Researchers from the Medical Center at the University of Freiburg, Germany, have demonstrated a new technique that will help improve the survival of hematopoietic stem cells in transplantation. The results of the work, published on September 7, 2017 in The Journal of Experimental Medicine, will reduce the number of donor stem cells needed for successful transplantation and limit the potential adverse side effects of transplantation to patients with leukemia, lymphoma and other blood disease.
Hematopoietic stem cells (HSCs) give rise to a variety of different types of blood cells and can be used to treat a variety of diseases, including multiple myeloma, leukemia, and sickle cell anemia. HSCs can be harvested from a suitable donor, and then transplanted to a patient. With a favorable outcome of the procedure, HSCs take root in the patient’s bone marrow and begin to generate healthy blood cells.
However, the transplantation process is stressful for hematopoietic stem cells and leads to their numerous deaths before they can successfully ensconce themselves in the patient’s bone marrow. This reduces the effectiveness of their transplantation, delaying resumption of hematopoiesis – increasing the risk of infection or bleeding — or even causing the transplant rejection.
HSCs death is particularly problematic if the number of donor cells is low to begin with. For example, umbilical cord blood generally contains insufficient number of stem cells for it to be used as a source of HSCs for transplantation into adult patients.
The death of HSCs occurs due to a process called apoptosis, driven by two proteins – BIM and BMF. Permanent inhibition of these proteins hinders the death of hematopoietic stem cells and increases the efficiency of their transplantation in mice. However, in such animals, autoimmune diseases and/or lymphomas soon begin to develop, because HSCs and the blood cells they produce do not die in due time.
“Thus, inhibiting apoptosis transiently during the stressful period of transplantation could be an attractive strategy to improve transplantation outcome without increasing the risk of long-term adverse effects”, – says co-author Dr. Miriam Erlacher.
Erlacher jointly with colleagues isolated HSCs from mice and infected them with genetically engineered adenovirus, which temporarily produces the human BCL-XL protein, an inhibitor of BIM and BMF proteins. Such infected hematopoietic stem cells were resistant to apoptosis for 7-9 days, during the BCL-XL expression period.
Upon transplantation into recipient mice, HSCs ability to establish themselves in the bone marrow and produce new blood cells was greatly enhanced. Moreover, since transplanted stem cells expressed BCL-XL for only a few days, they did not promote the formation of lymphoma in the recipient animals. However, adenovirus infection is slightly toxic to HSCs.
Therefore, the Erlacher’s group developed an alternative method of directly introducing BCL-XL into isolated stem cells. This approach also provided temporary protection of cells from apoptosis and improved their abilities in transplantation.
“Our findings suggest that transiently inhibiting apoptosis by manipulating donor HSCs increases the fitness of these cells without elevating the risk of adverse pathology”, – Erlacher says. “Transient apoptosis inhibition is therefore a promising approach to reduce the risk of graft failure and improve HSCs transplantation outcomes.”