Abstract
A tightly controlled balance between hematopoietic stem and progenitor cell compartments is required to maintain normal blood cell homeostasis throughout life, and this balance is regulated by intrinsic and extrinsic cellular factors. Cav-1 is a 22-kDa protein that is located in plasma membrane invaginations and is implicated in regulating neural stem cell and embryonic stem cell proliferation. However, the role of Cav-1 in hematopoietic stem cell (HSC) function is largely unknown. In this study, we used Cav-1−/− mice to investigate the role of Cav-1 in HSCs function during aging. The results showed that Cav-1−/− mice displayed a decreased percentage of B cells and an increased percentage of M cells in the bone marrow and peripheral blood, and these changes were due to an increased number of HSCs. FACS analysis showed that the numbers of Lin−Sca1+c-kit+ cells (LSKs), long-term HSCs (LT-HSCs), short-term HSCs and multipotent progenitors were increased in Cav-1−/− mice compared with Cav-1+/+ mice, and this increase became more pronounced with aging. An in vitro clonogenic assay showed that LT-HSCs from Cav-1−/− mice had reduced ability to self-renew. Consistently, an in vivo competitive transplantation assay showed that Cav-1−/− mice failed to reconstitute hematopoiesis. Moreover, a Cav-1 deletion disrupted the quiescence of LSKs and promoted cell cycle progression through G2/M phase. In addition, we found that Cav-1 deletion impaired the ability of HSCs to differentiate into mature blood cells. Taken together, these data suggest that Cav-1-deficient cells impaired HSCs quiescence and induced environmental alterations, which limited HSCs self-renewal and function.
Highlights
Adult tissue stem cells maintain and repair tissues by regulating an increased number of committed progenitor cells
We examined the clonogenic potential of LT-hematopoietic stem cell (HSC), bone marrow (BM) and spleen cells derived from Cav-1 þ / þ and Cav-1 À / À mice
We showed that Cav-1 has an important role in regulating HSC function
Summary
Adult tissue stem cells maintain and repair tissues by regulating an increased number of committed progenitor cells. A decline in tissue regenerative capacity and organ homeostasis is a major feature of aging that is associated with impaired stem cell function.[1,2,3] Hematopoietic stem cells (HSCs) are well-characterized stem cells that have the highest self-renewal capacity and differentiation potential into hematopoietic progenitor and precursor cells.[4] In aged mice, HSCs alter homing and mobilization properties, diminish the competitive repopulating ability and shift the lineage potential from lymphopoiesis toward myelopoiesis.[5] how HSCs change with aging is not clear. We used Cav-1 knockout mice to investigate the effect of Cav-1 on HSC self-renewal and proliferation during aging. HSCs from Cav-1 knockout mice increased reactive oxygen species (ROS) production and the percentage of cycling cells
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