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Rajput S, Malviya R, Uniyal P. Advances in the Treatment of Kidney Disorders using Mesenchymal Stem Cells. Curr Pharm Des 2024; 30:825-840. [PMID: 38482624 DOI: 10.2174/0113816128296105240305110312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/20/2024] [Indexed: 06/04/2024]
Abstract
Renal disease is a medical condition that poses a potential threat to the life of an individual and is related to substantial morbidity and mortality rates in clinical environments. The aetiology of this condition is influenced by multiple factors, and its incidence tends to increase with progressive aging. Although supportive therapy and kidney transplantation have potential advantages, they also have limitations in terms of mitigating the progression of KD. Despite significant advancements in the domain of supportive therapy, mortality rates in patients continue to increase. Due to their ability to self-renew and multidirectionally differentiate, stem cell therapy has been shown to have tremendous potential in the repair of the diseased kidney. MSCs (Mesenchymal stem cells) are a cell population that is extensively distributed and can be located in various niches throughout an individual's lifespan. The cells in question are characterised by their potential for indefinite replication and their aptitude for undergoing differentiation into fully developed cells of mesodermal origin under laboratory conditions. It is essential to emphasize that MSCs have demonstrated a favorable safety profile and efficacy as a therapeutic intervention for renal diseases in both preclinical as well as clinical investigations. MSCs have been found to slow the advancement of kidney disease, and this impact is thought to be due to their control over a number of physiological processes, including immunological response, tubular epithelial- mesenchymal transition, oxidative stress, renal tubular cell death, and angiogenesis. In addition, MSCs demonstrate recognised effectiveness in managing both acute and chronic kidney diseases via paracrine pathways. The proposal to utilise a therapy that is based on stem-cells as an effective treatment has been put forward in search of discovering novel therapies to promote renal regeneration. Preclinical researchers have demonstrated that various types of stem cells can provide advantages in acute and chronic kidney disease. Moreover, preliminary results from clinical trials have suggested that these interventions are both safe and well-tolerated. This manuscript provides a brief overview of the potential renoprotective effects of stem cell-based treatments in acute as well as chronic renal dysfunction. Furthermore, the mechanisms that govern the process of kidney regeneration induced by stem cells are investigated. This article will examine the therapeutic approaches that make use of stem cells for the treatment of kidney disorders. The analysis will cover various cellular sources that have been utilised, potential mechanisms involved, and the outcomes that have been achieved so far.
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Affiliation(s)
- Shivam Rajput
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Prerna Uniyal
- School of Pharmacy, Graphic Era Hill University, Dehradun, India
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Lasorsa F, Rutigliano M, Milella M, Ferro M, Pandolfo SD, Crocetto F, Autorino R, Battaglia M, Ditonno P, Lucarelli G. Cancer Stem Cells in Renal Cell Carcinoma: Origins and Biomarkers. Int J Mol Sci 2023; 24:13179. [PMID: 37685983 PMCID: PMC10487877 DOI: 10.3390/ijms241713179] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/14/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
The term "cancer stem cell" (CSC) refers to a cancer cell with the following features: clonogenic ability, the expression of stem cell markers, differentiation into cells of different lineages, growth in nonadhesive spheroids, and the in vivo ability to generate serially transplantable tumors that reflect the heterogeneity of primary cancers (tumorigenicity). According to this model, CSCs may arise from normal stem cells, progenitor cells, and/or differentiated cells because of striking genetic/epigenetic mutations or from the fusion of tissue-specific stem cells with circulating bone marrow stem cells (BMSCs). CSCs use signaling pathways similar to those controlling cell fate during early embryogenesis (Notch, Wnt, Hedgehog, bone morphogenetic proteins (BMPs), fibroblast growth factors, leukemia inhibitory factor, and transforming growth factor-β). Recent studies identified a subpopulation of CD133+/CD24+ cells from ccRCC specimens that displayed self-renewal ability and clonogenic multipotency. The development of agents targeting CSC signaling-specific pathways and not only surface proteins may ultimately become of utmost importance for patients with RCC.
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Affiliation(s)
- Francesco Lasorsa
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Monica Rutigliano
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Martina Milella
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Matteo Ferro
- Division of Urology, European Institute of Oncology, IRCCS, 71013 Milan, Italy
| | - Savio Domenico Pandolfo
- Department of Neurosciences and Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Felice Crocetto
- Department of Neurosciences and Reproductive Sciences and Odontostomatology, University of Naples “Federico II”, 80131 Naples, Italy
| | - Riccardo Autorino
- Department of Urology, Rush University Medical Center, Chicago, IL 60612, USA
| | - Michele Battaglia
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Pasquale Ditonno
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
| | - Giuseppe Lucarelli
- Department of Precision and Regenerative Medicine and Ionian Area-Urology, Andrology and Kidney Transplantation Unit, University of Bari “Aldo Moro”, 70124 Bari, Italy
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Takenaka T, Hasan A, Marumo T, Inoue T, Miyazaki T, Suzuki H, Kurosaki Y, Ishii N, Nishiyama A, Hayashi M. Klotho Supplementation Reverses Renal Dysfunction and Interstitial Fibrosis in Remnant Kidney. Kidney Blood Press Res 2023; 48:326-337. [PMID: 37019097 DOI: 10.1159/000530469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 03/10/2023] [Indexed: 04/07/2023] Open
Abstract
INTRODUCTION While recent investigations show that klotho exerts renoprotective actions, it has not been fully addressed whether klotho protein supplementation reverses renal damage. METHODS The impacts of subcutaneous klotho supplementation on rats with subtotal nephrectomy were examined. Animals were divided into 3 groups: group 1 (short remnant [SR]): remnant kidney for 4 weeks, group 2 (long remnant [LR]): remnant kidney for 12 weeks, and group 3 (klotho supplementation [KL]): klotho protein (20 μg/kg/day) supplementation on the remnant kidney. Blood pressure, blood and urine compositions with conventional methods such as enzyme-linked immunosorbent assay and radioimmunoassay, kidney histology, and renal expressions of various genes were analyzed. In vitro studies were also performed to support in vivo findings. RESULTS Klotho protein supplementation decreased albuminuria (-43%), systolic blood pressure (-16%), fibroblast growth factor (FGF) 23 (-51%) and serum phosphate levels (-19%), renal angiotensin II concentration (-43%), fibrosis index (-70%), renal expressions of collagen I (-55%), and transforming growth factor β (-59%) (p < 0.05 for all). Klotho supplementation enhanced fractional excretion of phosphate (+45%), glomerular filtration rate (+76%), renal expressions of klotho (+148%), superoxide dismutase (+124%), and bone morphogenetic protein (BMP) 7 (+174%) (p < 0.05 for all). CONCLUSION Our data indicated that klotho protein supplementation inactivated renal renin-angiotensin system, reducing blood pressure and albuminuria in remnant kidney. Furthermore, exogenous klotho protein supplementation elevated endogenous klotho expression to increase phosphate excretion with resultant reductions in FGF23 and serum phosphate. Finally, klotho supplementation reversed renal dysfunction and fibrosis in association with improved BMP7 in remnant kidney.
