Haematopoietic stem cell survival and transplantation efficacy is limited by the BH3-only proteins Bim and Bmf.
Bottom Line: 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.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.
Affiliation: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria. firstname.lastname@example.orgShow MeSH
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Mentions: We next asked whether the prolonged survival of bim−/− LSK cells under suboptimal conditions in vitro would translate into a better reconstitution of lethally irradiated mice. We also included bmf−/− LSK cells in our in vivo studies because Bmf mRNA was induced strongest after cytokine deprivation. To directly compare the reconstitution ability of bim−/− or bmf−/− to that of wt LSK cells, we performed competitive reconstitution experiments. Lethally irradiated Ly5.1+ recipients were reconstituted with a 50:50 mixture of LSK cells derived from a Ly5.1+ wt and a Ly5.2+ wt, bim−/−, bmf−/− or vav-bcl-2 tg mouse. After 16 weeks, recipient mice were sacrificed and haematological organs analysed. Mature splenic T and B cells of wt:wt BM chimeras displayed nearly the expected 50:50 ratio (Ly5.1+:Ly5.2+ = 44:56%) between the two donors (Fig 2A and Supporting Information Fig 2). In contrast, in wt:bim−/− chimeras almost all splenic T and B cells were derived from the Ly5.2+bim−/− donor. Of note, chimeras that received BM from vav-bcl-2 tg mice were not significantly different from those that received bim−/− cells, implicating that Bim is the major rate limiting BH3-only protein during reconstitution and accounts for all apoptotic cell death blocked by Bcl-2 overexpression (Fig 2A).
Affiliation: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria. email@example.com