Abstract
Specialized blood cells are generated through the entire life of an organism by differentiation of a small number of hematopoietic stem cells (HSC). There are strictly regulated mechanisms assuring a constant and controlled production of mature blood cells. Although such mechanisms are not completely understood, some factors regulating cell cycle and differentiation have been identified. We have previously shown that Caspase-3 is an important regulator of HSC homeostasis and cytokine responsiveness. p21cip1/waf1 is a known cell cycle regulator, however its role in stem cell homeostasis seems to be limited. Several reports indicate interactions between p21cip1/waf1 and Caspase-3 in a cell type dependent manner. Here we studied the impact of simultaneous depletion of both factors on HSC homeostasis. Depletion of both Caspase-3 and p21cip1/waf1 resulted in an even more pronounced increase in the frequency of hematopoietic stem and progenitor cells. In addition, simultaneous deletion of both genes revealed a further increase of cell proliferation compared to single knock-outs and WT control mice, while apoptosis or self-renewal ability were not affected in any of the genotypes. Upon transplantation, p21cip1/waf1-/- bone marrow did not reveal significant alterations in engraftment of lethally irradiated mice, while Caspase-3 deficient HSPC displayed a significant reduction of blood cell production. However, when both p21cip1/waf1 and Caspase-3 were eliminated this differentiation defect caused by Caspase-3 deficiency was abrogated.
Highlights
In mammals, mature blood cells are produced over the entire lifetime of an organism
The importance of Caspase-3 is undisputed in apoptosis, we found no detectable changes in the rate of apoptosis within the hematopoietic stem cell population in vivo
In this study we have investigated the effect of the simultaneous deletion of two proteins, p21Cip1/Waf1 and Caspase-3, in the regulation of murine hematopoiesis
Summary
Mature blood cells are produced over the entire lifetime of an organism. This process is tightly regulated in order to maintain a supply of mature blood cells and avoid HSC exhaustion and at the same time to prevent malignancies. Mechanisms strictly controlling differentiation and self-renewal of hematopoietic stem and progenitor cells (HSPCs) are critical. We have previously demonstrated the relevance of Caspase-3 in the regulation of hematopoietic stem cells [1]. Hereby Caspase-3 was found to regulate the proliferation of primitive hematopoietic cells by modulating their responsiveness to cytokines and selectively restraining specific signaling pathways to maintain stem cell quiescence. Deletion of Caspase-3 in osteoblasts causes a deceleration of their proliferation rate [4] whereas in splenic B lymphocytes Caspase-3 deficiency leads to hyperproliferation [5]
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