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      Comparison of the treatment efficacy of umbilical mesenchymal stem cell transplantation via renal subcapsular and parenchymal routes in AKI-CKD mice

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          Abstract

          Background

          Mesenchymal stem cells (MSCs) have emerged as a promising cell-based therapy for acute kidney injury (AKI). However, the optimal route of MSC transplantation remains controversial, and there have been no comparisons of the therapeutic benefits of MSC administration through different delivery routes.

          Methods

          In this study, we encapsulated MSCs into a collagen matrix to help achieve local MSC retention in the kidney and assessed the survival of MSCs in vitro and in vivo. After transplanting collagen matrix-encapsulated-MSCs (Col-MSCs) under the renal capsule or into the parenchyma using the same cell dose and suspension volume in an ischemia/reperfusion injury model, we evaluated the treatment efficacy of two local transplantation routes at different stages of AKI.

          Results

          We found that Col-MSCs could be retained in the kidney for at least 14 days. Both local MSC therapies could reduce tubular injury, promote the proliferation of renal tubular epithelial cells on Day 3 and alleviate renal fibrosis on Day 14 and 28. MSC transplantation via the subcapsular route exerts better therapeutic effects for renal functional and structural recovery after AKI than MSC administration via the parenchymal route.

          Conclusions

          Subcapsular MSC transplantation may be an ideal route of MSC delivery for AKI treatment, and collagen I can provide a superior microenvironment for cell–cell and cell–matrix interactions to stabilize the retention rate of MSCs in the kidney.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13287-022-02805-3.

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          Most cited references31

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          Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis.

          Acute kidney injury may increase the risk for chronic kidney disease and end-stage renal disease. In an attempt to summarize the literature and provide more compelling evidence, we conducted a systematic review comparing the risk for CKD, ESRD, and death in patients with and without AKI. From electronic databases, web search engines, and bibliographies, 13 cohort studies were selected, evaluating long-term renal outcomes and non-renal outcomes in patients with AKI. The pooled incidence of CKD and ESRD were 25.8 per 100 person-years and 8.6 per 100 person-years, respectively. Patients with AKI had higher risks for developing CKD (pooled adjusted hazard ratio 8.8, 95% CI 3.1-25.5), ESRD (pooled adjusted HR 3.1, 95% CI 1.9-5.0), and mortality (pooled adjusted HR 2.0, 95% CI 1.3-3.1) compared with patients without AKI. The relationship between AKI and CKD or ESRD was graded on the basis of the severity of AKI, and the effect size was dampened by decreased baseline glomerular filtration rate. Data were limited, but AKI was also independently associated with the risk for cardiovascular disease and congestive heart failure, but not with hospitalization for stroke or all-cause hospitalizations. Meta-regression did not identify any study-level factors that were associated with the risk for CKD or ESRD. Our review identifies AKI as an independent risk factor for CKD, ESRD, death, and other important non-renal outcomes.
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            Acute kidney injury.

            Acute kidney injury (formerly known as acute renal failure) is a syndrome characterised by the rapid loss of the kidney's excretory function and is typically diagnosed by the accumulation of end products of nitrogen metabolism (urea and creatinine) or decreased urine output, or both. It is the clinical manifestation of several disorders that affect the kidney acutely. Acute kidney injury is common in hospital patients and very common in critically ill patients. In these patients, it is most often secondary to extrarenal events. How such events cause acute kidney injury is controversial. No specific therapies have emerged that can attenuate acute kidney injury or expedite recovery; thus, treatment is supportive. New diagnostic techniques (eg, renal biomarkers) might help with early diagnosis. Patients are given renal replacement therapy if acute kidney injury is severe and biochemical or volume-related, or if uraemic-toxaemia-related complications are of concern. If patients survive their illness and do not have premorbid chronic kidney disease, they typically recover to dialysis independence. However, evidence suggests that patients who have had acute kidney injury are at increased risk of subsequent chronic kidney disease. Copyright © 2012 Elsevier Ltd. All rights reserved.
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              Mesenchymal stem cell therapy: Two steps forward, one step back.

              Mesenchymal stem cell (MSC) therapy is poised to establish a new clinical paradigm; however, recent trials have produced mixed results. Although MSC were originally considered to treat connective tissue defects, preclinical studies revealed potent immunomodulatory properties that prompted the use of MSC to treat numerous inflammatory conditions. Unfortunately, although clinical trials have met safety endpoints, efficacy has not been demonstrated. We believe the challenge to demonstrate efficacy can be attributed in part to an incomplete understanding of the fate of MSC following infusion. Here, we highlight the clinical status of MSC therapy and discuss the importance of cell-tracking techniques, which have advanced our understanding of the fate and function of systemically infused MSC and might improve clinical application. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                zongjinli@nankai.edu.cn
                caiguangyan@sina.com
                xmchen301@126.com
                Journal
                Stem Cell Res Ther
                Stem Cell Res Ther
                Stem Cell Research & Therapy
                BioMed Central (London )
                1757-6512
                25 March 2022
                25 March 2022
                2022
                : 13
                : 128
                Affiliations
                [1 ]GRID grid.414252.4, ISNI 0000 0004 1761 8894, Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People’s Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, , Beijing Key Laboratory of Kidney Disease Research, ; No.28 Fuxing Road, Beijing, 100853 China
                [2 ]GRID grid.33763.32, ISNI 0000 0004 1761 2484, Institute of Disaster and Emergency Medicine, , Tianjin University, ; Tianjin, 300072 China
                [3 ]GRID grid.33763.32, ISNI 0000 0004 1761 2484, Wenzhou Safety (Emergency) Institute, , Tianjin University, ; Wenzhou, 325000 China
                [4 ]GRID grid.216938.7, ISNI 0000 0000 9878 7032, School of Medicine, , Nankai University, ; Weijin 20 Road, Tianjin, 300071 China
                [5 ]GRID grid.216938.7, ISNI 0000 0000 9878 7032, The Key Laboratory of Bioactive Materials, Ministry of Education, , Nankai University, The College of Life Sciences, ; Tianjin, China
                Author information
                http://orcid.org/0000-0001-8774-6021
                Article
                2805
                10.1186/s13287-022-02805-3
                8953025
                35337372
                447d36aa-a422-4607-b787-0284fc79f660
                © The Author(s) 2022

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 22 December 2021
                : 7 March 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100012165, Key Technologies Research and Development Program;
                Award ID: 2017YFA0103203
                Award ID: 2018YFA0108803
                Award ID: 2021YFC3002203
                Award Recipient :
                Funded by: Beijing Natural Science Foundation
                Award ID: 7222169
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 82000631
                Award ID: 82030025
                Award ID: 82170686
                Award Recipient :
                Funded by: Young Elite Scientist Sponsorship Program by CAST 2020QNRC001
                Award ID: 2020QNRC001
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2022

                Molecular medicine
                mesenchymal stem cells,acute kidney injury,subcapsular transplantation,parenchymal transplantation,collagen i

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