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Meng Y, Sui L, Xu T, Zhao H, Yuan Q, Sun L. Research and Application Prospect of Nanomedicine in Kidney Disease: A Bibliometric Analysis From 2003 to 2024. Int J Nanomedicine 2025; 20:3007-3030. [PMID: 40093546 PMCID: PMC11910916 DOI: 10.2147/ijn.s510016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Accepted: 02/21/2025] [Indexed: 03/19/2025] Open
Abstract
Kidney disease is a major public health concern that has a significant effect on a patient's life span and quality of life. However, effective treatment for most kidney diseases is lacking. Nanotechnology mainly explores the design, characterization, production, and applications of objects in the nanoscale range and has been widely used in the medical field. To date, there has been an increasing amount of research on the application of nanotechnology in kidney disease. However, systematic bibliometric studies remain rare. In this review, data collected from the Web of Science Core Collection database until December 31, 2024, were subjected to a bibliometric analysis. A total of 1179 articles and reviews were included. The publication trends, countries, institutions, authors, co-authorship, co-citations, journals, keywords, and references pertaining to this topic were examined. The results showed that nanotechnology research in kidney disease is increasing. The leading country, organization, and author were China, Sichuan University, and Professor Peng Huang, respectively. ACS APPLIED MATERIALS & INTERFACES was the top journal among the 464 journals in which articles on nanotechnology in kidney disease were published. KIDNEY INTERNATIONAL was the most cited journal in the field. The most significant increases were shown for "acute kidney disease", "drug delivery", "oxidative stress", "diabetic nephropathy", and "chronic kidney disease", indicating the current research hotspots. Furthermore, the development prospects and challenges of nanotechnology in kidney disease were discussed in this review. How to achieve precise drug delivery to render kidney-targeting therapy a reality may be problematic in future studies.
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Affiliation(s)
- Yilin Meng
- Department of Nephrology, The First Hospital of China Medical University, Shenyang110001, People’s Republic of China
| | - Lu Sui
- Department of Nephrology, The First Hospital of China Medical University, Shenyang110001, People’s Republic of China
| | - Tianhua Xu
- Department of Nephrology, The First Hospital of China Medical University, Shenyang110001, People’s Republic of China
| | - Hainan Zhao
- Department of Nephrology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou121001, People’s Republic of China
| | - Quan Yuan
- Department of Orthopedics, Shengjing Hospital of China Medical University, Shenyang, 110004, People’s Republic of China
| | - Li Sun
- Department of Nephrology, The First Hospital of China Medical University, Shenyang110001, People’s Republic of China
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Lindoso RS, Collino F, Kasai-Brunswick TH, Costa MR, Verdoorn KS, Einicker-Lamas M, Vieira-Beiral HJ, Wessely O, Vieyra A. Resident Stem Cells in Kidney Tissue. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:159-203. [DOI: 10.1016/b978-0-443-15289-4.00009-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Franzin R, Stasi A, De Palma G, Picerno A, Curci C, Sebastiano S, Campioni M, Cicirelli A, Rizzo A, Di Lorenzo VF, Pontrelli P, Pertosa GB, Castellano G, Gesualdo L, Sallustio F. Human Adult Renal Progenitor Cells Prevent Cisplatin-Nephrotoxicity by Inducing CYP1B1 Overexpression and miR-27b-3p Down-Regulation through Extracellular Vesicles. Cells 2023; 12:1655. [PMID: 37371125 DOI: 10.3390/cells12121655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 06/29/2023] Open
Abstract
Cisplatin is one of the most effective chemotherapeutic agents strongly associated with nephrotoxicity. Tubular adult renal progenitor cells (tARPC) can regenerate functional tubules and participate in the repair processes after cisplatin exposition. This study investigated the molecular mechanisms underlying the protective effect of tARPC on renal epithelium during cisplatin nephrotoxicity. By performing a whole-genome transcriptomic analysis, we found that tARPC, in presence of cisplatin, can strongly influence the gene expression of renal proximal tubular cell [RPTEC] by inducing overexpression of CYP1B1, a member of the cytochrome P450 superfamily capable of metabolizing cisplatin and of hypoxia/cancer-related lncRNAs as MIR210HG and LINC00511. Particularly, tARPC exerted renoprotection and regeneration effects via extracellular vesicles (EV) enriched with CYP1B1 and miR-27b-3p, a well-known CYP1B1 regulatory miRNA. The expression of CYP1B1 by tARPC was confirmed by analyzing biopsies of cisplatin-treated renal carcinoma patients that showed the colocalization of CYP1B1 with the tARPC marker CD133. CYP1B1 was also overexpressed in urinary EV purified from oncologic patients that presented nephrotoxicity episodes after cisplatin treatment. Interestingly CYP1B1 expression significantly correlated with creatinine and eGFR levels. Taken together, our results show that tARPC are able to counteract cisplatin-induced nephrotoxicity via CYP1B1 release through EV. These findings provide a promising therapeutic strategy for nephrotoxicity risk assessment that could be related to abundance of renal progenitors.
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Affiliation(s)
- Rossana Franzin
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
- MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Alessandra Stasi
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
- MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Giuseppe De Palma
- Institutional BioBank, Experimental Oncology and Biobank Management Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy
| | - Angela Picerno
- Department Interdisciplinary of Medicine (DIM), University of Bari, 70124 Bari, Italy
| | - Claudia Curci
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
| | - Serena Sebastiano
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
| | - Monica Campioni
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
| | - Antonella Cicirelli
- Department Interdisciplinary of Medicine (DIM), University of Bari, 70124 Bari, Italy
| | - Alessandro Rizzo
- Struttura Semplice Dipartimentale di Oncologia Medica per la Presa in Carico Globale del Paziente Oncologico 'Don Tonino Bello', IRCCS Istituto Tumori 'Giovanni Paolo II', Viale Orazio Flacco 65, 70124 Bari, Italy
| | | | - Paola Pontrelli
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
| | - Giovanni Battista Pertosa
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
| | - Giuseppe Castellano
- Unit of Nephrology, Dialysis and Renal Transplantation, Fondazione IRCCS Ca'Granda Ospedale Maggiore Policlinico di Milano, 20122 Milan, Italy
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
- MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Fabio Sallustio
- Renal, Dialysis and Transplantation Unit, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari, 70124 Bari, Italy
- MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
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Sameri MJ, Savari F, Hoseinynejad K, Danyaei A, Mard SA. The hepato-protective effect of H2S-modified and non-modified mesenchymal stem cell exosomes on liver ischemia-reperfusion injury in mice: The role of MALAT1. Biochem Biophys Res Commun 2022; 635:194-202. [PMID: 36279681 DOI: 10.1016/j.bbrc.2022.09.111] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 09/21/2022] [Accepted: 09/28/2022] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Ischemia-reperfusion injury (IRI) by causing histopathological changes is considered one of the most important causes of liver failure and dysfunction after surgery which affect graft outcomes. Stem cells are new promising approaches to treating different diseases. One of the critical strategies to improve their function is the preconditioning of their culture medium. This study compared the effect of NaHS-modified and non-modified mesenchymal stem cell exosomes on liver ischemia-reperfusion injury in mice. METHODS Human umbilical cord-derived MSC (MSC) cultured in a 75 cm3 flask and when confluency reached about 80%, the culture medium replaced with a serum-free medium, and 48 h later supernatants collected, concentrated, and then MSC-Exo extracted. To obtain H2S-Exo, MSC was treated with NaHS (1 μmol),the supernatant collected after 48 h, concentrated and exosomes extracted. Twenty-four male mice were randomly divided into four groups (n = 6) including: 1-ischemia, 2-sham-operated, 3- MSC-Exo, and 4- H2S-Exo. To induce ischemia, the hepatic artery and portal vein clamped using an atraumatic clip for 60 min followed by 3 h of reperfusion. Just upon ending the time of ischemia (removal of clamp artery), animals in MSC-Exo, and H2S-Exo groups received 100 μg exosomes in 100 μl PBS via tail vein. At the end of reperfusion, blood, and liver samples were collected for further serological, molecular, and histological analyses. RESULTS Administration of both MSC-Exo and H2S-Exo improved liver function by reducing inflammatory cytokines, cellular apoptosis, liver levels of total oxidant status, and liver aminotransferases. The results showed that protecting effect of MSC exosomes enhanced following NaHS preconditioning of cell culture medium. CONCLUSION MSC-Exo and H2S-Exo had hepato-protective effects against injuries induced by ischemia-reperfusion in mice. NaHS preconditioning of mesenchymal stem cells could enhance the therapeutic effects of MSC-derived exosomes.
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Affiliation(s)
- Maryam J Sameri
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Feryal Savari
- Department of Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran
| | - Khojasteh Hoseinynejad
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Amir Danyaei
- Department of Medical Physics, The School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Ali Mard
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Okumura K, Grace H, Sogawa H, Yamanaga S. Acute kidney injury and the compensation of kidney function after nephrectomy in living donation. World J Transplant 2022; 12:223-230. [PMID: 36159072 PMCID: PMC9453297 DOI: 10.5500/wjt.v12.i8.223] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/27/2022] [Accepted: 08/05/2022] [Indexed: 02/05/2023] Open
Abstract
Acute kidney injury (AKI) incidence is growing rapidly, and AKI is one of the predictors of inpatient mortality. After nephrectomy, all the patients have decreased kidney function with AKI and recover from AKI. However, the characteristic and behavior of AKI is different from usual AKI and compensatory kidney function has been well known in the postoperative setting, especially in living donors. In this review, we have focused on the compensation of kidney function after nephrectomy in living donors. We discuss factors that have been identified as being associated with kidney recovery in donors including age, sex, body mass index, remnant kidney volume, estimated glomerular filtration rate, and various comorbidities.
