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Lee Y, Kim KH, Park J, Kang HM, Kim SH, Jeong H, Lee B, Lee N, Cho Y, Kim GD, Yu S, Gee HY, Bok J, Hamilton MS, Gewin L, Aronow BJ, Lim KM, Coffey RJ, Nam KT. Regenerative Role of Lrig1+ Cells in Kidney Repair. J Am Soc Nephrol 2024; 35:1702-1714. [PMID: 39120954 PMCID: PMC11617485 DOI: 10.1681/asn.0000000000000462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 08/05/2024] [Indexed: 08/11/2024] Open
Abstract
Key Points Lrig1 + cells exist long term during kidney homeostasis and become activated upon injury, contributing to regeneration. Lrig1 + cells and their progeny emerge during tubulogenesis and contribute to proximal tubule and inner medullary collecting duct development. Lrig1 + cells expand and differentiate into a mature nephron lineage in response to AKI to repair the proximal tubule. Background In response to severe kidney injury, the kidney epithelium displays remarkable regenerative capabilities driven by adaptable resident epithelial cells. To date, it has been widely considered that the adult kidney lacks multipotent stem cells; thus, the cellular lineages responsible for repairing proximal tubule damage are incompletely understood. Leucine-rich repeats and immunoglobulin-like domain protein 1–expressing cells (Lrig1 + cells) have been identified as a long-lived cell in various tissues that can induce epithelial tissue repair. Therefore, we hypothesized that Lrig1 + cells participate in kidney development and tissue regeneration. Methods We investigated the role of Lrig1 + cells in kidney injury using mouse models. The localization of Lrig1 + cells in the kidney was examined throughout mouse development. The function of Lrig1 + progeny cells in AKI repair was examined in vivo using a tamoxifen-inducible Lrig1 -specific Cre recombinase-based lineage tracing in three different kidney injury mouse models. In addition, we conducted single-cell RNA sequencing to characterize the transcriptional signature of Lrig1 + cells and trace their progeny. Results Lrig1 + cells were present during kidney development and contributed to formation of the proximal tubule and collecting duct structures in mature mouse kidneys. In three-dimensional culture, single Lrig1 + cells demonstrated long-lasting propagation and differentiated into the proximal tubule and collecting duct lineages. These Lrig1 + proximal tubule cells highly expressed progenitor-like and quiescence-related genes, giving rise to a novel cluster of cells with regenerative potential in adult kidneys. Moreover, these long-lived Lrig1 + cells expanded and repaired damaged proximal tubule in response to three types of AKIs in mice. Conclusions These findings highlight the critical role of Lrig1 + cells in kidney regeneration.
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Affiliation(s)
- Yura Lee
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Kwang H. Kim
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jihwan Park
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Hyun Mi Kang
- Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Sung-Hee Kim
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Haengdueng Jeong
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Buhyun Lee
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Nakyum Lee
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Yejin Cho
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Gyeong Dae Kim
- School of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju, Korea
| | - Seyoung Yu
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Heon Yung Gee
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jinwoong Bok
- Department of Anatomy, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Maxwell S. Hamilton
- Epithelial Biology Center and Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Leslie Gewin
- Division of Nephrology and Hypertension, Department of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
- Department of Medicine, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee
| | - Bruce J. Aronow
- Departments of Biomedical Informatics, Developmental Biology, and Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kyung-Min Lim
- College of Pharmacy, Ewha Womans University, Seoul, Korea
| | - Robert J. Coffey
- Epithelial Biology Center and Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee
- Department of Medicine, Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee
| | - Ki Taek Nam
- Department of Biomedical Sciences, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
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Cho CJ, Brown JW, Mills JC. Origins of cancer: ain't it just mature cells misbehaving? EMBO J 2024; 43:2530-2551. [PMID: 38773319 PMCID: PMC11217308 DOI: 10.1038/s44318-024-00099-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 03/15/2024] [Accepted: 03/22/2024] [Indexed: 05/23/2024] Open
Abstract
A pervasive view is that undifferentiated stem cells are alone responsible for generating all other cells and are the origins of cancer. However, emerging evidence demonstrates fully differentiated cells are plastic, can be coaxed to proliferate, and also play essential roles in tissue maintenance, regeneration, and tumorigenesis. Here, we review the mechanisms governing how differentiated cells become cancer cells. First, we examine the unique characteristics of differentiated cell division, focusing on why differentiated cells are more susceptible than stem cells to accumulating mutations. Next, we investigate why the evolution of multicellularity in animals likely required plastic differentiated cells that maintain the capacity to return to the cell cycle and required the tumor suppressor p53. Finally, we examine an example of an evolutionarily conserved program for the plasticity of differentiated cells, paligenosis, which helps explain the origins of cancers that arise in adults. Altogether, we highlight new perspectives for understanding the development of cancer and new strategies for preventing carcinogenic cellular transformations from occurring.
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Affiliation(s)
- Charles J Cho
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Jeffrey W Brown
- Division of Gastroenterology, Department of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA
| | - Jason C Mills
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA.
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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Bondue T, Kouraich A, Berlingerio SP, Veys K, Marie S, Alsaad KO, Al-Sabban E, Levtchenko E, van den Heuvel L. The Pitfall of White Blood Cell Cystine Measurement to Diagnose Juvenile Cystinosis. Int J Mol Sci 2023; 24:ijms24021253. [PMID: 36674769 PMCID: PMC9864853 DOI: 10.3390/ijms24021253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/05/2023] [Accepted: 01/05/2023] [Indexed: 01/11/2023] Open
Abstract
Cystinosis is an autosomal recessive lysosomal storage disease, caused by mutations in the CTNS gene, resulting in multi-organ cystine accumulation. Three forms of cystinosis are distinguished: infantile and juvenile nephropathic cystinosis affecting kidneys and other organs such as the eyes, endocrine system, muscles, and brain, and adult ocular cystinosis affecting only the eyes. Currently, elevated white blood cell (WBC) cystine content is the gold standard for the diagnosis of cystinosis. We present a patient with proteinuria at adolescent age and corneal cystine crystals, but only slightly elevated WBC cystine levels (1.31 ½ cystine/mg protein), precluding the diagnosis of nephropathic cystinosis. We demonstrate increased levels of cystine in skin fibroblasts and urine-derived kidney cells (proximal tubular epithelial cells and podocytes), that were higher than the values observed in the WBC and healthy control. CTNS gene analysis shows the presence of a homozygous missense mutation (c.590 A > G; p.Asn177Ser), previously described in the Arab population. Our observation underlines that low WBC cystine levels can be observed in patients with juvenile cystinosis, which may delay the diagnosis and timely administration of cysteamine. In such patients, the diagnosis can be confirmed by cystine measurement in slow-dividing cells and by molecular analysis of the CTNS gene.
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Affiliation(s)
- Tjessa Bondue
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven Campus Gasthuisberg, 3000 Leuven, Belgium
| | - Anas Kouraich
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven Campus Gasthuisberg, 3000 Leuven, Belgium
| | - Sante Princiero Berlingerio
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven Campus Gasthuisberg, 3000 Leuven, Belgium
| | - Koenraad Veys
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven Campus Gasthuisberg, 3000 Leuven, Belgium
- Department of Pediatrics, AZ Delta Campus Torhout, 8820 Torhout, Belgium
| | - Sandrine Marie
- Laboratory of Inherited Metabolic Diseases/Biochemical Genetics, Cliniques Universitaires Saint-Luc, UC Louvain, 1200 Brussels, Belgium
| | - Khaled O. Alsaad
- Section of Histopathology, Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh 11533, Saudi Arabia
| | - Essam Al-Sabban
- Section of Pediatric Nephrology, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre, Riyadh 11533, Saudi Arabia
| | - Elena Levtchenko
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven Campus Gasthuisberg, 3000 Leuven, Belgium
- Department of Pediatrics, University Hospitals Leuven Campus Gasthuisberg, 3000 Leuven, Belgium
| | - Lambertus van den Heuvel
- Laboratory of Pediatric Nephrology, Department of Development and Regeneration, KU Leuven Campus Gasthuisberg, 3000 Leuven, Belgium
- Department of Pediatrics, Division of Pediatric Nephrology, Amalia Children’s Hospital, Radboud University Medical Center, HB-6524 Nijmegen, The Netherlands
- Correspondence:
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Cetina-Palma A, Namorado-Tónix C, Rodríguez-Muñoz R, Vergara P, Reyes-Sánchez JL, Segovia J. Characterization of the pattern of expression of Gas1 in the kidney during postnatal development in the rat. PLoS One 2023; 18:e0284816. [PMID: 37093844 PMCID: PMC10124827 DOI: 10.1371/journal.pone.0284816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 04/09/2023] [Indexed: 04/25/2023] Open
Abstract
Growth Arrest-Specific 1 (Gas1) is a pleiotropic protein with different functions, in the adult kidney Gas1 acts as an endogenous inhibitor of cell proliferation but it is also necessary for the maintenance and proliferation of Renal Progenitor Cells (RPC) during early development, thus it fulfills important functions in the adult kidney. However, it is not known whether or not Gas1 is expressed during postnatal development, a critical stage for renal maturation. For this reason, the main objective of this work was to characterize the expression pattern of Gas1 in the different regions of the kidney by immunofluorescence and Western blot analysis during the postnatal development of the rat. We found that Gas1 is present and has a differential expression pattern in the various regions of the nephron during postnatal development. We observed that the highest levels of expression of Gas1 occur in the adult, however, Gas1 is also expressed in RPC and interestingly, the expression of RPC markers such as the Neural cell adhesion molecule (NCAM) and Cluster of differentiation 24 (CD24) were found to have an inverse pattern of expression to Gas1 (decreases as the kidney matures) during postnatal renal maturation, this indicates a role for Gas1 in the regulation of renal cell proliferation at this stage of development.
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Affiliation(s)
- Andrea Cetina-Palma
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City, Mexico
| | - Carmen Namorado-Tónix
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City, Mexico
| | - Rafael Rodríguez-Muñoz
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City, Mexico
| | - Paula Vergara
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City, Mexico
| | - José Luis Reyes-Sánchez
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City, Mexico
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City, Mexico
| | - José Segovia
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, Mexico City, Mexico
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Stamellou E, Leuchtle K, Moeller MJ. Regenerating tubular epithelial cells of the kidney. Nephrol Dial Transplant 2021; 36:1968-1975. [PMID: 32666119 DOI: 10.1093/ndt/gfaa103] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Indexed: 12/24/2022] Open
Abstract
Acute tubular injury accounts for the most common intrinsic cause for acute kidney injury. Normally, the tubular epithelium is mitotically quiescent. However, upon injury, it can show a brisk capacity to regenerate and repair. The scattered tubular cell (STC) phenotype was discovered as a uniform reaction of tubule cells triggered by injury. The STC phenotype is characterized by a unique protein expression profile, increased robustness during tubular damage and increased proliferation. Nevertheless, the exact origin and identity of these cells have been unveiled only in part. Here, we discuss the classical concept of renal regeneration. According to this model, surviving cells dedifferentiate and divide to replace neighbouring lost tubular cells. However, this view has been challenged by the concept of a pre-existing and fixed population of intratubular progenitor cells. This review presents a significant body of previous work and animal studies using lineage-tracing methods that have investigated the regeneration of tubular cells. We review the experimental findings and discuss whether they support the progenitor hypothesis or the classical concept of renal tubular regeneration. We come to the conclusion that any proximal tubular cell may differentiate into the regenerative STC phenotype upon injury thus contributing to regeneration, and these cells differentiate back into tubular cells once regeneration is finished.
