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Abstract 223: Modifiable Mesenchymal Stem Cell Defects In Veterans With Diabetes Mellitus

Diabetes Mellitus (DM) affects 34.2 million Americans. DM impairs the body’s reparative machinery leading to early onset chronic illness (peripheral arterial disease (PAD), neuropathy, nephropathy, and retinopathy, the latter being hallmarks of microvascular disease). Patients with DM+PAD have increased risk of major amputation. Mesenchymal stem cells (MSCs) are reparative cells found in all tissues providing paracrine and trophic support for new tissue. This study’s objective was to identify intracellular and epigenetic mechanisms of how DM impairs MSC function and test if these defects are modifiable with culture rejuvenation (CR).
 MSCs obtained from bone marrow of 13 consecutive, male Veterans undergoing lower limb major amputation were cultured in 10% fetal bovine serum or 5% human platelet lysate (PL) for CR. Groups were DM+PAD (n=8) and PAD no DM (n=5). Intracellular signaling was analyzed with multiplexed ELISA. Epigenetic differences were identified by ATAC-sequencing.
 DM+PAD MSCs had modifiable AKT signaling defects with PL (Fig 1) and a discrete DNA profile identified in their introns and intergenic regions (Fig 2). MSCs from PAD alone had increased transcription factor binding at Wnt and cGMP-PKG pathways (p=0.04). DM+PAD MSCs had increased binding at MAPK (p=0.01) and Rap1 (p=0.01) pathways.
 DM is a complex disease disrupting reparative mechanisms and can lead to major complications. MSC dysfunction in DM may have common mechanisms throughout the body. We have identified potentially druggable pathways that may provide therapeutic solutions to relieve chronic illness for endogenous MSCs and to expand MSC donor pool for regenerative medicine strategies.
 
 
 
 
 
