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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

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posted on 15.04.2021, 17:45 by LaTonya J. Hickson, Alfonso Eirin, Sabena M. Conley, Timucin Taner, Xiaohui Bian, Ahmed Saad, Sandra M. Herrmann, Ramila A. Mehta, Travis J. McKenzie, Todd A. Kellogg, James L. Kirkland, Tamar Tchkonia, Ishran M. Saadiq, Hui Tang, Kyra L. Jordan, Xiangyang Zhu, Mathew D. Griffin, Andrew D. Rule, Andre J. van Wijnen, Stephen C. Textor, Lilach O. Lerman
Mesenchymal stem/stromal cells (MSC) 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 DKD participants and 16 controls were assessed for cell surface markers, tri-lineage differentiation, RNA-sequencing (RNA-seq), in vitro function (co-culture 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- vs. 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 pro-repair factors (hepatocyte growth factor and stromal cell-derived factor-1) but lower Interleukin-6 vs. 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, gender, body mass index, hemoglobin A1c, kidney function or 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 MSC, DKD-MSC functionality, trophic factor secretion and immunomodulatory activities contributing to repair remained intact. These observations support testing patient-derived MSC therapy and may inform preconditioning regimens in DKD clinical trials.

Funding

This project was supported by funding from the Extramural Grant Program of Satellite Healthcare, a not-for-profit care provider (LJH), Regenerative Medicine Minnesota (RMM 091718; LJH), Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery (LJH), and the National Institute of Health (NIH) grant DK109134 (LJH), DK123492 (LJH), UL1 TR002377 (LJH; Mayo Clinic) & UL1 TR000135 (LJH; Mayo Clinic; CCaTS), and NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255. Additional support was provided by NIH grants R01 DK120292, DK122734, and AG062104 (LOL), R01 DK100081 (SCT), T32 DK07013 (SMC), Burroughs Wellcome Fund (SMC), DK106427 (AE), DK118120 (SMH), and AG013925 (JLK), AG062413 (JLK), the Ted Nash Long Life and Noaber Foundations (JLK), the Connor Group (JLK), and Robert J. and Theresa W. Ryan (JLK). SMC is supported by Burroughs Wellcome Fund. MDG is supported by the European Commission [Horizon 2020 Collaborative Health Project NEPHSTROM (Novel Stromal Cell Therapy for Diabetic Kidney Disease); grant 634086], by Science Foundation Ireland [CÚRAM Research Centre (grant number 13/RC/2073; MDG)] and by the European Regional Development Fund.

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