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Affiliation(s)
- Eleni Stamellou
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Katja Leuchtle
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
| | - Marcus J Moeller
- Division of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
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Ruiz-Ramirez C, Antaño-Martinez AR, Robles J, Gallegos-Corona MA, Gallegos-Reyes MA, Avila EE, Martinez-Alfaro M. Correlation between urinary KIM-1 and kidney protein expression of p-ERK following damage in rats exposed to gentamicin or lead acetate. J Biochem Mol Toxicol 2021; 35:e22875. [PMID: 34350654 DOI: 10.1002/jbt.22875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 07/19/2021] [Accepted: 07/24/2021] [Indexed: 11/11/2022]
Abstract
Kidney injury molecule-1 (KIM-1) is a membrane receptor upregulated in the proximal tubule cells following various types of kidney injuries. Notably, studies have suggested a correlation between KIM-1 expression and extracellular signal-regulated kinase (ERK) activation. In this study, we aimed to investigate the association between the kidney overexpression pattern of cytoplasmic phosphorylated-ERK (p-ERK) protein and increased urinary KIM-1 levels in rats exposed to gentamicin or lead acetate, both at the end of toxic exposure and after a 4-week recovery period. Although other proteins were evaluated, only kidney overexpression of cytoplasmic p-ERK protein correlated with increased urinary KIM-1 levels. For both toxic substances, the increased urinary KIM-1 levels corresponded with kidney inflammation. Our results suggest that KIM-1 and p-ERK share a common mechanism in kidney injury mediated by both toxic substances that induce proximal tubule damage.
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Affiliation(s)
| | | | - Juvencio Robles
- Pharmacy Department, DCNE, Universidad de Guanajuato, Guanajuato, Mexico
| | | | | | - Eva E Avila
- Biology Department, DCNE, Universidad de Guanajuato, Guanajuato, Mexico
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7
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Andrianova NV, Buyan MI, Zorova LD, Pevzner IB, Popkov VA, Babenko VA, Silachev DN, Plotnikov EY, Zorov DB. Kidney Cells Regeneration: Dedifferentiation of Tubular Epithelium, Resident Stem Cells and Possible Niches for Renal Progenitors. Int J Mol Sci 2019; 20:ijms20246326. [PMID: 31847447 PMCID: PMC6941132 DOI: 10.3390/ijms20246326] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/10/2019] [Accepted: 12/12/2019] [Indexed: 12/11/2022] Open
Abstract
A kidney is an organ with relatively low basal cellular regenerative potential. However, renal cells have a pronounced ability to proliferate after injury, which undermines that the kidney cells are able to regenerate under induced conditions. The majority of studies explain yielded regeneration either by the dedifferentiation of the mature tubular epithelium or by the presence of a resident pool of progenitor cells in the kidney tissue. Whether cells responsible for the regeneration of the kidney initially have progenitor properties or if they obtain a “progenitor phenotype” during dedifferentiation after an injury, still stays the open question. The major stumbling block in resolving the issue is the lack of specific methods for distinguishing between dedifferentiated cells and resident progenitor cells. Transgenic animals, single-cell transcriptomics, and other recent approaches could be powerful tools to solve this problem. This review examines the main mechanisms of kidney regeneration: dedifferentiation of epithelial cells and activation of progenitor cells with special attention to potential niches of kidney progenitor cells. We attempted to give a detailed description of the most controversial topics in this field and ways to resolve these issues.
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Affiliation(s)
- Nadezda V. Andrianova
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Marina I. Buyan
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Ljubava D. Zorova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Irina B. Pevzner
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Vasily A. Popkov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Valentina A. Babenko
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Denis N. Silachev
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Egor Y. Plotnikov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
- Sechenov First Moscow State Medical University, Institute of Molecular Medicine, 119991 Moscow, Russia
- Correspondence: (E.Y.P.); (D.B.Z.); Tel.: +7-495-939-5944 (E.Y.P.)
| | - Dmitry B. Zorov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
- Correspondence: (E.Y.P.); (D.B.Z.); Tel.: +7-495-939-5944 (E.Y.P.)
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Krawczyk KM, Nilsson H, Nyström J, Lindgren D, Leandersson K, Swärd K, Johansson ME. Localization and Regulation of Polymeric Ig Receptor in Healthy and Diseased Human Kidney. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1933-1944. [PMID: 31404540 DOI: 10.1016/j.ajpath.2019.06.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 05/29/2019] [Accepted: 06/28/2019] [Indexed: 12/11/2022]
Abstract
The polymeric Ig receptor (PIgR) constitutes an important part of the immune system by mediating transcytosis of dimeric IgA into mucosal fluids. Although well studied in organs such as the intestine, the regulation and localization of PIgR in human kidney are incompletely characterized. Herein, using immunohistochemistry, we show that in healthy human kidneys, PIgR is expressed by the progenitor-like tubular scattered cells of the proximal tubules and by parietal epithelial cells of glomeruli. We further show that proximal tubular expression of PIgR becomes widespread during kidney disease, correlating to elevated levels of urinary secretory IgA. Urinary secretory IgA levels also correlated to the degree of tubular fibrosis, plasma creatinine, and urea levels. In addition, primary tubular cells were cultured to study the function and regulation of PIgR in vitro. Cellular PIgR expression was induced by conditioned medium from activated human leukocytes, as well as by inflammatory cytokines, whereas transforming growth factor-β1 caused decreased expression. Furthermore, interferon-γ increased the transcytosis of dimeric IgA in cultured tubular cells. Finally, a correlation study of mRNA data from the Genotype-Tissue Expression portal indicated that PIGR mRNA expression in kidney correlates to the expression of TNFSF13, a cytokine involved in plasma cell class switching to IgA. These results indicate that PIgR induction is an integral part of the injury phenotype of renal tubular cells.
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Affiliation(s)
- Krzysztof M Krawczyk
- Center for Molecular Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Helén Nilsson
- Center for Molecular Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Jenny Nyström
- Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - David Lindgren
- Center for Translational Cancer Research, the Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Karin Leandersson
- Center for Cancer Immunology, Department of Translational Medicine, Lund University, Malmö, Sweden
| | - Karl Swärd
- Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Martin E Johansson
- Center for Molecular Pathology, Department of Translational Medicine, Lund University, Malmö, Sweden; Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
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Mayr U, Serra D, Liberali P. Exploring single cells in space and time during tissue development, homeostasis and regeneration. Development 2019; 146:146/12/dev176727. [DOI: 10.1242/dev.176727] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
ABSTRACT
Complex 3D tissues arise during development following tightly organized events in space and time. In particular, gene regulatory networks and local interactions between single cells lead to emergent properties at the tissue and organism levels. To understand the design principles of tissue organization, we need to characterize individual cells at given times, but we also need to consider the collective behavior of multiple cells across different spatial and temporal scales. In recent years, powerful single cell methods have been developed to characterize cells in tissues and to address the challenging questions of how different tissues are formed throughout development, maintained in homeostasis, and repaired after injury and disease. These approaches have led to a massive increase in data pertaining to both mRNA and protein abundances in single cells. As we review here, these new technologies, in combination with in toto live imaging, now allow us to bridge spatial and temporal information quantitatively at the single cell level and generate a mechanistic understanding of tissue development.
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Affiliation(s)
- Urs Mayr
- Department of Quantitative Biology, Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland
- University of Basel, Petersplatz 1, 4001 Basel, Switzerland
| | - Denise Serra
- Department of Quantitative Biology, Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland
- University of Basel, Petersplatz 1, 4001 Basel, Switzerland
| | - Prisca Liberali
- Department of Quantitative Biology, Friedrich Miescher Institute for Biomedical Research (FMI), Maulbeerstrasse 66, 4058 Basel, Switzerland
- University of Basel, Petersplatz 1, 4001 Basel, Switzerland
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10
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Renal lineage cells as a source for renal regeneration. Pediatr Res 2018; 83:267-274. [PMID: 28985199 DOI: 10.1038/pr.2017.255] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 09/29/2017] [Indexed: 12/24/2022]
Abstract
The mammalian kidney is a highly complex organ, composed of various cell types within a unique structural framework. Nonetheless, in recent years, giant leaps in our understanding of nephrogenesis and the origin of new cells in the adult kidney have resulted in novel routes to regenerate damaged nephrons. While several strategies can be envisioned to achieve this aim, one common theme is the reliance on renal lineage cells, as extrarenal cells, such as bone marrow-derived cells, have been shown to be devoid of renal differentiation capacity. Herein, we will present the main motivation for the pursuit for cell-based therapies, which is the ever growing problem of chronic kidney disease (CKD), and discuss different strategies toward replenishing the damaged renal parenchyma. These include transplantation of fetal kidney grafts or fetal kidney stem cells, directed differentiation of pluripotent stem cells into kidney epithelia, establishment of renal progenitors from the adult kidney, and genetic reprogramming of mature kidney cells into a progenitor state. Taken together with novel techniques recapitulating the three-dimensional developmental environment, these advances are expected to take the field into a new era, bringing us closer than ever to the day when kidney stem cell-based therapy becomes a viable therapeutic option.