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Affiliation(s)
- Kenji Okumura
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, NY 10595, United States
| | - Holly Grace
- Department of Surgery, New York Medical College, Valhalla, NY 10595, United States
| | - Hiroshi Sogawa
- Department of Surgery, Westchester Medical Center/New York Medical College, Valhalla, NY 10595, United States
| | - Shigeyoshi Yamanaga
- Department of Surgery, Japanese Red Cross Kumamoto Hospital, Kumamoto 861-8520, Japan
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Lee PW, Wu BS, Yang CY, Lee OKS. Molecular Mechanisms of Mesenchymal Stem Cell-Based Therapy in Acute Kidney Injury. Int J Mol Sci 2021; 22:11406. [PMID: 34768837 PMCID: PMC8583897 DOI: 10.3390/ijms222111406] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/18/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
Acute kidney injury (AKI) causes a lot of harm to human health but is treated by only supportive therapy in most cases. Recent evidence shows that mesenchymal stem cells (MSCs) benefit kidney regeneration through releasing paracrine factors and extracellular vesicles (EVs) to the recipient kidney cells and are considered to be promising cellular therapy for AKI. To develop more efficient, precise therapies for AKI, we review the therapeutic mechanism of MSCs and MSC-derived EVs in AKI and look for a better understanding of molecular signaling and cellular communication between donor MSCs and recipient kidney cells. We also review recent clinical trials of MSC-EVs in AKI. This review summarizes the molecular mechanisms of MSCs' therapeutic effects on kidney regeneration, expecting to comprehensively facilitate future clinical application for treating AKI.
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Grants
- Yin Yen-Liang Foundation Development and Construction Plan (107F-M01-0504) National Yang-Ming University
- MOST 108-2923-B-010-002-MY3, MOST 109-2314-B-010-053-MY3, MOST 109-2811-B-010-532, MOST 109-2926-I-010-502, MOST 109-2823-8-010-003-CV, MOST 109-2622-B-010-006, MOST 109-2321-B-010-006, MOST 110-2923-B-A49A-501-MY3, and MOST 110-2321-B-A49-003 Ministry of Science and Technology, Taiwan
- V106D25-003-MY3, VGHUST107-G5-3-3, VGHUST109-V5-1-2, and V110C-194 Taipei Veterans General Hospital
- Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B) Ministry of Education
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Affiliation(s)
- Pei-Wen Lee
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (P.-W.L.); (B.-S.W.)
- Hong Deh Clinic, Taipei 11251, Taiwan
| | - Bo-Sheng Wu
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (P.-W.L.); (B.-S.W.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Chih-Yu Yang
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (P.-W.L.); (B.-S.W.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Department of Medicine, Division of Nephrology, Taipei Veterans General Hospital, Taipei 11217, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-Devices (IDS2B), National Yang Ming Chiao Tung University, Hsinchu 30010, Taiwan
- Stem Cell Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Oscar Kuang-Sheng Lee
- Institute of Clinical Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; (P.-W.L.); (B.-S.W.)
- Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Stem Cell Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Department of Orthopedics, China Medical University Hospital, Taichung 40447, Taiwan
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Will cell therapies provide the solution for the shortage of transplantable organs? Curr Opin Organ Transplant 2020; 24:568-573. [PMID: 31389811 DOI: 10.1097/mot.0000000000000686] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PURPOSE OF REVIEW The potential to regenerate ischemically damaged kidneys while being perfused ex-vivo offers the best near-term solution to increasing kidney allografts for transplantation. RECENT FINDINGS There are a number of stem-cell sources including: stromal mesenchymal cells (MSC), induced adult pluripotent stem cells, fetal stem cells from placenta, membranes, amniotic fluid and umbilical cord and hematopoietic cells. MSC are increasingly the stem cell of choice and studies are primarily focused on novel induction immunosuppression to prevent rejection. Stem-cell therapies applied in vivo may be of limited benefit because the nonintegrating cells do not remain in the kidney and are not detectable in the body after several days. MSC therapies for transplantation have demonstrated early safety and feasibility. However, efficacy has not been clearly established. A more feasible application of a stem-cell therapy in transplantation is the administration of MSC to treat damaged renal allografts directly while being perfused ex vivo. Initial feasibility has been established demonstrating MSC-treatment results in statistically significant reduction of inflammatory responses, increased ATP and growth factor synthesis and mitosis. SUMMARY The ability to regenerate renal tissue ex-vivo sufficiently to result in immediate function could revolutionize transplantation by solving the chronic organ shortage.
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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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Lee SJ, Wang HJ, Kim TH, Choi JS, Kulkarni G, Jackson JD, Atala A, Yoo JJ. In Situ Tissue Regeneration of Renal Tissue Induced by Collagen Hydrogel Injection. Stem Cells Transl Med 2019; 7:241-250. [PMID: 29380564 PMCID: PMC5788870 DOI: 10.1002/sctm.16-0361] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 11/17/2017] [Indexed: 12/12/2022] Open
Abstract
Host stem/progenitor cells can be mobilized and recruited to a target location using biomaterials, and these cells may be used for in situ tissue regeneration. The objective of this study was to investigate whether host biologic resources could be used to regenerate renal tissue in situ. Collagen hydrogel was injected into the kidneys of normal mice, and rat kidneys that had sustained ischemia/reperfusion injury. After injection, the kidneys of both animal models were examined up to 4 weeks for host tissue response. The infiltrating host cells present within the injection regions expressed renal stem/progenitor cell markers, PAX‐2, CD24, and CD133, as well as mesenchymal stem cell marker, CD44. The regenerated renal structures were identified by immunohistochemistry for renal cell specific markers, including synaptopodin and CD31 for glomeruli and cytokeratin and neprilysin for tubules. Quantitatively, the number of glomeruli found in the injected regions was significantly higher when compared to normal regions of renal cortex. This phenomenon occurred in normal and ischemic injured kidneys. Furthermore, the renal function after ischemia/reperfusion injury was recovered after collagen hydrogel injection. These results demonstrate that introduction of biomaterials into the kidney is able to facilitate the regeneration of glomerular and tubular structures in normal and injured kidneys. Such an approach has the potential to become a simple and effective treatment for patients with renal failure. Stem Cells Translational Medicine2018;7:241–250
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Affiliation(s)
- Sang Jin Lee
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Hung-Jen Wang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.,Department of Urology, Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University Collagen of Medicine, Kaohsiung City, Taiwan, Republic of China
| | - Tae-Hyoung Kim
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.,Department of Urology, Chung-Ang University Hospital, Seoul, South Korea
| | - Jin San Choi
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Gauri Kulkarni
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - John D Jackson
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
| | - James J Yoo
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
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Abstract
Every year 13.3 million people suffer acute kidney injury (AKI), which is associated with a high risk of death or development of long-term chronic kidney disease (CKD) in a substantial percentage of patients besides other organ dysfunctions. To date, the mortality rate per year for AKI exceeds 50 % at least in patients requiring early renal replacement therapy and is higher than the mortality for breast and prostate cancer, heart failure and diabetes combined.Until now, no effective treatments able to accelerate renal recovery and improve survival post AKI have been developed. In search of innovative and effective strategies to foster the limited regeneration capacity of the kidney, several studies have evaluated the ability of mesenchymal stem cells (MSCs) of different origin as an attractive therapeutic tool. The results obtained in several models of AKI and CKD document that MSCs have therapeutic potential in repair of renal injury, preserving renal function and structure thus prolonging animal survival through differentiation-independent pathways. In this chapter, we have summarized the mechanisms underlying the regenerative processes triggered by MSC treatment, essentially due to their paracrine activity. The capacity of MSC to migrate to the site of injury and to secrete a pool of growth factors and cytokines with anti-inflammatory, mitogenic, and immunomodulatory effects is described. New modalities of cell-to-cell communication via the release of microvesicles and exosomes by MSCs to injured renal cells will also be discussed. The translation of basic experimental data on MSC biology into effective care is still limited to preliminary phase I clinical trials and further studies are needed to definitively assess the efficacy of MSC-based therapy in humans.
