| Authors |
Hickson LJ, Eirin A, Conley SM, Taner T, Bian X, MBBCh AS, Herrmann SM, Mehta
RA, McKenzie TJ, Kellogg TA, Kirkland JL, Tchkonia T, Saadiq IM, Tang H, Jordan
KL, Zhu X, MBBCh MDG, Rule AD, van Wijnen AJ, Textor SC, Lerman LO
|
| Submitted By |
LaTonya Hickson on 5/5/2021 |
| Status |
Published |
| Journal |
Diabetes |
| Year |
2021 |
| Date Published |
|
| Volume : Pages |
Not Specified : Not Specified |
| PubMed Reference |
33858824 |
| Abstract |
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-?
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-ß-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-ß-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.
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