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11
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Fujigaki Y, Tamura Y, Nagura M, Arai S, Ota T, Shibata S, Kondo F, Yamaguchi Y, Uchida S. Unique proximal tubular cell injury and the development of acute kidney injury in adult patients with minimal change nephrotic syndrome. BMC Nephrol 2017; 18:339. [PMID: 29179690 PMCID: PMC5704628 DOI: 10.1186/s12882-017-0756-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Accepted: 11/14/2017] [Indexed: 12/13/2022] Open
Abstract
Background Adult patients with minimal change nephrotic syndrome (MCNS) are often associated with acute kidney injury (AKI). To assess the mechanisms of AKI, we examined whether tubular cell injuries unique to MCNS patients exist. Methods We performed a retrospective analysis of clinical data and tubular cell changes using the immunohistochemical expression of vimentin as a marker of tubular injury and dedifferentiation at kidney biopsy in 37 adult MCNS patients. AKI was defined by the criteria of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI. Results Thirteen patients (35.1%) were designated with AKI at kidney biopsy. No significant differences in age, history of hypertension, chronic kidney disease, diuretics use, proteinuria, and serum albumin were noted between the AKI and non-AKI groups. Urinary N-acetyl-β-D-glucosaminidase (uNAG) and urinary alpha1-microglobulin (uA1MG) as markers of tubular injury were increased in both groups, but the levels were significantly increased in the AKI group compared with the non-AKI group. The incidence of vimentin-positive tubules was comparable between AKI (84.6%) and non-AKI (58.3%) groups, but vimentin-positive tubular area per interstitial area was significantly increased in the AKI group (19.8%) compared with the non-AKI group (6.8%) (p = 0.011). Vimentin-positive injured tubules with tubular simplification (loss of brush-border of the proximal tubule/dilated tubule with flattening of tubular epithelium) were observed in the vicinity of glomeruli in both groups, suggesting that the proximal convoluted tubules were specifically injured. Two patients exhibited relatively severe tubular injuries with vimentin positivity and required dialysis within 2 weeks after kidney biopsy. The percentage of the vimentin-positive tubular area was positively correlated with uNAG but not with uA1MG in the non-AKI group. Conclusions Proximal tubular injuries with increased uNAG exist in MCNS patients without renal dysfunction and were more severe in the AKI group than they were in the non-AKI group. The unique tubular injuries probably due to massive proteinuria might be a predisposing factor for the development of severe AKI in adult MCNS patients.
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Affiliation(s)
- Yoshihide Fujigaki
- Department of Internal Medicine and Central Laboratory, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan.
| | - Yoshifuru Tamura
- Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan
| | - Michito Nagura
- Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan
| | - Shigeyuki Arai
- Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan
| | - Tatsuru Ota
- Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan
| | - Shigeru Shibata
- Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan
| | - Fukuo Kondo
- Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan
| | - Yutaka Yamaguchi
- Department of Pathology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan
| | - Shunya Uchida
- Department of Internal Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, Tokyo, Japan
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12
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Gröne EF, Federico G, Nelson PJ, Arnold B, Gröne HJ. The hormetic functions of Wnt pathways in tubular injury. Pflugers Arch 2017; 469:899-906. [PMID: 28685176 PMCID: PMC5541077 DOI: 10.1007/s00424-017-2018-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 06/13/2017] [Accepted: 06/13/2017] [Indexed: 02/06/2023]
Abstract
Chronic tubulointerstitial damage with tubular epithelial atrophy and interstitial fibrosis is the hallmark of chronic kidney disease (CKD) and a predictor for progression of CKD.Several experiments have now provided evidence that the Wnt signaling pathways are significantly contributing to atrophy and fibrosis; in contrast, it also has been shown that the Wnt system fosters regenerative processes in acute tubular injury.We now have demonstrated that Dickkopf 3 (DKK3) is an agonist for canonical Wnt signaling in CKD and fosters chronic fibrosing inflammation of the tubulointerstitial compartment. Genetic- and antibody-mediated inhibition of DKK3 leads to a pronounced improvement of tubular differentiation and a reduction in fibrosis.In addition, the secreted glycoprotein DKK3 can be used as a non-invasive urinary marker for the extent of CKD in man.
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Affiliation(s)
- Elisabeth F Gröne
- Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Giuseppina Federico
- Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Peter J Nelson
- Clinical Biochemistry, Ludwig Maximilian University, Munich, Bavaria, Germany
| | - Bernd Arnold
- Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
| | - Hermann-Josef Gröne
- Department of Cellular and Molecular Pathology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany. h.-
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13
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Abstract
Over a decade ago, it was proposed that the regulation of tubular repair in the kidney might involve the recapitulation of developmental pathways. Although the kidney cannot generate new nephrons after birth, suggesting a low level of regenerative competence, the tubular epithelial cells of the nephrons can proliferate to repair the damage after AKI. However, the debate continues over whether this repair involves a persistent progenitor population or any mature epithelial cell remaining after injury. Recent reports have highlighted the expression of Sox9, a transcription factor critical for normal kidney development, during postnatal epithelial repair in the kidney. Indeed, the proliferative response of the epithelium involves expression of several pathways previously described as being involved in kidney development. In some instances, these pathways are also apparently involved in the maladaptive responses observed after repeated injury. Whether development and repair in the kidney are the same processes or we are misinterpreting the similar expression of genes under different circumstances remains unknown. Here, we review the evidence for this link, concluding that such parallels in expression may more correctly represent the use of the same pathways in a distinct context, likely triggered by similar stressors.
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Affiliation(s)
- Melissa Helen Little
- Murdoch Children's Research Institute, Melbourne, Australia; and .,Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
| | - Pamela Kairath
- Murdoch Children's Research Institute, Melbourne, Australia; and.,Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
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14
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Myszczyszyn A, Czarnecka AM, Matak D, Szymanski L, Lian F, Kornakiewicz A, Bartnik E, Kukwa W, Kieda C, Szczylik C. The Role of Hypoxia and Cancer Stem Cells in Renal Cell Carcinoma Pathogenesis. Stem Cell Rev Rep 2016. [PMID: 26210994 PMCID: PMC4653234 DOI: 10.1007/s12015-015-9611-y] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The cancer stem cell (CSC) model has recently been approached also in renal cell carcinoma (RCC). A few populations of putative renal tumor-initiating cells (TICs) were identified, but they are indifferently understood; however, the first and most thoroughly investigated are CD105-positive CSCs. The article presents a detailed comparison of all renal CSC-like populations identified by now as well as their presumable origin. Hypoxic activation of hypoxia-inducible factors (HIFs) contributes to tumor aggressiveness by multiple molecular pathways, including the governance of immature stem cell-like phenotype and related epithelial-to-mesenchymal transition (EMT)/de-differentiation, and, as a result, poor prognosis. Due to intrinsic von Hippel-Lindau protein (pVHL) loss of function, clear-cell RCC (ccRCC) develops unique pathological intra-cellular pseudo-hypoxic phenotype with a constant HIF activation, regardless of oxygen level. Despite satisfactory evidence concerning pseudo-hypoxia importance in RCC biology, its influence on putative renal CSC-like largely remains unknown. Thus, the article discusses a current knowledge of HIF-1α/2α signaling pathways in the promotion of undifferentiated tumor phenotype in general, including some experimental findings specific for pseudo-hypoxic ccRCC, mostly dependent from HIF-2α oncogenic functions. Existing gaps in understanding both putative renal CSCs and their potential connection with hypoxia need to be filled in order to propose breakthrough strategies for RCC treatment.
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Affiliation(s)
- Adam Myszczyszyn
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland
| | - Anna M Czarnecka
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.
| | - Damian Matak
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.,School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Lukasz Szymanski
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.,Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | - Fei Lian
- Emory School of Medicine, Atlanta, GA, USA
| | - Anna Kornakiewicz
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.,School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.,Department of General Surgery and Transplantology, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Bartnik
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland.,Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Wojciech Kukwa
- Department of Otolaryngology, Czerniakowski Hospital, Medical University of Warsaw, Warsaw, Poland
| | - Claudine Kieda
- Centre de Biophysique Moléculaire, CNRS UPR 4301, Orléans, France
| | - Cezary Szczylik
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland
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15
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O'Connor M, Patil R, Yu J, Hickey R, Premanand K, Kajdacsy-Balla A, Benedetti E, Bartholomew A. Mesenchymal Stem Cells Synergize with 635, 532, and 405 nm Laser Wavelengths in Renal Fibrosis: A Pilot Study. Photomed Laser Surg 2016; 34:556-563. [PMID: 27244220 DOI: 10.1089/pho.2015.4025] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVE To address whether a single treatment of one of three visible light wavelengths, 635, 532, and 405 nm (constant wave, energy density 2.9 J/m2), could affect the hallmarks of established renal fibrosis and whether these wavelengths could facilitate mesenchymal stem cell (MSC) beneficence. BACKGROUND DATA Chronic kidney disease is a global health problem with only 20% receiving care worldwide. Kidneys with compromised function have ongoing inflammation, including increased oxidative stress and apoptosis, peritubular capillary loss, tubular atrophy, and tubulointerstitial fibrosis. Promising studies have highlighted the significant potential of MSC-based strategies to mitigate fibrosis; however, reversal of established fibrosis has been problematic, suggesting that methods to potentiate MSC effects require further development. Laser treatments at visible wavelengths have been reported to enhance mitochondrial potential and available cellular ATP, facilitate proliferation, and inhibit apoptosis. We hypothesized that laser-delivered energy might provide wavelength-specific effects in the fibrotic kidney and enhance MSC responses. MATERIALS AND METHODS Renal fibrosis, established in C57BL6 mice following 21 days of unilateral ureter obstruction (UUO), was treated with one of three wavelengths alone or with autologous MSC. Mitochondrial activity, cell proliferation, apoptosis, and cytokines were measured 24 h later. RESULTS Wavelengths 405, 532, and 635 nm all significantly synergized with MSC to enhance mitochondrial activity and reduce apoptosis. Proliferative activity was observed in the renal cortices following combined treatment with the 532 nm laser and MSC; endothelial proliferation increased in response to the 635 nm laser alone and to the combined effects of MSC and the 405 nm wavelength. Reductions of transforming growth factor-β were observed with 532 nm alone and when combined with MSC. CONCLUSIONS Specific wavelengths of laser energy appear to induce different responses in renal fibrotic tissue. These findings support further study in the development of a customized laser therapy program of combined wavelengths to optimize MSC effects in the treatment of renal fibrosis.