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Affiliation(s)
- Marina Morigi
- IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126, Bergamo, Italy.
| | - Cinzia Rota
- IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126, Bergamo, Italy
| | - Giuseppe Remuzzi
- IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126, Bergamo, Italy
- Unit of Nephrology and Dialysis, A.O. Papa Giovanni XXIII, 24127, Bergamo, Italy
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Gnecchi M, Danieli P, Malpasso G, Ciuffreda MC. Paracrine Mechanisms of Mesenchymal Stem Cells in Tissue Repair. Methods Mol Biol 2017; 1416:123-46. [PMID: 27236669 DOI: 10.1007/978-1-4939-3584-0_7] [Citation(s) in RCA: 294] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Tissue regeneration from transplanted mesenchymal stromal cells (MSC) either through transdifferentiation or cell fusion was originally proposed as the principal mechanism underlying their therapeutic action. However, several studies have now shown that both these mechanisms are very inefficient. The low MSC engraftment rate documented in injured areas also refutes the hypothesis that MSC repair tissue damage by replacing cell loss with newly differentiated cells. Indeed, despite evidence of preferential homing of MSC to the site of myocardial ischemia, exogenously administered MSC show poor survival and do not persist in the infarcted area. Therefore, it has been proposed that the functional benefits observed after MSC transplantation in experimental models of tissue injury might be related to the secretion of soluble factors acting in a paracrine fashion. This hypothesis is supported by pre-clinical studies demonstrating equal or even improved organ function upon infusion of MSC-derived conditioned medium (MSC-CM) compared with MSC transplantation. Identifying key MSC-secreted factors and their functional role seems a reasonable approach for a rational design of nextgeneration MSC-based therapeutics. Here, we summarize the major findings regarding both different MSC-mediated paracrine actions and the identification of paracrine mediators.
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Affiliation(s)
- Massimiliano Gnecchi
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy. .,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. .,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. .,Department of Medicine, University of Cape Town, Cape Town, South Africa.
| | - Patrizia Danieli
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy.,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Giuseppe Malpasso
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy.,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Maria Chiara Ciuffreda
- Department of Molecular Medicine, Unit of Cardiology, University of Pavia, Pavia, Italy.,Department of Cardiothoracic and Vascular Sciences - Coronary Care Unit and Laboratory of Clinical and Experimental Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.,Laboratory of Experimental Cardiology for Cell and Molecular Therapy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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12
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Francoz C, Nadim MK, Durand F. Kidney biomarkers in cirrhosis. J Hepatol 2016; 65:809-824. [PMID: 27238754 DOI: 10.1016/j.jhep.2016.05.025] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Revised: 05/10/2016] [Accepted: 05/18/2016] [Indexed: 12/14/2022]
Abstract
Impaired renal function due to acute kidney injury (AKI) and/or chronic kidney diseases (CKD) is frequent in cirrhosis. Recurrent episodes of AKI may occur in end-stage cirrhosis. Differential diagnosis between functional (prerenal and hepatorenal syndrome) and acute tubular necrosis (ATN) is crucial. The concept that AKI and CKD represent a continuum rather than distinct entities, is now emerging. Not all patients with AKI have a potential for full recovery. Precise evaluation of kidney function and identification of kidney changes in patients with cirrhosis is central in predicting reversibility. This review examines current biomarkers for assessing renal function and identifying the cause and mechanisms of impaired renal function. When CKD is suspected, clearance of exogenous markers is the reference to assess glomerular filtration rate, as creatinine is inaccurate and cystatin C needs further evaluation. Recent biomarkers may help differentiate ATN from hepatorenal syndrome. Neutrophil gelatinase-associated lipocalin has been the most extensively studied biomarker yet, however, there are no clear-cut values that differentiate each of these conditions. Studies comparing ATN and hepatorenal syndrome in cirrhosis, do not include a gold standard. Combinations of innovative biomarkers are attractive to identify patients justifying simultaneous liver and kidney transplantation. Accurate biomarkers of underlying CKD are lacking and kidney biopsy is often contraindicated in this population. Urinary microRNAs are attractive although not definitely validated. Efforts should be made to develop biomarkers of kidney fibrosis, a common and irreversible feature of CKD, whatever the cause. Biomarkers of maladaptative repair leading to irreversible changes and CKD after AKI are also promising.
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Affiliation(s)
- Claire Francoz
- Hepatology and Liver Intensive Care, Hospital Beaujon, Clichy, France; University Paris VII Diderot, Paris, France; INSERM U1149, Paris, France; Département Hospitalo-Universitaire UNITY, Clichy, France.
| | - Mitra K Nadim
- Division of Nephrology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - François Durand
- Hepatology and Liver Intensive Care, Hospital Beaujon, Clichy, France; University Paris VII Diderot, Paris, France; INSERM U1149, Paris, France; Département Hospitalo-Universitaire UNITY, Clichy, France
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13
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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: 67] [Impact Index Per Article: 7.4] [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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14
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Manson SR, Austin PF, Guo Q, Moore KH. BMP-7 Signaling and its Critical Roles in Kidney Development, the Responses to Renal Injury, and Chronic Kidney Disease. VITAMINS AND HORMONES 2016; 99:91-144. [PMID: 26279374 DOI: 10.1016/bs.vh.2015.05.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic kidney disease (CKD) is a significant health problem that most commonly results from congenital abnormalities in children and chronic renal injury in adults. The therapeutic potential of BMP-7 was first recognized nearly two decades ago with studies demonstrating its requirement for kidney development and ability to inhibit the pathogenesis of renal injury in models of CKD. Since this time, our understanding of CKD has advanced considerably and treatment strategies have evolved with the identification of many additional signaling pathways, cell types, and pathologic processes that contribute to disease progression. The purpose of this review is to revisit the seminal studies that initially established the importance of BMP-7, highlight recent advances in BMP-7 research, and then integrate this knowledge with current research paradigms. We will provide an overview of the evolutionarily conserved roles of BMP proteins and the features that allow BMP signaling pathways to function as critical signaling nodes for controlling biological processes, including those related to CKD. We will discuss the multifaceted functions of BMP-7 during kidney development and the potential for alterations in BMP-7 signaling to result in congenital abnormalities and pediatric kidney disease. We will summarize the renal protective effects of recombinant BMP-7 in experimental models of CKD and then propose a model to describe the potential physiological role of endogenous BMP-7 in the innate repair mechanisms of the kidneys that respond to renal injury. Finally, we will highlight emerging clinical approaches for applying our knowledge of BMP-7 toward improving the treatment of patients with CKD.
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Affiliation(s)
- Scott R Manson
- Department of Surgery, Division of Urology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri, USA.
| | - Paul F Austin
- Department of Surgery, Division of Urology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri, USA
| | - Qiusha Guo
- Department of Surgery, Division of Urology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri, USA
| | - Katelynn H Moore
- Department of Surgery, Division of Urology, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, Missouri, USA
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15
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Kramer J, Schwanbeck R, Pagel H, Cakiroglu F, Rohwedel J, Just U. Inhibition of Notch Signaling Ameliorates Acute Kidney Failure and Downregulates Platelet-Derived Growth Factor Receptor β in the Mouse Model. Cells Tissues Organs 2016; 201:109-17. [PMID: 26939110 DOI: 10.1159/000442463] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/16/2015] [Indexed: 11/19/2022] Open
Abstract
Ischemic acute kidney injury (AKI) is associated with high morbidity and frequent complications. Repeated episodes of AKI may lead to end-stage renal failure. The pathobiology of regeneration in AKI is not well understood and there is no effective clinical therapy that improves regeneration. The Notch signaling pathway plays an essential role in kidney development and has been implicated in tissue repair in the adult kidney. Here, we found that kidneys after experimental AKI in mice showed increased expression of Notch receptors, specifically Notch1-3, of the Notch ligands Jagged-1 (Jag1), Jag2 and Delta-like-4 (Dll4) and of the Notch target genes Hes1, Hey2, HeyL, Sox9 and platelet-derived growth factor receptor β (Pdgfrb). Treatment of ischemic mice with the x03B3;-secretase inhibitor DBZ blocked Notch signaling and specifically downregulated the expression of Notch3 and the Notch target genes Hes1, Hey2, HeyL and Pdgfrb. After DBZ treatment, the mice developed less interstitial edema and displayed altered interstitial inflammation patterns. Furthermore, serum urea and creatinine levels were significantly decreased from 6 h onwards when compared to control mice treated with DMSO only. Our data are consistent with an amelioration of the severity of kidney injury by blocking Notch activation following AKI, and suggest an involvement of Notch-regulated Pdgfrb in AKI pathogenesis.
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Affiliation(s)
- Jan Kramer
- Department of Virology and Cell Biology, University of Lx00FC;beck, Lx00FC;beck, Germany
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16
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Hatcher HC, Tesfay L, Torti SV, Torti FM. Cytoprotective Effect of Ferritin H in Renal Ischemia Reperfusion Injury. PLoS One 2015; 10:e0138505. [PMID: 26379029 PMCID: PMC4574775 DOI: 10.1371/journal.pone.0138505] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 08/31/2015] [Indexed: 01/08/2023] Open
Abstract
Oxidative stress is a major contributor to kidney injury following ischemia reperfusion. Ferritin, a highly conserved iron-binding protein, is a key protein in the maintenance of cellular iron homeostasis and protection from oxidative stress. Ferritin mitigates oxidant stress by sequestering iron and preventing its participation in reactions that generate reactive oxygen species. Ferritin is composed of two subunit types, ferritin H and ferritin L. Using an in vivo model that enables conditional tissue-specific doxycycline-inducible expression of ferritin H in the mouse kidney, we tested the hypothesis that an increased level of H-rich ferritin is renoprotective in ischemic acute renal failure. Prior to induction of ischemia, doxycycline increased ferritin H in the kidneys of the transgenic mice nearly 6.5-fold. Following reperfusion for 24 hours, induction of neutrophil gelatinous-associated lipocalin (NGAL, a urine marker of renal dysfunction) was reduced in the ferritin H overexpressers compared to controls. Histopathologic examination following ischemia reperfusion revealed that ferritin H overexpression increased intact nuclei in renal tubules, reduced the frequency of tubular profiles with luminal cast materials, and reduced activated caspase-3 in the kidney. In addition, generation of 4-hydroxy 2-nonenal protein adducts, a measurement of oxidant stress, was decreased in ischemia-reperfused kidneys of ferritin H overexpressers. These studies demonstrate that ferritin H can inhibit apoptotic cell death, enhance tubular epithelial viability, and preserve renal function by limiting oxidative stress following ischemia reperfusion injury.
