Abstract
IntroductionSeveral cellular sources of stem cells have been tested in the attempt to yield innovative interventions in acute kidney injury (AKI). Human liver stem cells (HLSCs) are cells isolated from the normal adult human liver which are gaining attention for their therapeutic potential. In the present study, we investigated whether HLSCs and the derived extracellular vesicles may promote tubular regeneration after AKI induced by glycerol injection in severe-combined immune-deficient mice.MethodsHLSCs were expanded and conditioned medium (CM) and extracellular vesicles (EVs) were purified. HLSCs and their bioproducts were tested in a model of AKI induced by intra-muscle glycerol injection. Renal function and morphology were evaluated five days after induction of damage. The effect of EVs on proliferation and apoptosis of murine renal tubular cells was tested in vitro.ResultsWe found that intravenous injection of 3.5×105 HLSCs into mice three days after induction of AKI significantly improved functional and morphological recovery. The injection of HLSCs decreased creatinine and urea, as well as hyaline cast formation, tubular necrosis and enhanced in vivo tubular cell proliferation. The effect of soluble factors release by HLSCs in the regenerative processes was also studied. CM produced by HLSCs, mimicked the effect of the cells. However, depletion of EVs significantly reduced the functional and morphological recovery of CM. Moreover, we found that purified HLSC-derived EVs ameliorated renal function and morphology in a manner comparable to the cells. In vitro HLSC-derived EVs were shown to stimulate proliferation and inhibit apoptosis of murine renal tubular cells.ConclusionsThese results indicate that HLSCs increase recovery after AKI. EVs are the main component of HLSC-derived CM capable of promoting regeneration in experimental AKI.
Highlights
Several cellular sources of stem cells have been tested in the attempt to yield innovative interventions in acute kidney injury (AKI)
At day 3 after injury, 0.75 × 105 and 3.5 × 105 Human liver stem cells (HLSCs) were injected in AKI mice that were sacrificed at day 5
AKI mice treated with 0.75 × 105 and 3.5 × 105 HLSCs had a significantly lower number of hyaline cast formations and lower number of necrotic tubules compared with AKI mice treated with vehicle alone (Figure 1C and D)
Summary
Several cellular sources of stem cells have been tested in the attempt to yield innovative interventions in acute kidney injury (AKI). We demonstrated the therapeutic potential of HLSCs in several experimental models of liver injury [1,2]. We found that HLSCs contribute to regeneration of the liver parenchyma in from stem cells have been shown to contribute to renal recovery after AKI [6,7]. EVs-derived from MSCs reduced injury and stimulated recovery in a model of renal ischemia/reperfusion [7]. HLSC-derived EVs induced in vitro proliferation and apoptosis resistance of human and rat hepatocytes and accelerated in vivo the morphological and functional recovery of the liver in a model of 70% hepatectomy in rats [11]
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