Haematopoietic stem cell survival and transplantation efficacy is limited by the BH3‐only proteins Bim and Bmf

EMBO Molecular Medicine

Verena Labi⁴  Daniela Bertele¹  Claudia Woess²  Denise Tischner²  Florian J. Bock²  Sven Schwemmers⁵  Heike L. Pahl⁵  Stephan Geley³  Mirjam Kunze⁶  Charlotte M. Niemeyer¹  Andreas Villunger² 

[1] Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Hospital of Freiburg, Freiburg, Germany;Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria;Division of Molecular Pathophysiology, Biocenter, Innsbruck Medical University, Innsbruck, Austria;E-mail address: 关键词: apoptosis;    Bcl‐2 protein family;    Bmf;    Bim;    haematopoietic stem cell transplantation;   

DOI  :  10.1002/emmm.201201235

来源: Wiley

【 摘 要 】

Abstract

Anti-apoptotic Bcl-2 family members are critical for the regulation of haematopoietic stem and progenitor cell (HSPC) survival. Little is known about the role of their pro-apoptotic antagonists, i.e. ‘BH3-only’ proteins, in this cell compartment. Based on the analysis of cytokine deprivation-induced changes in mRNA expression levels of Bcl-2 family proteins, we determined the consequences of BH3-only protein depletion on HSPC survival in culture and, for selected candidates, on engraftment in vivo. Thereby, we revealed a critical role for Bim and Bmf as regulators of HSPC dynamics both during early engraftment and long-term reconstitution. HSPCs derived from wild-type donors were readily displaced by Bim- or Bmf-deficient or Bcl-2-overexpressing HSPCs as early as 10 days after engraftment. Moreover, in the absence of Bim, significantly lower numbers of transplanted HSPCs were able to fully engraft radio-depleted recipients. Finally, we provide proof of principle that RNAi-based reduction of BIM or BMF, or overexpression of BCL-2 in human CD34⁺ cord blood cells may be an attractive therapeutic option to increase stem cell survival and transplantation efficacy.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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