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Affiliation(s)
- Heather C. Hatcher
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Lia Tesfay
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Suzy V. Torti
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
- Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
| | - Frank M. Torti
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
- Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States of America
- * E-mail:
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17
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Feng J, Hu W, Feng C, Mao X, Jin K, Ye Y. Increasing Proliferation of Intrinsic Tubular Cells after Renal Ischemia-reperfusion Injury in Adult Rat. Aging Dis 2015; 6:228-35. [PMID: 26236544 DOI: 10.14336/ad.2014.0917] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 09/11/2014] [Accepted: 09/17/2014] [Indexed: 02/02/2023] Open
Abstract
The kidney is capable of regeneration following injury. However, whether renal stem/progenitor cells contribute to the repair process after injury, as well as the origin of the cells that repair and replace damaged renal tubule cells remains debated. Therefore, better understanding of the repair process will be critical to developing new strategies for the treatment of acute renal failure. Using an ischemia-reperfusion injury mode and an immunocytochemistry method, we counted the number of BrdU-positive cells in damged regions at different durations of reperfusion. We found that BrdU, a cell proliferative marker, was mainly incorporated in the tubular cells of both medulla and cortex 1 day after reperfusion. The number of BrdU-positive cells reached a peak at 3 days and lasted for two months after injury. BrdU-positive cells were barely found in the renal glomerulus and the parietal layer of Bowman's capsule after injury, and only a few were found in the intersititium. PAX2, an embryonic renal marker, was also increased in renal tubule cells. Confocal images show that BrdU-positive cells co-expressed PAX2, but not the activated form of caspase-3, a cell death marker. Our data suggest that renal stem-like cells or dedifferentiation of surviving renal tubular cells in both the medulla and cortex may predominantly contribute to the repair process after renal ischemia-reperfusion injury in rat.
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Affiliation(s)
- Jian Feng
- Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang 310016, China
| | - Weiming Hu
- Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang 310016, China
| | - Chunyue Feng
- Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang 310016, China
| | - XiaoOu Mao
- Buck Institute for Research on Aging, Novato, CA94945, USA
| | - Kunlin Jin
- Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX76107, USA
| | - Youxin Ye
- Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang 310016, China
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18
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Simkin J, Sammarco MC, Dawson LA, Schanes PP, Yu L, Muneoka K. The mammalian blastema: regeneration at our fingertips. ACTA ACUST UNITED AC 2015; 2:93-105. [PMID: 27499871 PMCID: PMC4895320 DOI: 10.1002/reg2.36] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Revised: 03/14/2015] [Accepted: 03/16/2015] [Indexed: 02/06/2023]
Abstract
In the mouse, digit tip regeneration progresses through a series of discrete stages that include inflammation, histolysis, epidermal closure, blastema formation, and redifferentiation. Recent studies reveal how each regenerative stage influences subsequent stages to establish a blastema that directs the successful regeneration of a complex mammalian structure. The focus of this review is on early events of healing and how an amputation wound transitions into a functional blastema. The stepwise formation of a mammalian blastema is proposed to provide a model for how specific targeted treatments can enhance regenerative performance in humans.
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Affiliation(s)
- Jennifer Simkin
- Division of Developmental Biology, Department of Cell and Molecular Biology Tulane University New Orleans Louisiana 70118 USA
| | - Mimi C Sammarco
- Division of Developmental Biology, Department of Cell and Molecular Biology Tulane University New Orleans Louisiana 70118 USA
| | - Lindsay A Dawson
- Division of Developmental Biology, Department of Cell and Molecular Biology Tulane University New Orleans Louisiana 70118 USA
| | - Paula P Schanes
- Division of Developmental Biology, Department of Cell and Molecular Biology Tulane University New Orleans Louisiana 70118 USA
| | - Ling Yu
- Division of Developmental Biology, Department of Cell and Molecular Biology Tulane University New Orleans Louisiana 70118 USA
| | - Ken Muneoka
- Division of Developmental Biology, Department of Cell and Molecular Biology Tulane University New Orleans Louisiana 70118 USA
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19
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Trophic Factors from Tissue Stem Cells for Renal Regeneration. Stem Cells Int 2015; 2015:537204. [PMID: 26089918 PMCID: PMC4452108 DOI: 10.1155/2015/537204] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 01/09/2015] [Accepted: 01/09/2015] [Indexed: 12/23/2022] Open
Abstract
Stem cell therapies against renal injury have been advancing. The many trials for renal regeneration are reported to be effective in many kinds of renal injury models. Regarding the therapeutic mechanism, it is believed that stem cells contribute to make regeneration via not only direct stem cell differentiation in the injured space but also indirect effect via secreted factors from stem cells. Direct differentiation from stem cells to renal composed cells has been reported. They differentiate to renal composed cells and make functions. However, regarding renal regeneration, stem cells are discussed to secrete many kinds of growth factors, cytokines, and chemokines in paracrine or autocrine manner, which protect against renal injury, too. In addition, it is reported that stem cells have the ability to communicate with nearby cells via microvesicle-related RNA and proteins. Taken together from many reports, many secreted factors from stem cells were needed for renal regeneration orchestrally with harmony. In this review, we focused on the effects and insights of stem cells and regenerative factors from stem cells.
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20
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Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol 2015; 11:264-76. [PMID: 25643664 DOI: 10.1038/nrneph.2015.3] [Citation(s) in RCA: 619] [Impact Index Per Article: 61.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Acute kidney injury is an increasingly common complication of hospital admission and is associated with high levels of morbidity and mortality. A hypotensive, septic, or toxic insult can initiate a cascade of events, resulting in impaired microcirculation, activation of inflammatory pathways and tubular cell injury or death. These processes ultimately result in acutely impaired kidney function and initiation of a repair response. This Review explores the various mechanisms responsible for the initiation and propagation of acute kidney injury, the prototypic mechanisms by which a substantially damaged kidney can regenerate its normal architecture, and how the adaptive processes of repair can become maladaptive. These mechanisms, which include G2/M cell-cycle arrest, cell senescence, profibrogenic cytokine production, and activation of pericytes and interstitial myofibroblasts, contribute to the development of progressive fibrotic kidney disease. The end result is a state that mimics accelerated kidney ageing. These mechanisms present important opportunities for the design of targeted therapeutic strategies to promote adaptive renal recovery and minimize progressive fibrosis and chronic kidney disease after acute insults.
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21
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Beltramo E, Lopatina T, Berrone E, Mazzeo A, Iavello A, Camussi G, Porta M. Extracellular vesicles derived from mesenchymal stem cells induce features of diabetic retinopathy in vitro. Acta Diabetol 2014; 51:1055-64. [PMID: 25374383 DOI: 10.1007/s00592-014-0672-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 10/20/2014] [Indexed: 12/12/2022]
Abstract
AIMS Loss of pericytes in the early phases of diabetic retinopathy (DR) may disrupt their stable association with endothelial cells (EC), leading to EC proliferation and, eventually, angiogenesis. Extracellular vesicles (EV) are small membrane particles derived from different cells which contain biologically active proteins and RNA and are known to promote phenotypic changes in target cells. In diabetic-like conditions, EV derived from MSC may play a role in vessel destabilization by interfering with the strict interactions between EC/pericytes and pericyte/extracellular matrix. METHODS We examined the behaviour of retinal pericytes exposed to EV derived from MSC cultured in physiological and diabetic-like conditions (high glucose and/or hypoxia). RESULTS MSC-derived EV are able to enter the pericytes, cause their detachment and migration from the substrate, and increase blood-barrier permeability. Moreover, EV added to EC/pericytes co-cultures in Matrigel promote in vitro angiogenesis. These effects may be mediated by matrix metalloproteinase-2, expressed by both EV and EV-stimulated pericytes, and are exacerbated if MSC are previously cultured in conditions (high glucose and/or hypoxia) mimicking the diabetic microvascular milieu. CONCLUSIONS We confirm that MSC-derived EV contribute to angiogenesis, showing that they may not only exert a direct stimulus to EC proliferation, but also induce pericyte detachment, thus leaving EC free to proliferate. In addition, we demonstrate a possible link between EV and the early stages of the pathogenesis of DR. Diabetic-like conditions may influence vessel remodelling during angiogenesis through EV paracrine signalling.
