The Role of Apoptosis in the Regulation of Hematopoietic Stem Cells: Overexpression of BCL-2 Increases Both Their Number and Repopulation Potential

doi:10.1084/jem.191.2.253

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© The Rockefeller University Press, 0022-1007/2000/1/253/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 2, January 17, 2000 253-264

Original Article

The Role of Apoptosis in the Regulation of Hematopoietic Stem Cells: Overexpression of BCL-2 Increases Both Their Number and Repopulation Potential

Jos Domen^a, Samuel H. Cheshier^a, and Irving L. Weissman^a
^a Department of Pathology and Developmental Biology, Stanford University School of Medicine, Stanford, California 94305-5428

Correspondence to: Jos Domen, Department of Pathology and Developmental Biology, B263 Beckman Center, Stanford University School of Medicine, Stanford CA 94305-5428. Tel:650-723-6419 Fax:650-498-6255 E-mail:domen{at}stanford.edu.

Hematopoietic stem cells (HSC) give rise to cells of all hematopoieticlineages, many of which are short lived. HSC face developmentalchoices: self-renewal (remain an HSC with long-term multilineagerepopulating potential) or differentiation (become an HSC withshort-term multilineage repopulating potential and, eventually,a mature cell). There is a large overcapacity of differentiatinghematopoietic cells and apoptosis plays a role in regulatingtheir numbers. It is not clear whether apoptosis plays a directrole in regulating HSC numbers. To address this, we have employeda transgenic mouse model that overexpresses BCL-2 in all hematopoieticcells, including HSC: H2K-BCL-2. Cells from H2K-BCL-2 mice havebeen shown to be protected against a wide variety of apoptosis-inducingchallenges. This block in apoptosis affects their HSC compartment.H2K-BCL-2–transgenic mice have increased numbers of HSCin bone marrow (2.4x wild type), but fewer of these cells arein the S/G₂/M phases of the cell cycle (0.6x wild type). TheirHSC have an increased plating efficiency in vitro, engraft atleast as well as wild-type HSC in vivo, and have an advantagefollowing competitive reconstitution with wild-type HSC.

Key Words: hematopoietic stem cells, apoptosis, BCL-2, homeostasis

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