期刊
ONCOGENE
卷 28, 期 22, 页码 2238-2243出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2009.94
关键词
stem cells; hematopoiesis; ageing; senescence
资金
- Swedish Medical Research Council
- Swedish Strategic Research Foundation
- Swedish Cancer Society
- Crafoord foundation and the Medical Faculty at Lund University
Somatic stem cells are ultimately responsible for mediating appropriate organ homeostasis and have therefore been proposed to represent a cellular origin of the ageing process-a state often characterized by inappropriate homeostasis. Specifically, it has been suggested that ageing stem cells might succumb to replicative senescence by a mechanism involving the cyclin-dependent kinase inhibitor p16(INK4A). Here, we tested multiple functional and molecular parameters indicative of p16(INK4A) activity in primary aged murine hematopoietic stem cells (HSCs). We found no evidence that replicative senescence accompanies stem cell ageing in vivo, and in line with p16(INK4A) being a critical determinant of such processes, most aged HSCs (>99%) failed to express p16(INK4A) at the mRNA level. Moreover, whereas loss of epigenetically guided repression of the INK4A/ARF locus accompanied replicative senescent murine embryonic fibroblasts, such repression was maintained in aged stem cells. Taken together, these studies indicate that increased senescence as mediated by the p16(INK4A) tumor suppressor has only a minor function as an intrinsic regulator of steady-state HSC ageing in vivo. Oncogene (2009) 28, 2238-2243; doi: 10.1038/onc.2009.94; published online 27 April 2009
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