Effect of Aging and 5-Fluorouracil Treatment on Bone Marrow Stem Cell Dynamics

Abstract

Lifelong homeostasis of bone marrow is maintained by the resident stem cells that include the quiescent very small embryonic-like stem cells (VSELs) and lineage restricted, tissue committed ‘progenitors’ hematopoietic stem cells (HSCs). Niche providing mesenchymal stromal cells (MSCs) regulate the function of VSELs/HSCs by providing crucial paracrine support. Any dysfunction of stem cells and/or their niche leads to disease state. The stem cells biology gets affected with age leading to a myeloid bias in differentiation of HSCs and increased incidence of myeloid leukemia. Present study was undertaken to enumerate VSELs, HSCs and MSCs and evaluate their response on D4 and D10 after chemotherapy with 5-Fluorouracil (5-FU) in young and aged mouse bone marrow. Stem cells were activated in response to 5-FU induced stress in an attempt to restore homeostasis. Although absolute numbers of VSELs and HSCs did not differ much between young and aged mice, their tendency to proliferate was higher on D4 in aged mice. However, ability to revert back to basal numbers and their differentiation was affected on D10 in aged marrow. Stem cells from aged bone marrow showed greater ability to form CFUs on D10 after 5-FU treatment. CD44 positive aged MSCs also showed increased proliferation on D10. Transplanting MSCs from young mice in 5-FU treated aged marrow helped improve hematopoiesis. The results suggest that no significant intrinsic changes occur as proliferative ability of stem cells remains unaffected but the niche gets affected with age leading to excessive self-renewal and compromised differentiation. This may explain increased incidence of leukemia with age.

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Acknowledgments

The help from Dr. Mukherjee, Ms. Gayatri and Ms. Sushma in flow cytometry studies and from Ms. Reshma and Ms. Shobha in confocal studies is also acknowledged. We thank Dr. Ekta Khattar (NMIMS Sunandan Divatia School of Science) for providing the antibodies for TRF2 and γH2AX. We also thank Indian Council of Medical Research and Department of Science and Technology, Government of India, New Delhi for providing financial support for the study and supporting RG with Women Scientist Fellowship under Scheme-A (SR/WOSA/LS-1318/2014).

Funding

Financial Support for the study was provided by Indian Council of Medical Research and Department of Science and Technology, Government of India, New Delhi, India.

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Contributions

RG: Study design, Collection of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript; SA: Collection of data, Data analysis and interpretation, Manuscript writing, Final approval of manuscript; SM: Experimental help in animal transplantation experiments, Final approval of manuscript; DB: Study design, Data analysis and interpretation, Manuscript writing, Final approval of manuscript.

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Correspondence to Deepa Bhartiya.

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The study was approved by Institute Animal Ethics Committee and we have approval from NIRRH to submit this manuscript.

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Ganguly, R., Anand, S., Metkari, S. et al. Effect of Aging and 5-Fluorouracil Treatment on Bone Marrow Stem Cell Dynamics. Stem Cell Rev and Rep (2020). https://doi.org/10.1007/s12015-020-09998-1

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Keywords

  • Stem cells
  • Niche
  • HSCs
  • VSELs
  • MSCs
  • Proliferation
  • Differentiation