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Peek JL, Wilson MH. Cell and gene therapy for kidney disease. Nat Rev Nephrol 2023:10.1038/s41581-023-00702-3. [PMID: 36973494 DOI: 10.1038/s41581-023-00702-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2023] [Indexed: 03/29/2023]
Abstract
Kidney disease is a leading cause of morbidity and mortality across the globe. Current interventions for kidney disease include dialysis and renal transplantation, which have limited efficacy or availability and are often associated with complications such as cardiovascular disease and immunosuppression. There is therefore a pressing need for novel therapies for kidney disease. Notably, as many as 30% of kidney disease cases are caused by monogenic disease and are thus potentially amenable to genetic medicine, such as cell and gene therapy. Systemic disease that affects the kidney, such as diabetes and hypertension, might also be targetable by cell and gene therapy. However, although there are now several approved gene and cell therapies for inherited diseases that affect other organs, none targets the kidney. Promising recent advances in cell and gene therapy have been made, including in the kidney research field, suggesting that this form of therapy might represent a potential solution for kidney disease in the future. In this Review, we describe the potential for cell and gene therapy in treating kidney disease, focusing on recent genetic studies, key advances and emerging technologies, and we describe several crucial considerations for renal genetic and cell therapies.
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Affiliation(s)
- Jennifer L Peek
- Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Matthew H Wilson
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
- Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
- Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN, USA.
- Department of Veterans Affairs, Tennessee Valley Health Services, Nashville, TN, USA.
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Hun M, Wen H, Han P, Vun T, Zhao M, He Q. Bibliometric analysis of scientific papers on extracellular vesicles in kidney disease published between 1999 and 2022. Front Cell Dev Biol 2023; 10:1070516. [PMID: 36684427 PMCID: PMC9849820 DOI: 10.3389/fcell.2022.1070516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 12/09/2022] [Indexed: 01/07/2023] Open
Abstract
Background: In recent years, there has been an increasing interest in using extracellular vesicles (EVs) as potential therapeutic agents or natural drug delivery systems in kidney-related diseases. However, a detailed and targeted report on the current condition of extracellular vesicle research in kidney-related diseases is lacking. Therefore, this prospective study was designed to investigate the use of bibliometric analysis to comprehensively overview the current state of research and frontier trends on extracellular vesicle research in kidney-related diseases using visualization tools. Methods: The Web of Science Core Collection (WoSCC) database was searched to identify publications related to extracellular vesicle research in kidney-related diseases since 1999. Citespace, Microsoft Excel 2019, VOSviewer software, the R Bibliometrix Package, and an online platform were used to analyze related research trends to stratify the publication data and collaborations. Results: From 1 January 1999 to 26 June 2022, a total of 1,122 EV-related articles and reviews were published, and 6,486 authors from 1,432 institutions in 63 countries or regions investigated the role of extracellular vesicles in kidney-related diseases. We found that the number of articles on extracellular vesicles in kidney-related diseases increased every year. Dozens of publications were from China and the United States. China had the most number of related publications, in which the Southeast University (China) was the most active institution in all EV-related fields. Liu Bi-cheng published the most papers on extracellular vesicles, while Clotilde Théry had the most number of co-citations. Most papers were published by The International Journal of Molecular Sciences, while Kidney International was the most co-cited journal for extracellular vesicles. We found that exosome-related keywords included exosome, exosm, expression, extracellular vesicle, microRNA, microvesicle, and liquid biopsy, while disease- and pathological-related keywords included biomarker, microRNA, apoptosis, mechanism, systemic lupus erythematosus, EGFR, acute kidney injury, and chronic kidney disease. Acute kidney disease (AKI), CKD, SLE, exosome, liquid biopsy, and extracellular vesicle were the hotspot in extracellular vesicle and kidney-related diseases research. Conclusion: The field of extracellular vesicles in kidney-related disease research is rapidly growing, and its domain is likely to expand in the next decade. The findings from this comprehensive analysis of extracellular vesicles in kidney-related disease research could help investigators to set new diagnostic, therapeutic, and prognostic ideas or methods in kidney-related diseases.