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Affiliation(s)
- Elena Beltramo
- Department of Medical Sciences, University of Turin, Corso Dogliotti 14, 10126, Turin, Italy,
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22
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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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23
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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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24
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Takaori K, Yanagita M. Kidney regeneration and stem cells. Anat Rec (Hoboken) 2013; 297:129-36. [PMID: 24293404 DOI: 10.1002/ar.22801] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2013] [Accepted: 09/13/2013] [Indexed: 12/31/2022]
Abstract
The kidney has the capacity to recover from ischemic and toxic insults. Although there has been debate about the origin of cells that replace injured epithelial cells, it is now widely recognized that intrinsic surviving tubular cells are responsible for the repair. On the other hand, the cells, which have stem cell-like characteristics, have been isolated in the kidney using various methods, but it remains unknown if these stem cells actually exist in the adult kidney and if they are involved in kidney regeneration. This review will focus on the pathophysiology of kidney regeneration and the contribution of renal stem cells. We also discuss possible therapeutic applications to kidney disease.
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Affiliation(s)
- Koji Takaori
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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25
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Lee J, Marrero L, Yu L, Dawson LA, Muneoka K, Han M. SDF-1α/CXCR4 signaling mediates digit tip regeneration promoted by BMP-2. Dev Biol 2013; 382:98-109. [PMID: 23916851 DOI: 10.1016/j.ydbio.2013.07.020] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Revised: 06/29/2013] [Accepted: 07/23/2013] [Indexed: 12/16/2022]
Abstract
Previously we demonstrated that BMP signaling is required for endogenous digit tip regeneration, and that treatment with BMP-2 or -7 induces a regenerative response following amputation at regeneration-incompetent levels (Yu et al., 2010, 2012). Both endogenous regeneration and BMP-induced regeneration are associated with the transient formation of a blastema, however the formation of a regeneration blastema in mammals is poorly understood. In this study, we focus on how blastema cells respond to BMP signaling during neonatal digit regeneration in mice. First, we show that blastema cells retain regenerative properties after expansion in vitro, and when re-introduced into the amputated digit, these cells display directed migration in response to BMP-2. However, in vitro studies demonstrate that BMP-2 alone does not influence blastema cell migration, suggesting a requirement of another pivotal downstream factor for cell recruitment. We show that blastema cell migration is stimulated by the cytokine, SDF-1α, and that SDF-1α is expressed by the wound epidermis as well as endothelial cells of the blastema. Blastema cells express both SDF-1α receptors, CXCR4 and CXCR7, although the migration response is inhibited by the CXCR4-specific antagonist, AMD3100. Mice treated with AMD3100 display a partial inhibition of skeletal regrowth associated with the regeneration response. We provide evidence that BMP-2 regulates Sdf-1α expression in endothelial cells but not cells of the wound epidermis. Finally, we show that SDF-1α-expressing COS1 cells engrafted into a regeneration-incompetent digit amputation wound resulted in a locally enhanced population of CXCR4 positive cells, and induced a partial regenerative response. Taken together, this study provides evidence that one downstream mechanism of BMP signaling during mammalian digit regeneration involves activation of SDF-1α/CXCR4 signaling by endothelial cells to recruit blastema cells.
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Affiliation(s)
- Jangwoo Lee
- Division of Developmental Biology, Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA
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26
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Human mesenchymal stem cells derived from adipose tissue reduce functional and tissue damage in a rat model of chronic renal failure. Clin Sci (Lond) 2013; 125:199-210. [PMID: 23480877 DOI: 10.1042/cs20120644] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Therapeutic approaches for CKD (chronic kidney disease) have been able to reduce proteinuria, but not diminish the disease progression. We have demonstrated beneficial effects by injection of BM (bone marrow)-derived MSCs (mesenchymal stem cells) from healthy donors in a rat model with CKD. However, it has recently been reported that BM-MSCs derived from uraemic patients failed to confer functional protection in a similar model. This suggests that autologous BM-MSCs are not suitable for the treatment of CKD. In the present study, we have explored the potential of MSCs derived from adipose tissue (AD-MSCs) as an alternative source of MSCs for the treatment of CKD. We have isolated AD-MSCs and evaluated their effect on the progression of CKD. Adult male SD (Sprague-Dawley) rats subjected to 5/6 NPX (nephrectomy) received a single intravenous infusion of 0.5×10(6) AD-MSCs or MSC culture medium alone. The therapeutic effect was evaluated by plasma creatinine measurement, structural analysis and angiogenic/epitheliogenic protein expression. AD-MSCs were detected in kidney tissues from NPX animals. This group had a significant reduction in plasma creatinine levels and a lower expression of damage markers ED-1 and α-SMA (α-smooth muscle actin) (P<0.05). In addition, treated rats exhibited a higher level of epitheliogenic [Pax-2 and BMP-7 (bone morphogenetic protein 7)] and angiogenic [VEGF (vascular endothelial growth factor)] proteins. The expression of these biomarkers of regeneration was significantly related to the improvement in renal function. Although many aspects of the cell therapy for CKD remain to be investigated, we provide evidence that AD-MSCs, a less invasive and highly available source of MSCs, exert an important therapeutic effect in this pathology.
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Błogowski W, Dolegowska B, Budkowska M, Sałata D, Domański L, Starzynska T. Perioperative release of pro-regenerative biochemical signals from human renal allografts subjected to ischemia-reperfusion injury. Innate Immun 2013; 20:126-32. [PMID: 23608824 DOI: 10.1177/1753425913482018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Complement-derived molecules modulate the intensity of renal ischemia-reperfusion injury and may lead to the generation of biochemical signals [such as stromal-derived factor-1 (SDF-1) or sphingosine-1-phosphate (S1P)], which stimulate tissue/organ regeneration after injury. We tested the association between perioperative C5b-9/membrane attack complex (MAC) levels and intensified erythrocyte lysis, and asked whether significant changes in the levels of pro-regenerative substances occur during the early phase of renal allograft reperfusion. Seventy-five recipients were enrolled and divided into the early, slow, and delayed graft function (DGF) groups. Perioperative blood samples were collected from the renal vein during consecutive minutes of reperfusion. Extracellular hemoglobin (eHb), albumin (plasma S1P transporter), 8-iPF2α-III isoprostane, SDF-1 and S1P concentrations were measured. Throughout the reperfusion period, erythrocyte lysis intensified and was most pronounced in the DGF group. However, perioperative eHb levels did not correlate significantly with C5b-9/MAC values, but rather with the intensity of oxidative stress. No significant changes were observed in S1P, its plasma transporter (albumin) or SDF-1 levels, which were relatively low in all groups throughout the reperfusion period. Our study therefore demonstrates that no known biochemical signal for bone marrow-derived stem cell mobilization is released from human renal allografts to the periphery during the early phase of reperfusion.
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Affiliation(s)
- Wojciech Błogowski
- 1Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
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Mesenchymal stem cell injection ameliorates chronic renal failure in a rat model. Clin Sci (Lond) 2011; 121:489-99. [PMID: 21675962 DOI: 10.1042/cs20110108] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
CKD (chronic kidney disease) has become a public health problem. The therapeutic approaches have been able to reduce proteinuria, but have not been successful in limiting disease progression. In this setting, cell therapies associated with regenerative effects are attracting increasing interest. We evaluated the effect of MSC (mesenchymal stem cells) on the progression of CKD and the expression of molecular biomarkers associated with regenerative effects. Adult male Sprague-Dawley rats subjected to 5/6 NPX (nephrectomy) received a single intravenous infusion of 0.5×106 MSC or culture medium. A sham group subjected to the same injection was used as the control. Rats were killed 5 weeks after MSC infusion. Dye tracking of MSC was followed by immunofluorescence analysis. Kidney function was evaluated using plasma creatinine. Structural damage was evaluated by H&E (haematoxylin and eosin) staining, ED-1 abundance (macrophages) and interstitial α-SMA (α-smooth muscle actin). Repairing processes were evaluated by functional and structural analyses and angiogenic/epitheliogenic protein expression. MSC could be detected in kidney tissues from NPX animals treated with intravenous cell infusion. This group presented a marked reduction in plasma creatinine levels and damage markers ED-1 and α-SMA (P<0.05). In addition, treated rats exhibited a significant induction in epitheliogenic [Pax-2, bFGF (basic fibroblast growth factor) and BMP-7 (bone morphogenetic protein-7)] and angiogenic [VEGF (vascular endothelial growth factor) and Tie-2] proteins. The expression of these biomarkers of regeneration was significantly related to the increase in renal function. Many aspects of the cell therapy in CKD remain to be investigated in more detail: for example, its safety, low cost and the possible need for repeated cell injections over time. Beyond the undeniable importance of these issues, what still needs to be clarified is whether MSC administration has a real effect on the treatment of this pathology. It is precisely to this point that the present study aims to contribute.
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Swanhart LM, Cosentino CC, Diep CQ, Davidson AJ, de Caestecker M, Hukriede NA. Zebrafish kidney development: basic science to translational research. ACTA ACUST UNITED AC 2011; 93:141-56. [PMID: 21671354 DOI: 10.1002/bdrc.20209] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The zebrafish has become a significant model system for studying renal organogenesis and disease, as well as for the quest for new therapeutics, because of the structural and functional simplicity of the embryonic kidney. Inroads to the nature and disease states of kidney-related ciliopathies and acute kidney injury (AKI) have been advanced by zebrafish studies. This model organism has been instrumental in the analysis of mutant gene function for human disease with respect to ciliopathies. Additionally, in the AKI field, recent work in the zebrafish has identified a bona fide adult zebrafish renal progenitor (stem) cell that is required for neo-nephrogenesis, both during the normal lifespan and in response to renal injury. Taken together, these studies solidify the zebrafish as a successful model system for studying the broad spectrum of ciliopathies and AKI that affect millions of humans worldwide, and point to a very promising future of zebrafish drug discovery. The emphasis of this review will be on the role of the zebrafish as a model for human kidney-related ciliopathies and AKI, and how our understanding of these complex pathologies is being furthered by this tiny teleost.
