<a>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), <i>in vitro</i> 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- <i>vs</i>. 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 </a><a>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. </a>These observations
support testing patient-derived MSC therapy and may inform preconditioning
regimens in DKD clinical trials.
Targeting cellular drivers and counter-regulators of hyperglycaemia- and transforming growth factor-β1-associated profibrotic responses in diabetic kidney disease