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Affiliation(s)
- Tsuneo Takenaka
- Department of Nephrology, International University of Health and Welfare, Tokyo, Japan
| | - Arif Hasan
- Department of Nephrology, International University of Health and Welfare, Tokyo, Japan
| | - Takeshi Marumo
- Department of Nephrology, International University of Health and Welfare, Tokyo, Japan
| | - Tsutomu Inoue
- Department of Nephrology, Saitama Medical University, Iruma, Japan
| | - Takashi Miyazaki
- Department of Nephrology, Saitama Medical University, Iruma, Japan
| | - Hiromichi Suzuki
- Department of Nephrology, Saitama Medical University, Iruma, Japan
| | | | - Naohito Ishii
- Department of Biochemistry, Kitasato University, Sagamihara, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Kagawa University, Takamatsu, Japan
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Choi M, Yang YB, Park S, Rahaman S, Tripathi G, Lee BT. Effect of Co-culture of mesenchymal stem cell and glomerulus endothelial cell to promote endothelialization under optimized perfusion flow rate in whole renal ECM scaffold. Mater Today Bio 2022; 17:100464. [PMID: 36325425 PMCID: PMC9619032 DOI: 10.1016/j.mtbio.2022.100464] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 10/04/2022] [Accepted: 10/13/2022] [Indexed: 11/11/2022] Open
Abstract
In recent era, many researches on implantable bio-artificial organs has been increased owing to large gap between donors and receivers. Comprehensive organ based researches on perfusion culture for cell injury using different flow rate have not been conducted at the cellular level. The present study investigated the co-culture of rat glomerulus endothelial cell (rGEC) and rat bone marrow mesenchymal stem cells (rBMSC) to develop micro vascularization in the kidney scaffolds culturing by bioreactor system. To obtain kidney scaffold, extracted rat kidneys were decellularized by 1% sodium dodecyl sulfate (SDS), 1% triton X-100, and distilled water. Expanded rGECs were injected through decellularized kidney scaffold artery and cultured using bioreactor system. Vascular endothelial cells adhered and proliferated on the renal ECM scaffold in the bioreactor system for 3, 7 and 14 days. Static, 1 ml/min and 2 ml/min flow rates (FR) were tested and among them, 1 ml/min flow rate was selected based on cell viability, glomerulus character, inflammation/endothelialization proteins expression level. However, the flow injury was still existed on primary cell cultured at vessel in kidney scaffold. Therefore, co-culture of rGEC + rBMSC found suitable to possibly solve this problem and resulted increased cell proliferation and micro-vascularization in the glomerulus, reducing inflammation and cell death which induced by flow injury. The optimized perfusion rate under rGEC + rBMSC co-culture conditions resulted in enhanced endocellularization to make ECM derived implantable renal scaffold and might be useful as a way of treatment of the acute renal failure.
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Affiliation(s)
- Minji Choi
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, South Korea
| | - Yu-Bin Yang
- Institute of Tissue Regeneration, Soonchunhyang University, Cheonan, South Korea
| | - Seongsu Park
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, South Korea
| | - Sohanur Rahaman
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, South Korea
| | - Garima Tripathi
- Institute of Tissue Regeneration, Soonchunhyang University, Cheonan, South Korea
| | - Byong-Taek Lee
- Department of Regenerative Medicine, College of Medicine, Soonchunhyang University, South Korea,Institute of Tissue Regeneration, Soonchunhyang University, Cheonan, South Korea,Corresponding author. Department of Regenerative Medicine, College of Medicine, Soonchunhyang University.
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Rafiee Z, Orazizadeh M, Nejad Dehbashi F, Neisi N, Babaahmadi-Rezaei H, Mansouri E. Mesenchymal stem cells derived from the kidney can ameliorate diabetic nephropathy through the TGF-β/Smad signaling pathway. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:53212-53224. [PMID: 35278177 DOI: 10.1007/s11356-021-17954-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 12/01/2021] [Indexed: 06/14/2023]
Abstract
Diabetic nephropathy (DN) has been introduced as one of the main microvascular complications in diabetic patients, the most common cause of end-stage renal disease (ESRD). Based on the therapeutic potential of mesenchymal stem cells in tissue repair, we aimed to test the hypothesis that kidney stem cells (KSCs) might be effective in the kidney regeneration process. Stem cells from rat kidney were separated, and the surface stem cell markers were determined by flow cytometry analysis. Thirty-two Sprague Dawley rats were divided into four groups (control, control that received kidney stem cells, diabetic, diabetic treated with stem cells). To establish diabetic, model STZ (streptozotocin) (60 mg/kg) was used. The KSCs were injected into experimental groups via tail vein (2 × 106 cells/rat). In order to determine the impact of stem cells on the function and structure of the kidney, biochemical and histological parameters were measured. Further, the expression of miRNA-29a, miR-192, IL-1β, and TGF-β was determined through the real-time PCR technique. Phosphorylation of Smad2/3 was evaluated by using the standard western blotting. The KSCs significantly reduced blood nitrogen (BUN), serum creatinine (Scr), and 24-h urinary proteins in DN (P < 0.05). IL-1β and TGF-β significantly increased in the kidney of diabetic rats. In addition, the expression of miR-29a is significantly increased, whereas miR-192 decreased after treatment with KSCs (P < 0.05). Diabetic rats showed an increased level of phosphorylation of both Smad2 and Smad3 (P < 0.05). Periodic acid-Schiff (PAS) staining showed improved histopathological changes in the presence of KSCs. Stem cells derived from adult rat kidney may be an option for treating the early DN to improve the functions and structure of kidneys in rats with DN.
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Affiliation(s)
- Zeinab Rafiee
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran
| | - Mahmoud Orazizadeh
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran
| | - Fereshteh Nejad Dehbashi
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Niloofar Neisi
- Alimentary Tract Research Center, Imam Khomeini Hospital Clinical Research Development Unit, Infectious and Tropical Diseases Research Center, Department of Virology, the School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Babaahmadi-Rezaei
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Esrafil Mansouri
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran.
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Tracy EP, Stielberg V, Rowe G, Benson D, Nunes SS, Hoying JB, Murfee WL, LeBlanc AJ. State of the field: cellular and exosomal therapeutic approaches in vascular regeneration. Am J Physiol Heart Circ Physiol 2022; 322:H647-H680. [PMID: 35179976 PMCID: PMC8957327 DOI: 10.1152/ajpheart.00674.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/19/2023]
Abstract
Pathologies of the vasculature including the microvasculature are often complex in nature, leading to loss of physiological homeostatic regulation of patency and adequate perfusion to match tissue metabolic demands. Microvascular dysfunction is a key underlying element in the majority of pathologies of failing organs and tissues. Contributing pathological factors to this dysfunction include oxidative stress, mitochondrial dysfunction, endoplasmic reticular (ER) stress, endothelial dysfunction, loss of angiogenic potential and vascular density, and greater senescence and apoptosis. In many clinical settings, current pharmacologic strategies use a single or narrow targeted approach to address symptoms of pathology rather than a comprehensive and multifaceted approach to address their root cause. To address this, efforts have been heavily focused on cellular therapies and cell-free therapies (e.g., exosomes) that can tackle the multifaceted etiology of vascular and microvascular dysfunction. In this review, we discuss 1) the state of the field in terms of common therapeutic cell population isolation techniques, their unique characteristics, and their advantages and disadvantages, 2) common molecular mechanisms of cell therapies to restore vascularization and/or vascular function, 3) arguments for and against allogeneic versus autologous applications of cell therapies, 4) emerging strategies to optimize and enhance cell therapies through priming and preconditioning, and, finally, 5) emerging strategies to bolster therapeutic effect. Relevant and recent clinical and animal studies using cellular therapies to restore vascular function or pathologic tissue health by way of improved vascularization are highlighted throughout these sections.
