Comparison of Regenerative and Immune Modulatory Effects of Bone Marrow and Intestinal Mesenchymal Stem Cells in Intestinal Damage Models

Abstract

Allogeneic hematopoietic stem cell transplantation is the only treatment option for certain malignant or non-malignant hematological diseases. Graft versus host disease (GvHD) occurs after allo-HSCT due to a generalized response of donor-derived T cells to Major Histocompatibility Complex (MHC) proteins on the surface of recipient cells. Current preclinical studies of aGvHD require the use of many mice causing considerable discomfort that may even lead to death. Therefore, in the framework of this thesis, we aimed to develop alternative intestinal aGvHD models that induce less harm, while still functioning as a representative disease model. We generated a mouse model of Inflammatory Bowel Disease (IBD) using DSS treatment of immunodeficient Balb/c-Rag2-/- (Rag2) mice to test the applicability of the current scoring systems of intestinal damage for our model and adapted these protocols for use in further studies. We then developed models of intestinal aGvHD using a low dose of Busulfan in Rag2 mice in vivo and Rag2-derived colonoids in vitro, followed by infusion/co-culture with activated MHC-mismatched T cells. We then tested the effects of bone marrow and intestinal mesenchymal stromal/stem cells on aGvHD severity and assessed the migratory, immune modulatory and regenerative potential of these cells. The Rag2 intestinal aGvHD model allowed us to study intestinal damage in the absence of overt other tissue involvement, requiring less animals for use. In addition, our in vitro aGvHD-in-a-dish model shows great similarity to the in vivo model and can therefore be used to model intestinal aGvHD.