The list of diseases that can be treated or even cured using stem cell transplant numbers in the hundreds, and includes diseases ranging from leukemia to multiple sclerosis. Having the transplanted stem cells settle into their new body, though, remains a challenge.
Failure to graft – where the stem cells fail to take root, and die shortly after transplantation – represents a common and life-threatening complication following stem cell transplantation. By repurposing a drug typically used to treat rheumatoid arthritis, however, researchers from the University of Toronto have started making strides towards solving this problem.
In a typical hematopoietic stem cell transplant, the patient’s own stem cells, which might be at the root of an auto-immune disease or a malignant cancer, are destroyed by irradiation or chemotherapy. Donor stem cells are then infused into the patient, where, in ideal circumstances, they settle and proliferate, establishing a new healthy blood and immune system.
In reality, however, the percentage of donated stem cells that successfully engraft is relatively low, necessitating a huge number of stem cells to maximize the chances of a successful procedure. This is not only wasteful, but such large numbers of donor stem cells are not always available, particularly in the many cases where umbilical cord blood is the only suitable stem cell source.
Using a mouse model, Zandstra and his colleagues pinpointed one of the factors contributing to poor stem cell engraftment efficiency: tumor necrosis factor-α, or TNFα. Following their transplantation, some of the donated cells react negatively to their new neighbours, producing a variety of inflammatory signals including TNFα, that negatively impact their own survival and proliferation. These cells are, after all, being transplanted into a foreign environment that in most cases has been recently damaged by irradiation or chemotherapy. The group showed that a subset of cells within the donated stem cells were releasing a large amount of TNFα.
Fortunately, there’s a number of drugs already clinically approved and available to neutralize TNFα due to its involvement in a number of autoimmune diseases, such as rheumatoid arthritis and psoriasis. Zandstra’s group asked whether attenuating TNFα using one of these drugs, specifically etanercept, could improve engraftment efficiency.
The group performed a blood stem cell transplant into a stem cell-less irradiated mouse, but this time, treated the mouse post-transplant with injections of etanercept to sweep up the toxic TNFα. Their experiments showed that treatment with etanercept not only increased the number of surviving blood stem cells from the transplant, but also increased the diversity of resulting cell types, a critical indicator of hematopoietic recovery.
While Zandstra and his colleagues recognize that more work is needed to evaluate TNFα-neutralization as a clinical therapy for use in humans, these results are promising. Improving stem cell survival post transplantation would allow treatment with a smaller number of donor cells, making stem cell transplantation, an already powerful therapy, more widely available.