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Affiliation(s)
- Marady Hun
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Huai Wen
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Phanna Han
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Tharith Vun
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Mingyi Zhao
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Mingyi Zhao, ; Qingnan He,
| | - Qingnan He
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China,*Correspondence: Mingyi Zhao, ; Qingnan He,
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Age-Associated Loss in Renal Nestin-Positive Progenitor Cells. Int J Mol Sci 2022; 23:ijms231911015. [PMID: 36232326 PMCID: PMC9569966 DOI: 10.3390/ijms231911015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/13/2022] [Accepted: 09/17/2022] [Indexed: 12/03/2022] Open
Abstract
The decrease in the number of resident progenitor cells with age was shown for several organs. Such a loss is associated with a decline in regenerative capacity and a greater vulnerability of organs to injury. However, experiments evaluating the number of progenitor cells in the kidney during aging have not been performed until recently. Our study tried to address the change in the number of renal progenitor cells with age. Experiments were carried out on young and old transgenic nestin-green fluorescent protein (GFP) reporter mice, since nestin is suggested to be one of the markers of progenitor cells. We found that nestin+ cells in kidney tissue were located in the putative niches of resident renal progenitor cells. Evaluation of the amount of nestin+ cells in the kidneys of different ages revealed a multifold decrease in the levels of nestin+ cells in old mice. In vitro experiments on primary cultures of renal tubular cells showed that all cells including nestin+ cells from old mice had a lower proliferation rate. Moreover, the resistance to damaging factors was reduced in cells obtained from old mice. Our data indicate the loss of resident progenitor cells in kidneys and a decrease in renal cells proliferative capacity with aging.
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Tetta C, Deregibus MC, Camussi G. Stem cells and stem cell-derived extracellular vesicles in acute and chronic kidney diseases: mechanisms of repair. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:570. [PMID: 32775371 PMCID: PMC7347774 DOI: 10.21037/atm.2020.03.19] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Acute and chronic renal failure have long been described and now renamed as acute kidney injury (AKI) and chronic kidney disease (CKD). New concepts are emerging in the pathophysiology of kidney diseases. AKI is often caused by triggering factors (e.g., toxic, ischemic, immunologic) either individually or combined such as in sepsis (inflammation and hypoxia), and it is initiated at a defined time. Several experimental models of AKI have provided deep insight and have convincingly shown important proof-of-concepts of therapeutic relevance over the years. CKD is now considered a slowly developing disease with often an insidious course, lasting many years whereby co-morbidities (e.g., diabetes, hypertension, dysmetabolic syndrome) may act as worsening factors. It has become increasingly evident that even a single event of AKI may lead to a higher predisposition to develop a progressive CKD. In the present review, we will report studies on the renal protection by adult stem cells in different experimental models and clinical trials. The emerging role of extracellular vesicles (EVs) in cell-to-cell communication and their predominant effect in the paracrine mechanisms of stem cell-dependent actions have prompted several studies on their ability to attenuate both AKI and fibrosis occurring in CKD. We discuss several critical issues that need to be addressed before EVs may have a therapeutic application in humans.
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Affiliation(s)
- Ciro Tetta
- Unicyte Srl, University of Turin, Turin, Italy
| | - Maria Chiara Deregibus
- Department of Medical Sciences, University of Turin, Turin, Italy.,2i3T Incubator and Technology Transfer, University of Turin, Turin, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Turin, Italy
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Intracellular Reactive Oxygen Species Mediate the Therapeutic Effect of Induced Pluripotent Stem Cells for Acute Kidney Injury. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:1609638. [PMID: 32308798 PMCID: PMC7136790 DOI: 10.1155/2020/1609638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 02/03/2020] [Accepted: 02/19/2020] [Indexed: 11/17/2022]
Abstract
Aims Treatment for acute kidney injury (AKI) is challenging. Induced pluripotent stem cells (iPSCs) have great therapeutic potential. This study sought to determine whether iPSCs attenuate AKI and the role of reactive oxygen species (ROS). Results We intravenously injected isogenic iPSCs into mice 2 h after renal ischemia-reperfusion injury (IRI). The cells were selectively trafficked to ischemia/reperfusion-injured kidney where they decreased kidney ROS and inflammatory cytokines and improved kidney function and morphology. Pretreating the cells with ROS inhibitors before administration decreased iPSC engraftment and abolished the protective effect of iPSCs. In contrast, pretreating iPSCs with hydrogen peroxide increased iPSC engraftment and therapeutic effect. Although the intravenously administered iPSCs trafficked to the IRI kidney, the cells did not differentiate into proximal or distal tubular epithelial cells. In vitro, the capabilities of the iPSC-released substances to promote proliferation and decrease apoptosis of renal epithelial cells were increased by ROS pretreatment of iPSCs. Moreover, pretreatment of the iPSCs with ROS inhibitor had the opposite effect. Similarly, moderate concentrations of ROS increased while ROS inhibitors decreased iPSC mobility, adhesion to the extracellular matrix, and mitochondrial metabolism. Innovation and Conclusion. iPSCs decreased renal ischemia/reperfusion injury mainly through iPSC-released substances. The therapeutic effect, mitochondrial metabolism, mobility, and kidney trafficking of iPSCs were ROS dependent.
