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 li neages, 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 repopulatin g potential and, eventually, a mature cell). There is a large overcapacity of differentiating hematopoietic cells and apoptosis plays a role in regula ting their numbers. It is not clear whether apoptosis plays a direct role i n regulating HSC numbers. To address this, we have employed a transgenic mo use model that overexpresses BCL-2 in all hematopoietic cells, including HS C: H2K-BCL-2. Cells from H2K-BCL-2 mice have been shown to be protected aga inst a wide variety of apoptosis-inducing challenges. This block in apoptos is 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 ar e 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 wil d-type HSC in vivo, and have an advantage following competitive reconstitut ion with wild-type HSC.