The role of apoptosis in the regulation of hematopoietic stem cells:: Overexpression of BCL-2 increases both their number and repopulation potential

Hematopoietic stern cells (HSC) give:rise to cells of all henlatopoietic lineages, many of which are short lived. HSC face developmental choices. self-renewal (remain an HSC with long-term multilineage repopulating potential) or differentiation (become an HSC with Short-term multilineage repopulating potential and, eventually, a mature cell). There is a large overcapacity of differentiating hematopoietic cells and apoptosis plays a role in regulating their numbers. It is not clear whether apoptosis plays a direct role in regulating HSC numbers. To address this, we have employed a transgenic mouse model that overexpresses BCL-2 in all hematopoietic cells, including HSC: H2K-BCL-2. Cells from H2K-BCL-2 mice have been shown to be protected against a wide variety of apoptosis-inducing challenges. This block in apoptosis affects their HSC compartment. H2K-BCL-2-transgenic mice have increased numbers of HSC in bone marrow (2.4X wild type), but fewer of these cells are in the S/G(2)/M phases of the cell cycle (0.6X wild type). Their HSC have all increased plating efficiency in vitro, engraft at least as well as wild-type HSC in vivo, and have an advantage following competitive reconstitution with wild-type HSC.