Abstract
Mesenchymal stromal cells (MSCs) are renoprotective and drive regeneration following injury, although cellular targets of such an effect are still ill-defined. Here, we show that human umbilical cord (UC)-MSCs transplanted into mice stimulate tubular cells to regain mitochondrial mass and function, associated with enhanced microtubule-rich projections that appear to mediate mitochondrial trafficking to create a reparative dialogue among adjacent tubular cells. Treatment with UC-MSCs in mice with cisplatin-induced acute kidney injury (AKI) regulates mitochondrial biogenesis in proximal tubuli by enhancing PGC1α expression, NAD+ biosynthesis and Sirtuin 3 (SIRT3) activity, thus fostering antioxidant defenses and ATP production. The functional role of SIRT3 in tubular recovery is highlighted by data that in SIRT3-deficient mice with AKI, UC-MSC treatment fails to induce renoprotection. These data document a previously unrecognized mechanism through which UC-MSCs facilitate renal repair, so as to induce global metabolic reprogramming of damaged tubular cells to sustain energy supply.
Highlights
Mesenchymal stromal cells (MSCs) are renoprotective and drive regeneration following injury, cellular targets of such an effect are still ill-defined
We found a remarkable difference in gene expression profile between resting and injured tubular cells, especially when exposed to umbilical cord (UC)-MSCs, suggesting that cell-based therapy primes the transcriptional induction of several genes in tubular cells that are possibly involved in the processes of renal repair
Enrichment analysis revealed a stark difference between resting cells and injured renal proximal tubular epithelial cells (RPTECs) exposed to UC-derived MSCs (UC-MSCs), in terms of a high recurrence of genes involved in mitochondrial energy production, including aminoacid catabolism, urea cycle, fatty acid metabolism, and electron transport chain components
Summary
Mesenchymal stromal cells (MSCs) are renoprotective and drive regeneration following injury, cellular targets of such an effect are still ill-defined. The functional role of SIRT3 in tubular recovery is highlighted by data that in SIRT3-deficient mice with AKI, UC-MSC treatment fails to induce renoprotection These data document a previously unrecognized mechanism through which UC-MSCs facilitate renal repair, so as to induce global metabolic reprogramming of damaged tubular cells to sustain energy supply. Results from studies in several experimental models of AKI have shown that treatments with rodent and human MSCs of different origins have an amazing protective effect on renal function impairment and structural damage, by reducing apoptosis and activating tubular cell turnover[5,6,7,8,9]. Pharmacological manipulations with agents able to restore renal SIRT3 levels and impaired mitochondrial dynamics resulted in kidney repair in the AKI animals[20]
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