Renoprotective Effect of Human Umbilical Cord–Derived Mesenchymal Stem Cells in Immunodeficient Mice Suffering from Acute Kidney Injury

Te-Chao Fang,Dah-Ching Ding,Cheng-Yoong Pang,Rong-Kung Tsai,Sheng-Chun Chiu,Paolo Fiorina

doi:10.1371/journal.pone.0046504

Abstract

It is unknown whether human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) can improve the renal function of patients suffering from acute kidney injury. Moreover, before beginning clinical trials, it is necessary to investigate this renoprotective effect of hUC-MSCs in a xenogeneic model of acute kidney injury. However, no previous studies have examined the application of hUC-MSCs to immunodeficient mice suffering from acute kidney injury. The objectives of this study were to examine whether hUC-MSCs could improve renal function in nonobese diabetic-severe combined immune deficiency (NOD-SCID) mice suffering from acute kidney injury, and to investigate the mechanism(s) for hUC-MSCs to improve renal function in this xenogeneic model. Early (3 hr) and late (12 hr) administrations of hUC-MSCs (106 cells) were performed via the external jugular vein into NOD-SCID mice suffering from either folic acid (FA) (250 mg/kg body weight) or vehicle. The results showed that early administration of hUC-MSCs improved the renal function of NOD-SCID mice suffering from FA-induced acute kidney injury, as evidenced by decreased serum urea nitrogen and serum creatinine levels, as well as a reduced tubular injury score. The beneficial effects of hUC-MSCs were through reducing apoptosis and promoting proliferation of renal tubular cells. These benefits were independent of inflammatory cytokine effects and transdifferentiation. Furthermore, this study is the first one to show that the reduced apoptosis of renal tubular cells by hUC-MSCs in this xenogeneic model is mediated through the mitochondrial pathway, and through the increase of Akt phosphorylation.

Highlights

Acute renal failure (ARF) is a common disease that accounts for 2%–15% of hospitalized patients
Our previous study showed that endogenous bone marrow (BM) cells could contribute to the renal tubular epithelial cell population and regeneration of the renal tubular epithelium by DNA synthesis after folic acid-induced acute kidney injury (AKI), most (90%) of the renal tubular regeneration came from indigenous cells [3]
These observations indicate that cells isolated from Wharton’s Jelly of human umbilical cord have the same surface markers as those of mesenchymal stem cells (MSCs), which were consistent with observations of bone marrow MSCs [24]

Summary

Introduction

Acute renal failure (ARF) is a common disease that accounts for 2%–15% of hospitalized patients. Our previous study showed that endogenous bone marrow (BM) cells could contribute to the renal tubular epithelial cell population and regeneration of the renal tubular epithelium by DNA synthesis after folic acid-induced acute kidney injury (AKI), most (90%) of the renal tubular regeneration came from indigenous cells [3]. These results have been supported by another study [4]

Objectives

Methods

Results

Conclusion