The intent of this Funding Opportunity Announcement (FOA) is to facilitate the use of stem cell based therapies, including Mesenchymal Stem Cells (MSCs), for regenerative medicine. As stipulated in this FOA, given the wide range of tissue sources, the recognition of subpopulations with specific properties, and the frequent production of functional alterations upon expansion in cell culture, extensive characterization of MSCs and development of improved techniques are required. Most importantly, there is relatively limited understanding of the normal biological functions of MSCs and the mechanisms by which they participate in tissue repair. Our proposal is exquisitely responsive to the aims of this FOA and it sought after scope of research and will seek to address issues germane to the translational use of MSCs for treatment of Crohn's disease. The clinical use of MSCs for treatment of colitis can be meaningfully informed by an improved understanding of the mechanism of action of MSCs as a transfusional cell product. Our group has generated compelling pre-clinical murine data strongly supporting the use of marrow-derived MSCs as a cell-based therapy for colitis and that ?-interferon (IFN?) activation of human MSCs significantly augments their immune modulatory properties. We here propose a comparative biology approach where we interrogate immune and regenerative mechanisms of action shared between human MSCs derived from subjects with Crohn's disease enrolled in our clinical trial to murine MSCs in the setting of experimental coliti. Our hypotheses are: (i) specific factors constitutively expressed by MSCs [CCL2, IL6] directly influence the immune response against epithelial cells in colitis; (ii) ex vivo IFN? priming furthr enhances the potency of MSCs in alleviating colitis via PD-L1/PD-1 pathway and upregulation of other immune regulatory factors [MHCI, MHCII, IDO and CXCL9/10/11]; (iii) adhesion molecule expression by MSC and IFN? primed derivatives [ICAM-1 and integrin components] determines in vivo biodistribution of transfused MSCs and leads to reprogramming of transcriptome and immune plasticity of MSCs. Importantly, we have already demonstrated our ability to navigate the regulatory pathway required to obtain a FDA IND to engage in a MSC based early phase clinical trial NCT01659762 entitled A Phase I Study Evaluating Autologous Bone Marrow Derived Mesenchymal Stromal for Crohn's Disease. The results of this proposal will inform a new IND application in support of use of IFN? primed MSCs for colitis.
to Public Health: The development of innovative stem cell therapies for inflammatory bowel disease addresses an important unmet medical need. Knowledge gained from the proposed research on mesenchymal stromal cells will lead to practical and effective remedies for Crohn's colitis.
| Chinnadurai, Raghavan; Rajan, Devi; Qayed, Muna et al. (2018) Potency Analysis of Mesenchymal Stromal Cells Using a Combinatorial Assay Matrix Approach. Cell Rep 22:2504-2517 |
| Lewis, Holly C; Chinnadurai, Raghavan; Bosinger, Steven E et al. (2017) The IDO inhibitor 1-methyl tryptophan activates the aryl hydrocarbon receptor response in mesenchymal stromal cells. Oncotarget 8:91914-91927 |
| Chinnadurai, Raghavan; Rajan, Devi; Ng, Spencer et al. (2017) Immune dysfunctionality of replicative senescent mesenchymal stromal cells is corrected by IFN? priming. Blood Adv 1:628-643 |