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Affiliation(s)
- Megan O'Connor
- 1 Department of Surgery, University of Illinois at Chicago , Chicago, Illinois
| | - Rachana Patil
- 1 Department of Surgery, University of Illinois at Chicago , Chicago, Illinois
| | - Jiangzhou Yu
- 1 Department of Surgery, University of Illinois at Chicago , Chicago, Illinois
| | - Richard Hickey
- 1 Department of Surgery, University of Illinois at Chicago , Chicago, Illinois
| | - Kavitha Premanand
- 1 Department of Surgery, University of Illinois at Chicago , Chicago, Illinois
| | - Andre Kajdacsy-Balla
- 2 Department of Pathology, University of Illinois at Chicago , Chicago, Illinois
| | - Enrico Benedetti
- 1 Department of Surgery, University of Illinois at Chicago , Chicago, Illinois.,3 Department of Transplant Surgery, University of Illinois at Chicago , Chicago, Illinois
| | - Amelia Bartholomew
- 1 Department of Surgery, University of Illinois at Chicago , Chicago, Illinois
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16
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Omata M, Doke Y, Yamada C, Kawashima K, Sho R, Enomoto K, Furuya M, Inomata N. Hepatocyte Nuclear Factor-1β Induces Redifferentiation of Dedifferentiated Tubular Epithelial Cells. PLoS One 2016; 11:e0154912. [PMID: 27196561 PMCID: PMC4873210 DOI: 10.1371/journal.pone.0154912] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 04/21/2016] [Indexed: 11/19/2022] Open
Abstract
Tubular epithelial cells (TECs) can be dedifferentiated by repetitive insults, which activate scar-producing cells generated from interstitial cells such as fibroblasts, leading to the accumulation and deposition of extracellular matrix molecules. The dedifferentiated TECs play a crucial role in the development of renal fibrosis. Therefore, renal fibrosis may be attenuated if dedifferentiated TECs are converted back to their normal state (re-epithelialization). However, the mechanism underlying the re-epithelialization remains to be elucidated. In the present study, TGF-β1, a profibrotic cytokine, induced dedifferentiation of cultured TECs, and the dedifferentiated TECs were re-epithelialized by the removal of TGF-β1 stimulation. In the re-epithelialization process, transcription factor hepatocyte nuclear factor 1, beta (HNF-1β) was identified as a candidate molecule involved in inducing re-epithelialization by means of DNA microarray and biological network analysis. In functional validation studies, the re-epithelialization by TGF-β1 removal was abolished by HNF-1β knockdown. Furthermore, the ectopic expression of HNF-1β in the dedifferentiated TECs induced the re-epithelialization without the inhibition of TGF-β/Smad signaling, even in the presence of TGF-β1 stimulation. In mouse renal fibrosis model, unilateral ureteral obstruction model, HNF-1β expression in the TECs of the kidney was suppressed with fibrosis progression. Furthermore, the HNF-1β downregulated TECs resulted in dedifferentiation, which was characterized by expression of nestin. In conclusion, HNF-1β suppression in TECs is a crucial event for the dedifferentiation of TECs, and the upregulation of HNF-1β in TECs has a potential to restore the dedifferentiated TECs into their normal state, leading to the attenuation of renal fibrosis.
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17
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Iwakura T, Fujigaki Y, Fujikura T, Ohashi N, Kato A, Yasuda H. Acquired resistance to rechallenge injury after acute kidney injury in rats is associated with cell cycle arrest in proximal tubule cells. Am J Physiol Renal Physiol 2016; 310:F872-F884. [PMID: 26823281 DOI: 10.1152/ajprenal.00380.2015] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Accepted: 01/27/2016] [Indexed: 01/26/2023] Open
Abstract
Rats that have recovered from severe proximal tubule (PT) injury induced by uranyl acetate (UA), a toxic stimulus, developed resistance to subsequent UA treatment. We investigated cell cycle status and progression in PT cells in relation to this acquired resistance. Fourteen days after pretreatment with saline (vehicle group) or UA [acute kidney injury (AKI) group], rats were injected with UA or lead acetate (a proliferative stimulus). Cell cycle status (G0/G1/S/G2/M) was analyzed by flow cytometry. The expression of cell cycle markers, cyclin-dependent kinase inhibitors, and phenotypic markers were examined by immunohistochemistry. Cell cycle status in PT cells in the AKI group was comparable to those of the vehicle group. However, more early G1-phase cells (cyclin D1- or Ki67-) and p21+ or p27+ cells were found in the PT of the AKI group than in that of the vehicle group. UA induced G1 arrest and inhibited S phase progression with earlier dedifferentiation and less apoptosis in PT cells of the AKI group. Lead acetate induced proliferation without dedifferentiation but with delayed G0-G1 transition and inhibited S phase progression in PT cells in the AKI group. Sustained p21 and increased p27 expression in PT cells were found in the AKI group in response to UA and lead acetate. PT cells in the AKI group inhibited cell cycle progression by enhanced G1 arrest, probably via p21/p27 modulation as an injury or proliferation response, resulting in cytoresistance to rechallenge injury.
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Affiliation(s)
- Takamasa Iwakura
- Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yoshihide Fujigaki
- Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan; Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan; and
| | - Tomoyuki Fujikura
- Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Naro Ohashi
- Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Akihiko Kato
- Blood Purification Unit, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hideo Yasuda
- Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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18
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Borgal L, Rinschen MM, Dafinger C, Liebrecht VI, Abken H, Benzing T, Schermer B. Jade-1S phosphorylation induced by CK1α contributes to cell cycle progression. Cell Cycle 2016; 15:1034-45. [PMID: 26919559 PMCID: PMC4889251 DOI: 10.1080/15384101.2016.1152429] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Accepted: 02/04/2016] [Indexed: 12/13/2022] Open
Abstract
The PHD zinc finger protein Jade-1S is a component of the HBO1 histone acetyltransferase complex and binds chromatin in a cell cycle-dependent manner. Jade-1S also acts as an E3 ubiquitin ligase for the canonical Wnt effector protein β-catenin and is influenced by CK1α-mediated phosphorylation. To further elucidate the functional impact of this phosphorylation, we used a stable, low-level expression system to express either wild-type or mutant Jade-1S lacking the N-terminal CK1α phosphorylation motif. Interactome analyses revealed that the Jade-1S mutant unable to be phosphorylated by CK1α has an increased binding affinity to proteins involved in chromatin remodelling, histone deacetylation, transcriptional repression, and ribosome biogenesis. Interestingly, cells expressing the mutant displayed an elongated cell shape and a delay in cell cycle progression. Finally, phosphoproteomic analyses allowed identification of a Jade-1S site phosphorylated in the presence of CK1α but closely resembling a PLK1 phosphorylation motif. Our data suggest that Jade-1S phosphorylation at an N-terminal CK1α motif creates a PLK1 phospho-binding domain. We propose CK1α phosphorylation of Jade 1S to serve as a molecular switch, turning off chromatin remodelling functions of Jade-1S and allowing timely cell cycle progression. As Jade-1S protein expression in the kidney is altered upon renal injury, this could contribute to understanding mechanisms underlying epithelial injury repair.
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Affiliation(s)
- Lori Borgal
- Department II of Internal Medicine; University of Cologne; Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC); University of Cologne; Cologne, Germany
| | - Markus M. Rinschen
- Department II of Internal Medicine; University of Cologne; Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC); University of Cologne; Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne; Cologne, Germany
| | - Claudia Dafinger
- Department II of Internal Medicine; University of Cologne; Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC); University of Cologne; Cologne, Germany
| | - Valérie I. Liebrecht
- Center for Molecular Medicine Cologne (CMMC); University of Cologne; Cologne, Germany
- Department I of Internal Medicine; University of Cologne; Cologne, Germany
| | - Hinrich Abken
- Center for Molecular Medicine Cologne (CMMC); University of Cologne; Cologne, Germany
- Department I of Internal Medicine; University of Cologne; Cologne, Germany
| | - Thomas Benzing
- Department II of Internal Medicine; University of Cologne; Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC); University of Cologne; Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne; Cologne, Germany
- Systems Biology of Ageing Cologne; University of Cologne; Cologne, Germany
| | - Bernhard Schermer
- Department II of Internal Medicine; University of Cologne; Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC); University of Cologne; Cologne, Germany
- Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne; Cologne, Germany
- Systems Biology of Ageing Cologne; University of Cologne; Cologne, Germany
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19
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A population of mitochondrion-rich cells in the pars recta of mouse kidney. Cell Tissue Res 2015; 363:791-803. [PMID: 26337515 DOI: 10.1007/s00441-015-2273-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 08/04/2015] [Indexed: 01/08/2023]
Abstract
Following perfusion of adult mouse kidney with a solution of nitroblue tetrazolium (NBT), certain epithelial cells in the pars recta (S3) segments of proximal tubules react to form cytoplasmic deposits of blue diformazan particles. Such cells are characterized by dark cytoplasm, small and often elliptical nuclei, elaborate, process-bearing profiles, and abundant mitochondria. The atypical epithelial cells display the additional characteristic of immunoreactivity for a wide spectrum of antigens, including mesenchymal proteins such as vimentin. Though present in kidneys of untreated or sham-operated animals, they are particularly evident under experimental conditions such as unilateral ureteral obstruction (UUO), appearing in both contralateral and obstructed kidneys over the course of a week's duration, but disappearing from the obstructed kidney as it undergoes the profound atrophy attributable to deterioration of the population of its proximal tubules. The cells do not appear in neonatal kidneys, even those undergoing UUO, but begin to be recognizable soon after weaning (28 days). It is possible that diformazan-positive cells in the mouse S3 tubular segment constitute a resident population of cells that can replenish or augment the tubule. Although somewhat similar cells, with dark cytoplasm and vimentin expression, have been described in human, rat, and transgenic mouse kidney (Smeets et al. in J Pathol 229: 645-659, 2013; Berger et al. in Proc Natl Acad Sci U S A 111: 1533-1538, 2014), those cells-known as "scattered tubule cells" or "proximal tubule rare cells"- differ from the S3-specific cells in that they are present throughout the entire proximal tubule, often lack a brush border, and have only a few mitochondria.
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20
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Abstract
INTRODUCTION Kidney diseases are a global public health problem whose incidence is rapidly growing due to a global rise in the aged population and the increasing prevalence of cardiovascular disease, hypertension and diabetes. With the emergence of stem cells as potential therapeutic agents, attempts in using them to significantly reduce the burden of these diseases have increased. AREAS COVERED Several types of stem cells have been proven to be likely candidates for treating kidney diseases. We discuss in detail the potential use of mesenchymal stem cells in preclinical and clinical works, with additional populations that have been studied briefly described. Moreover, we discuss current knowledge on endogenous kidney regeneration ability and on the possibility to modulate it using chemical and biological agents. EXPERT OPINION Stem cell therapy is a promising new treatment for kidney disease documented in many animal studies. Mesenchymal stem cells have emerged as a promising cell type, but their efficacy in clinical trials is still controversial. Identification of progenitor cells in the adult kidney is another step forward in regenerative medicine, suggesting the repair potential of the adult kidney and the possible modulation of renal progenitors in situ using pharmacological approaches.
