Chemotherapy Drugs On Normal Hematopoietic Stem Cells And Its Mechanism

Objective:To investigate the effect of chemotherapeutic drug cyclophosphamide(CTX) to normal murine bone marrow cells, especially the self-renewal, proliferation and differentiation of HSCs, and explore the possible mechanism involved in.Methods:Two CTX-treated mouse models were established according to previous reports. By monitoring the recovery of differential blood counts and the frequencies of LKS+cells in BMMNCs, one of the two models was chosen for the further study and the exact time to permit the seemingly complete recovery was determined. The function of HSCs such as self-renewal, proliferation and differentiation were assessed by non-competitive and competitive bone marrow transplantation. In addition, p16Ink4a mRNA relative expression and SA-β-gal staining of bone marrow cells from serial-transplantation model were analyzed to investigate the potential effect of CTX on senescence.Results:In our study, treatment with CTX caused a rapid decrease in the number of WBC and a transient increase in the frequency of LKS+cells. Thereafter, these two parameters rapidly recovered in a time-dependent manner, and almost return to normal on day20. In addition, blood cell counts including red blood cell(RBC), lymphocyte(LYM) and platelets(PLT) in peripheral blood could also recover to normal level. However, CTX could induce long-term but latent damage to HSCs function and lead to the decrease in the competence capacity of HSCs to reconstitute while permitting a complete seemingly recovery. Furthermore, using a serial-transplantation model, BMMNCs exhibited a high expression of p16Ink4a and SA-β-gal staining which were2commonly used biomarkers of cellular senescence. This implicates that senescence may play an important role in CTX-induced long-term injury to HSCs.Conclusion:CTX could result in long-term but latent damage to bone marrow cells especially the self-renewal ability of HSCs by inducing bone marrow cells senescence. Hence it is possible to develop new interventions to circumvent chemotherapy-induced long-term BM toxicity and to prolong the life-span of the patients.