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 explore the possibility of a beneficial effect of apoptosis modulation for HSCT in humans, we isolated fresh cord blood-derived CD34+ cells, a cell population enriched for HSPCs and used as a source of HSCT grafts in certain transplantation regimens such as haplo-identical transplantations. Subjecting these cells to cytokine withdrawal in vitro revealed that human CD34+ cells were generally less susceptible to cytokine deprivation-induced apoptosis than murine LSK cells (comp. Fig 1B and Supporting Information Fig 5A). RT-MLPA analysis performed 14 h after cytokine withdrawal indicated a more restricted upregulation of BH3-only proteins with significant induction noted only for BIM and BMF mRNA (2.1- and 9.5-fold, respectively) and only minor induction of PUMA mRNA (1.6-fold), an observation again confirmed by qRT-PCR (Fig 5A and Supporting Information Fig 5B).
Affiliation: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria. firstname.lastname@example.org