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 2021-04-15, 17:45 authored 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. LermanMesenchymal 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.