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Affiliation(s)
- Evan Paul Tracy
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Virginia Stielberg
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Gabrielle Rowe
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Daniel Benson
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
- Department of Bioengineering, University of Louisville, Louisville, Kentucky
| | - Sara S Nunes
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
| | - James B Hoying
- Advanced Solutions Life Sciences, Manchester, New Hampshire
| | - Walter Lee Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | - Amanda Jo LeBlanc
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
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Golchin A, Shams F, Basiri A, Ranjbarvan P, Kiani S, Sarkhosh-Inanlou R, Ardeshirylajimi A, Gholizadeh-Ghaleh Aziz S, Sadigh S, Rasmi Y. Combination Therapy of Stem Cell-derived Exosomes and Biomaterials in the Wound Healing. Stem Cell Rev Rep 2022; 18:1892-1911. [PMID: 35080745 DOI: 10.1007/s12015-021-10309-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/22/2021] [Indexed: 12/19/2022]
Abstract
Wound healing is a serious obstacle due to the complexity of evaluation and management. While novel approaches to promoting chronic wound healing are of critical interest at the moment, several studies have demonstrated that combination therapy is critical for the treatment of a variety of diseases, particularly chronic wounds. Among the various approaches that have been proposed for wound care, regenerative medicine-based methods have garnered the most attention. As is well known, regenerative medicine's three primary tools are gene/cell therapy, biomaterials, and tissue engineering. Multifunctional biomaterials composed of synthetic and natural components are highly advantageous for exosome carriers, which utilizing them is an exciting wound healing method. Recently, stem cell-secreted exosomes and certain biomaterials have been identified as critical components of the wound healing process, and their combination therapy appears to produce significant results. This paper presents a review of literature and perspectives on the use of stem cell-derived exosomes and biomaterials in wound healing, particularly chronic wounds, and discusses the possibility of future clinical applications.
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Affiliation(s)
- Ali Golchin
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.
| | - Forough Shams
- Department of Medical Biotechnology, School of Advanced Technologies in MedicineShahid, Beheshti University of Medical Sciences, Tehran, Iran.
| | - Arefeh Basiri
- Department of Biomaterials and Tissue Engineering, School of Advanced Technologies in Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Parviz Ranjbarvan
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Samaneh Kiani
- Department of Tissue Engineering & Regenerative Medicine, School of Advanced Technologies in Medicine, Mazandaran University of Medical Sciences, Mazandaran, Iran
| | - Roya Sarkhosh-Inanlou
- Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
| | | | - Shiva Gholizadeh-Ghaleh Aziz
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Sanaz Sadigh
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Rasmi
- Department of Clinical Biochemistry and Applied Cell Sciences, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Cellular and Molecular Medicine Institute, Urmia University of Medical Sciences, Urmia, Iran
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Jin Y, Zhang M, Li M, Zhang H, Zhang F, Zhang H, Yin Z, Zhou M, Wan X, Li R, Cao C. Generation of Urine-Derived Induced Pluripotent Stem Cell Line from Patients with Acute Kidney Injury. Cell Reprogram 2021; 23:290-303. [PMID: 34648385 DOI: 10.1089/cell.2021.0051] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Acute kidney injury (AKI) is mainly characterized by rapid decline of renal function. Currently, the strategy of stem cells might be a therapy to treat AKI. The objective of this study was to obtain human urine-derived cells (HUCs) from patients with AKI, followed by establishing induced pluripotent stem (iPS) cell line. We isolated urine cells from patients with AKI and found that the cells could survive long term with epithelioid morphology and maintain a normal karyotype. The cell line had expression of renal-specific markers and renal development-related genes. After induction, the urine cells cotransfecting with TET-ON vectors were converted into iPS cells. The HUC-derived iPS (HUC-iPS) was positive for alkaline phosphatase staining, and had expression of pluripotency markers, consistent with human embryonic fibroblast-derived iPS cell. Notably, HUC-iPS could be induced to undergo directional kidney precursor cells (KPCs) differentiation under defined conditions, and transplantation of KPCs resulted in reducing kidney damage from ischemia-reperfusion injury in mice. Therefore, we successfully established HUC-iPS cell from patients with AKI and provided a novel stem cell resource for cell therapy in AKI.
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Affiliation(s)
- Yong Jin
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Manling Zhang
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Meishuang Li
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Hao Zhang
- Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Feng Zhang
- Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Hong Zhang
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Zhibao Yin
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Meng Zhou
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Xin Wan
- Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Rongfeng Li
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Changchun Cao
- Department of Nephrology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
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Huang J, Kong Y, Xie C, Zhou L. Stem/progenitor cell in kidney: characteristics, homing, coordination, and maintenance. Stem Cell Res Ther 2021; 12:197. [PMID: 33743826 PMCID: PMC7981824 DOI: 10.1186/s13287-021-02266-0] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/02/2021] [Indexed: 02/06/2023] Open
Abstract
Renal failure has a high prevalence and is becoming a public health problem worldwide. However, the renal replacement therapies such as dialysis are not yet satisfactory for its multiple complications. While stem/progenitor cell-mediated tissue repair and regenerative medicine show there is light at the end of tunnel. Hence, a better understanding of the characteristics of stem/progenitor cells in kidney and their homing capacity would greatly promote the development of stem cell research and therapy in the kidney field and open a new route to explore new strategies of kidney protection. In this review, we generally summarize the main stem/progenitor cells derived from kidney in situ or originating from the circulation, especially bone marrow. We also elaborate on the kidney-specific microenvironment that allows stem/progenitor cell growth and chemotaxis, and comment on their interaction. Finally, we highlight potential strategies for improving the therapeutic effects of stem/progenitor cell-based therapy. Our review provides important clues to better understand and control the growth of stem cells in kidneys and develop new therapeutic strategies.
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Affiliation(s)
- Jiewu Huang
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China
| | - Yaozhong Kong
- Department of Nephrology, the First People's Hospital of Foshan, Foshan, Guangdong, China
| | - Chao Xie
- Department of Nephrology, the First People's Hospital of Foshan, Foshan, Guangdong, China
| | - Lili Zhou
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Division of Nephrology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Ave, Guangzhou, 510515, China. .,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
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10
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Kerstan A, Niebergall-Roth E, Esterlechner J, Schröder HM, Gasser M, Waaga-Gasser AM, Goebeler M, Rak K, Schrüfer P, Endres S, Hagenbusch P, Kraft K, Dieter K, Ballikaya S, Stemler N, Sadeghi S, Tappenbeck N, Murphy GF, Orgill DP, Frank NY, Ganss C, Scharffetter-Kochanek K, Frank MH, Kluth MA. Ex vivo-expanded highly pure ABCB5 + mesenchymal stromal cells as Good Manufacturing Practice-compliant autologous advanced therapy medicinal product for clinical use: process validation and first in-human data. Cytotherapy 2021; 23:165-175. [PMID: 33011075 PMCID: PMC8310651 DOI: 10.1016/j.jcyt.2020.08.012] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 08/05/2020] [Accepted: 08/29/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AIM Mesenchymal stromal cells (MSCs) hold promise for the treatment of tissue damage and injury. However, MSCs comprise multiple subpopulations with diverse properties, which could explain inconsistent therapeutic outcomes seen among therapeutic attempts. Recently, the adenosine triphosphate-binding cassette transporter ABCB5 has been shown to identify a novel dermal immunomodulatory MSC subpopulation. METHODS The authors have established a validated Good Manufacturing Practice (GMP)-compliant expansion and manufacturing process by which ABCB5+ MSCs can be isolated from skin tissue and processed to generate a highly functional homogeneous cell population manufactured as an advanced therapy medicinal product (ATMP). This product has been approved by the German competent regulatory authority to be tested in a clinical trial to treat therapy-resistant chronic venous ulcers. RESULTS As of now, 12 wounds in nine patients have been treated with 5 × 105 autologous ABCB5+ MSCs per cm2 wound area, eliciting a median wound size reduction of 63% (range, 32-100%) at 12 weeks and early relief of pain. CONCLUSIONS The authors describe here their GMP- and European Pharmacopoeia-compliant production and quality control process, report on a pre-clinical dose selection study and present the first in-human results. Together, these data substantiate the idea that ABCB5+ MSCs manufactured as ATMPs could deliver a clinically relevant wound closure strategy for patients with chronic therapy-resistant wounds.
