Therapy of Hypoxic Preconditioned Allogeneic Mesenchymal Stromal Cell in Renal Ischemia-reperfusion Injury : Preclinical Study for Approval

Abstract

BACKGROUND Although clinical studies using stromal cells to renal ischemia-reperfusion injury (IRI) have been performed or are ongoing, there is little consensus on the optimal protocol. The purpose of this study was to determine route for cell delivery, the optimal cell injection dose and injection time of cell at the therapeutic effects of HP-hBMSC in a rat model of renal IRI. MATERIALS AND METHODS We conducted, in order, an optimal injection route study (renal arterial injection, renal parenchymal injection and tail venous injection), a dose finding study (low-dose: 1x106, moderate-dose: 2x106 and high-dose: 4x106) and an optimal injection timing study (pre-IRI, concurrent-IRI and post-IRI). RESULTS In optimal injection route study, two and one of mortality cases were observed in the renal parenchymal and tail venous injection groups, respectively. Renal arterial injection significantly reduced the extent of decrease in glomerular filtration rate compared with the IRI control group 2 and 4 days after IRI. The therapeutic effects and histological recoveries of renal arterial injection were significantly increased compared with other groups. From the dose finding study, one mortality case was observed in the IRI control group. High-dose injection significantly reduced the extent of decrease in glomerular filtration rate compared with the IRI control group 3 days after IRI. The therapeutic effects and histological recoveries of high-dose injection group were significantly increased compared with other groups. In optimal injection timing study, one mortality case was observed in the IRI control group. Concurrent-IRI injection reduced the extent of elevation in serum creatinine compared with the IRI control group 1 day (p=0.054) after IRI. Pre-IRI injection significantly reduced the extent of decrease in glomerular filtration rate compared with the IRI control group 1 day after IRI. The therapeutic effects and histological recoveries of the concurrent-IRI group were significantly increased compared with the groups of pre-IRI and post-IRI. CONCLUSIONS To inject high dose HP-hBMSC via renal artery at the same time IRI results in the best recovery of renal function after renal IRI. We have shown that stimulation of MSCs with hypoxic preconditioning decreased deterioration of renal function and enhanced anti-fibrotic, anti-oxidative and anti-apoptotic effects after renal IRI in rat model. It can be a basis for clinical study of renal IRI.