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. ? ?
|Saha, Asim; Aoyama, Kazutoshi; Taylor, Patricia A et al. (2013) Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood 122:3062-73|
|Palpant, Nathan J; Bedada, Fikru B; Peacock, Brandon et al. (2011) Cardiac disease in mucopolysaccharidosis type I attributed to catecholaminergic and hemodynamic deficiencies. Am J Physiol Heart Circ Physiol 300:H356-65|
|Highfill, Steven L; Rodriguez, Paulo C; Zhou, Qing et al. (2010) Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1-dependent mechanism that is up-regulated by interleukin-13. Blood 116:5738-47|
|Wagner, John E; Ishida-Yamamoto, Akemi; McGrath, John A et al. (2010) Bone marrow transplantation for recessive dystrophic epidermolysis bullosa. N Engl J Med 363:629-39|
|Highfill, Steven L; Kelly, Ryan M; O'Shaughnessy, Matthew J et al. (2009) Multipotent adult progenitor cells can suppress graft-versus-host disease via prostaglandin E2 synthesis and only if localized to sites of allopriming. Blood 114:693-701|
|Tolar, Jakub; Ishida-Yamamoto, Akemi; Riddle, Megan et al. (2009) Amelioration of epidermolysis bullosa by transfer of wild-type bone marrow cells. Blood 113:1167-74|
|Tolar, Jakub; Braunlin, Elizabeth; Riddle, Megan et al. (2009) Gender-related dimorphism in aortic insufficiency in murine mucopolysaccharidosis type I. J Heart Valve Dis 18:524-9|
|Osborn, Mark J; McElmurry, Ron T; Peacock, Brandon et al. (2008) Targeting of the CNS in MPS-IH using a nonviral transferrin-alpha-L-iduronidase fusion gene product. Mol Ther 16:1459-66|
|Orchard, Paul J; Blazar, Bruce R; Wagner, John et al. (2007) Hematopoietic cell therapy for metabolic disease. J Pediatr 151:340-6|
|Serafini, Marta; Dylla, Scott J; Oki, Masayuki et al. (2007) Hematopoietic reconstitution by multipotent adult progenitor cells: precursors to long-term hematopoietic stem cells. J Exp Med 204:129-39|
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