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Affiliation(s)
- Andreas Kerstan
- Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, Würzburg, Germany
| | | | | | | | - Martin Gasser
- Department of Surgery, University Hospital Würzburg, Würzburg, Germany
| | - Ana M Waaga-Gasser
- Department of Surgery, University Hospital Würzburg, Würzburg, Germany; Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Matthias Goebeler
- Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, Würzburg, Germany
| | - Katrin Rak
- Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, Würzburg, Germany
| | - Philipp Schrüfer
- Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, Würzburg, Germany
| | - Sabrina Endres
- Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, Würzburg, Germany
| | - Petra Hagenbusch
- Department of Dermatology, Venereology, and Allergology, University Hospital Würzburg, Würzburg, Germany
| | | | | | | | | | | | | | - George F Murphy
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Dennis P Orgill
- Division of Plastic Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Natasha Y Frank
- Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts, USA; Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA
| | - Christoph Ganss
- TICEBA GmbH, Heidelberg, Germany; RHEACELL GmbH & Co. KG, Heidelberg, Germany
| | | | - Markus H Frank
- Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Transplant Research Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA; School of Medical and Health Sciences, Edith Cowan University, Perth, Australia
| | - Mark A Kluth
- TICEBA GmbH, Heidelberg, Germany; RHEACELL GmbH & Co. KG, Heidelberg, Germany.
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11
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Ahmadi A, Rad NK, Ezzatizadeh V, Moghadasali R. Kidney Regeneration: Stem Cells as a New Trend. Curr Stem Cell Res Ther 2020; 15:263-283. [DOI: 10.2174/1574888x15666191218094513] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/05/2019] [Accepted: 11/06/2019] [Indexed: 12/23/2022]
Abstract
Renal disease is a major worldwide public health problem that affects one in ten people.
Renal failure is caused by the irreversible loss of the structural and functional units of kidney (nephrons)
due to acute and chronic injuries. In humans, new nephrons (nephrogenesis) are generated until
the 36th week of gestation and no new nephron develops after birth. However, in rodents, nephrogenesis
persists until the immediate postnatal period. The postnatal mammalian kidney can partly repair
their nephrons. The kidney uses intrarenal and extra-renal cell sources for maintenance and repair.
Currently, it is believed that dedifferentiation of surviving tubular epithelial cells and presence of resident
stem cells have important roles in kidney repair. Many studies have shown that stem cells obtained
from extra-renal sites such as the bone marrow, adipose and skeletal muscle tissues, in addition
to umbilical cord and amniotic fluid, have potential therapeutic benefits. This review discusses the
main mechanisms of renal regeneration by stem cells after a kidney injury.
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Affiliation(s)
- Amin Ahmadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar K. Rad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Vahid Ezzatizadeh
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Reza Moghadasali
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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12
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Liao Y, Li G, Zhang X, Huang W, Xie D, Dai G, Zhu S, Lu D, Zhang Z, Lin J, Wu B, Lin W, Chen Y, Chen Z, Peng C, Wang M, Chen X, Jiang MH, Xiang AP. Cardiac Nestin + Mesenchymal Stromal Cells Enhance Healing of Ischemic Heart through Periostin-Mediated M2 Macrophage Polarization. Mol Ther 2020; 28:855-873. [PMID: 31991111 DOI: 10.1016/j.ymthe.2020.01.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 12/31/2019] [Accepted: 01/01/2020] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) show potential for treating cardiovascular diseases, but their therapeutic efficacy exhibits significant heterogeneity depending on the tissue of origin. This study sought to identify an optimal source of MSCs for cardiovascular disease therapy. We demonstrated that Nestin was a suitable marker for cardiac MSCs (Nes+cMSCs), which were identified by their self-renewal ability, tri-lineage differentiation potential, and expression of MSC markers. Furthermore, compared with bone marrow-derived MSCs (Nes+bmMSCs) or saline-treated myocardial infarction (MI) controls, intramyocardial injection of Nes+cMSCs significantly improved cardiac function and decreased infarct size after acute MI (AMI) through paracrine actions, rather than transdifferentiation into cardiac cells in infarcted heart. We further revealed that Nes+cMSC treatment notably reduced pan-macrophage infiltration while inducing macrophages toward an anti-inflammatory M2 phenotype in ischemic myocardium. Interestingly, Periostin, which was highly expressed in Nes+cMSCs, could promote the polarization of M2-subtype macrophages, and knockdown or neutralization of Periostin remarkably reduced the therapeutic effects of Nes+cMSCs by decreasing M2 macrophages at lesion sites. Thus, the present work systemically shows that Nes+cMSCs have greater efficacy than do Nes+bmMSCs for cardiac healing after AMI, and that this occurs at least partly through Periostin-mediated M2 macrophage polarization.
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Affiliation(s)
- Yan Liao
- Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510623, China; Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Guilan Li
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China
| | - Xiaoran Zhang
- Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510623, China; Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Weijun Huang
- Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510623, China; Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Dongmei Xie
- Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510630, China; Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Gang Dai
- NHC Key Laboratory of Assisted Circulation, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Shuanghua Zhu
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Dihan Lu
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Zhongyuan Zhang
- Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510623, China; Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Junyi Lin
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Bingyuan Wu
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Wanwen Lin
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Yang Chen
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Zhihong Chen
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Chaoquan Peng
- Department of Cardiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Maosheng Wang
- The Cardiovascular Center, Gaozhou People's Hospital, Maoming, Guangdong 525200, China
| | - Xinxin Chen
- Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510623, China.
| | - Mei Hua Jiang
- Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510623, China; Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Department of Anatomy, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
| | - Andy Peng Xiang
- Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510623, China; Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510080, China.
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13
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Oh SY, Choi DH, Jin YM, Yu Y, Kim HY, Kim G, Park YS, Jo I. Optimization of Microenvironments Inducing Differentiation of Tonsil-Derived Mesenchymal Stem Cells into Endothelial Cell-Like Cells. Tissue Eng Regen Med 2019; 16:631-643. [PMID: 31824825 PMCID: PMC6879685 DOI: 10.1007/s13770-019-00221-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/04/2019] [Accepted: 09/17/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Stem cell engineering is appealing consideration for regenerating damaged endothelial cells (ECs) because stem cells can differentiate into EC-like cells. In this study, we demonstrate that tonsil-derived mesenchymal stem cells (TMSCs) can differentiate into EC-like cells under optimal physiochemical microenvironments. METHODS TMSCs were preconditioned with Dulbecco's Modified Eagle Medium (DMEM) or EC growth medium (EGM) for 4 days and then replating them on Matrigel to observe the formation of a capillary-like network under light microscope. Microarray, quantitative real time polymerase chain reaction, Western blotting and immunofluorescence analyses were used to evaluate the expression of gene and protein of EC-related markers. RESULTS Preconditioning TMSCs in EGM for 4 days and then replating them on Matrigel induced the formation of a capillary-like network in 3 h, but TMSCs preconditioned with DMEM did not form such a network. Genome analyses confirmed that EGM preconditioning significantly affected the expression of genes related to angiogenesis, blood vessel morphogenesis and development, and vascular development. Western blot analyses revealed that EGM preconditioning with gelatin coating induced the expression of endothelial nitric oxide synthase (eNOS), a mature EC-specific marker, as well as phosphorylated Akt at serine 473, a signaling molecule related to eNOS activation. Gelatin-coating during EGM preconditioning further enhanced the stability of the capillary-like network, and also resulted in the network more closely resembled to those observed in human umbilical vein endothelial cells. CONCLUSION This study suggests that under specific conditions, i.e., EGM preconditioning with gelatin coating for 4 days followed by Matrigel, TMSCs could be a source of generating endothelial cells for treating vascular dysfunction.
