Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. May 26, 2015; 7(4): 776-788
Published online May 26, 2015. doi: 10.4252/wjsc.v7.i4.776
Fetal kidney stem cells ameliorate cisplatin induced acute renal failure and promote renal angiogenesis
Ashwani Kumar Gupta, Sachin H Jadhav, Naresh Kumar Tripathy, Soniya Nityanand
Ashwani Kumar Gupta, Sachin H Jadhav, Naresh Kumar Tripathy, Soniya Nityanand, Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow 226014, India
Author contributions: Gupta AK designed and performed the experiments and analyzed the data; Jadhav SH, Tripathy NK and Nityanand S designed the study and analyzed the data; Nityanand S provided the reagents and analytical tools; Gupta AK, Jadhav SH, Tripathy NK and Nityanand S wrote the manuscript.
Correspondence to: Dr. Soniya Nityanand, MD, PhD, FNASc, FASc, Professor and Head, Department of Hematology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Rae Bareli Road, Lucknow 226014, India.
Telephone: +91-522-2494291 Fax: +91-522-2668017
Received: November 13, 2014
Revised: February 5, 2015
Accepted: March 5, 2015
Published online: May 26, 2015

AIM: To investigate whether fetal kidney stem cells (fKSC) ameliorate cisplatin induced acute renal failure (ARF) in rats and promote renal angiogenesis.

METHODS: The fKSC were isolated from rat fetuses of gestation day 16 and expanded in vitro up to 3rd passage. They were characterized for the expression of mesenchymal and renal progenitor markers by flow cytometry and immunocytochemistry, respectively. The in vitro differentiation of fKSC towards epithelial lineage was evaluated by the treatment with specific induction medium and their angiogenic potential by matrigel induced tube formation assay. To study the effect of fKSC in ARF, fKSC labeled with PKH26 were infused in rats with cisplatin induced ARF and, the blood and renal tissues of the rats were collected at different time points. Blood biochemical parameters were studied to evaluate renal function. Renal tissues were evaluated for renal architecture, renal cell proliferation and angiogenesis by immunohistochemistry, renal cell apoptosis by terminal deoxynucleotidyl transferase nick-end labeling assay and early expression of angiogenic molecules viz. vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1α and endothelial nitric oxide synthase (eNOS) by western blot.

RESULTS: The fKSC expressed mesenchymal markers viz. CD29, CD44, CD73, CD90 and CD105 as well as renal progenitor markers viz. Wt1, Pax2 and Six2. They exhibited a potential to form CD31 and Von Willebrand factor expressing capillary-like structures and could be differentiated into cytokeratin (CK)18 and CK19 positive epithelial cells. Administration of fKSC in rats with ARF as compared to administration of saline alone, resulted in a significant improvement in renal function and histology on day 3 (2.33 ± 0.33 vs 3.50 ± 0.34, P < 0.05) and on day 7 (0.83 ± 0.16 vs 2.00 ± 0.25, P < 0.05). The infused PKH26 labeled fKSC were observed to engraft in damaged renal tubules and showed increased proliferation and reduced apoptosis (P < 0.05) of renal cells. The kidneys of fKSC as compared to saline treated rats had a higher capillary density on day 3 [13.30 ± 1.54 vs 7.10 ± 1.29, capillaries/high-power fields (HPF), P < 0.05], and on day 7 (21.10 ± 1.46 vs 15.00 ± 1.30, capillaries/HPF, P < 0.05). In addition, kidneys of fKSC treated rats had an up-regulation of angiogenic proteins hypoxia-inducible factor-1α, VEGF and eNOS on day 3 (P < 0.05).

CONCLUSION: Our study shows that fKSC ameliorate cisplatin induced ARF in rats and promote renal angiogenesis, which may be an important therapeutic mechanism of these stem cells in the disease.

Keywords: Fetal kidney stem cells, Mesenchymal and renal progenitor markers, Acute renal failure, Stem cell therapy, Angiogenesis

Core tip: This study provides novel data on the therapeutic effect of culture expanded fetal kidney stem cells (fKSC) in acute renal failure (ARF). The fKSC represent primitive renal stem cells that express mesenchymal and renal progenitor markers. They exhibit in vitro angiogenesis and potential to differentiate into renal epithelial cells. On administration in ARF rats, they rapidly improve renal function and histology. The therapeutic effects of fKSC are accompanied with increased capillary density in kidney tissues suggesting that induction of renal angiogenesis may be an important therapeutic mechanism of these stem cells.