Optimal Repair of Diabetic Kidney Disease Could Be Facilitated by Repair of Dysfunction Intrinsic to Mesenchymal Stromal Cells (MSCs) from Patients with Diabetes

Background: MSCs are found in all organs & are primarily responsible for maintenance & repair of injured tissue. Their immunemodulatory & anti-inflammatory actions make them effective Regenerative Medicine tools for Diabetic complications. Intrinsic MSCs from T1 & T2DM subjects exhibit dysfunctions that may contribute to the comorbidities & inflammation associated with DM. Culture expansion in a non-diabetic milieu does not repair the dysfunctions, suggesting that DM “reprograms” these cells. We & others showed that MSCs from healthy donors are renoprotective & beneficial to patients with DM suggesting they may affect the patient's own MSCs. To test this hypothesis, we assessed here whether conditioned medium from healthy MSCs could restore the dysfunctions of MSCs isolated from patients with either T1 or T2 DM. Methods: MSCs from healthy, T1DM, and T2DM donors were culture expanded 5-10 doublings in low glucose DMEM, or conditioned medium (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 or following INF-gamma exposure using rtPCR and ELISA. Results: Wound healing abilities were impaired ~50% in T1 and T2 DM MSCs vs healthy controls. Exposure to CM from healthy MSCs fully restored wound healing capacities of both cell types. 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. IGF1 & IL6 levels are unaffected by culture in CM. When healthy MSCs are cultured in CM from T1DM MSCs, the expression of CXCL10 in healthy MSCs increases by 8.5-fold. Results suggest that secreted factors influence these genes' expression. 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. Funding: Commercial Support - SymbioCellTech