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DOI: 10.1055/s-0036-1582501
Transient apoptosis inhibition in hematopoietic stem and progenitor cells of donors increases efficacy of stem cell transplantation without increasing the risk of leukemogenesis
Introduction: The only curative treatment for many hematological disorders is hematopoietic stem cell transplantation (HSCT) which unfortunately bears different transplantation-associated risks like graft failure or graft-versus-host disease. Since it is known that higher donor cell numbers accelerate the engraftment and lower the risk of graft failure, many experimental approaches aim to expand donor cell numbers ex vivo. However, these approaches largely failed due to differentiation of stem cells.
Methods: Our aim is therefore to assess, whether apoptosis inhibition during HSCT is able to increase its efficacy and reduce transplantation-associated morbidity. This strategy could serve as a novel therapeutic approach to increase resistance of hematopoietic stem and progenitor cells (HSPCs) towards transplantation-related stress signals. For therapeutic application, apoptosis inhibition has to be transient, however, in order to reduce the risk of malignant transformation or autoimmunity.
Results: Here we show that transient, adenovirally mediated overexpression of the Bcl-2 family member Bcl-xL is sufficient to confer apoptosis resistance to lethal stimuli in vitro and to increase in vivo competitiveness of HSPCs. Importantly, adenovirally mediated transient apoptosis inhibition does not accelerate lymphomagenesis, neither on a wildtype nor on a tumor prone murine background. Since adenoviral infection was in part toxic to murine HSPCs, we transfected full length Bcl-xL protein linked to a protein transduction domain. Bcl-xL protein protected murine HSPCs in vitro for up to 6 days against different stimuli compared to untreated cells without showing any toxicity. In addition, Bcl-xL protein transduction resulted in an increased reconstitution potency of HSPCs during transplantation.
Conclusion: Our study shows the benefit of transient apoptosis inhibition in donor HSPCs during HSCT and contributes to on-going efforts aiming at improving transplantation medicine.