Kallikrein-Modified Mesenchymal Stem Cell Implantation Provides Enhanced Protection Against Acute Ischemic Kidney Injury by Inhibiting Apoptosis and Inflammation

Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Human gene therapy (Impact Factor: 3.76). 07/2008; 19(8):807-19. DOI: 10.1089/hgt.2008.016
Source: PubMed


Mesenchymal stem cells (MSCs) migrate to sites of tissue injury and serve as an ideal vehicle for cellular gene transfer. As tissue kallikrein has pleiotropic effects in protection against oxidative organ damage, we investigated the potential of kallikrein-modified MSCs (TK-MSCs) in healing injured kidney after acute ischemia/reperfusion (I/R). TK-MSCs secreted recombinant human kallikrein with elevated vascular endothelial growth factor levels in culture medium, and were more resistant to oxidative stress-induced apoptosis than control MSCs. Expression of human kallikrein was identified in rat glomeruli after I/R injury and systemic TK-MSC injection. Engrafted TK-MSCs exhibited advanced protection against renal injury by reducing blood urea nitrogen, serum creatinine levels, and tubular injury. Six hours after I/R, TK-MSC implantation significantly reduced renal cell apoptosis in association with decreased inducible nitric oxide synthase expression and nitric oxide levels. Forty-eight hours after I/R, TK-MSCs inhibited interstitial neutrophil and monocyte/macrophage infiltration and decreased myeloperoxidase activity, superoxide formation, p38 mitogen-activated protein kinase phosphorylation, and expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1. In addition, tissue kallikrein and kinin significantly inhibited H2O2-induced apoptosis and increased Akt phosphorylation and cell viability in cultured proximal tubular cells. These results indicate that implantation of kallikrein-modified MSCs in the kidney provides advanced benefits in protection against ischemia-induced kidney injury by suppression of apoptosis and inflammation.

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    • "Several strategies have been developed to improve the survival of engrafted stem cells in ischemic kidney. These strategies include genetic modification of stem cells [8] [9], pretreatment of MSCs [7] [10], and the use of tissue engineering scaffolds [11]. Despite the improved survival of stem cells in ischemic kidney, the strategies still have problems for further clinical application. "
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    ABSTRACT: It has been shown that administration of adipose derived mesenchymal stem cells (AdMSCs) enhanced structural and functional recovery of renal ischemia-reperfusion (IR) injury. Low engraftment of stem cells, however, limits the therapeutic effects of AdMSCs. The present study was designed to enhance the therapeutic effects of AdMSCs by delivering AdMSCs in a three-dimensional (3D) aggregates form. Microwell was used to produce 3D AdMSCs aggregates. In vitro data indicated that AdMSCs in 3D aggregates were less susceptible to oxidative and hypoxia stress induced by 200 μ M peroxide and hypoxia/reoxygenation, respectively, compared with those cultured in two-dimensional (2D) monolayer. Furthermore, AdMSCs in 3D aggregates secreted more proangiogenic factors than those cultured in 2D monolayer. 2D AdMSCs or 3D AdMSCs aggregates were injected into renal cortex immediately after induction of renal IR injury. In vivo data revealed that 3D aggregates enhanced the effects of AdMSCs in recovering function and structure after renal IR injury. Improved grafted AdMSCs were observed in kidney injected with 3D aggregates compared with AdMSCs cultured in 2D monolayer. Our results demonstrated that 3D AdMSCs aggregated produced by microwell enhanced the retention and therapeutic effects of AdMSCs for renal IR injury.
    Full-text · Article · Jan 2016 · Stem cell International
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    • "Cell therapy as a prominent tool has currently recently been applied in regenerative medicine, given their multipotency, low immunogenicity, self-renewal, and amenability to ex vivo expansion. Previous studies have revealed the protective effects of MSCs on ischemic animal models of cerebral infarction [16], myocardial infarction [17], renal I/R injury [18], and even hepatic I/R injury [6], [12], [15]. However, the mechanism of the beneficial effects of MSCs remains unclear. "
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    ABSTRACT: Objective To evaluate the impact of mesenchymal stem cells (MSCs) against hepatic I/R injury and explore the role of N-acetyltransferase 8 (NAT8) in the process. Methods We investigated the potential of injected MSCs systemically via the tail vein in healing injuried liver of the SD rat model of 70% hepatic I/R injury by measuring the biochemical and pathologic alterations. Subsequently, we evaluated the expression levels of NAT8 by western blotting in vivo. Concurrently, hydrogen peroxide (H2O2)-induced apoptosis in the human normal liver cell line L02 was performed in vitro to evaluate the protective effects of MSC conditioned medium (MSC-CM) on L02 cells. In addition, we downregulated and upregulated NAT8 expression in L02 cells and induced apoptosis by using H2O2 to study the protective role of NAT8. Results MSCs implantation led to a significant reduced liver enzyme levels, an advanced protection in the histopathological findings of the acutely injured liver and a significantly lower percentage of TUNEL-positive cells, which were increased after I/R injury. In vitro assays, MSC-CM inhibited hepatocyte apoptosis induced by H2O2. Moreover, overexpression or downregulation of NAT8 prevented or aggravated hepatocyte apoptosis induced by H2O2, respectively. Conclusions MSC transplantation provides support to the I/R-injured liver by inhibiting hepatocellular apoptosis and stimulating NAT8 regeneration.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "In another study with ischemic AKI, kallikrein-modified mesenchymal stem cells (TK-MSCs) can provide enhanced protection against AKI by inhibiting apoptosis and inflammation. The expression of proinflammatory mediators CCL-2 and ICAM-1 was significantly reduced in the TK-MSCs group [66]. "
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    ABSTRACT: Acute kidney injury (AKI) remains to be an independent risk factor for mortality and morbidity. Inflammation is believed to play a major role in the pathophysiology of AKI. Exogenous mesenchymal stem cells (MSCs) are now under extensive investigation as a potential therapy for AKI. Various preclinical studies indicated the beneficial effects of MSCs in alleviating renal injury and accelerating tissue repair. However the mechanisms responsible for these effects are incompletely understood. In the recent years, anti-inflammatory/immunoregulatory properties of MSCs have become one of the important issues in the treatment of AKI. This review will summarize the current literature on the regulation of inflammatory mediators via exogenous MSCs contributing to the recovery from AKI.
    Full-text · Article · Apr 2014 · Mediators of Inflammation
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