Dynamics of Bone Marrow VSELs and HSCs in Response to Treatment with Gonadotropin and Steroid Hormones, During Pregnancy and Evidence to Support Their Asymmetric/Symmetric Cell Divisions

Gender plays an important role in the incidence of hematological malignancies and recently hematopoietic stem cells (HSCs) were found to proliferate more in females that gets further augmented during pregnancy. It was suggested that since basal numbers of HSCs remain the same in both sexes, possibly HSCs in females undergo increased self-renewal and apoptosis. Then how is self-renewal of stem cells regulated in males? More important, do HSCs undergo asymmetric cell divisions (ACD) or a more primitive population of pluripotent, very small embryonic-like stem cells (VSELs) undergo ACD to self-renew and specify into HSCs? Lot more clarity is required on the bone marrow stem cells biology. Present study was undertaken to evaluate whether similar dimorphism reported for HSCs also exists among VSELs. Bone marrow VSELs and HSCs were studied in bilaterally ovariectomized and castrated mice by flow cytometry after treating with gonadotropin (FSH) and sex steroid (estrogen & progesterone) hormones and during pregnancy. Differential expression of pluripotent (Oct-4A, Sox2, Nanog) and differentiation (Oct-4, Sca1, c-Kit, Ikaros) specific transcripts was studied. Basal BrdU uptake was more in both VSELs (p < 0.01) and HSCs (p < 0.05) in female bone marrow. FSH exerted a more profound effect compared to estradiol in both the sexes. Flow cytometry results showed ten-fold increase in spleen VSELs by mid-gestation associated with approximately two-fold increase in HSCs. These results point to a novel yet unreported role of spleen VSELs during pregnancy. Furthermore, VSELs underwent ACD to self-renew and give rise to slightly bigger HSCs based on unequal expression of NUMB, CD45 and OCT-4.