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Affiliation(s)
- Se-Young Oh
- Department of Molecular Medicine, College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
- Ewha Tonsil-derived Mesenchymal Stem Cells Research Center (ETSRC), College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
| | - Da Hyeon Choi
- School of Biological Sciences, College of Natural Sciences, Chungbuk National University, Chungdae-ro 1, Seowon-Gu, Cheongju, Chungbuk 28644 Republic of Korea
| | - Yoon Mi Jin
- Department of Molecular Medicine, College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
- Ewha Tonsil-derived Mesenchymal Stem Cells Research Center (ETSRC), College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
| | - Yeonsil Yu
- Department of Molecular Medicine, College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
- Ewha Tonsil-derived Mesenchymal Stem Cells Research Center (ETSRC), College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
| | - Ha Yeong Kim
- Department of Molecular Medicine, College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
- Ewha Tonsil-derived Mesenchymal Stem Cells Research Center (ETSRC), College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
| | - Gyungah Kim
- Department of Molecular Medicine, College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
- Ewha Tonsil-derived Mesenchymal Stem Cells Research Center (ETSRC), College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
| | - Yoon Shin Park
- School of Biological Sciences, College of Natural Sciences, Chungbuk National University, Chungdae-ro 1, Seowon-Gu, Cheongju, Chungbuk 28644 Republic of Korea
| | - Inho Jo
- Department of Molecular Medicine, College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
- Ewha Tonsil-derived Mesenchymal Stem Cells Research Center (ETSRC), College of Medicine, Ewha Womans University, 260 Gonghang-daero, Gangseo-gu Seoul, 07804 Republic of Korea
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An immortalized cell line derived from renal erythropoietin-producing (REP) cells demonstrates their potential to transform into myofibroblasts. Sci Rep 2019; 9:11254. [PMID: 31375751 PMCID: PMC6677766 DOI: 10.1038/s41598-019-47766-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 07/23/2019] [Indexed: 12/22/2022] Open
Abstract
The erythroid growth factor erythropoietin (Epo) is produced by renal interstitial fibroblasts, called REP (renal Epo-producing) cells, in a hypoxia-inducible manner. In chronic kidney disease (CKD), REP cells lose their Epo-production ability, leading to renal anaemia. Concurrently, REP cells are suggested to be transformed into myofibroblasts, which are the major player of renal fibrosis. Although establishment of cultured cell lines derived from REP cells has been a long-term challenge, we here successfully established a REP-cell-derived immortalized and cultivable cell line (Replic cells) by using a genetically modified mouse line. Replic cells exhibited myofibroblastic phenotypes and lost their Epo-production ability, reflecting the situation in renal fibrosis. Additionally, we found that cell-autonomous TGFβ signalling contributes to maintenance of the myofibroblastic features of Replic cells. Furthermore, the promoters of genes for Epo and HIF2α, a major activator of Epo gene expression, were highly methylated in Replic cells. Thus, these results strongly support our contention that REP cells are the origin of myofibroblasts in fibrotic kidneys and demonstrate that cell-autonomous TGFβ signalling and epigenetic silencing are involved in renal fibrosis and renal anaemia, respectively, in CKD. The Replic cell line is a useful tool to further investigate the molecular mechanisms underlying renal fibrosis.
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15
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Role of bone marrow-derived stem cells, renal progenitor cells and stem cell factor in chronic renal allograft nephropathy. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2013.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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16
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Potential Role of the Resident Mesenchymal Stem-Like Cells in Renal Fibrogenesis after Ureteral Obstruction. Stem Cells Int 2019; 2019:2543171. [PMID: 30949209 PMCID: PMC6425387 DOI: 10.1155/2019/2543171] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/03/2019] [Accepted: 01/15/2019] [Indexed: 01/06/2023] Open
Abstract
The mechanisms of renal fibrogenesis after ureteral obstruction remain unclear. We tried to primarily expand mesenchymal stem cells from renal tissues and then investigated their role in fibrogenesis after ureteral obstruction. Unilateral ureteral obstruction was induced by ligating the left ureteral duct of adult C57BL/6 mice. We collected the kidneys for experiments at 2, 7, and 14 days after operation. Histological analysis showed obviously fibrotic changes in the left kidney at 7 days and further increased at 14 days after ureteral obstruction. To expand mesenchymal stem cells, we minced the renal tissues into small explants (about 1 mm3) and cultured onto 10 cm dishes. Interestingly, the outgrowth of cells was observed significantly earlier from the explants of the obstructed left kidney than that of the unobstructed right kidney. These expanded cells showed the potency of adipogenic, osteogenic, and chondrogenic differentiations and positively expressed with CD44 and partly expressed with CD90, CD105, and CD106, but negatively expressed with CD34, CD45, and FSP1, suggesting the phenotype of mesenchymal stem-like cells (MSLCs). The mouse fibrosis RT2 profiler PCR array showed that many genes were changed over 2-fold in the MSLCs expanded from both kidneys at 2, 7, and 14 days after operation. Interestingly, profibrotic genes were prevalently enhanced in the left kidney with ureteral obstruction. Histological analysis also showed obviously infiltration of inflammatory cells in the left kidney at 14 days after operation. Our data indicate the potential role of resident MSLCs in renal fibrogenesis after ureteral obstruction, but further experiments are required to understand the relevant mechanisms.
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Abstract
The number of individuals affected by acute kidney injury (AKI) and chronic kidney disease (CKD) is constantly rising. In light of the limited availability of treatment options and their relative inefficacy, cell based therapeutic modalities have been studied. However, not many efforts are put into safety evaluation of such applications. The aim of this study was to review the existing published literature on adverse events reported in studies with genetically modified cells for treatment of kidney disease. A systematic review was conducted by searching PubMed and EMBASE for relevant articles published until June 2018. The search results were screened and relevant articles selected using pre-defined criteria, by two researchers independently. After initial screening of 6894 abstracts, a total number of 97 preclinical studies was finally included for full assessment. Of these, 61 (63%) presented an inappropriate study design for the evaluation of safety parameters. Only 4 studies (4%) had the optimal study design, while 32 (33%) showed sub-optimal study design with either direct or indirect evidence of adverse events. The high heterogeneity of studies included regarding cell type and number, genetic modification, administration route, and kidney disease model applied, combined with the consistent lack of appropriate control groups, makes a reliable safety evaluation of kidney cell-based therapies impossible. Only a limited number of relevant studies included looked into essential safety-related outcomes, such as inflammatory (48%), tumorigenic and teratogenic potential (12%), cell biodistribution (82%), microbiological safety with respect to microorganism contamination and latent viruses' reactivation (1%), as well as overall well-being and animal survival (19%). In conclusion, for benign cell-based therapies, well-designed pre-clinical studies, including all control groups required and good manufacturing processes securing safety, need to be done early in development. Preferably, this should be performed side by side with efficacy evaluation and according to the official guidelines of leading health organizations.
