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- Title
Diabetic Kidney Disease Alters the Transcriptome and Function of Human Adipose-Derived Mesenchymal Stromal Cells but Maintains Immunomodulatory and Paracrine Activities Important for Renal Repair.
- Authors
Hickson, LaTonya J.; Eirin, Alfonso; Conley, Sabena M.; Taner, Timucin; Bian, Xiaohui; Saad, Ahmed; Herrmann, Sandra M.; Mehta, Ramila A.; McKenzie, Travis J.; Kellogg, Todd A.; Kirkland, James L.; Tchkonia, Tamar; Saadiq, Ishran M.; Tang, Hui; Jordan, Kyra L.; Zhu, Xiangyang; Griffin, Mathew D.; Rule, Andrew D.; van Wijnen, Andre J.; Textor, Stephen C.
- Abstract
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-γ 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-β-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 A1c, kidney function, and urine albumin excretion. However, senescence-associated β-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.
- Subjects
STROMAL cells; HEPATOCYTE growth factor; CELLULAR aging; KIDNEY physiology; DIABETIC nephropathies; PARACRINE mechanisms; DNA mismatch repair; RESEARCH; CELL culture; RESEARCH methodology; IMMUNE system; IMMUNOLOGY technique; APOPTOSIS; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; GENE expression profiling; RESEARCH funding; T cells; ADIPOSE tissues
- Publication
Diabetes, 2021, Vol 70, Issue 7, p1561
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db19-1268