive lipids (S1P, C1P), and extracellular nucleotides (ATP, UTP), affect MSC biology and migration. In parallel, evidence has accumulated that the most primitive mesodermal precursors of MSCs (small BM-residing and peripheral blood (PB)-circulating Sca-1⁺Lin^–CD45^– cells in mice and CD133⁺Lin^–CD45^– cells in humans) express certain embryonic stem cell markers, such as the transcription factor Oct-4 and the SSEA-1/4 antigens (Stem Cells Dev. 2014;23:689-701), and also express several genes characteristic of migrating primordial germ cells (Leukemia 2010; 24:1450–1461).

Hypothesis: Pursuing observations that most primitive human and murine precursors of MSCs express several germline markers, we became interested in whether murine and human MSCs also express gonadotropic hormone receptors, such as receptors for follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL), and whether these receptors are functional.

Materials and Methods: Murine and human MSCs were expanded from a population of adherent murine BM or human umbilical cord blood cells, and cells with low passage numbers were employed for analysis. The expression of gonadotropic receptors (FSH-R, LH-R, and PRL-R) was evaluated by RT-PCR, and the functionality of these receptors was tested in assays for proliferation, chemotaxis, adhesion, and phosphorylation of MAPKp42/44 and AKT. In addition, we also evaluated the expression of gonadotropin receptors by purified murine SKL cells and human CD34⁺ cells.

Results. We report here for the first time that both human and murine MSCs and HSPCs express functional gonadotropin receptors. We found that FSH strongly enhanced proliferation of MSCs in vitro as well as expanded the number of these cells in murine BM after prolonged administration in vivo. We found that all these hormones stimulated chemotaxis and adhesion of murine and human MSCs. These functional responses were correlated with phosphorylation of MAPKp42/44 and AKT. At the same time, we observed that pituitary gonadotropin receptors are expressed by murine and human HSPCs and that these hormones stimulate proliferation and expansion of these cells in vivo in BM as well as in clonogeneic assays in vitro if added along with suboptimal doses of colony-stimulating growth factors. Of note, we did not observe significant differences in the effects of FSH, LH, and PRL between male and female cells.

Conclusions. We provide for the first time evidence for the existence of a functional pituitary gonadotropin–hematopoiesis signaling axis, which has important implications for hematopoiesis in young individuals, and we will present gene-array data on changes in gene expression in MSCs after stimulation with gonadotropins. Moreover, since the levels of FSH and LH increase in response to a decrease in gonadal function with advanced age, elevated levels of FSH and LH may affect hematopoiesis and may be factors contributing to the development of leukemia. The stimulatory effect of pituitary gonadotropins on MSCs and HSPCs could also be exploited in the clinic in selected cases as a means to enhance hematopoiesis.