The Distinct Roles Of Cyclin-Dependent Kinase Inhibitors In Regulating Self-renewal Of Hematopoietic Stem Cells

Further understanding the mechanisms regulating the self-renewal of hematopoietic stem cells (HSCs), is crucial to the ex vivo expansion of HSCs for further development of stem cell-based therapies. In the present study, we took the approaches of competitive bone marrow transplantation (cBMT) and competitive repopulation unit (CRU) to directly assess the possible impact of p18 gene absence on self-renewal and long-term engraftment of HSCs in sublethally irradiated mice, with p27^-/- transplantation model as control group; the effect of HOXB4 regulating HSCs self-renewal and its mechanisms were studied with murine stem cells/progenitor cells overexpressing H0XB4 gene mediated by retrovirus vectors. The results shown: (1) Unlike the absence of p21 or p27, the absence of p18 can significantly enhance the self-renewal potential of HSCs and increase the long-term engraftment efficiency of HSCs. (2) The overexpression of H0XB4 gene in hematopoietic cells can also enhance the long-term engraftment of hematopoietic cells, owing to increased self-renewal or proliferation of both HSC and progenitor cell populations. At the transcription level, p18, p21 and p27 genes are not the direct downstream targets of HOXB4 in HSCs.