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18
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Marcheque J, Bussolati B, Csete M, Perin L. Concise Reviews: Stem Cells and Kidney Regeneration: An Update. Stem Cells Transl Med 2018; 8:82-92. [PMID: 30302937 PMCID: PMC6312445 DOI: 10.1002/sctm.18-0115] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 08/03/2018] [Indexed: 02/06/2023] Open
Abstract
Significant progress has been made to advance stem cell products as potential therapies for kidney diseases: various kinds of stem cells can restore renal function in preclinical models of acute and chronic kidney injury. Nonetheless this literature contains contradictory results, and for this reason, we focus this review on reasons for apparent discrepancies in the literature, because they contribute to difficulty in translating renal regenerative therapies. Differences in methodologies used to derive and culture stem cells, even those from the same source, in addition to the lack of standardized renal disease animal models (both acute and chronic), are important considerations underlying contradictory results in the literature. We propose that harmonized rigorous protocols for characterization, handling, and delivery of stem cells in vivo could significantly advance the field, and present details of some suggested approaches to foster translation in the field of renal regeneration. Our goal is to encourage coordination of methodologies (standardization) and long‐lasting collaborations to improve protocols and models to lead to reproducible, interpretable, high‐quality preclinical data. This approach will certainly increase our chance to 1 day offer stem cell therapeutic options for patients with all‐too‐common renal diseases. Stem Cells Translational Medicine2019;8:82–92
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Affiliation(s)
- Julia Marcheque
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Children's Hospital Los Angeles, Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, California
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
| | - Marie Csete
- Medical Engineering, California Institute of Technology, Los Angeles, California.,Department of Anesthesiology, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Laura Perin
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Children's Hospital Los Angeles, Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, California
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Fan M, Zhang J, Xin H, He X, Zhang X. Current Perspectives on Role of MSC in Renal Pathophysiology. Front Physiol 2018; 9:1323. [PMID: 30294285 PMCID: PMC6158317 DOI: 10.3389/fphys.2018.01323] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2018] [Accepted: 08/31/2018] [Indexed: 01/06/2023] Open
Abstract
In the course of the development and worsening of kidney disease, the treatments available are expensive and may cause adverse effects such as immune rejection, inadequate renal resources, or post-operative complications. Therefore, there is an urgent to develop more effective treatments. The advent of mesenchymal stem cells (MSCs) represents a new direction in this context. The current use of MSCs for the treatment of kidney disease has mostly involved experimental studies on animals and only a few clinical trials have been conducted. This review focused on the mechanisms of MSC involvement from different sources in the improvement of renal pathophysiology in recent years. These mechanisms include homing to damaged kidney tissue, and differentiating into or fusing with the innate cells of the kidney. The paracrine or endocrine action through secreting protective cytokines and/or releasing microvesicle from MSCs also plays a critical role in amelioration of kidney disease. With modern engineering technology like microRNA delivery and a combinational therapy approach such as reduction of renal fibrosis in obstructive nephropathy with MSCs and serelaxin, MSC may make great contribution to the improvement of renal pathophysiology. However, the therapeutic effects of MSC are still controversial and several problems remain unsolved. While it is too early to state that MSCs are useful for the treatment of renal diseases in clinic, it is thought that solutions to the existing problems will enable effective modulation of the biological characteristics of MSCs, thereby providing new and effective approaches for the treatment of renal diseases.
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Affiliation(s)
- Min Fan
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Jing Zhang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Hong Xin
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Xiaozhou He
- The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Xuemei Zhang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
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Marofi F, Vahedi G, hasanzadeh A, Salarinasab S, Arzhanga P, Khademi B, Farshdousti Hagh M. Mesenchymal stem cells as the game‐changing tools in the treatment of various organs disorders: Mirage or reality? J Cell Physiol 2018; 234:1268-1288. [DOI: 10.1002/jcp.27152] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 07/05/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Faroogh Marofi
- Department of Hematology Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
| | - Ghasem Vahedi
- Faculty of Veterinary Medicine, University of Tehran Tehran Iran
| | - Ali hasanzadeh
- Department of Hematology Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
| | - Sadegh Salarinasab
- Department of Biochemistry and Clinical Laboratories Faculty of Medicine, Tabriz University of Medical Science Tabriz Iran
| | - Pishva Arzhanga
- Department of Biochemistry and Diet Therapy Faculty of Nutrition and Food Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Bahareh Khademi
- Department of Medical Genetic Faculty of Medicine, Tabriz University of Medical Sciences Tabriz Iran
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Li CL, Xu ZB, Fan XL, Chen HX, Yu QN, Fang SB, Wang SY, Lin YD, Fu QL. MicroRNA-21 Mediates the Protective Effects of Mesenchymal Stem Cells Derived from iPSCs to Human Bronchial Epithelial Cell Injury Under Hypoxia. Cell Transplant 2018; 27:571-583. [PMID: 29806480 PMCID: PMC6038046 DOI: 10.1177/0963689718767159] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Airway epithelial cell injury is a key triggering event to activate allergic airway inflammation, such as asthma. We previously reported that administration of mesenchymal stem cells (MSCs) significantly alleviated allergic inflammation in a mouse model of asthma, and the mmu-miR-21/ACVR2A axis may be involved. However, whether MSCs protect against bronchial epithelial cell injury induced by hypoxia, and the underlying mechanism, remain unknown. In our study, the human bronchial epithelial cell line BEAS-2B was induced to undergo apoptosis with a hypoxia mimic of cobalt chloride (CoCl2) damage. Treatment of MSCs derived from induced pluripotent stem cells (iPSCs) significantly decreased apoptosis of BEAS-2B cells. There was high miR-21 expression in injured BEAS-2B cells after MSC treatment. Transfection of the miR-21 mimic significantly decreased apoptosis of BEAS-2B, and transfection of a miR-21 inhibitor significantly increased apoptosis. More importantly, the protective effects of MSCs on injured BEAS-2B were reversed by transfection of the miR-21 inhibitor. Binding sites of human miR-21 were identified in the 3’UTR of human ACVR2A. We further determined that CoCl2 stimulation increased ACVR2A expression at both the mRNA and protein levels. Moreover, transfection of the miR-21 mimic further up-regulated ACVR2A expression induced by CoCl2, whereas transfection of the miR-21 inhibitor down-regulated ACVR2A expression. In addition, MSCs increased ACVR2A expression in BEAS-2B cells; however, this effect was reversed after transfection of the miR-21 inhibitor. Our data suggested that MSCs protect bronchial epithelial cells from hypoxic injury via miR-21, which may represent an important target. These findings suggest the potentially wide application of MSCs for epithelial cell injury during hypoxia.
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Affiliation(s)
- Cheng-Lin Li
- 1 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,2 Centre for Stem Cell Clinical Research and Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Bin Xu
- 1 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,2 Centre for Stem Cell Clinical Research and Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xing-Liang Fan
- 1 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,2 Centre for Stem Cell Clinical Research and Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - He-Xin Chen
- 1 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qiu-Ning Yu
- 1 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shu-Bin Fang
- 1 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shu-Yue Wang
- 1 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yong-Dong Lin
- 1 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qing-Ling Fu
- 1 Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,2 Centre for Stem Cell Clinical Research and Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Herrera GA, Teng J, Zeng C, Xu H, Liang M, Alexander JS, Liu B, Boyer C, Turbat-Herrera EA. Phenotypic plasticity of mesenchymal stem cells is crucial for mesangial repair in a model of immunoglobulin light chain-associated mesangial damage. Ultrastruct Pathol 2018; 42:262-288. [PMID: 29668344 DOI: 10.1080/01913123.2018.1449772] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
Mesangiopathies produced by glomerulopathic monoclonal immunoglobulin light chains (GLCs) acting on the glomerular mesangium produce two characteristic lesions: AL-amyloidosis (AL-Am) and light chain deposition disease (LCDD). In both cases, the pathology is centered in the mesangium, where initial and progressive damage occurs. In AL-Am the mesangial matrix is destroyed and replaced by amyloid fibrils and in LCDD, the mesangial matrix is increased and remodeled. The collagen IV rich matrix is replaced by tenascin. In both conditions, mesangial cells (MCs) become apoptotic as a direct effect of the GLCs. MCs were incubated in-vitro with GLCs and animal kidneys were perfused ex-vivo via the renal artery with GLCs, producing expected lesions, and then mesenchymal stem cells (MSCs) were added to both platforms. Each of the two platforms provided unique information that when put together created a comprehensive evaluation of the processes involved. A "cocktail" with growth and differentiating factors was used to study its effect on mesangial repair. MSCs displayed remarkable phenotypic plasticity during the repair process. The first role of the MSCs after migrating to the affected areas was to dispose of the amyloid fibrils (in AL-Am), the altered mesangial matrix (in LCDD) and apoptotic MCs/debris. To accomplish this task, MSCs transformed into facultative macrophages acquiring an abundance of lysosomes and endocytotic capabilities required to engage in phagocytic functions. Once the mesangial cleaning was completed, MSCs transformed into functional MCs restoring the mesangium to normal. "Cocktail" made the repair process more efficient.
