Administration of BMSCs with Muscone in Rats with Gentamicin-Induced AKI Improves Their Therapeutic Efficacy

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Abstract

The therapeutic action of bone marrow-derived mesenchymal stem cells (BMSCs) in acute kidney injury (AKI) has been reported by several groups. However, recent studies indicated that BMSCs homed to kidney tissues at very low levels after transplantation. The lack of specific homing of exogenously infused cells limited the effective implementation of BMSC-based therapies. In this study, we provided evidence that the administration of BMSCs combined with muscone in rats with gentamicin-induced AKI intravenously, was a feasible strategy to drive BMSCs to damaged tissues and improve the BMSC-based therapeutic effect. The effect of muscone on BMSC bioactivity was analyzed in vitro and in vivo. The results indicated that muscone could promote BMSC migration and proliferation. Some secretory capacity of BMSC still could be improved in some degree. The BMSC-based therapeutic action was ameliorated by promoting the recovery of biochemical variables in urine or blood, as well as the inhibition of cell apoptosis and inflammation. In addition, the up-regulation of CXCR4 and CXCR7 expression in BMSCs could be the possible mechanism of muscone amelioration. Thus, our study indicated that enhancement of BMSCs bioactivities with muscone could increase the BMSC therapeutic potential and further developed a new therapeutic strategy for the treatment of AKI.

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Acute kidney injury, mortality, length of stay, and costs in hospitalized patients.

Glenn Chertow, Elisabeth Burdick, Melissa M Honour … (2005)

The marginal effects of acute kidney injury on in-hospital mortality, length of stay (LOS), and costs have not been well described. A consecutive sample of 19,982 adults who were admitted to an urban academic medical center, including 9210 who had two or more serum creatinine (SCr) determinations, was evaluated. The presence and degree of acute kidney injury were assessed using absolute and relative increases from baseline to peak SCr concentration during hospitalization. Large increases in SCr concentration were relatively rare (e.g., >or=2.0 mg/dl in 105 [1%] patients), whereas more modest increases in SCr were common (e.g., >or=0.5 mg/dl in 1237 [13%] patients). Modest changes in SCr were significantly associated with mortality, LOS, and costs, even after adjustment for age, gender, admission International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis, severity of illness (diagnosis-related group weight), and chronic kidney disease. For example, an increase in SCr >or=0.5 mg/dl was associated with a 6.5-fold (95% confidence interval 5.0 to 8.5) increase in the odds of death, a 3.5-d increase in LOS, and nearly 7500 dollars in excess hospital costs. Acute kidney injury is associated with significantly increased mortality, LOS, and costs across a broad spectrum of conditions. Moreover, outcomes are related directly to the severity of acute kidney injury, whether characterized by nominal or percentage changes in serum creatinine.

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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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Stem cell homing and repopulation are not well understood. The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 were found to be critical for murine bone marrow engraftment by human severe combined immunodeficient (SCID) repopulating stem cells. Treatment of human cells with antibodies to CXCR4 prevented engraftment. In vitro CXCR4-dependent migration to SDF-1 of CD34+CD38-/low cells correlated with in vivo engraftment and stem cell function. Stem cell factor and interleukin-6 induced CXCR4 expression on CD34+ cells, which potentiated migration to SDF-1 and engraftment in primary and secondary transplanted mice. Thus, up-regulation of CXCR4 expression may be useful for improving engraftment of repopulating stem cells in clinical transplantation.

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Author and article information

Contributors

Pranela Rameshwar: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 13 May 2014

Volume: 9

Issue: 5

Electronic Location Identifier: e97123

Affiliations

[1 ]Department of Regeneration Medicine, School of Pharmaceutical Science, Jilin University, Changchun, P.R. China

[2 ]Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, P.R. China

[3 ]Department of Laboratory Medicine, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, P.R. China

[4 ]Department of Anesthesiology, Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen, P.R. China

Rutgers - New Jersey Medical School, United States of America

Author notes

* E-mail: zhaoleicx@ 123456126.com (LZ); zhouyl@ 123456jlu.edu.cn (YZ); wangyi@ 123456jlu.ecu.cn (YW)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: PL YF YZ ZZ. Performed the experiments: PL YF CD DY BL XC. Analyzed the data: PL YW LZ. Contributed reagents/materials/analysis tools: PL YW. Wrote the paper: PL LZ.

Article

Publisher ID: PONE-D-14-11717

DOI: 10.1371/journal.pone.0097123

PMC ID: 4019657

PubMed ID: 24824427

SO-VID: 3fbd76ca-7611-47bc-8106-5a9374efb841

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 15 March 2014

Date accepted : 14 April 2014

Page count

Pages: 14

Funding

This study was supported by the grants from the Basic Research Project of Knowledge Innovation Program of Shenzhen City (No. 201404163000377), Graduate Innovation Fund of Jilin University, the Science and Technology Project of Shenzhen City (No. 200702120, 200602035), the Scientific Research of Health Department of Jilin Province (No. 2009Z043) and Science and Technology Development Project of Jilin Province (No. 20120955). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Administration of BMSCs with Muscone in Rats with Gentamicin-Induced AKI Improves Their Therapeutic Efficacy

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Abstract

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Most cited references 52

Acute kidney injury, mortality, length of stay, and costs in hospitalized patients.

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

Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4.

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