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Affiliation(s)
- Elena Lazzeri
- a University of Florence; Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE) , Florence, Italy +390552758342 ; ;
| | - Paola Romagnani
- a University of Florence; Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE) , Florence, Italy +390552758342 ; ;
| | - Laura Lasagni
- a University of Florence; Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE) , Florence, Italy +390552758342 ; ;
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21
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Atlas of Cellular Dynamics during Zebrafish Adult Kidney Regeneration. Stem Cells Int 2015; 2015:547636. [PMID: 26089919 PMCID: PMC4451991 DOI: 10.1155/2015/547636] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 01/07/2015] [Indexed: 12/20/2022] Open
Abstract
The zebrafish is a useful animal model to study the signaling pathways that orchestrate kidney regeneration, as its renal nephrons are simple, yet they maintain the biological complexity inherent to that of higher vertebrate organisms including mammals. Recent studies have suggested that administration of the aminoglycoside antibiotic gentamicin in zebrafish mimics human acute kidney injury (AKI) through the induction of nephron damage, but the timing and details of critical phenotypic events associated with the regeneration process, particularly in existing nephrons, have not been characterized. Here, we mapped the temporal progression of cellular and molecular changes that occur during renal epithelial regeneration of the proximal tubule in the adult zebrafish using a platform of histological and expression analysis techniques. This work establishes the timing of renal cell death after gentamicin injury, identifies proliferative compartments within the kidney, and documents gene expression changes associated with the regenerative response of proliferating cells. These data provide an important descriptive atlas that documents the series of events that ensue after damage in the zebrafish kidney, thus availing a valuable resource for the scientific community that can facilitate the implementation of zebrafish research to delineate the mechanisms that control renal regeneration.
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22
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Endo T, Nakamura J, Sato Y, Asada M, Yamada R, Takase M, Takaori K, Oguchi A, Iguchi T, Higashi AY, Ohbayashi T, Nakamura T, Muso E, Kimura T, Yanagita M. Exploring the origin and limitations of kidney regeneration. J Pathol 2015; 236:251-63. [PMID: 25664690 DOI: 10.1002/path.4514] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 01/12/2015] [Accepted: 02/03/2015] [Indexed: 11/11/2022]
Abstract
Epidemiological findings indicate that acute kidney injury (AKI) increases the risk for chronic kidney disease (CKD), although the molecular mechanism remains unclear. Genetic fate mapping demonstrated that nephrons, functional units in the kidney, are repaired by surviving nephrons after AKI. However, the cell population that repairs damaged nephrons and their repair capacity limitations remain controversial. To answer these questions, we generated a new transgenic mouse strain in which mature proximal tubules, the segment predominantly damaged during AKI, could be genetically labelled at desired time points. Using this strain, massive proliferation of mature proximal tubules is observed during repair, with no dilution of the genetic label after the repair process, demonstrating that proximal tubules are repaired mainly by their own proliferation. Furthermore, acute tubular injury caused significant shortening of proximal tubules associated with interstitial fibrosis, suggesting that proximal tubules have a limited capacity to repair. Understanding the mechanism of this limitation might clarify the mechanism of the AKI-to-CKD continuum.
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Affiliation(s)
- Tomomi Endo
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | - Jin Nakamura
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuki Sato
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Misako Asada
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ryo Yamada
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Masayuki Takase
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan.,Development II, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan
| | - Koji Takaori
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akiko Oguchi
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Taku Iguchi
- Development II, Pharmacology Research Laboratories II, Research Division, Mitsubishi Tanabe Pharma Corporation, Saitama, Japan.,TMK Project, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Atsuko Y Higashi
- Department of Pharmacology, Kansai Medical University, Osaka, Japan
| | - Tetsuya Ohbayashi
- Division of Laboratory Animal Science, Research Center for Bioscience and Technology, Tottori University, Tottori, Japan
| | | | - Eri Muso
- Department of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | - Takeshi Kimura
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Motoko Yanagita
- Department of Nephrology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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23
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Tetteh PW, Farin HF, Clevers H. Plasticity within stem cell hierarchies in mammalian epithelia. Trends Cell Biol 2015; 25:100-8. [DOI: 10.1016/j.tcb.2014.09.003] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 09/08/2014] [Accepted: 09/12/2014] [Indexed: 12/20/2022]
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25
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Iwakura T, Fujigaki Y, Fujikura T, Ohashi N, Kato A, Yasuda H. A high ratio of G1 to G0 phase cells and an accumulation of G1 phase cells before S phase progression after injurious stimuli in the proximal tubule. Physiol Rep 2014; 2:e12173. [PMID: 25293601 PMCID: PMC4254098 DOI: 10.14814/phy2.12173] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 09/09/2014] [Accepted: 09/10/2014] [Indexed: 12/25/2022] Open
Abstract
Proximal tubule (PT) cells can proliferate explosively after injurious stimuli. To investigate this proliferative capacity, we examined cell cycle status and the expression of cyclin-dependent kinase inhibitor p27, a G1 phase mediator, in PT cells after a proliferative or injurious stimulus. Rats were treated with lead acetate (proliferative stimulus) or uranyl acetate (UA; injurious stimulus). Isolated tubular cells were separated into PT and distal tubule (DT) cells by density-gradient centrifugation. Cell cycle status was analyzed with flow cytometry by using the Hoechst 33342/pyronin Y method. Most PT and DT cells from control rats were in G0/G1 phase, with a higher percentage of PT cells than DT cells in G1 phase. Lead acetate and UA administration promoted the G0-G1 transition and the accumulation of G1 phase cells before S phase progression. In PT cells from rats treated with lead acetate or a subnephrotoxic dose of UA, p27 levels increased or did not change, possibly reflecting G1 arrest. In contrast, p27 became undetectable before the appearance of apoptotic cells in rats treated with a nephrotoxic dose of UA. The decrease in p27 might facilitate rapid cell cycling. The decreased number of p27-positive cells was associated with PT cell proliferation in renal tissues after a proliferative or injurious stimulus. The findings suggest that a high ratio of G1 to G0 phase cells and a rapid accumulation of G1 phase cells before S phase progression in the PT is a biological strategy for safe, timely, and explosive cell proliferation in response to injurious stimuli.
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Affiliation(s)
- Takamasa Iwakura
- Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yoshihide Fujigaki
- Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Tomoyuki Fujikura
- Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Naro Ohashi
- Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Akihiko Kato
- Blood Purification Unit, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hideo Yasuda
- Internal Medicine I, Division of Nephrology, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Tögel F, Westenfelder C. Recent advances in the understanding of acute kidney injury. F1000PRIME REPORTS 2014; 6:83. [PMID: 25343040 PMCID: PMC4166934 DOI: 10.12703/p6-83] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Acute kidney injury (AKI) is a common clinical entity associated with high morbidity and mortality and clinical costs. The pathophysiology is multifaceted and involves inflammation, tubular injury, and vascular damage. Recently identified components include necroptosis, a special form of cell death, and autophagy. Most of the pathophysiological knowledge is obtained from animal models but these do not directly reflect the reality of the clinical situation. Tubular cells have a remarkable capacity to regenerate, and the role of stem/progenitor cells is discussed. Acute kidney injury is frequently associated with chronic kidney disease, and the implications are widespread.
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Affiliation(s)
- Florian Tögel
- Division of Renal (Kidney) Medicine, Brigham and Women's Hospital45 Francis Street, Boston, MA 02115USA
| | - Christof Westenfelder
- Department of Medicine, Division of Nephrology, Department of PhysiologyUniversity of Utah, Salt Lake City, UTUSA
- George E. Wahlen VA HSC Medical Center500 Foothill Boulevard, Salt Lake City, UT 84148USA
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27
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Xing L, Cui R, Peng L, Ma J, Chen X, Xie RJ, Li B. Mesenchymal stem cells, not conditioned medium, contribute to kidney repair after ischemia-reperfusion injury. Stem Cell Res Ther 2014; 5:101. [PMID: 25145540 PMCID: PMC4159523 DOI: 10.1186/scrt489] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2013] [Accepted: 08/12/2014] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Studies have shown that stem cells exert their therapeutic effects on acute kidney injury (AKI) through paracrine/endocrine actions. If the protective effect is mediated in an endocrine manner, the injection of the factors that these cells secrete could be effective, but the effect of conditioned medium (CM) remains controversial. METHODS In this study, we cultured mesenchymal stem cells (MSCs) and then transplanted them into an ischemia-reperfusion (I/R) injury model. CM was also injected into mice, and the histological changes, level of cell proliferation, loss of peritubular capillaries and anti-inflammatory and anti-apoptotic effects were examined at different time points. RESULTS The results showed that MSC infusion improved renal function and histological alterations, leading to significantly reduced mortality. MSC administration also promoted kidney microvasculature repair, attenuated kidney peritubular capillary loss, increased the proliferation of parenchymal cells and decreased CD68-positive macrophage infiltration and apoptotic cells. Although we determined that CM contained proangiogenic factors, including hepatocyte growth factor (HGF), vascular endothelial growth factor-A (VEGF-A) and insulin-like growth factor-1 (IGF-1), no favorable effects were observed during the course of repair. CONCLUSIONS Our data show that MSC infusion promotes kidney repair in a variety of ways, including enhancement of the repair of peritubular capillaries and tubular epithelial cells and anti-inflammatory and anti-apoptotic effects. MSCs can secrete high levels of proangiogenic growth factors, but CM results in a nonsignificant improvement, indicating that MSCs play a role in kidney repair through paracrine rather than endocrine mechanisms. These results indicate that MSC infusion is a promising therapeutic strategy for promoting kidney repair after injury.
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Dziedzic K, Pleniceanu O, Dekel B. Kidney stem cells in development, regeneration and cancer. Semin Cell Dev Biol 2014; 36:57-65. [PMID: 25128731 DOI: 10.1016/j.semcdb.2014.08.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Revised: 08/03/2014] [Accepted: 08/05/2014] [Indexed: 12/17/2022]
Abstract
The generation of nephrons during development depends on differentiation via a mesenchymal to epithelial transition (MET) of self-renewing, tissue-specific stem cells confined to a specific anatomic niche of the nephrogenic cortex. These cells may transform to generate oncogenic stem cells and drive pediatric renal cancer. Once nephron epithelia are formed the view of post-MET tissue renal growth and maintenance by adult tissue-specific epithelial stem cells becomes controversial. Recently, genetic lineage tracing that followed clonal evolution of single kidney cells showed that the need for new cells is constantly driven by fate-restricted unipotent clonal expansions in varying kidney segments arguing against a multipotent adult stem cell model. Lineage-restriction was similarly maintained in kidney organoids grown in culture. Importantly, kidney cells in which Wnt was activated were traced to give significant clonal progeny indicating a clonogenic hierarchy. In vivo nephron epithelia may be endowed with the capacity akin to that of unipotent epithelial stem/progenitor such that under specific stimuli can clonally expand/self renew by local proliferation of mature differentiated cells. Finding ways to ex vivo preserve and expand the observed in vivo kidney-forming capacity inherent to both the fetal and adult kidneys is crucial for taking renal regenerative medicine forward. Some of the strategies used to achieve this are sorting human fetal nephron stem/progenitor cells, growing adult nephrospheres or reprogramming differentiated kidney cells toward expandable renal progenitors.