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Rangel EB, Gomes SA, Kanashiro-Takeuchi R, Saltzman RG, Wei C, Ruiz P, Reiser J, Hare JM. Kidney-derived c-kit + progenitor/stem cells contribute to podocyte recovery in a model of acute proteinuria. Sci Rep 2018; 8:14723. [PMID: 30283057 PMCID: PMC6170432 DOI: 10.1038/s41598-018-33082-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 09/18/2018] [Indexed: 02/06/2023] Open
Abstract
Kidney-derived c-kit+ cells exhibit progenitor/stem cell properties and can regenerate epithelial tubular cells following ischemia-reperfusion injury in rats. We therefore investigated whether c-kit+ progenitor/stem cells contribute to podocyte repair in a rat model of acute proteinuria induced by puromycin aminonucleoside (PAN), the experimental prototype of human minimal change disease and early stages of focal and segmental glomerulosclerosis. We found that c-kit+ progenitor/stem cells accelerated kidney recovery by improving foot process effacement (foot process width was lower in c-kit group vs saline treated animals, P = 0.03). In particular, these cells engrafted in small quantity into tubules, vessels, and glomeruli, where they occasionally differentiated into podocyte-like cells. This effect was related to an up regulation of α-Actinin-4 and mTORC2-Rictor pathway. Activation of autophagy by c-kit+ progenitor/stem cells also contributed to kidney regeneration and intracellular homeostasis (autophagosomes and autophagolysosomes number and LC3A/B-I and LC3A/B-II expression were higher in the c-kit group vs saline treated animals, P = 0.0031 and P = 0.0009, respectively). Taken together, our findings suggest that kidney-derived c-kit+ progenitor/stem cells exert reparative effects on glomerular disease processes through paracrine effects, to a lesser extent differentiation into podocyte-like cells and contribution to maintenance of podocyte cytoskeleton after injury. These findings have clinical implications for cell therapy of glomerular pathobiology.
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Affiliation(s)
- Erika B Rangel
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of Medicine University of Miami, Miami, 33136, Florida, USA.
- Hospital Israelita Albert Einstein Hospital, São Paulo, 05652, São Paulo, Brazil.
- Federal University of São Paulo, São Paulo, 04023, São Paulo, Brazil.
| | - Samirah A Gomes
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of Medicine University of Miami, Miami, 33136, Florida, USA
- Laboratory of Cellular, Genetic, and Molecular Nephrology, Renal Division, University of São Paulo, 01246, São Paulo, Brazil
| | - Rosemeire Kanashiro-Takeuchi
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of Medicine University of Miami, Miami, 33136, Florida, USA
- Department of Molecular and Cellular Pharmacology, Leonard M Miller School of Medicine, University of Miami, Miami, 33136, Florida, USA
| | - Russell G Saltzman
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of Medicine University of Miami, Miami, 33136, Florida, USA
| | - Changli Wei
- Department of Medicine, Rush University Medical Center, Chicago, 60612, Illinois, USA
| | - Phillip Ruiz
- Departments of Surgery and Pathology, Leonard M Miller School of Medicine University of Miami, Miami, 33136, Florida, USA
| | - Jochen Reiser
- Department of Medicine, Rush University Medical Center, Chicago, 60612, Illinois, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, Leonard M Miller School of Medicine University of Miami, Miami, 33136, Florida, USA.
- Department of Molecular and Cellular Pharmacology, Leonard M Miller School of Medicine, University of Miami, Miami, 33136, Florida, USA.
- Division of Cardiology, Leonard M Miller School of Medicine University of Miami, Miami, 33136, Florida, USA.
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Gomes SA, Hare JM, Rangel EB. Kidney-Derived c-Kit + Cells Possess Regenerative Potential. Stem Cells Transl Med 2018; 7:317-324. [PMID: 29575816 PMCID: PMC5866938 DOI: 10.1002/sctm.17-0232] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Revised: 12/15/2017] [Accepted: 01/14/2018] [Indexed: 12/27/2022] Open
Abstract
Kidney-derived c-Kit+ cells exhibit progenitor/stem cell properties in vitro (self-renewal capacity, clonogenicity, and multipotentiality). These cells can regenerate epithelial tubular cells following ischemia-reperfusion injury and accelerate foot processes effacement reversal in a model of acute proteinuria in rats. Several mechanisms are involved in kidney regeneration by kidney-derived c-Kit+ cells, including cell engraftment and differentiation into renal-like structures, such as tubules, vessels, and podocytes. Moreover, paracrine mechanisms could also account for kidney regeneration, either by stimulating proliferation of surviving cells or modulating autophagy and podocyte cytoskeleton rearrangement through mTOR-Raptor and -Rictor signaling, which ultimately lead to morphological and functional improvement. To gain insights into the functional properties of c-Kit+ cells during kidney development, homeostasis, and disease, studies on lineage tracing using transgenic mice will unveil their fate. The results obtained from these studies will set the basis for establishing further investigation on the therapeutic potential of c-Kit+ cells for treatment of kidney disease in preclinical and clinical studies. Stem Cells Translational Medicine 2018;7:317-324.
