Identification of the optimal source of human mesenchymal stromal cells for the treatment of acute graft-versus-host disease (aGVHD)

Abstract

Acute graft-versus-host disease (aGVHD) is a life-threatening complication that can arise when allogeneic hematopoietic stem cells are transplanted for treatment of hematological and non-hematological disorders. Around 38% of patients who receive matched unrelated allogeneic hematopoietic stem cells transplantation in Hong Kong develop aGVHD, but only approximately 50% of aGVHD patients will respond to conventional steroid therapy. Patients with severe or steroid resistant aGVHD have few therapeutic alternatives with no established treatment protocol. Alternative treatment options are desperately needed. Human mesenchymal stem cells (hMSCs) have strong immunosuppressive properties and have shown efficacy in the treatment of aGVHD. hMSCs are multipotent stem cells present in virtually all organs and connective tissues and have the capacity to differentiate into multiple lineages of tissues such as bone, fat and umbilical cord. hMSCs are also potent modulators of the immune system and can overcome HLA barrier, bypassing the need of immunosuppressive regime even under allogeneic transplantation setting. All these properties make hMSCs excellent candidate for use in cell-based therapy.

hMSCs can be generated from various tissues but it is unclear which cell source can generate hMSCs most suitable for treatment of aGVHD. hMSCs were traditionally isolated from bone marrow (BM) but the use of BM-hMSCs is not always acceptable due to the scarcity of samples, the invasiveness of the harvesting procedure and decrease in proliferation potential with increasing donor age. Adipose tissue (AT) and umbilical cord (UC) represent alternative sources of hMSCs for immunosuppressive therapy. Since these hMSCs exhibit different behavior in vitro, in terms of population doubling time, differentiation potential and ability to suppress specific components of the immune system, their clinical efficacy are expected to vary. However, there has been no comparative study to evaluate the effectiveness of different types of hMSCs in vivo.

In this thesis, I aim to identify the optimal source of hMSCs for the treatment of aGVHD by comparing the yield, proliferation potential, in vitro and in vivo immunomodulatory potencies of BM-, AT- and UC-hMSCs. Our results showed that hMSCs could be successfully derived from AT, BM and UC. They all modulate multiple components of the immune system in vitro and protect the mice against aGVHD. Particularly, AT-hMSCs had better proliferative potential, and were more effective in maintaining survival in aGVHD mouse model. AT-hMSCs also ameliorated the clinical signs of aGVHD better than BM- and UC-hMSCs.