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Affiliation(s)
- Guillermo A Herrera
- a Departments of Pathology and Translational Pathobiology and Cell Biology and Anatomy , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Jiamin Teng
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Chun Zeng
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Hongzhi Xu
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Man Liang
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - J Steven Alexander
- c Department of Molecular and Cellular Physiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Bing Liu
- b Department of Pathology and Translational Pathobiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Chris Boyer
- c Department of Molecular and Cellular Physiology , Louisiana State Health Sciences Center , Shreveport , LA , USA
| | - Elba A Turbat-Herrera
- d Departments of Pathology and Translational Pathobiology , Medicine, and Cell Biology and Anatomy, Louisiana State Health Sciences Center , Shreveport , LA , USA
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24
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Pan Y, Chen J, Yu Y, Dai K, Wang J, Liu C. Enhancement of BMP-2-mediated angiogenesis and osteogenesis by 2-N,6-O-sulfated chitosan in bone regeneration. Biomater Sci 2018; 6:431-439. [DOI: 10.1039/c7bm01006k] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Sulfated polysaccharides are attractive semi-synthesized materials that can be used as a mimic of heparan sulfate to modulate the protein activity and other physiological processes.
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Affiliation(s)
- Yuanzhong Pan
- The State Key Laboratory of Bioreactor Engineering
- East China University of Science and Technology
- Shanghai
- 200237 People's Republic of China
- Engineering Research Center for Biomedical Materials of Ministry of Education
| | - Jie Chen
- The State Key Laboratory of Bioreactor Engineering
- East China University of Science and Technology
- Shanghai
- 200237 People's Republic of China
- Engineering Research Center for Biomedical Materials of Ministry of Education
| | - Yuanman Yu
- The State Key Laboratory of Bioreactor Engineering
- East China University of Science and Technology
- Shanghai
- 200237 People's Republic of China
- Engineering Research Center for Biomedical Materials of Ministry of Education
| | - Kai Dai
- The State Key Laboratory of Bioreactor Engineering
- East China University of Science and Technology
- Shanghai
- 200237 People's Republic of China
- Engineering Research Center for Biomedical Materials of Ministry of Education
| | - Jing Wang
- The State Key Laboratory of Bioreactor Engineering
- East China University of Science and Technology
- Shanghai
- 200237 People's Republic of China
- Engineering Research Center for Biomedical Materials of Ministry of Education
| | - Changsheng Liu
- The State Key Laboratory of Bioreactor Engineering
- East China University of Science and Technology
- Shanghai
- 200237 People's Republic of China
- Engineering Research Center for Biomedical Materials of Ministry of Education
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25
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Bettini S, Franceschini V, Astolfi L, Simoni E, Mazzanti B, Martini A, Revoltella RP. Human mesenchymal stromal cell therapy for damaged cochlea repair in nod-scid mice deafened with kanamycin. Cytotherapy 2017; 20:189-203. [PMID: 29246648 DOI: 10.1016/j.jcyt.2017.11.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 09/05/2017] [Accepted: 11/03/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Kanamycin, mainly used in the treatment of drug-resistant-tuberculosis, is known to cause irreversible hearing loss. Using the xeno-transplant model, we compared both in vitro and in vivo characteristics of human mesenchymal stromal cells (MSCs) derived from adult tissues, bone marrow (BM-MSCs) and adipose tissue (ADSCs). These tissues were selected for their availability, in vitro multipotency and regenerative potential in vivo in kanamycin-deafened nod-scid mice. METHODS MSCs were isolated from informed donors and expanded ex vivo. We evaluated their proliferation capacity in vitro using the hexosaminidase assay, the phenotypic profile using flow-cytometry of a panel of surface antigens, the osteogenic potential using alkaline phosphatase activity and the adipogenic potential using oil-red-O staining. MSCs were intravenously injected in deafened mice and cochleae, liver, spleen and kidney were sampled 7 and 30 days after transplantation. The dissected organs were analyzed using lectin histochemistry, immunohistochemistry, polymerase chain reaction (PCR) and dual color fluorescence in situ hybridization (DC-FISH). RESULTS MSCs showed similar in vitro characteristics, but ADSCs appeared to be more efficient after prolonged expansion. Both cell types engrafted in the cochlea of damaged mice, inducing regeneration of the damaged sensory structures. Several hybrid cells were detected in engrafted tissues. DISCUSSION BM-MSCs and ADSCs showed in vitro characteristics suitable for tissue regeneration and fused with resident cells in engrafted tissues. The data suggest that paracrine effect is the prevalent mechanism inducing tissue recovery. Overall, BM-MSCs and ADSCs appear to be valuable tools in regenerative medicine for hearing loss recovery.
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Affiliation(s)
- Simone Bettini
- Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy
| | - Valeria Franceschini
- Department of Biological, Geological and Environmental Sciences, University of Bologna, Bologna, Italy; Foundation Onlus 'Staminali e Vita', Padua, Italy.
| | - Laura Astolfi
- Foundation Onlus 'Staminali e Vita', Padua, Italy; Bioacoustics Research Laboratory, Department of Neurosciences, University of Padua, Padua, Italy
| | - Edi Simoni
- Bioacoustics Research Laboratory, Department of Neurosciences, University of Padua, Padua, Italy
| | - Benedetta Mazzanti
- Department of Clinical and Experimental Medicine, University of Florence, Florence, Italy
| | - Alessandro Martini
- Foundation Onlus 'Staminali e Vita', Padua, Italy; Bioacoustics Research Laboratory, Department of Neurosciences, University of Padua, Padua, Italy
| | - Roberto P Revoltella
- Foundation Onlus 'Staminali e Vita', Padua, Italy; Institute for Chemical, Physical Processes, Centro Nazionale delle Ricerche (C.N.R.), Pisa, Italy
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Sun Q, Hong L, Huang Z, Na N, Hua X, Peng Y, Zhao M, Cao R, Sun Q. Allogeneic mesenchymal stem cell as induction therapy to prevent both delayed graft function and acute rejection in deceased donor renal transplantation: study protocol for a randomized controlled trial. Trials 2017; 18:545. [PMID: 29145879 PMCID: PMC5689202 DOI: 10.1186/s13063-017-2291-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2016] [Accepted: 10/30/2017] [Indexed: 12/12/2022] Open
Abstract
Background Using kidneys from deceased donors is an available strategy to meet the growing need of grafts. However, higher incidences of delayed graft function (DGF) and acute rejection exert adverse effects on graft outcomes. Since ischemia-reperfusion injury (IRI) and ongoing process of immune response to grafts are the major causes of DGF and acute rejection, the optimal induction intervention should possess capacities of both repairing renal structure injury and suppressing immune response simultaneously. Mesenchymal stem cells (MSCs) with potent anti-inflammatory, regenerative and immune-modulatory properties are considered as a candidate to prevent both DGF and acute rejection in renal transplantation. Previous studies just focused on the safety of autologous MSCs on living-related donor renal transplants, and lack of concomitant controls and the sufficient sample size and source of MSCs. Here, we propose a prospective multicenter controlled study to assess the clinical value of allogeneic MSCs in preventing both DGF and acute rejection simultaneously as induction therapy in deceased-donor renal transplantation. Methods/design Renal allograft recipients (n = 100) will be recruited and divided into trial and control groups, and 50 patients in the trial group will be administered with a dose of 2 × 106 per kilogram human umbilical-cord-derived MSCs (UC-MSCs) via peripheral vein injection preoperatively, and a dose of 5 × 106 cells via renal arterial injection during surgery, with standard induction therapy. Incidences of postoperative DGF and biopsy-proved acute rejection (BPAR) will be recorded and analyzed. Additionally, other clinical parameters such as baseline demographics, graft and recipient survival and other severe postoperative complications, including complicated urinary tract infection, severe pneumonia, and severe bleeding, will be also assessed. Discussion This study will clarify the clinical value of UC-MSCs in preventing DGF and acute rejection simultaneously in deceased-donor renal transplantation, and provide evidence as to whether allogeneic MSCs can be used as clinically feasible and safe induction therapy. Trial registration ClinicalTrials.gov, NCT02490020. Registered on 29 June 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2291-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Qipeng Sun
- Department of Renal Transplantation, Lingnan Hospital, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Liangqing Hong
- Department of Renal Transplantation, Lingnan Hospital, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Zhengyu Huang
- Department of Renal Transplantation, Lingnan Hospital, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Ning Na
- Department of Renal Transplantation, Lingnan Hospital, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Xuefeng Hua
- Department of Renal Transplantation, Lingnan Hospital, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China
| | - Yanwen Peng
- Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Tianhe Road 600, Guangzhou, 510630, People's Republic of China
| | - Ming Zhao
- Department of Renal Transplantation, Zhujiang Hospital, Southern Medical University, Gongye Road 253, Guangzhou, 510280, People's Republic of China
| | - Ronghua Cao
- Department of Renal Transplantation, The Second Affiliated Hospital, Guangzhou Traditional Chinese Medicine University, Inner Ring Road 55, University City, Guangzhou, 510280, People's Republic of China
| | - Qiquan Sun
- Department of Renal Transplantation, Lingnan Hospital, The Third Affiliated Hospital, Sun Yat-sen University, Kaichuang Road 2693, Huangpu District, Guangzhou, 510530, People's Republic of China.
