Mesenchymal stem cell therapy promotes the improvement and recovery of renal function in a preclinical model

Abstract

Acute renal failure (ARF) is an extremely important public health issue in need of novel therapies. The present study aimed to evaluate the capacity of mesenchymal stem cell (MSC) therapy to promote the improvement and recovery of renal function in a preclinical model. Wistar rats were used as the experimental model, and our results show that cisplatin (5mg/kg) can efficiently induce ARF, as measured by changes in biochemical (urea and creatinine) and histological parameters. MSC therapy performed 24h after the administration of chemotherapy resulted in normalized plasma urea and creatinine levels 30 and 45d after the onset of kidney disease. Furthermore, MSC therapy significantly reduced histological changes (intratubular cast formation in protein overload nephropathy and tubular hydropic degeneration) in this ARF model. Thus, considering that current therapies for ARF are merely palliative and that MSC therapy can promote the improvement and recovery of renal function in this model system, we suggest that innovative/alternative therapies involving MSCs should be considered for clinical studies in humans to treat ARF.

Figure 1. MSC are able to differentiate into adipogenic, osteogenic (scale bars: 50 μm) and chondrogenic (scale bars: 20 μm) lineages, as shown by the staining.

Figure 2. DAPI staining: (A) MSC stained with DAPI; (B) renal cortex without MSC infiltration; (C) renal cortex with MSC infiltration, 48 h after the transplant. Scale bars: 20 μm.

Figure 3. Urea and creatinine plasmatic concentration (mean ± SD). A and B) Confirmation of acute renal failure. ARFG-48h: Acute renal failure group; animals were treated with cisplatin, evaluated seven days before and 48 h after the administration of the chemotherapy. C and D) Animals were evaluated 30 days after the administration of the chemotherapy. E and F) Animals were evaluated 45 days after the administration of the chemotherapy. CG: Control group. ARFG: Acute renal failure group; animals treated with cisplatin. ARFG+MSC: In this group, MSC were transplanted to animals with acute renal failure 24 h after the chemotherapy administration. Statistical analysis: A and B: Mann-Whitney, *statistically significant differences, p £ 0,05; C to F: Kruskal-Wallis with Dunn's post-hoc test; different letters indicate statistically significant differences, p ≤ 0.05.

Figure 4. Data from the histopathological cuts according the Banff 97 classification. A) ARFG-48h: Acute renal failure group; animals were treated with cisplatin, evaluated seven days before and 48 h after the administration of the chemotherapy. B and C) ARFG: Acute renal failure group; animals treated with cisplatin. ARFG+MSC: In this group, MSC were transplanted to animals with acute renal failure 24 h after the chemotherapy administration. B) 30d – animals evaluated after 30 days of the administration of the chemotherapy. C) 45d – animals evaluated after 45 days of the administration of the chemotherapy. Statistical analysis: Mann-Whitney, *statistically significant differences, p ≤ 0.05.

Figure 5. Histological sections of the kidneys from cisplatin treated and MSC transplanted animals. A) Hydropic degeneration (>) and interstitial infiltration (*); scale bar: 100 μm. B) Intratubular cast formation (>>); scale bar: 25 mm. C) interstitial fibrosis (>) and interstitial infiltration (*); scale bar: 100μm.