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      Cell Therapy for Kidney Injury: Different Options and Mechanisms - Kidney Progenitor Cells

      *

      Cardiorenal Medicine

      S. Karger AG

      Cell therapy, Acute kidney injury, Kidney progenitor cells

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          Abstract

          Background: Since no specific or radical treatments have yet been established for acute kidney injury (AKI), the development of cell transplantation therapy using renal progenitors is desirable as a new therapeutic option for AKI. The recent advances in developmental biology, stem cell biology, and nephrology have led to an increased availability of renal progenitors from multiple sources. Summary: Four main sources of renal progenitors have been described so far: isolation from (1) embryonic or (2) adult kidneys, (3) directed differentiation of pluripotent stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), and (4) cellular reprogramming of fully differentiated adult renal cells. Renal progenitors from adult kidneys may not be equivalent to those from embryonic kidneys, and they contain several different cell populations identified by various methods. The methods used for the directed differentiation of ESCs/iPSCs and reprogramming of differentiated adult renal cells into renal progenitors have not been fully established. The therapeutic effects of progenitor cell transplantation in AKI animal models have been examined in a small number of reports using renal progenitors from adult kidneys, while no reports have described the therapeutic potential of renal progenitors from other sources. Key Messages: Renal progenitor transplantation might provide a novel therapeutic strategy for AKI. Further research efforts toward the clinical application of this strategy are needed, including a detailed characterization of embryonic or adult renal progenitors and the development of in vitro expansion methods and therapeutically effective transplantation methods for these cell types. More experience and knowledge should be accumulated regarding the directed differentiation of pluripotent stem cells and cellular reprogramming to generate renal progenitor cells.

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          Most cited references 21

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

          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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            Six2 defines and regulates a multipotent self-renewing nephron progenitor population throughout mammalian kidney development.

            Nephrons, the basic functional units of the kidney, are generated repetitively during kidney organogenesis from a mesenchymal progenitor population. Which cells within this pool give rise to nephrons and how multiple nephron lineages form during this protracted developmental process are unclear. We demonstrate that the Six2-expressing cap mesenchyme represents a multipotent nephron progenitor population. Six2-expressing cells give rise to all cell types of the main body of the nephron during all stages of nephrogenesis. Pulse labeling of Six2-expressing nephron progenitors at the onset of kidney development suggests that the Six2-expressing population is maintained by self-renewal. Clonal analysis indicates that at least some Six2-expressing cells are multipotent, contributing to multiple domains of the nephron. Furthermore, Six2 functions cell autonomously to maintain a progenitor cell status, as cap mesenchyme cells lacking Six2 activity contribute to ectopic nephron tubules, a mechanism dependent on a Wnt9b inductive signal. Taken together, our observations suggest that Six2 activity cell-autonomously regulates a multipotent nephron progenitor population.
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              Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys.

              Regenerative medicine represents a critical clinical goal for patients with ESRD, but the identification of renal adult multipotent progenitor cells has remained elusive. It is demonstrated that in human adult kidneys, a subset of parietal epithelial cells (PEC) in the Bowman's capsule exhibit coexpression of the stem cell markers CD24 and CD133 and of the stem cell-specific transcription factors Oct-4 and BmI-1, in the absence of lineage-specific markers. This CD24+CD133+ PEC population, which could be purified from cultured capsulated glomeruli, revealed self-renewal potential and a high cloning efficiency. Under appropriate culture conditions, individual clones of CD24+CD133+ PEC could be induced to generate mature, functional, tubular cells with phenotypic features of proximal and/or distal tubules, osteogenic cells, adipocytes, and cells that exhibited phenotypic and functional features of neuronal cells. The injection of CD24+CD133+ PEC but not of CD24-CD133- renal cells into SCID mice that had acute renal failure resulted in the regeneration of tubular structures of different portions of the nephron. More important, treatment of acute renal failure with CD24+CD133+ PEC significantly ameliorated the morphologic and functional kidney damage. This study demonstrates the existence and provides the characterization of a population of resident multipotent progenitor cells in adult human glomeruli, potentially opening new avenues for the development of regenerative medicine in patients who have renal diseases.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                978-3-318-02677-1
                978-3-318-02678-8
                1660-2129
                2014
                May 2014
                19 May 2014
                : 126
                : 2
                : 64-69
                Affiliations
                Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
                Author notes
                *Kenji Osafune, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan), E-Mail osafu@cira.kyoto-u.ac.jp
                Article
                360668 Nephron Exp Nephrol 2014;126:64-69
                10.1159/000360668
                24854643
                © 2014 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 1, Pages: 6
                Categories
                Further Section

                Cardiovascular Medicine, Nephrology

                Kidney progenitor cells, Cell therapy, Acute kidney injury

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