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Affiliation(s)
- Klaudyna Dziedzic
- Pediatric Stem Cell Research Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel Aviv University, Israel
| | - Oren Pleniceanu
- Pediatric Stem Cell Research Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel Aviv University, Israel
| | - Benjamin Dekel
- Pediatric Stem Cell Research Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler School of Medicine, Tel Aviv University, Israel.
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Abstract
PURPOSE OF REVIEW The review summarizes the most recent advances in stem cell and regenerative approaches to treat kidney injury, and highlights areas of active controversy. Over the past year, a number of findings have been reported that have brought this field much closer to clinical translation. RECENT FINDINGS Recent progress in regenerative nephrology includes the directed differentiation of embryonic stem cells to kidney fates, understanding the proliferative capacity of tubules after injury, the use of mesenchymal stem cells for kidney disease and tissue engineering approaches to renal replacement. Controversies persist, however, including whether adult epithelial stem cells exist at all, the best therapeutic strategy for the treatment of kidney injury and how to use mesenchymal stem cells optimally for the prevention of acute kidney injury. SUMMARY Although recent progress in kidney regeneration is very encouraging, current controversies must be resolved before clinical breakthroughs can occur.
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30
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Johansson ME. Tubular Regeneration: When Can the Kidney Regenerate from Injury and What Turns Failure into Success. ACTA ACUST UNITED AC 2014; 126:76. [DOI: 10.1159/000360671] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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31
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Cirio MC, de Groh ED, de Caestecker MP, Davidson AJ, Hukriede NA. Kidney regeneration: common themes from the embryo to the adult. Pediatr Nephrol 2014; 29:553-64. [PMID: 24005792 PMCID: PMC3944192 DOI: 10.1007/s00467-013-2597-2] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 07/26/2013] [Accepted: 07/29/2013] [Indexed: 02/07/2023]
Abstract
The vertebrate kidney has an inherent ability to regenerate following acute damage. Successful regeneration of the injured kidney requires the rapid replacement of damaged tubular epithelial cells and reconstitution of normal tubular function. Identifying the cells that participate in the regeneration process as well as the molecular mechanisms involved may reveal therapeutic targets for the treatment of kidney disease. Renal regeneration is associated with the expression of genetic pathways that are necessary for kidney organogenesis, suggesting that the regenerating tubular epithelium may be "reprogrammed" to a less-differentiated, progenitor state. This review will highlight data from various vertebrate models supporting the hypothesis that nephrogenic genes are reactivated as part of the process of kidney regeneration following acute kidney injury (AKI). Emphasis will be placed on the reactivation of developmental pathways and how our understanding of the resulting regeneration process may be enhanced by lessons learned in the embryonic kidney.
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Affiliation(s)
- M. Cecilia Cirio
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Eric D. de Groh
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Mark P. de Caestecker
- Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, TN, United States of America
| | - Alan J. Davidson
- Department of Molecular Medicine and Pathology, School of Medical Sciences, University of Auckland, Auckland, New Zealand
| | - Neil A. Hukriede
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA, United States of America
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32
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The bigger the better: determining nephron size in kidney. Pediatr Nephrol 2014; 29:525-30. [PMID: 23974984 PMCID: PMC3944135 DOI: 10.1007/s00467-013-2581-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2013] [Revised: 07/12/2013] [Accepted: 07/15/2013] [Indexed: 10/26/2022]
Abstract
The main functions of the kidney are to excrete metabolic waste products and actively reabsorb essential molecules such as amino acids, ions, glucose and water. In humans, a wide range of genetic disorders exist characterized by wasting of metabolically important compounds. At the cellular level, more than 20 highly specialized renal epithelial cell types located in different segments of the nephron contribute to the reabsorption process. In particular, proximal tubular cells play a crucial role and are uniquely adapted to maximize reabsorption efficiency. They accommodate high numbers of transporters and channels by increasing the apical surface area in contact with the primary filtrate by forming a brush border as well as undergoing hypertrophy and hyperplasia. This adaptation is evolutionarily conserved and is detected in the primitive pronephric kidney of fish and amphibians as well as the metanephric kidney of higher vertebrates. Surprisingly, signaling pathways regulating these three processes have remained largely unknown. Here we summarize recent studies that highlight the early phases of kidney development as a critical juncture in establishing proximal tubule size.
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33
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p21(WAF1/CIP1) Expression is Differentially Regulated by Metformin and Rapamycin. Int J Chronic Dis 2014; 2014:327640. [PMID: 26464852 PMCID: PMC4590942 DOI: 10.1155/2014/327640] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Revised: 02/03/2014] [Accepted: 02/13/2014] [Indexed: 12/14/2022] Open
Abstract
The mammalian target of rapamycin (mTOR) pathway plays an important role in the development of diabetic nephropathy and other age-related diseases. One of the features of DN is the elevated expression of p21WAF1/CIP1. However, the importance of the mTOR signalling pathway in p21 regulation is poorly understood. Here we investigated the effect of metformin and rapamycin on mTOR-related phenotypes in cell lines of epithelial origin. This study reports that metformin inhibits high glucose-induced p21 expression. High glucose opposed metformin in regulating cell size, proliferation, and protein synthesis. These effects were associated with reduced AMPK activation, affecting downstream mTOR signalling. However, the inhibition of the mTOR pathway by rapamycin did not have a negative effect on p21 expression, suggesting that metformin regulates p21 upstream of mTOR. These findings provide support for the hypothesis that AMPK activation may regulate p21 expression, which may have implications for diabetic nephropathy and other age-related pathologies.
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34
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Tiong HY, Huang P, Xiong S, Li Y, Vathsala A, Zink D. Drug-induced nephrotoxicity: clinical impact and preclinical in vitro models. Mol Pharm 2014; 11:1933-48. [PMID: 24502545 DOI: 10.1021/mp400720w] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The kidney is a major target for drug-induced toxicity. Drug-induced nephrotoxicity remains a major problem in the clinical setting, where the use of nephrotoxic drugs is often unavoidable. This leads frequently to acute kidney injury, and current problems are discussed. One strategy to avoid such problems would be the development of drugs with decreased nephrotoxic potential. However, the prediction of nephrotoxicity during preclinical drug development is difficult and nephrotoxicity is typically detected only late. Also, the nephrotoxic potential of newly approved drugs is often underestimated. Regulatory approved or validated in vitro models for the prediction of nephrotoxicity are currently not available. Here, we will review current approaches on the development of such models. This includes a discussion of three-dimensional and microfluidic models and recently developed stem cell based approaches. Most in vitro models have been tested with a limited number of compounds and are of unclear predictivity. However, some studies have tested larger numbers of compounds and the predictivity of the respective in vitro model had been determined. The results showed that high predictivity can be obtained by using primary or stem cell derived human renal cells in combination with appropriate end points.
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Affiliation(s)
- Ho Yee Tiong
- Yong Loo Lin School of Medicine, National University Health System , 1E Kent Ridge Road, NUHS Tower Block, Singapore 119228, Singapore
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35
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Berkenkamp B, Susnik N, Baisantry A, Kuznetsova I, Jacobi C, Sörensen-Zender I, Broecker V, Haller H, Melk A, Schmitt R. In vivo and in vitro analysis of age-associated changes and somatic cellular senescence in renal epithelial cells. PLoS One 2014; 9:e88071. [PMID: 24505380 PMCID: PMC3913727 DOI: 10.1371/journal.pone.0088071] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 01/05/2014] [Indexed: 12/22/2022] Open
Abstract
Acute kidney injury is a major clinical problem and advanced age is associated with ineffective renal regeneration and poor functional outcome. Data from kidney injury models suggest that a loss of tubular epithelial proliferation contributes to a decrease in renal repair capacity with aging, but aging can also lead to a higher severity of inflammation and damage which may influence repair. In this study we tested intrinsic age-dependent changes in tubular epithelial proliferation in young and old mice, by injecting low-dose lead acetate as a non-injurious mitogen. In parallel, we explored in vitro techniques of studying cellular senescence in primary tubular epithelial cells (PTEC). Lead acetate induced tubular epithelial proliferation at a significantly higher rate in young as compared to old mice. Old kidneys showed significantly more senescence as demonstrated by increased p16 (INK4a), senescence associated β-galactosidase, and γH2AX(+)/Ki-67(-) cells. This was paralleled in old kidneys by a higher number of Cyclin D1 positive tubular cells. This finding was corroborated by a positive correlation between Cyclin D1 positivity and age in human renal biopsies. When tubular cells were isolated from mouse kidneys they rapidly lost their age-associated differences under culture conditions. However, senescence was readily induced in PTEC by γ-irradiation representing a future model for study of cellular senescence in the renal epithelium. Together, our data indicate that the tubular epithelium of aged kidney has an intrinsically reduced proliferative capacity probably due to a higher load of senescent cells. Moreover, stress induced models of cellular senescence are preferable for study of the renal epithelium in vitro. Finally, the positive correlation of Cyclin D1 with age and cellular senescence in PTEC needs further evaluation as to a functional role of renal epithelial aging.
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Affiliation(s)
- Birgit Berkenkamp
- Department of Pediatric Nephrology and Gastroenterology, Medical School Hannover, Hannover, Lower Saxony, Germany
| | - Nathan Susnik
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Lower Saxony, Germany
| | - Arpita Baisantry
- Department of Pediatric Nephrology and Gastroenterology, Medical School Hannover, Hannover, Lower Saxony, Germany
| | - Inna Kuznetsova
- Department of Pediatric Nephrology and Gastroenterology, Medical School Hannover, Hannover, Lower Saxony, Germany
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Lower Saxony, Germany
| | - Christoph Jacobi
- Department of Pediatric Nephrology and Gastroenterology, Medical School Hannover, Hannover, Lower Saxony, Germany
| | - Inga Sörensen-Zender
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Lower Saxony, Germany
| | - Verena Broecker
- Department of Pathology, Medical School Hannover, Hannover, Lower Saxony, Germany
| | - Hermann Haller
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Lower Saxony, Germany
| | - Anette Melk
- Department of Pediatric Nephrology and Gastroenterology, Medical School Hannover, Hannover, Lower Saxony, Germany
- * E-mail: (RS); (AM)
| | - Roland Schmitt
- Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Lower Saxony, Germany
- * E-mail: (RS); (AM)
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36
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McCampbell KK, Wingert RA. New tides: using zebrafish to study renal regeneration. Transl Res 2014; 163:109-22. [PMID: 24183931 PMCID: PMC3946610 DOI: 10.1016/j.trsl.2013.10.003] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2013] [Revised: 09/24/2013] [Accepted: 10/08/2013] [Indexed: 12/30/2022]
Abstract
Over the past several decades, the zebrafish has become one of the major vertebrate model organisms used in biomedical research. In this arena, the zebrafish has emerged as an applicable system for the study of kidney diseases and renal regeneration. The relevance of the zebrafish model for nephrology research has been increasingly appreciated as the understanding of zebrafish kidney structure, ontogeny, and the response to damage has steadily expanded. Recent studies have documented the amazing regenerative characteristics of the zebrafish kidney, which include the ability to replace epithelial populations after acute injury and to grow new renal functional units, termed nephrons. Here we discuss how nephron composition is conserved between zebrafish and mammals, and highlight how recent findings from zebrafish studies utilizing transgenic technologies and chemical genetics can complement traditional murine approaches in the effort to dissect how the kidney responds to acute damage and identify therapeutics that enhance human renal regeneration.
