Concise Review: Cheating Death for a Better Transplant

Hematopoietic stem cell transplantation is routinely performed for the treatment of various malignant and non-malignant hematological diseases. Successful transplantation depends on the number and fitness of donor stem and progenitor cells, whose quality is substantially influenced by the sampling procedure, sample handling, and cryopreservation. BCL-2 proteins are central to the survival and maintenance of stem and progenitor cells under both, physiological and stress conditions. Transplantation-associated apoptosis of donor cells is mediated by the pro-apoptotic BCL-2 proteins BIM and BMF and prevented by overexpression of their antagonists, BCL-2 and BCL-XL. We have previously reported that deletion of BIM or BMF stabilizes donor stem cell numbers during transplantation and improves cellular fitness and transplantation outcomes, albeit posing a risk for lymphoma and autoimmunity in recipient mice. Short-term apoptosis inhibition in donor cells appears equally effective in improving the outcome of transplantation, but in contrast does not cause pathology. In this review, we discuss the role of BCL-2 proteins in the context of factors that negatively impact donor stem and progenitor cell fitness and viability. Finally, we suggest approaches to improve graft quality and transplantation procedures with an emphasis on the inhibition of BCL-2 regulated apoptosis. Stem Cells 2018;36:1646-1654.