Regulation Of Hematopoietic Stem Cell Homeostasis Research Articles

Simultaneous deletion of p21Cip1/Waf1 and caspase-3 accelerates proliferation and partially rescues the differentiation defects of caspase-3 deficient hematopoietic stem cells.

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.

Osteoclasts and hematopoiesis

The skeletal tissue is closely associated with the hematopoietic tissue lodged in its inner cavities. Besides the well-known role of the endosteal osteoblasts in the maintenance of the hematopoietic stem cell (HSC) niche, it is an emerging concept that osteoclasts are involved in the regulation of hematopoiesis as well, although published data are still incomplete and somehow controversial. We reviewed the literature, and report here our perspective on the close relationship between bone resorption and HSC permanence in bone or egress to the circulation. We discussed the pressure that bone diseases exert on the development of hematological alterations, as well as the role of calcium and osteoclast enzymes in the regulation of HSC homeostasis. Genetic studies and preclinical experiments are described, which unveiled how bone disorders and treatments aimed at restoring the bone mass affect hematopoiesis, with consequent clinical implications. We conclude that this new field of investigation must be extended to unequivocally establish the role of osteoclasts in myelopoiesis and lymphopoiesis, and to envision treatments that can help hematological failures to be cured along with the associated bone alterations.

Calmodulin-dependent Protein Kinase IV Regulates Hematopoietic Stem Cell Maintenance

The hematopoietic stem cell (HSC) gives rise to all mature, terminally differentiated cells of the blood. Here we show that calmodulin-dependent protein kinase IV (CaMKIV) is present in c-Kit+ ScaI+ Lin(-/low) hematopoietic progenitor cells (KLS cells) and that its absence results in hematopoietic failure, characterized by a diminished KLS cell population and by an inability of these cells to reconstitute blood cells upon serial transplantation. KLS cell failure in the absence of CaMKIV is correlated with increased apoptosis and proliferation of these cells in vivo and in vitro. In turn, these cell biological defects are correlated with decreases in CREB-serine 133 phosphorylation as well as in CREB-binding protein (CBP) and Bcl-2 levels. Re-expression of CaMKIV in Camk4-/- KLS cells results in the rescue of the proliferation defects in vitro as well as in the restoration of CBP and Bcl-2 to wild type levels. These studies show that CaMKIV is a regulator of HSC homeostasis and suggest that its effects may be in part mediated via regulation of CBP and Bcl-2.