Journal
DIABETES
Volume 70, Issue 7, Pages 1561-1574Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db19-1268
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Funding
- Extramural Grant Program of Satellite Healthcare
- Regenerative Medicine Minnesota [RMM 091718]
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery
- National Institutes of Health (NIH) [DK-109134, DK123492, UL1-TR-002377, UL1-TR-000135]
- National Institute of Diabetes and Digestive and Kidney Diseases Diabetic Complications Consortium [RRID:SCR_001415, DK-076169, DK-115255]
- NIH [DK-106427, T32-DK-07013, DK-118120, AG-013925, AG-062413, R01-DK-100081, R01-DK-120292, DK-122734, AG-062104]
- Ted Nash Long Life Foundation
- Connor Group
- Burroughs Wellcome Fund
- European Commission (Horizon 2020 Collaborative Health Project NEPHSTROM) [634086]
- Science Foundation Ireland (CURAM Research Centre) [13/RC/2073]
- European Regional Development Fund
- Noaber Foundation
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This study investigated the impact of diabetic kidney disease (DKD) on human adipose-derived MSCs, finding that DKD reduced the migration capability of MSCs but did not affect their function, secretome profile, and immunomodulatory activities contributing to repair. Few DKD-MSC functions were affected by patient characteristics, but DKD-MSC from participants on metformin therapy showed lower senescence-associated beta-galactosidase activity.
Mesenchymal stem/stromal cells (MSCs) facilitate repair in experimental diabetic kidney disease (DKD). However, the hyperglycemic and uremic milieu may diminish regenerative capacity of patient-derived therapy. We hypothesized that DKD reduces human MSC paracrine function. Adipose-derived MSC from 38 participants with DKD and 16 control subjects were assessed for cell surface markers, trilineage differentiation, RNA sequencing (RNA-seq), in vitro function (coculture or conditioned medium experiments with T cells and human kidney cells [HK-2]), secretome profile, and cellular senescence abundance. The direction of association between MSC function and patient characteristics were also tested. RNA-seq analysis identified 353 differentially expressed genes and downregulation of several immunomodulatory genes/pathways in DKD-MSC versus Control-MSC. DKD-MSC phenotype, differentiation, and tube formation capacity were preserved, but migration was reduced. DKD-MSC with and without interferon-gamma priming inhibited T-cell proliferation greater than Control-MSC. DKD-MSC medium contained higher levels of anti-inflammatory cytokines (indoleamine 2,3-deoxygenase 1 and prostaglandin-E2) and prorepair factors (hepatocyte growth factor and stromal cell-derived factor 1) but lower IL-6 versus control-MSC medium. DKD-MSC medium protected high glucose plus transforming growth factor-beta-exposed HK-2 cells by reducing apoptotic, fibrotic, and inflammatory marker expression. Few DKD-MSC functions were affected by patient characteristics, including age, sex, BMI, hemoglobin A(1c), kidney function, and urine albumin excretion. However, senescence-associated beta-galactosidase activity was lower in DKD-MSC from participants on metformin therapy. Therefore, while DKD altered the transcriptome and migratory function of culture-expanded MSCs, DKD-MSC functionality, trophic factor secretion, and immunomodulatory activities contributing to repair remained intact. These observations support testing of patient-derived MSC therapy and may inform preconditioning regimens in DKD clinical trials.
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