Renovascular Disease and Mitochondrial Dysfunction in Human Mesenchymal Stem Cells.

Abstract

Renovascular disease leads to renal ischemia, hypertension, and eventual kidney failure. Autologous transplantation of adipose tissue-derived mesenchymal stem/stromal cells (MSCs) improves perfusion and oxygenation in stenotic human kidneys, but associated atherosclerosis and hypertension might blunt their effectiveness. We hypothesized that renovascular disease alters the human MSC transcriptome and impairs their reparative potency. MSCs were harvested from subcutaneous abdominal fat of renovascular disease patients and healthy volunteers (n=3 each), characterized and subsequently injected (5x10^5/200μL) into mice 2 weeks after renal artery stenosis or sham surgery (n=6/group). Two weeks later, mice underwent imaging and tissue studies. Healthy volunteer- and renovascular disease-MSCs were also characterized by mRNA/microRNA (miRNA)-sequencing. Based on these, MSC proliferation and mitochondrial damage were assessed in-vitro before and after miRNA modulation, and in-vivo in additional renal artery stenosis mice administered with renovascular disease-MSCs pre-treated with miR-378h mimic (n=5) or inhibitor (n=4). MSCs engrafted in stenotic mouse kidneys. Healthy volunteer-MSCs (but not renovascular disease-MSCs) decreased blood pressure, improved serum creatinine levels and stenotic-kidney cortical perfusion and oxygenation, and attenuated peritubular capillary loss, tubular injury, and fibrosis. Genes upregulated in renovascular disease-MSCs versus healthy volunteer-MSCs were mostly implicated in transcription and cell proliferation, whereas those downregulated encoded mainly mitochondrial proteins. Upregulated miRNAs, including miR-378h, primarily target nuclear-encoded mitochondrial genes, whereas downregulated miRNAs mainly target genes implicated in transcription and cell proliferation. MSC proliferation was similar, but their mitochondrial structure and reparative function both in vivo and in vitro improved after miR-378h inhibition. Renovascular disease impaired the reparative capacity of human MSCs, possibly by dysregulating miR-378h that targets mitochondrial genes.