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Affiliation(s)
| | - Rebecca A Wingert
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Ind.
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37
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Abstract
Acute kidney injury (AKI) is associated with high morbidity and mortality. Recent genetic fate mapping studies demonstrated that recovery from AKI occurs from intrinsic tubular cells. It is unresolved whether these intrinsic cells (so-called "scattered tubular cells") represent fixed progenitor cells or whether recovery involves any surviving tubular cell. Here, we show that the doxycycline-inducible parietal epithelial cell (PEC)-specific PEC-reverse-tetracycline transactivator (rtTA) transgenic mouse also efficiently labels the scattered tubular cell population. Proximal tubular cells labeled by the PEC-rtTA mouse coexpressed markers for scattered tubular cells (kidney injury molecule 1, annexin A3, src-suppressed C-kinase substrate, and CD44) and showed a higher proliferative index. The PEC-rtTA mouse labeled more tubular cells upon different tubular injuries but was independent of cellular proliferation as determined in physiological growth of the kidney. To resolve whether scattered tubular cells are fixed progenitors, cells were irreversibly labeled before ischemia reperfusion injury (genetic cell fate mapping). During recovery, the frequency of labeled tubular cells remained constant, arguing against a fixed progenitor population. In contrast, when genetic labeling was induced during ischemic injury and subsequent recovery, the number of labeled cells increased significantly, indicating that scattered tubular cells arise from any surviving tubular cell. In summary, scattered tubular cells do not represent a fixed progenitor population but rather a phenotype that can be adopted by almost any proximal tubular cell upon injury. Understanding and modulating these phenotypic changes using the PEC-rtTA mouse may lead to more specific therapies in AKI.
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Herrera M, Mirotsou M. Stem cells: potential and challenges for kidney repair. Am J Physiol Renal Physiol 2013; 306:F12-23. [PMID: 24197069 DOI: 10.1152/ajprenal.00238.2013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Renal damage resulting from acute and chronic kidney injury poses an important problem to public health. Currently, patients with end-stage renal disease rely solely on kidney transplantation or dialysis for survival. Emerging therapies aiming to prevent and reverse kidney damage are thus in urgent need. Although the kidney was initially thought to lack the capacity for self-repair, several studies have indicated that this might not be the case; progenitor and stem cells appear to play important roles in kidney repair under various pathological conditions. In this review, we summarize recent findings on the role of progenitor/stem cells on kidney repair as well as discuss their potential as a therapeutic approach for kidney diseases.
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Affiliation(s)
- Marcela Herrera
- Division of Cardiology, Genome Research Bldg. II, Rm. 4022, 210 Research Drive, Duke Univ. Medical Center, Durham, NC 27710.
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39
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Differentiated kidney epithelial cells repair injured proximal tubule. Proc Natl Acad Sci U S A 2013; 111:1527-32. [PMID: 24127583 DOI: 10.1073/pnas.1310653110] [Citation(s) in RCA: 362] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Whether kidney proximal tubule harbors a scattered population of epithelial stem cells is a major unsolved question. Lineage-tracing studies, histologic characterization, and ex vivo functional analysis results conflict. To address this controversy, we analyzed the lineage and clonal behavior of fully differentiated proximal tubule epithelial cells after injury. A CreER(T2) cassette was knocked into the sodium-dependent inorganic phosphate transporter SLC34a1 locus, which is expressed only in differentiated proximal tubule. Tamoxifen-dependent recombination was absolutely specific to proximal tubule. Clonal analysis after injury and repair showed that the bulk of labeled cells proliferate after injury with increased clone size after severe compared with mild injury. Injury to labeled proximal tubule epithelia induced expression of CD24, CD133, vimentin, and kidney-injury molecule-1, markers of putative epithelial stem cells in the human kidney. Similar results were observed in cultured proximal tubules, in which labeled clones proliferated and expressed dedifferentiation and injury markers. When mice with completely labeled kidneys were subject to injury and repair there was no dilution of fate marker despite substantial proliferation, indicating that unlabeled progenitors do not contribute to kidney repair. During nephrogenesis and early kidney growth, single proximal tubule clones expanded, suggesting that differentiated cells also contribute to tubule elongation. These findings provide no evidence for an intratubular stem-cell population, but rather indicate that terminally differentiated epithelia reexpress apparent stem-cell markers during injury-induced dedifferentiation and repair.
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40
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Kaissling B, LeHir M, Kriz W. Renal epithelial injury and fibrosis. Biochim Biophys Acta Mol Basis Dis 2013; 1832:931-9. [DOI: 10.1016/j.bbadis.2013.02.010] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Revised: 02/07/2013] [Accepted: 02/09/2013] [Indexed: 12/20/2022]
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41
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Li Y, Wingert RA. Regenerative medicine for the kidney: stem cell prospects & challenges. Clin Transl Med 2013; 2:11. [PMID: 23688352 PMCID: PMC3665577 DOI: 10.1186/2001-1326-2-11] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 05/14/2013] [Indexed: 12/22/2022] Open
Abstract
The kidney has key roles in maintaining human health. There is an escalating medical crisis in nephrology as growing numbers of patients suffer from kidney diseases that culminate in organ failure. While dialysis and transplantation provide life-saving treatments, these therapies are rife with limitations and place significant burdens on patients and healthcare systems. It has become imperative to find alternative ways to treat existing kidney conditions and preemptive means to stave off renal dysfunction. The creation of innovative medical approaches that utilize stem cells has received growing research attention. In this review, we discuss the regenerative and maladaptive cellular responses that occur during acute and chronic kidney disease, the emerging evidence about renal stem cells, and some of the issues that lie ahead in bridging the gap between basic stem cell biology and regenerative medicine for the kidney.
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Affiliation(s)
- Yue Li
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Rebecca A Wingert
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556, USA
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Smeets B, Boor P, Dijkman H, Sharma SV, Jirak P, Mooren F, Berger K, Bornemann J, Gelman IH, Floege J, van der Vlag J, Wetzels JFM, Moeller MJ. Proximal tubular cells contain a phenotypically distinct, scattered cell population involved in tubular regeneration. J Pathol 2013; 229:645-59. [PMID: 23124355 DOI: 10.1002/path.4125] [Citation(s) in RCA: 165] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2012] [Revised: 09/21/2012] [Accepted: 10/05/2012] [Indexed: 12/12/2022]
Abstract
Regeneration of injured tubular cells occurs after acute tubular necrosis primarily from intrinsic renal cells. This may occur from a pre-existing intratubular stem/progenitor cell population or from any surviving proximal tubular cell. In this study, we characterize a CD24-, CD133-, and vimentin-positive subpopulation of cells scattered throughout the proximal tubule in normal human kidney. Compared to adjacent 'normal' proximal tubular cells, these CD24-positive cells contained less cytoplasm, fewer mitochondria, and no brush border. In addition, 49 marker proteins are described that are expressed within the proximal tubules in a similar scattered pattern. For eight of these markers, we confirmed co-localization with CD24. In human biopsies of patients with acute tubular necrosis (ATN), the number of CD24-positive tubular cells was increased. In both normal human kidneys and the ATN biopsies, around 85% of proliferating cells were CD24-positive - indicating that this cell population participates in tubular regeneration. In healthy rat kidneys, the novel cell subpopulation was absent. However, upon unilateral ureteral obstruction (UUO), the novel cell population was detected in significant amounts in the injured kidney. In summary, in human renal biopsies, the CD24-positive cells represent tubular cells with a deviant phenotype, characterized by a distinct morphology and marker expression. After acute tubular injury, these cells become more numerous. In healthy rat kidneys, these cells are not detectable, whereas after UUO, they appeared de novo - arguing against the notion that these cells represent a pre-existing progenitor cell population. Our data indicate rather that these cells represent transiently dedifferentiated tubular cells involved in regeneration.
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Affiliation(s)
- Bart Smeets
- Division of Nephrology and Immunology, University Hospital of the Aachen University of Technology (RWTH), Aachen, Germany.
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Cianciolo Cosentino C, Skrypnyk NI, Brilli LL, Chiba T, Novitskaya T, Woods C, West J, Korotchenko VN, McDermott L, Day BW, Davidson AJ, Harris RC, de Caestecker MP, Hukriede NA. Histone deacetylase inhibitor enhances recovery after AKI. J Am Soc Nephrol 2013; 24:943-53. [PMID: 23620402 DOI: 10.1681/asn.2012111055] [Citation(s) in RCA: 142] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
At present, there are no effective therapies to ameliorate injury, accelerate recovery, or prevent postinjury fibrosis after AKI. Here, we sought to identify candidate compounds that accelerate recovery after AKI by screening for small molecules that increase proliferation of renal progenitor cells in zebrafish embryos. One compound identified from this screen was the histone deacetylase inhibitor methyl-4-(phenylthio)butanoate, which we subsequently administered to zebrafish larvae and mice 24-48 hours after inducing AKI. In zebrafish, treatment with the compound increased larval survival and proliferation of renal tubular epithelial cells. In mice, treatment accelerated recovery, reduced postinjury tubular atrophy and interstitial fibrosis, and increased the regenerative capacity of actively cycling renal tubular cells by decreasing the number of cells in G2/M arrest. These data suggest that accelerating recovery may be a viable approach to treating AKI and provide proof of concept that a screen in zebrafish embryos can identify therapeutic candidates for kidney injury.
