1381-P: Optimal Prevention and Repair of Diabetes-Associated Complications Could Be Facilitated by the Restoration of the Systemic Dysfunction Exhibited by Mesenchymal Stromal Cells (MSCS) in DM Patients

Introduction and Objective: MSCs are found in all organs & are primarily responsible for maintenance & repair of injured tissue. Their immune-modulatory & anti-inflammatory actions make them effective Regenerative Medicine tools for diabetic complications. However, intrinsic T1 & T2 MSCs exhibit dysfunctions that aggravate comorbidities & inflammation associated with DM. MSCs from healthy donors are renoprotective & beneficial to patients with DM, suggesting they may repair a patient's dysfunctional MSCs. We assessed here whether conditioned medium (CM) from healthy MSCs could restore the dysfunctions of MSCs from patients with T1 or T2DM. Methods: MSCs from healthy, T1DM, and T2DM donors were culture expanded 5-10 doublings in low glucose DMEM, or CM from either healthy or T1 DM MSCs. Their wound healing abilities (scratch wound assay) and inflammatory responses (IDO-1, CCL8, CXCL9, CXCL10, IL-6, PD-L1, FGF2) were assessed at baseline and following INFγ exposure by rtPCR and ELISA. Results: Wound healing was significantly impaired ~50% in T1 and T2 DM MSCs vs. healthy controls. Exposure to CM from healthy MSCs fully restored wound healing capacities of both MSCs. IDO-1 and IL6 protein expression are 2-4-fold higher at baseline in T1 & T2DM MSCs vs. control. IDO-1, CCL8, IL6, and IGF1 are elevated 10-40-fold at baseline; IDO1, CXCL-9, CXCL10, IL6, FGF-2, and PD-L1 are elevated 10-200-fold upon stimulation with INFγ in T1 & T2 DM MSCs vs. healthy MSCs. Culture of T1DM & T2DM MSCs in CM from healthy MSCs restores expression of all but IGF1 & IL6 to near normal, while CM from T1DM MSCs does not. When healthy MSCs are cultured in CM from T1DM MSCs, the expression of CXCL10 increases 8.5-fold. Conclusion: We demonstrate that healthy MSCs can influence and significantly reset the dysfunctional phenotypes exhibited by T1 & T2DM MSCs, likely by its secretome. These data identify a novel mechanism whereby administration of healthy MSCs is an effective therapy in T1 & T2DM patients. Disclosure A. Gooch: Board Member; Current; SymbioCellTech, LLC. Employee; Current; SymbioCellTech, LLC. C.M. Westenfelder: Board Member; Current; SymbioCellTech, LLC.