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Affiliation(s)
- Lisa M Swanhart
- Department of Developmental Biology, University of Pittsburgh, Pennsylvania 15213, USA
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Abstract
Developing new therapeutic approaches to treat acute kidney injury requires a detailed understanding of endogenous cellular repair. Genetic fate mapping defines cellular hierarchies in vivo and we used this technique to assess a possible contribution of non-epithelial stem cells to renal repair after ischemic injury. Mice with efficient labeling of renal epithelial cells, but not non-epithelial interstitial cells, were subjected to a single cycle or sequential cycles of kidney injury and repair. No dilution of the epithelial cell fate marker was observed despite robust epithelial cell proliferation. Thus, non-tubular cells do not have the ability to migrate across the basement membrane and differentiate into epithelial cells in this model. Instead, surviving tubular epithelial cells are responsible for repair of the damaged nephron. Future studies will need to distinguish between uniform dedifferentiation and proliferation of all epithelial cells after injury versus selective expansion of an intratubular epithelial stem cell.
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From kidney development to drug delivery and tissue engineering strategies in renal regenerative medicine. J Control Release 2011; 152:177-85. [DOI: 10.1016/j.jconrel.2011.01.034] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 01/28/2011] [Indexed: 01/05/2023]
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Abstract
Acute kidney injury (AKI) as a consequence of ischemia is a common clinical event leading to unacceptably high morbidity and mortality, development of chronic kidney disease (CKD), and transition from pre-existing CKD to end-stage renal disease. Data indicate a close interaction between the many cell types involved in the pathophysiology of ischemic AKI, which has critical implications for the treatment of this condition. Inflammation seems to be the common factor that links the various cell types involved in this process. In this Review, we describe the interactions between these cells and their response to injury following ischemia. We relate these events to patients who are at high risk of AKI, and highlight the characteristics that might predispose these patients to injury. We also discuss how therapy targeting specific cell types can minimize the initial and subsequent injury following ischemia, thereby limiting the extent of acute changes and, hopefully, long-term structural and functional alterations to the kidney.
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Ye Y, Wang B, Jiang X, Hu W, Feng J, Li H, Jin M, Ying Y, Wang W, Mao X, Jin K. Proliferative capacity of stem/progenitor-like cells in the kidney may associate with the outcome of patients with acute tubular necrosis. Hum Pathol 2011; 42:1132-41. [PMID: 21315412 DOI: 10.1016/j.humpath.2010.11.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2010] [Revised: 10/22/2010] [Accepted: 11/05/2010] [Indexed: 10/18/2022]
Abstract
Animal studies indicate that adult renal stem/progenitor cells can undergo rapid proliferation in response to renal injury, but whether the same is true in humans is largely unknown. To examine the profile of renal stem/progenitor cells responsible for acute tubular necrosis in human kidney, double and triple immunostaining was performed using proliferative marker and stem/progenitor protein markers on sections from 10 kidneys with acute tubular necrosis and 4 normal adult kidneys. The immunopositive cells were recorded using 2-photon confocal laser scanning microscopy. We found that dividing cells were present in the tubules of the cortex and medulla, as well as the glomerulus in normal human kidney. Proliferative cells in the parietal layer of Bowman capsule expressed CD133, and dividing cells in the tubules expressed immature cell protein markers paired box gene 2, vimentin, and nestin. After acute tubular necrosis, Ki67-positive cells in the cortex tubules significantly increased compared with normal adult kidney. These Ki67-positive cells expressed CD133 and paired box gene 2, but not the cell death marker, activated caspase-3. In addition, the number of dividing cells increased significantly in patients with acute tubular necrosis who subsequently recovered, compared with patients with acute tubular necrosis who consequently developed protracted acute tubular necrosis or died. Our data suggest that renal stem/progenitor cells may reside not only in the parietal layer of Bowman capsule but also in the cortex and medulla in normal human kidney, and the proliferative capacity of renal stem/progenitor cells after acute tubular necrosis may be an important determinant of a patient's outcome.
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Affiliation(s)
- Youxin Ye
- Department of Nephrology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang 310016, China.
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Yeagy BA, Harrison F, Gubler MC, Koziol JA, Salomon DR, Cherqui S. Kidney preservation by bone marrow cell transplantation in hereditary nephropathy. Kidney Int 2011; 79:1198-206. [PMID: 21248718 DOI: 10.1038/ki.2010.537] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The prospect of cell-based therapy for kidney disease remains controversial despite its immense promise. We had previously shown that transplanting bone marrow and hematopoietic stem cells could generate renal cells and lead to the preservation of kidney function in a mouse model for cystinosis (Ctns(-/-)) that develops chronic kidney injury, 4 months post transplantation. Here, we determined the long-term effects of bone marrow stem cell transplantation on the kidney disease of Ctns(-/-) mice 7 to 15 months post transplantation. Transfer of bone marrow stem cells expressing a functional Ctns gene provided long-term protection to the kidney. Effective therapy, however, depended on achieving a relatively high level of donor-derived blood cell engraftment of Ctns-expressing cells, which was directly linked to the quantity of these cells within the kidney. In contrast, kidney preservation was dependent neither on renal cystine content nor on the age of the mice at the time of transplant. Most of the bone marrow-derived cells within the kidney were interstitial and not epithelial, suggesting that the mechanism involved an indirect protection of the tubules. Thus, our model may help in developing strategies to enhance the potential success of cell-based therapy for kidney injury and in understanding some of the discrepancies currently existing in the field.
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Affiliation(s)
- Brian A Yeagy
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
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Stokman G, Stroo I, Claessen N, Teske GJD, Weening JJ, Leemans JC, Florquin S. Stem cell factor expression after renal ischemia promotes tubular epithelial survival. PLoS One 2010; 5:e14386. [PMID: 21200435 PMCID: PMC3006174 DOI: 10.1371/journal.pone.0014386] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2010] [Accepted: 11/30/2010] [Indexed: 11/18/2022] Open
Abstract
Background Renal ischemia leads to apoptosis of tubular epithelial cells and results in decreased renal function. Tissue repair involves re-epithelialization of the tubular basement membrane. Survival of the tubular epithelium following ischemia is therefore important in the successful regeneration of renal tissue. The cytokine stem cell factor (SCF) has been shown to protect the tubular epithelium against apoptosis. Methodology/Principal Findings In a mouse model for renal ischemia/reperfusion injury, we studied how expression of c-KIT on tubular epithelium and its ligand SCF protect cells against apoptosis. Administration of SCF specific antisense oligonucleotides significantly decreased specific staining of SCF following ischemia. Reduced SCF expression resulted in impaired renal function, increased tubular damage and increased tubular epithelial apoptosis, independent of inflammation. In an in vitro hypoxia model, stimulation of tubular epithelial cells with SCF activated survival signaling and decreased apoptosis. Conclusions/Significance Our data indicate an important role for c-KIT and SCF in mediating tubular epithelial cell survival via an autocrine pathway.
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Affiliation(s)
- Geurt Stokman
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Duration of acute kidney injury impacts long-term survival after cardiac surgery. Ann Thorac Surg 2010; 90:1142-8. [PMID: 20868804 DOI: 10.1016/j.athoracsur.2010.04.039] [Citation(s) in RCA: 243] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2010] [Revised: 04/07/2010] [Accepted: 04/08/2010] [Indexed: 12/31/2022]
Abstract
BACKGROUND Acute kidney injury (AKI) after cardiac surgery is associated with worse outcomes. However, it is not known how adverse long-term consequences vary according to the duration of AKI. We sought to determine the association between duration of AKI and survival. METHODS Medical records of 4,987 cardiac surgery patients from 2002 through 2007 with serum creatinine (SCr) collection at a medical center in northern New England were reviewed. Acute kidney injury was defined as at least a 0.3 (mg/dL) or at least a 50% increase in SCr from baseline and further classified into AKI Network stages. Duration of AKI was defined by the number of days AKI was present and categorized as no AKI and AKI for 1 to 2, 3 to 6, and at least 7 days. RESULTS Thirty-nine percent of patients exhibited AKI. Long-term survival was significantly different by AKI duration (p < 0.001). The proportion of patients with AKI duration, adjusted hazard ratio, and 95% confidence interval for mortality (no AKI as referent) were as follows: 1 to 2 days (18%; adjusted hazard ratio, 1.66; 95% confidence interval, 1.32 to 2.09), 3 to 6 days (11%; adjusted hazard ratio, 1.94; 95% confidence interval, 1.51 to 2.49), ≥7 days (9%; adjusted hazard ratio, 3.40; 95% confidence interval, 2.73 to 4.25). This graded relationship of duration of AKI with long-term mortality persisted when patients who died during hospitalization were excluded from analysis (p < 0.001). Propensity-matched analysis confirmed results. CONCLUSIONS The duration of AKI after cardiac surgery is directly proportional to long-term mortality. This AKI dose-dependent effect on long-term mortality helps to close the gap between association and causation, whereby AKI stages and AKI duration have important implications for patient care and can aid clinicians in evaluating the risk of in-hospital and postdischarge death.
