Improvement of hematopoietic stem cell transplantations by ex vivo manipulation of donor stem and progenitor cells

Many hematologic disorders can only be cured by hematopoietic stem cell transplantation (HSCT). Clinical experience has shown that higher donor stem cell (HSC) counts are able to accelerate engraftment while lowering transplantation-associated risks. Therefore, much effort is put into strategies to enhance HSC numbers (i.e. expansion).

We have previously shown that a relevant number of HSCs dies during engraftment and that the pro-apoptotic Bcl-2 proteins Bim and Bmf are central players. Inhibition of either protein was sufficient to increase stem cell survival and transplantation efficacy. However, since permanent apoptosis inhibition is associated with an increased risk of lymphomagenesis, apoptosis inhibition has to be transient when used therapeutically. We could show that transient apoptosis inhibition by means of adenovirus-mediated Bcl-xL overexpression is able to counteract cytokine deprivation as well as etoposide-induced apoptosis in vitro. To evaluate whether transient apoptosis inhibition is sufficient to enhance engraftment in vivo, competitive reconstitution experiments are in progress. Furthermore, we are testing chemical apoptosis inhibitors as well as cell penetrating peptides.