Klin Padiatr 2012; 224 - A21
DOI: 10.1055/s-0032-1310488

Haematopoietic Stem Cell Survival and Transplantation Efficacy is Limited by the BH3-only Proteins Bim and Bmf

D Bertele 1, V Labi 2, C Woess 2, G Grothe 1, S Schwemmers 3, HL Pahl 3, S Geley 4, M Kunze 5, CM Niemeyer 1, A Villunger 2, M Erlacher 1
  • 1Department of Pediatrics and Adolescent Medicine, Division of PediatricHematology and Oncology, University Hospital of Freiburg
  • 2Division of Developmental Immunology, Biocenter, Innsbruck Medical University
  • 3Section of Experimental Anesthesiology, Center for Clinical Research, University Hospital Freiburg
  • 4Division of Molecular Pathophysiology, Biocenter, Innsbruck Medical University
  • 5Department of Obstetrics and Gynecology, University Hospital Freiburg, Germany

Cell death occurring in haematopoietic stem cells (HSC) is critically involved in limiting successful stem cell transfer. It is known that HSC homeostasis is regulated by anti-apoptotic Bcl-2 family members, but little is known about the role of their antagonists, the “BH3-only” proteins. We determined the consequences of BH3-only protein depletion on HSC survival in vitro and in vivo. Thereby, we identified two BH3-only proteins, Bim and Bmf, as regulators of HSC survival. Bim-/- or bmf-/- HSC performed better during early engraftment and long term reconstitution of the haematopoietic system. In competitive transplantation experiments, wild type HSC were readily displaced by bim-/- or bmf-/- HSC as early as 10 days after transplantation. Moreover, in the absence of Bim, lower numbers of HSC were required for successful host reconstitution.

Finally, we provide evidence that Bim and BMF have conserved functions between mice and men. Downregulation of either protein in cord blood derived huCD34+ cells lead to a superior reconstitution of rag2-/-γc-/- mice. We therefore believe, that Bim and Bmf may be attractive therapeutic targets to increase HSC survival and transplantation efficacy.