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Feng Z, Ting J, Alfonso Z, Strem BM, Fraser JK, Rutenberg J, Kuo HC, Pinkernell K. Fresh and cryopreserved, uncultured adipose tissue-derived stem and regenerative cells ameliorate ischemia-reperfusion-induced acute kidney injury. Nephrol Dial Transplant 2010; 25:3874-84. [PMID: 20921297 PMCID: PMC2989793 DOI: 10.1093/ndt/gfq603] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background. Acute kidney injury (AKI) represents a major clinical problem with high mortality and limited causal treatments. The use of cell therapy has been suggested as a potential modality to improve the course and outcome of AKI. Methods. We investigated the possible renoprotection of freshly isolated, uncultured adipose tissue-derived stem and regenerative cells (ADRCs) before and after cryopreservation in a rat ischemia–reperfusion (I–R) model of AKI. Results. We demonstrated that ADRC therapy drastically reduced mortality (survival 100% vs. 57%, ADRC vs. controls, respectively) and significantly reduced serum creatinine (sCr on Day 3: 3.03 ± 1.58 vs. 7.37 ± 2.32 mg/dL, ADRC vs. controls, respectively). Histological analysis further validated a significantly reduced intratubular cast formation, ameliorated acute tubular epithelial cell necrosis and mitigated macrophage infiltration. Furthermore, a reduced RNA expression of CXCL2 and IL-6 was found in the ADRC group which could explain the reduced macrophage recruitment. Use of cryopreserved ADRCs resulted in an equally high survival (90% vs. 33% in the control group) and similarly improved renal function (sCr on Day 3: 4.64 ± 2.43 vs. 7.24 ± 1.40 mg/dL in controls). Conclusions. Collectively, these results suggest a potential clinical role for ADRC therapy in patients with AKI. Importantly, cryopreservation of ADRCs could offer an autologous treatment strategy for patients who are at high risk for AKI during planned interventions.
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Affiliation(s)
- Zheng Feng
- Department of Regenerative Cell Technology, Cytori Therapeutics, Inc., 3020 Callan Road, San Diego, CA 92121, USA
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Arrigoni FI, Matarin M, Thompson PJ, Michaelides M, McClements ME, Redmond E, Clarke L, Ellins E, Mohamed S, Pavord I, Klein N, Hunt DM, Moore AT, Halcox J, Sisodiya SM. Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy. Eur J Hum Genet 2010; 19:131-7. [PMID: 20859302 DOI: 10.1038/ejhg.2010.147] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Mutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, we examined two kindreds with the same R373C PROM1 missense mutation using our established paradigm to study brain structure and function. As the protein encoded by PROM1, known as CD133, is used to identify stem/progenitor cells that can be found in peripheral blood and reflect endothelial reparatory mechanisms, other parameters were subsequently examined that included measures of vascular function, endothelial function and angiogenic capacity. We found that aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C PROM1 mutation, with impaired adhesion capacity and higher levels of cellular damage. We also noted renal infections, haematuria and recurrent miscarriages possibly reflecting consequences of abnormal tubular modelling. Further studies are needed to confirm these findings.
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Morigi M, Rota C, Montemurro T, Montelatici E, Lo Cicero V, Imberti B, Abbate M, Zoja C, Cassis P, Longaretti L, Rebulla P, Introna M, Capelli C, Benigni A, Remuzzi G, Lazzari L. Life-sparing effect of human cord blood-mesenchymal stem cells in experimental acute kidney injury. Stem Cells 2010; 28:513-22. [PMID: 20049901 DOI: 10.1002/stem.293] [Citation(s) in RCA: 122] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
In search for new sources of mesenchymal stem cells (MSCs) for renal repair in acute kidney injury (AKI), we investigated the potential of human cord blood (CB)-MSCs to cure mice with AKI. Infusion of CB-MSCs in immunodeficient mice with cisplatin-induced AKI ameliorated both renal function and tubular cell injury, and prolonged survival. Transplanted CB-MSCs localized in peritubular areas, limited capillary alterations and neutrophil infiltration. Apoptosis reduced and tubular cell proliferation increased by virtue of stem cell capacity to produce growth factors. The reno-protective effect of CB-MSCs was further confirmed by their ability to inhibit oxidative damage and to induce the prosurvival factor Akt in tubular cells. The evidence that CB-MSCs in vitro increased the production of growth factors and inhibited IL-1 beta and TNFalpha synthesis when cocultured with damaged proximal tubular cells indicates a regenerative and anti-inflammatory action of stem cell treatment. Altogether these results highlight the potential of human CB-MSCs as future cell therapy for testing in human AKI.
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Affiliation(s)
- Marina Morigi
- Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
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Terryn S, Devuyst O, Antignac C. Cell therapy for cystinosis. Nephrol Dial Transplant 2010; 25:2103-6. [PMID: 20395258 DOI: 10.1093/ndt/gfq198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
In the September 2009 issue of Blood, Syres et al. [1] report on syngeneic bone marrow cell (BMC) and haematopoietic stem cell (HSC) therapy as a successful treatment in a mouse model of cystinosis, an autosomal recessive metabolic disease caused by a defect in the transport of cystine across the lysosomal membrane. The accumulation of cystine crystals in lysosomes leads to a multi-organ dysfunction including proximal tubulopathy and renal failure, corneal deposits, myopathy and central nervous system defects. By using Ctns knock-out (Ctns(-/-)) mice as a model for cystinosis, Syres et al. show that BMC transplantation leads to a major reduction of cystine content in all tissues tested, reflected by a significant attenuation of the development and progression of kidney injury and reduction in the number of mice with corneal cystine crystals. These changes were correlated with the engraftment of donor BMC producing a functional cystine transporter in the tissues tested. The transplantation of mouse HSC had the same therapeutic effect than whole BMC in this model, which is important as such HSC can readily be isolated from peripheral blood in humans. This work suggests that BMC or HSC transplantation is a potential treatment for cystinosis and other renal tubular disorders.
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Affiliation(s)
- Sara Terryn
- Division of Nephrology, Université catholique de Louvain Medical School, B-1200 Brussels, Belgium
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41
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Ross EA, Williams MJ, Hamazaki T, Terada N, Clapp WL, Adin C, Ellison GW, Jorgensen M, Batich CD. Embryonic stem cells proliferate and differentiate when seeded into kidney scaffolds. J Am Soc Nephrol 2009; 20:2338-47. [PMID: 19729441 DOI: 10.1681/asn.2008111196] [Citation(s) in RCA: 276] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The scarcity of transplant allografts for diseased organs has prompted efforts at tissue regeneration using seeded scaffolds, an approach hampered by the enormity of cell types and complex architectures. Our goal was to decellularize intact organs in a manner that retained the matrix signal for differentiating pluripotent cells. We decellularized intact rat kidneys in a manner that preserved the intricate architecture and seeded them with pluripotent murine embryonic stem cells antegrade through the artery or retrograde through the ureter. Primitive precursor cells populated and proliferated within the glomerular, vascular, and tubular structures. Cells lost their embryonic appearance and expressed immunohistochemical markers for differentiation. Cells not in contact with the basement membrane matrix became apoptotic, thereby forming lumens. These observations suggest that the extracellular matrix can direct regeneration of the kidney, and studies using seeded scaffolds may help define differentiation pathways.
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Affiliation(s)
- Edward A Ross
- Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, FL 32610-0224, USA.
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Herrera MB, Fonsato V, Gatti S, Deregibus MC, Sordi A, Cantarella D, Calogero R, Bussolati B, Tetta C, Camussi G. Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. J Cell Mol Med 2009; 14:1605-18. [PMID: 19650833 PMCID: PMC3060338 DOI: 10.1111/j.1582-4934.2009.00860.x] [Citation(s) in RCA: 224] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Several studies indicate that adult stem cells may improve the recovery from acute tissue injury. It has been suggested that they may contribute to tissue regeneration by the release of paracrine factors promoting proliferation of tissue resident cells. However, the factors involved remain unknown. In the present study we found that microvesicles (MVs) derived from human liver stem cells (HLSC) induced in vitro proliferation and apoptosis resistance of human and rat hepatocytes. These effects required internalization of MVs in the hepatocytes by an alpha(4)-integrin-dependent mechanism. However, MVs pre-treated with RNase, even if internalized, were unable to induce hepatocyte proliferation and apoptosis resistance, suggesting an RNA-dependent effect. Microarray analysis and quantitative RT-PCR demonstrated that MVs were shuttling a specific subset of cellular mRNA, such as mRNA associated in the control of transcription, translation, proliferation and apoptosis. When administered in vivo, MVs accelerated the morphological and functional recovery of liver in a model of 70% hepatectomy in rats. This effect was associated with increase in hepatocyte proliferation and was abolished by RNase pre-treatment of MVs. Using human AGO2, as a reporter gene present in MVs, we found the expression of human AGO2 mRNA and protein in the liver of hepatectomized rats treated with MVs. These data suggested a translation of the MV shuttled mRNA into hepatocytes of treated rats. In conclusion, these results suggest that MVs derived from HLSC may activate a proliferative program in remnant hepatocytes after hepatectomy by a horizontal transfer of specific mRNA subsets.
