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. email@example.comShow MeSH
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Mentions: To analyse which BH3-only proteins are induced in the absence of cytokine-mediated survival signals and may therefore mediate HSPC apoptosis, we isolated LSK cells from BM of wt mice and cultured them in the presence or absence of the cytokines TPO, Flt3L and SCF. Employing RT-MLPA® analysis allowed us to screen relative changes in the mRNA expression of all known Bcl-2 family members as well as different additional apoptosis-related genes (Eldering et al, 2003). We observed cytokine deprivation-induced changes in the mRNA levels of Bim (2.0-fold), Bmf (3.3-fold), Puma (2.3-fold) and Noxa (1.9-fold), but not Bad, Bid (Fig 1A) or Bik (not expressed). Induction of mRNA levels was independently confirmed by qRT-PCR (Supporting Information Fig 1A). No upregulation of Bax or Bak was observed whereas their pro-survival antagonists Bcl-2 and Bcl-xL were downregulated at the mRNA level (0.5-fold, both; Fig 1A and Supporting Information Fig 1A). The levels of Mcl-1 or A1 mRNA (Fig 1A) as well as of all remaining genes monitored were found to be largely unchanged (Supporting Information Table II).
Affiliation: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria. firstname.lastname@example.org