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      VEGF is a mediator of the renoprotective effects of multipotent marrow stromal cells in acute kidney injury

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          Abstract

          Adult stem cell treatment of complex disorders is a promising therapeutic approach and multipotent marrow stromal cells (MSCs) have been shown to be effective in various animal models of diseases. Acute kidney injury (AKI) is a common and serious problem in hospitalized patients and bone marrow derived multipotent MSCs have been shown to be effective in different models of AKI. The mechanism of action of MSCs is complex but involves paracrine actions including growth factor secretion. Knockdown of vascular enthothelial growth factor (VEGF) by siRNA reduced effectiveness of MSCs in the treatment of ischemic AKI in a rat model. Animals treated with MSCs had increased renal microvessel density compared to VEGF knockdown MSC‐treated and vehicle‐treated animals. These results show that VEGF is an important mediator of the early and late phase of renoprotective action after AKI in the context of stem cell treatment.

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          Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.

          Florian Tögel, Zhuma Hu, Kathleen A. Weiss … (2005)
          Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (approximately 10(6)/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-alpha, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.
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            Stromal cells protect against acute tubular injury via an endocrine effect.

            Baoyuan Bi, Roland Schmitt, Malika Israilova … (2007)
            Emerging evidence suggests that the intravenous injection of bone marrow-derived stromal cells (BMSC) improves renal function after acute tubular injury, but the mechanism of this effect is controversial. In this article, we confirm that intravenous infusion of male BMSC reduced the severity of cisplatin-induced acute renal failure in adult female mice. This effect was also seen when BMSC (or adipocyte-derived stromal cells (AdSC)), were given by intraperitoneal injection. Infusion of BMSC enhanced tubular cell proliferation after injury and decreased tubular cell apoptosis. Using the Y chromosome as a marker of donor stromal cells, examination of multiple kidney sections at one or four days after cell infusion failed to reveal any examples of stromal cells within the tubules, and only rare examples of stromal cells within the renal interstitium. Furthermore, conditioned media from cultured stromal cells induced migration and proliferation of kidney-derived epithelial cells and significantly diminished cisplatin-induced proximal tubule cell death in vitro. Intraperitoneal administration of this conditioned medium to mice injected with cisplatin diminished tubular cell apoptosis, increased survival, and limited renal injury. Thus, marrow stromal cells protect the kidney from toxic injury by secreting factors that limit apoptosis and enhance proliferation of the endogenous tubular cells, suggesting that transplantation of the cells themselves is not necessary. Identification of the stromal cell-derived protective factors may provide new therapeutic options to explore in humans with acute kidney injury.
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              Angiogenic effects of human multipotent stromal cell conditioned medium activate the PI3K-Akt pathway in hypoxic endothelial cells to inhibit apoptosis, increase survival, and stimulate angiogenesis.

              Wan-Ching Hsu, R Pochampally, Darwin J Prockop … (2007)
              Recent reports indicated that vascular remodeling and angiogenesis are promoted by conditioned medium from the cells referred to as multipotent stromal cells (MSCs). However, the molecular events triggered by MSC-conditioned medium (CdM) were not defined. We examined the effects of CdM from human MSCs on cultures of primary human aortic endothelial cells (HAECs). The CdM inhibited hypoxia-induced apoptosis and cell death of HAECs. It also promoted tube formation by HAECs in an assay in vitro. Conditioned medium from multipotent stromal cells incubated under hypoxic conditions in serum-free endothelial basal medium for 2 days (CdM(Hyp)) from hypoxic culture of MSCs was more effective than conditioned medium from MSCs incubated under normoxic conditions in serum-free endothelial basal medium for 2 days from normoxic cultures of MSCs, an observation in part explained by its higher content of antiapoptotic and angiogenic factors, such as interleukin (IL)-6, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein (MCP)-1. The effects of CdM(Hyp) on hypoxic HAECs were partially duplicated by the addition of IL-6 in a dose-dependent manner; however, anti-IL-6, anti-MCP-1, and anti-VEGF blocking antibodies added independently did not attenuate the effects. Also, addition of CdM(Hyp) activated the PI3K-Akt pathway; the levels of p-Akt and several of its downstream targets were increased by CdM(Hyp), and both the increase in p-Akt and the increase in angiogenesis were blocked by an inhibitor of PI3K-Akt or by expression of a dominant negative gene for PI3K. CdM(Hyp) also increased the levels of p-extracellular signal-regulated kinase (ERK), but there was a minimal effect on p-signal transducer and activator of transcription-3, and an inhibitor of the ERK1/2 pathway had no effect on hypoxia-induced apoptosis of the HAECs. The results are consistent with suggestions that administration of MSCs or factors secreted by MSCs may provide a therapeutic method of decreasing apoptosis and enhancing angiogenesis.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Cell Mol Med
                Journal ID (iso-abbrev): J. Cell. Mol. Med
                Journal ID (doi): 10.1111/(ISSN)1582-4934
                Journal ID (publisher-id): JCMM
                Title: Journal of Cellular and Molecular Medicine
                Publisher: Blackwell Publishing Ltd (Oxford, UK )
                ISSN (Print): 1582-1838
                ISSN (Electronic): 1582-4934
                Publication date (Electronic): 29 December 2008
                Publication date (Print): August 2009
                Volume: 13
                Issue: 8b ( doiID: 10.1111/jcmm.2009.13.issue-8b )
                Pages: 2109-2114
                Affiliations
                [ 1 ]University of Utah, Division of Nephrology, Department of Medicine, Salt Lake City, UT, USA
                [ 2 ]VA Medical Center, Section of Nephrology, Salt Lake City, UT, USA
                [ 3 ]Department of Physiology, University of Utah, Salt Lake City, UT, USA
                Author notes
                [*] [* ] Correspondence to: Christof WESTENFELDER, M.D., Section of Nephrology (111N), VA Medical Center, 500 Foothill Blvd., Salt Lake City, UT 84148, USA.
Tel.: +801‐584‐1270
Fax: 801‐583‐9624
E‐mail: Christof.Westenfelder@ 123456hsc.utah.edu
                Article
                Publisher ID: JCMM641
                DOI: 10.1111/j.1582-4934.2008.00641.x
                PMC ID: 4940776
                PubMed ID: 19397783
                SO-VID: 4c6bd5dc-c668-40dd-a40b-813339063670
                Copyright © No claim to original US government works Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
                History
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 19, Pages: 6
                Categories
                Subject: Molecular Medicine
                Custom metadata
                source-schema-version-number 2.0
                cover-date August 2009
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:11.07.2016

                ScienceOpen disciplines: Molecular medicine
                Keywords: paracrine,apoptosis,vascularity,vegf,msc,bone marrow derived stem cells,aki,treatment
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: paracrine, apoptosis, vascularity, vegf, msc, bone marrow derived stem cells, aki, treatment

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