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Affiliation(s)
- Samirah A. Gomes
- Laboratory of Cellular, Genetic, and Molecular Nephrology, Renal DivisionUniversity of São PauloSão PauloSão PauloBrazil
| | - Joshua M. Hare
- Interdisciplinary Stem Cell InstituteLeonard M Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Department of Molecular and Cellular PharmacologyLeonard M Miller School of Medicine, University of MiamiMiamiFloridaUSA
- Division of CardiologyLeonard M Miller School of Medicine, University of MiamiMiamiFloridaUSA
| | - Erika B. Rangel
- Instituto Israelita de Ensino e Pesquisa Albert Einstein, Hospital Israelita Albert EinsteinSão PauloSão PauloBrazil
- Division of NephrologyFederal University of São PauloSão PauloSão PauloBrazil
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Shen WC, Chou YH, Lin SL. Enthusiasm for induced pluripotent stem cell-based therapies in kidney regeneration. J Formos Med Assoc 2016; 115:593-4. [DOI: 10.1016/j.jfma.2014.06.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2014] [Accepted: 06/22/2014] [Indexed: 01/02/2023] Open
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Habib R, Haneef K, Naeem N, Khan I, Jamall S, Atta-Ur-Rahman, Salim A. Hypoxic stress and IL-7 gene overexpression enhance the fusion potential of rat bone marrow mesenchymal stem cells with bovine renal epithelial cells. Mol Cell Biochem 2015; 403:125-137. [PMID: 25666089 DOI: 10.1007/s11010-015-2343-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2014] [Accepted: 01/30/2015] [Indexed: 01/08/2023]
Abstract
Transplantation of mesenchymal stem cells (MSCs) has been shown to enhance the improvement in kidney function following injury. However, the poor survival and grafting of the stem cells to the site of injury has restricted their therapeutic efficacy. Accelerated regeneration potential of MSCs has been observed when they were exposed to hypoxic stress or genetic modulation by various cytokines and growth factors. These preconditioning strategies may stimulate endogenous mechanisms resulting in multiple cellular responses. In this study, we used IL-7 gene to transfect MSCs. IL-7 is a hematopoietic growth factor that plays an important role in cell survival, proliferation, and differentiation. MSCs were also subjected to hypoxic stress for 8 and 24 h. These preconditioned MSCs were co-cultured with cisplatin-treated injured Mardin-Darby bovine kidney (MDBK) cells and their fusion potential was analyzed. Flow cytometry of fluorescently labeled preconditioned MSCs and injured MDBK cells revealed evidence of significant (P < 0.001) cell fusion compared to that of the normal MSCs. In addition, we also observed improved migration ability of these preconditioned MSCs in the in vitro wound healing assay, as compared to the normal MSCs. We conclude that hypoxic stress and IL-7 overexpression can enhance the renal regeneration potential of MSCs. This study would help in designing more potent therapeutic strategy in which preconditioned MSCs can be used for renal regeneration.
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Affiliation(s)
- Rakhshinda Habib
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
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Hishikawa K, Takase O, Yoshikawa M, Tsujimura T, Nangaku M, Takato T. Adult stem-like cells in kidney. World J Stem Cells 2015; 7:490-494. [PMID: 25815133 PMCID: PMC4369505 DOI: 10.4252/wjsc.v7.i2.490] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/31/2014] [Accepted: 12/10/2014] [Indexed: 02/06/2023] Open
Abstract
Human pluripotent cells are promising for treatment for kidney diseases, but the protocols for derivation of kidney cell types are still controversial. Kidney tissue regeneration is well confirmed in several lower vertebrates such as fish, and the repair of nephrons after tubular damages is commonly observed after renal injury. Even in adult mammal kidney, renal progenitor cell or system is reportedly presents suggesting that adult stem-like cells in kidney can be practical clinical targets for kidney diseases. However, it is still unclear if kidney stem cells or stem-like cells exist or not. In general, stemness is defined by several factors such as self-renewal capacity, multi-lineage potency and characteristic gene expression profiles. The definite use of stemness may be obstacle to understand kidney regeneration, and here we describe the recent broad findings of kidney regeneration and the cells that contribute regeneration.
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