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Fujigaki Y. Different modes of renal proximal tubule regeneration in health and disease. World J Nephrol 2012; 1:92-9. [PMID: 24175246 PMCID: PMC3782202 DOI: 10.5527/wjn.v1.i4.92] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 06/10/2012] [Accepted: 07/20/2012] [Indexed: 02/06/2023] Open
Abstract
Tissues are equipped with reasonable strategies for repair and regeneration and the renal proximal tubule (PT) is no exception. New information has become available on the mode of PT regeneration in mammals. Unlike the intestinal epithelium with a high rate of turnover maintained by the stem cell system, the kidney has low turnover under normal physiological conditions. The PT seems to be maintained physiologically by hyperplasia, a regenerating system with self-renewal of mature tubular cells. This mode of regeneration is advantageous for effective replenishment of randomly isolated and eliminated tubular cells by self-renewal of adjacent cells. On the other hand, it has been suggested that dedifferentiation of mature tubular cells plays a role in regeneration after acute kidney injury. Recent studies employing genetic labeling and DNA-labeling techniques have confirmed that the proliferation of preexisting injured mature tubular cells contributes mainly to PT regeneration in ischemic reperfusion injury. This mode of regeneration is beneficial with regard to the rapid reparation of focally injured tubules often induced by ischemic reperfusion injury. What happens, however, when the PT is homogeneously injured with almost no remaining surviving cells Is the PT equipped with another backup regeneration system, e.g., the stem cell system Is it possible that certain types of renal injuries evoke a stem cell response whereas others do not This review focuses on all three possible modes of tissue regeneration (compensatory hyperplasia, dedifferentiation and stem cell system) in mammals and their involvement in PT regeneration in health and disease.
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Affiliation(s)
- Yoshihide Fujigaki
- Yoshihide Fujigaki, First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan
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Abstract
The kidney is widely regarded as an organ without regenerative abilities. However, in recent years this dogma has been challenged on the basis of observations of kidney recovery following acute injury, and the identification of renal populations that demonstrate stem cell characteristics in various species. It is currently speculated that the human kidney can regenerate in some contexts, but the mechanisms of renal regeneration remain poorly understood. Numerous controversies surround the potency, behaviour and origins of the cell types that are proposed to perform kidney regeneration. The present review explores the current understanding of renal stem cells and kidney regeneration events, and examines the future challenges in using these insights to create new clinical treatments for kidney disease.
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Axelson H, Johansson ME. Renal stem cells and their implications for kidney cancer. Semin Cancer Biol 2012; 23:56-61. [PMID: 22766133 DOI: 10.1016/j.semcancer.2012.06.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2012] [Accepted: 06/05/2012] [Indexed: 12/22/2022]
Abstract
The renal cell carcinomas (RCC) denote a diverse set of neoplasias with unique genetic and histological features. The RCCs emanate from the renal tubule, a highly heterogeneous epithelial structure, and depending on which cell is malignified the resulting cancer displays unique characteristics. Notwithstanding this, the cells of origin for the RCC forms are far from established, and only inferred by the accumulated weight of marker similarities, not always providing an unequivocal picture. The tubular epithelium is normally mitotically quiescent, but demonstrates a considerable regenerative capacity upon renal injury. Recently the hypothesis that regeneration is driven by adult stem cells has been added experimental support, providing further complexity to the issue of renal carcinogenesis. Whether these cells are linked to RCC is an open question. In the present review we therefore present the prevailing theories regarding kidney regeneration, since a better understanding of this process might be of relevance when considering the different malignancies that arise from kidney epithelium. Our own results show that papillary renal cell carcinoma displays considerable similarities to proximal tubular progenitor cells and we suggest that this tumor form may develop in a multi-step fashion via benign renal adenomas. The putative connection between renal stem cells and carcinomas is, however, not clarified, since the current understanding of the renal stem cell system is not complete. It is clear that the efforts to isolate and characterize renal progenitor/stem cells suffer from numerous technical limitations and that it remains likely that the kidney harbors different stem cell pools with a restricted differentiation potential.
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Affiliation(s)
- Håkan Axelson
- Center for Molecular Pathology, Department of Laboratory Medicine, Lund University, Skåne University Hospital, SE-205 02 Malmö, Sweden
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Little MH, McMahon AP. Mammalian kidney development: principles, progress, and projections. Cold Spring Harb Perspect Biol 2012; 4:a008300. [PMID: 22550230 PMCID: PMC3331696 DOI: 10.1101/cshperspect.a008300] [Citation(s) in RCA: 304] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The mammalian kidney is a vital organ with considerable cellular complexity and functional diversity. Kidney development is notable for requiring distinct but coincident tubulogenic processes involving reciprocal inductive signals between mesenchymal and epithelial progenitor compartments. Key molecular pathways mediating these interactions have been identified. Further, advances in the analysis of gene expression and gene activity, coupled with a detailed knowledge of cell origins, are enhancing our understanding of kidney morphogenesis and unraveling the normal processes of postnatal repair and identifying disease-causing mechanisms. This article focuses on recent insights into central regulatory processes governing organ assembly and renal disease, and predicts future directions for the field.
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Affiliation(s)
- Melissa H Little
- Institute for Molecular Bioscience, The University of Queensland, St. Lucia, Brisbane, Australia.
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Romaker D, Zhang B, Wessely O. An immunofluorescence method to analyze the proliferation status of individual nephron segments in the Xenopus pronephric kidney. Methods Mol Biol 2012; 886:121-132. [PMID: 22639256 PMCID: PMC3425951 DOI: 10.1007/978-1-61779-851-1_11] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Organ development requires the coordination of proliferation and differentiation of various cell types. This is particularly challenging in the kidney, where up to 26 different cell types with highly specialized functions are present. Moreover, even though the nephron initially develops from a common progenitor pool, the individual nephron segments are ultimately quite different in respect to cell numbers. This suggests that some cells in the nephron have a higher proliferative index (i.e., cell cycle length) than others. Here, we describe two different immunofluorescence-based approaches to accurately quantify such growth rates in the pronephric kidney of Xenopus laevis. Rapidly dividing cells were identified with the mitosis marker phospho-Histone H3, while slowly cycling cells were labeled using the thymidine analogue EdU. In addition, individual nephron segments were marked using cell type-specific antibodies. To accurately assess the number of positively stained cells, embryos were then serially sectioned and analyzed by immunofluorescence microscopy. Growth rates were established by counting the mitosis or S-phase events in relation to the overall cells present in the nephron segment of interest. This experimental design is very reproducible and can easily be modified to fit other animal models and organ systems.
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Affiliation(s)
- Daniel Romaker
- Lerner Research Institute/Cleveland Clinic, Department of Cell Biology, 9500 Euclid Avenue/NC10, Cleveland, OH 44195, USA
| | - Bo Zhang
- Lerner Research Institute/Cleveland Clinic, Department of Cell Biology, 9500 Euclid Avenue/NC10, Cleveland, OH 44195, USA
- LSU Health Sciences Center, Department of Cell Biology & Anatomy, MEB 6A12, 1901 Perdido Street, New Orleans, LA 70112, USA
| | - Oliver Wessely
- Lerner Research Institute/Cleveland Clinic, Department of Cell Biology, 9500 Euclid Avenue/NC10, Cleveland, OH 44195, USA
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Miya M, Maeshima A, Mishima K, Sakurai N, Ikeuchi H, Kuroiwa T, Hiromura K, Nojima Y. Age-related decline in label-retaining tubular cells: implication for reduced regenerative capacity after injury in the aging kidney. Am J Physiol Renal Physiol 2011; 302:F694-702. [PMID: 22169012 DOI: 10.1152/ajprenal.00249.2011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Recovery after acute kidney injury is impaired in the elderly, but the precise mechanism for such age-related incompetence remains unclear. By in vivo bromodeoxyuridine (BrdU) labeling, renal progenitor cells (label-retaining cells; LRCs) were identified in tubules of normal rat kidney and were shown to be the origin of proliferating cells after injury. In the present study, the involvement of LRCs in the age-related decline of tubular recovery after injury was examined. After 1 wk of BrdU labeling followed by a 2-wk chase period, ischemia-reperfusion injury was induced in 7-wk-, 7-mo-, and 12-mo-old rats. Age-related decreases in DNA synthesis and cell proliferation in renal tubules after injury were found. The number of LRCs also significantly declined with age. At 24 h after reperfusion, the number of LRCs significantly increased in all ages of rats tested. There was no significant difference in the ratio of LRC division among rats of different ages. The area of the rat endothelial cell antigen (RECA)-1-positive capillary network declined with age. When renal tubules isolated from rats treated with BrdU label were cocultured with human umbilical vein endothelial cells (HUVEC), the number of LRCs significantly increased compared with tubules cultured without HUVEC. These data suggest that the reduced capacity of tubular regeneration in the aging kidney is partly explained by the shortage of LRC reserves. The size of the LRC pool might be regulated by the surrounding peritubular capillary network.
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Affiliation(s)
- Masaaki Miya
- Dept. of Medicine and Clinical Science, Gunma Univ. Graduate School of Medicine, 3-39-15 Showa, Maebashi 371-8511, Japan
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Welsh-Bacic D, Nowik M, Kaissling B, Wagner CA. Proliferation of acid-secretory cells in the kidney during adaptive remodelling of the collecting duct. PLoS One 2011; 6:e25240. [PMID: 22039408 PMCID: PMC3200326 DOI: 10.1371/journal.pone.0025240] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2011] [Accepted: 08/29/2011] [Indexed: 01/07/2023] Open
Abstract
The renal collecting duct adapts to changes in acid-base metabolism by remodelling and altering the relative number of acid or alkali secreting cells, a phenomenon termed plasticity. Acid secretory A intercalated cells (A-IC) express apical H(+)-ATPases and basolateral bicarbonate exchanger AE1 whereas bicarbonate secretory B intercalated cells (B-IC) express basolateral (and apical) H(+)-ATPases and the apical bicarbonate exchanger pendrin. Intercalated cells were thought to be terminally differentiated and unable to proliferate. However, a recent report in mouse kidney suggested that intercalated cells may proliferate and that this process is in part dependent on GDF-15. Here we extend these observations to rat kidney and provide a detailed analysis of regional differences and demonstrate that differentiated A-IC proliferate massively during adaptation to systemic acidosis. We used markers of proliferation (PCNA, Ki67, BrdU incorporation) and cell-specific markers for A-IC (AE1) and B-IC (pendrin). Induction of remodelling in rats with metabolic acidosis (with NH(4)Cl for 12 hrs, 4 and 7 days) or treatment with acetazolamide for 10 days resulted in a larger fraction of AE1 positive cells in the cortical collecting duct. A large number of AE1 expressing A-IC was labelled with proliferative markers in the cortical and outer medullary collecting duct whereas no labeling was found in B-IC. In addition, chronic acidosis also increased the rate of proliferation of principal collecting duct cells. The fact that both NH(4)Cl as well as acetazolamide stimulated proliferation suggests that systemic but not urinary pH triggers this response. Thus, during chronic acidosis proliferation of AE1 containing acid-secretory cells occurs and may contribute to the remodelling of the collecting duct or replace A-IC due to a shortened life span under these conditions.
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Affiliation(s)
- Desa Welsh-Bacic
- Institute of Anatomy, University of Zurich, Zurich, Switzerland
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Marta Nowik
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | | | - Carsten A. Wagner
- Institute of Physiology, University of Zurich, Zurich, Switzerland
- Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
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