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Affiliation(s)
- M B Herrera
- Department of Internal Medicine, Research Center for Experimental Medicine (CeRMS), and Center for Molecular Biotechnology, Torino, Italy
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Successful treatment of the murine model of cystinosis using bone marrow cell transplantation. Blood 2009; 114:2542-52. [PMID: 19506297 DOI: 10.1182/blood-2009-03-213934] [Citation(s) in RCA: 90] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The defective gene is CTNS encoding the lysosomal cystine transporter, cystinosin. Cystine accumulates in every organ in the body and leads to organ damage and dysfunction, including renal defects. Using the murine model for cystinosis, Ctns(-/-) mice, we performed syngeneic bone marrow cell (BMC), hematopoietic stem cell (HSC), and mesenchymal stem cell transplantation. Organ-specific cystine content was reduced by 57% to 94% in all organs tested in the BMC-treated mice. Confocal microscopy and quantitative polymerase chain reaction revealed a large quantity of transplanted BMC in all organs tested, from 5% to 19% of the total cells. Most of these cells were not from the lymphoid lineage but part of the intrinsic structure of the organ. The natural progression of renal dysfunction was prevented, and deposition of corneal cystine crystals was significantly improved in the BMC-treated mice. HSC had the same therapeutic effect as whole BMC. In contrast, mesenchymal stem cell did not integrate efficiently in any organ. This work is a proof of concept for using HSC transplantation as a therapy for cystinosis and highlights the efficiency of this strategy for a chronic, progressive degenerative disease.
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Singh SR, Hou SX. Multipotent stem cells in the Malpighian tubules of adult Drosophila melanogaster. ACTA ACUST UNITED AC 2009; 212:413-23. [PMID: 19151216 DOI: 10.1242/jeb.024216] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Excretion is an essential process of an organism's removal of the waste products of metabolism to maintain a constant chemical composition of the body fluids despite changes in the external environment. Excretion is performed by the kidneys in vertebrates and by Malpighian tubules (MTs) in Drosophila. The kidney serves as an excellent model organ to investigate the cellular and molecular mechanisms underlying organogenesis. Mammals and Drosophila share common principles of renal development. Tissue homeostasis, which is accomplished through self-renewal or differentiation of stem cells, is critical for the maintenance of adult tissues throughout the lifetime of an animal. Growing evidence suggests that stem cell self-renewal and differentiation is controlled by both intrinsic and extrinsic factors. Deregulation of stem cell behavior results in cancer formation, tissue degeneration, and premature aging. The mammalian kidney has a low rate of cellular turnover but has a great capacity for tissue regeneration following an ischemic injury. However, there is an ongoing controversy about the source of regenerating cells in the adult kidney that repopulate injured renal tissues. Recently, we identified multipotent stem cells in the MTs of adult Drosophila and found that these stem cells are able to proliferate and differentiate in several types of cells in MTs. Furthermore, we demonstrated that an autocrine JAK-STAT (Janus kinase-signal transducers and activators of transcription) signaling regulates stem cell self-renewal or differentiation of renal stem cells. The Drosophila MTs provide an excellent in vivo system for studying the renal stem cells at cellular and molecular levels. Understanding the molecular mechanisms governing stem cell self-renewal or differentiation in vivo is not only crucial to using stem cells for future regenerative medicine and gene therapy, but it also will increase our understanding of the mechanisms underlying cancer formation, aging and degenerative diseases. Identifying and understanding the cellular processes underlying the development and repair of the mammalian kidney may enable more effective, targeted therapies for acute and chronic kidney diseases in humans.
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Affiliation(s)
- Shree Ram Singh
- Mouse Cancer Genetics Program, National Institutes of Health, National Cancer Institute, MD 21702, USA
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Bruno S, Grange C, Deregibus MC, Calogero RA, Saviozzi S, Collino F, Morando L, Busca A, Falda M, Bussolati B, Tetta C, Camussi G. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 2009; 20:1053-67. [PMID: 19389847 DOI: 10.1681/asn.2008070798] [Citation(s) in RCA: 1014] [Impact Index Per Article: 63.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI). The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44- and beta1-integrin-dependent incorporation into tubular cells. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles in vitro and in vivo, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.
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Affiliation(s)
- Stefania Bruno
- Department of Internal Medicine, Research Center for Experimental Medicine, University of Torino, Torino, Italy
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Stroo I, Stokman G, Teske GJD, Florquin S, Leemans JC. Haematopoietic stem cell migration to the ischemic damaged kidney is not altered by manipulating the SDF-1/CXCR4-axis. Nephrol Dial Transplant 2009; 24:2082-8. [PMID: 19223274 PMCID: PMC2698094 DOI: 10.1093/ndt/gfp050] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Background. Haematopoietic stem cells (HSC) have been shown to migrate to the ischemic kidney. The factors that regulate the trafficking of HSC to the ischemic damaged kidney are not fully understood. The stromal cell-derived factor-1 (SDF-1)/CXCR4-axis has been identified as the central signalling axis regulating trafficking of HSC to the bone marrow. Therefore, we hypothesized that SDF-1/CXCR4 interactions are implicated in the migration of HSC to the injured kidney. Methods. HSC were isolated from mouse bone marrow and labelled with a cell tracker. Acceptor mice were subjected to unilateral ischemia and received HSC intravenously directly after reperfusion. In addition, in separate groups of acceptor mice, endogenous SDF-1 or HSC-associated CXCR4 was blocked or kidneys were injected with SDF-1. Results. Exogenous HSC could be detected in the tubules and interstitium of the kidney 24 h after ischemic injury. Importantly, the amount of HSC in the ischemic kidney was markedly higher compared to the contralateral kidney. Neutralizing endogenous SDF-1 or HSC-associated CXCR4 did not prevent the migration of HSC. No increase in the number of labelled HSC could be observed after local administration of SDF-1, as was also determined in bilateral kidney ischemia. Conclusion. In conclusion, systemically administered HSC preferentially migrate to the ischemic injured kidney. This migration could not be prevented by blocking the SDF-1/CXCR4-axis or increased after local administration of SDF-1.
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Affiliation(s)
- Ingrid Stroo
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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Wei LN. Post-translational modifications of orphan nuclear receptor TR2 - new insights into drug targets for stem cell therapy and the effect of retinoic acid. Proteomics Clin Appl 2009; 3:279-285. [DOI: 10.1002/prca.200800100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Fedorova S, Miyamoto R, Harada T, Isogai S, Hashimoto H, Ozato K, Wakamatsu Y. Renal glomerulogenesis in medaka fish, Oryzias latipes. Dev Dyn 2009; 237:2342-52. [PMID: 18729228 DOI: 10.1002/dvdy.21687] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
We provide an overview of glomerulogenesis in medaka from the embryo to the adult by means of in situ hybridization with the wt1 gene as a marker as well as histology and three-dimensional images. The pronephric glomus starts to develop in the intermediate mesoderm during early somitogenesis, is completed before hatching, and persists throughout the lifetime of the fish. Within 5 days after hatching, mesonephric glomerulus formation begins in the caudomedial end of the pronephric sinus and duct area. The number of glomeruli reaches approximately 200-300 in each kidney within 2 months after hatching. wt1 expression during nephron maturation served as a marker for the formation of the mesenchymal condensate and the nephrogenic body. Existence of mesenchymal condensates and persistence of wt1 expression in the adult kidney suggest that the mesonephros retains precursor cells that may be capable of contributing to neoglomerulogenesis during adulthood.
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Affiliation(s)
- Svetlana Fedorova
- Laboratory of Freshwater Fish Stocks, Bioscience and Biotechnology Center, Nagoya University, Nagoya, Japan
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Bi B, Guo J, Marlier A, Lin SR, Cantley LG. Erythropoietin expands a stromal cell population that can mediate renoprotection. Am J Physiol Renal Physiol 2008; 295:F1017-22. [PMID: 18653480 PMCID: PMC2576137 DOI: 10.1152/ajprenal.90218.2008] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2008] [Accepted: 07/21/2008] [Indexed: 01/13/2023] Open
Abstract
Recent studies have demonstrated that erythropoietin (EPO) receptors are expressed on tubular epithelial cells and that EPO can protect tubular cells from injury in vitro and in vivo. Separate studies have demonstrated that marrow stromal cells (MSCs) exert a renoprotective effect in ischemia-reperfusion and cisplatin tubular injury via the secretion of factors that reduce apoptosis and increase proliferation of tubular epithelial cells. In the present study we demonstrate that MSCs express EPO receptors and that EPO can protect MSCs from serum deprivation-induced cell death and can stimulate MSC proliferation in vitro. The administration of EPO to mice resulted in the expansion of CD45-Flk1-CD105+ MSCs in the bone marrow and in the spleen and mobilized these cells as well as CD45-Flk1+ endothelial progenitor cells into the peripheral circulation. Consistent with previous reports, the administration of EPO diminished the decline in renal function associated with cisplatin administration. This effect was partially reproduced by intraperitoneal injection of cultured EPO-mobilized cells in cisplatin-treated mice. Thus the in vivo expansion and/or activation of these cells may contribute to the renoprotective effects of EPO to protect tubular cells from toxic injury.
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Affiliation(s)
- Baoyuan Bi
- Yale University School of Medicine, 333 Cedar St., PO Box 208029, New Haven, CT 06510, USA
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