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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

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Abstract

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.

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Abbreviations

E2:

Estradiol beta

P:

Progesterone

FSH:

Follicle stimulating hormone

BrdU:

5-bromo-2-deoxyuridine

VSELs:

Very small embryonic-like stem cells

HSCs:

Hematopoietic stem cells

DAPI:

4’,6-diamidino-2-phenylindole

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Acknowledgements

Thanks to Department of Science and Technology, Government of India, New Delhi for providing RG with Woman Scientist Fellowship under Scheme-A. SR/WOSa/LS-1318/2014. We thank Ankita for her help; Gayatri and Sushma for flow cytometry, Vaibhab for art work and Reshma and Shobha for confocal microscopy.

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Authors and Affiliations

  1. Stem Cell Biology Department, ICMR - National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India

    Ranita Ganguly & Deepa Bhartiya

  2. Experimental Animal Facility, ICMR - National Institute for Research in Reproductive Health, Jehangir Merwanji Street, Parel, Mumbai, 400 012, India

    Sidhanath Metkari

Authors
  1. Ranita Ganguly
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  2. Sidhanath Metkari
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Contributions

RG: Designed and carried out all experiments, data analysis and manuscript preparation. SM: Helped with the surgeries. DB: Arranged finances, experiments design, results interpretation and manuscript preparation. All authors read and agree with the final version of the manuscript [RA/521/08.2017].

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Correspondence to Deepa Bhartiya.

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Authors declare no conflict of interest.

Financial Support

Financial support for the study was provided by Department of Science and Technology, Government of India under Woman Scientist Scheme-A [SR/WOSA/LS-1318/2014] and NIRRH core support provided by Indian Council of Medical Research, Government of India, New Delhi.

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Ganguly, R., Metkari, S. & Bhartiya, D. 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. Stem Cell Rev and Rep 14, 110–124 (2018). https://doi.org/10.1007/s12015-017-9781-x

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