Our long-term goals are to develop non-hematopoietic cellular approaches to improve bone marrow transplantation (BMT) for the treatment of non-malignant and malignant disorders. We will test 2 non-hematopoietic cells. Mesenchymal stem cells (MSCs) can differentiate into multiple non-hematopoietic lineages, inhibit in vitro allogeneic T cell responses and are being tested clinically to reduce graft-versus-host disease (GVHD). Much remains unknown about their immune suppressive and multi-organ system regenerative potential.
In aim 1, we hypothesize that infused mMSCs will suppress allogeneic T cell responses that generate GVHD and BM graft rejection. We will determine the responsible mechanism(s) and whether suppression is alloantigen-specific or non-specific, findings that have clinical implications. We hypothesize that mMSCs will contribute to post-BMT regeneration of GVHD organs and regimen-related toxicity (RRT). MAPCs are multipotent progenitor cells that can be induced to differentiate into endodermal, mesodermal, or ectodermal lineages. We hypothesize that MAPCs may be superior to MSCs in tissue regeneration post-BMT by their broad tissue differentiation. MAPCs also suppress in vitro allogeneic responses. We hypothesize that MSCs may be superior to MAPCs for suppression in vivo. BMT injury from RRT or GVHD may benefit from MSCs or MAPCs. Tissue injury can occur in storage disorders. Mucopolysaccaridosis type IH (MPS IH) (Hurler syndrome) is caused by (-L-iduronidase (IDUA) enzyme deficiency. Although BMT reduces some symptoms, the CNS, cardiac and bone are more recalcitrant to correction. We hypothesize that MSCs or MAPCs may be additive with BMT in correcting MPSIH recipients since both populations can give rise to bone, cartilage and pulmonary cells. We hypothesize that MAPCs may be superior to MSCs for use in MPSIH by their in vivo differentiation potential to cardiac cells and into CNS cells after systemic injection in adult rodents. We will test these in a congeneic and then allogeneic BMT model. ? ?
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