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27
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The Neuroprotective Effects of Muscle-Derived Stem Cells via Brain-Derived Neurotrophic Factor in Spinal Cord Injury Model. BIOMED RESEARCH INTERNATIONAL 2017; 2017:1972608. [PMID: 28758111 PMCID: PMC5516736 DOI: 10.1155/2017/1972608] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/22/2017] [Revised: 04/06/2017] [Accepted: 04/13/2017] [Indexed: 12/17/2022]
Abstract
Muscle-derived stem cells (MDSCs) possess multipotent differentiation and self-renewal capacities; however, the effects and mechanism in neuron injury remain unclear. The aim of this study was to investigate the effects of MDSCs on neuron secondary injury, oxidative stress-induced apoptosis. An in vivo study showed the Basso, Beattie, and Bresnahan (BBB) score and number of neurons significantly increased after MDSCs' transplantation in spinal cord injury (SCI) rats. An in vitro study demonstrated that MDSCs attenuated neuron apoptosis, and the expression of antioxidants was upregulated as well as the ratio of Bcl-2 and Bax in the MNT (MDSCs cocultured with injured neurons) group compared with the NT (injured neurons) group. Both LC3II/LC3I and β-catenin were enhanced in the MNT group, while XAV939 (a β-catenin inhibitor) decreased the expression of nuclear erythroid-related factor 2 (Nrf2) and LC3II/LC3I. Moreover, MDSCs became NSE- (neuron-specific enolase-) positive neuron-like cells with brain-derived neurotrophic factor (BDNF) treatment. The correlation analysis indicated that there was a significant relation between the level of BDNF and neuron injury. These findings suggest that MDSCs may protect the spinal cord from injury by inhibiting apoptosis and replacing injured neurons, and the increased BDNF and β-catenin could contribute to MDSCs' effects.
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Mesenchymal Stem Cell-Based Therapies against Podocyte Damage in Diabetic Nephropathy. Tissue Eng Regen Med 2017; 14:201-210. [PMID: 30603477 DOI: 10.1007/s13770-017-0026-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 05/25/2016] [Accepted: 06/13/2016] [Indexed: 01/02/2023] Open
Abstract
Injury to podocytes is an early event in diabetic nephropathy leading to proteinuria with possible progression to end-stage renal failure. The podocytes are unique and highly specialized cells that cover the outer layer of kidney ultra-filtration barrier and play an important role in glomerular function. In the past few decades, adult stem cells, such as mesenchymal stem cells (MSCs) with a regenerative and differentiative capacity have been extensively used in cell-based therapies. In addition to their capability for regeneration and differentiation, MSCs contributes to their milieu by paracrine action of a series of growth factors via antiapoptotic, mitogenic and other cytokine actions that actively participate in treatment of podocyte damage through prevention of podocyte effacement, detachment and apoptosis. It is hoped that novel stem cell-based therapies will be developed in the future to prevent podocyte injury, thereby reducing the burden of kidney disease.
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29
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Li CL, Leng Y, Zhao B, Gao C, Du FF, Jin N, Lian QZ, Xu SY, Yan GL, Xia JJ, Zhuang GH, Fu QL, Qi ZQ. Human iPSC-MSC-Derived Xenografts Modulate Immune Responses by Inhibiting the Cleavage of Caspases. Stem Cells 2017; 35:1719-1732. [PMID: 28520232 DOI: 10.1002/stem.2638] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Revised: 04/05/2017] [Accepted: 04/20/2017] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem cells (MSCs) negatively modulate immune properties. Induced pluripotent stem cells (iPSCs)-derived MSCs are alternative source of MSCs. However, the effects of iPSC-MSCs on T cells phenotypes in vivo remain unclear. We established an iPSC-MSC-transplanted host versus graft reaction mouse model using subcapsular kidney injection. Th1, Th2, regulatory T cells (Treg), and Th17 phenotypes and their cytokines were investigated in vivo and in vitro. The role of caspases and the soluble factors involved in the effects of MSCs were examined. We found that iPSC-MSC grafts led to more cell survival and less infiltration of inflammatory cells in mice. iPSC-MSC transplantation inhibited T cell proliferation, decreased Th1 and Th2 phenotypes and cytokines, upregulated Th17 and Treg subsets. Moreover, iPSC-MSCs inhibited the cleavage of caspases 3 and 8 and inhibition of caspases downregulated Th1, Th2 responses and upregulated Th17, Treg responses. Soluble factors were determined using protein array and TGF-β1/2/3, IL-10, and MCP-1 were found to be highly expressed in iPSC-MSCs. The administration of the soluble factors decreased Th1/2 response, upregulated Treg response and inhibited the cleavage of caspases. Our results demonstrate that iPSC-MSCs regulate T cell responses as a result of a combined action of the above soluble factors secreted by iPSC-MSCs. These factors suppress T cell responses by inhibiting the cleavage of caspases. These data provide a novel immunomodulatory mechanism for the underlying iPSC-MSC-based immunomodulatory effects on T cell responses. Stem Cells 2017;35:1719-1732.
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Affiliation(s)
- Cheng-Lin Li
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Yun Leng
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, People's Republic of China.,Xiamen Key Laboratory of Regenerative Medicine, Xiamen, Fujian, People's Republic of China
| | - Bin Zhao
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, People's Republic of China.,Xiamen Key Laboratory of Regenerative Medicine, Xiamen, Fujian, People's Republic of China
| | - Chang Gao
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, People's Republic of China.,Xiamen Key Laboratory of Regenerative Medicine, Xiamen, Fujian, People's Republic of China
| | - Fei-Fei Du
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, People's Republic of China.,Xiamen Key Laboratory of Regenerative Medicine, Xiamen, Fujian, People's Republic of China
| | - Ning Jin
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, People's Republic of China.,Xiamen Key Laboratory of Regenerative Medicine, Xiamen, Fujian, People's Republic of China
| | - Qi-Zhou Lian
- Department of Ophthalmology, and Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, People's Republic of China
| | - Shuang-Yue Xu
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, People's Republic of China.,Xiamen Key Laboratory of Regenerative Medicine, Xiamen, Fujian, People's Republic of China
| | - Guo-Liang Yan
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, People's Republic of China.,Xiamen Key Laboratory of Regenerative Medicine, Xiamen, Fujian, People's Republic of China
| | - Jun-Jie Xia
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, People's Republic of China.,Xiamen Key Laboratory of Regenerative Medicine, Xiamen, Fujian, People's Republic of China
| | - Guo-Hong Zhuang
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, People's Republic of China.,Xiamen Key Laboratory of Regenerative Medicine, Xiamen, Fujian, People's Republic of China
| | - Qing-Ling Fu
- Otorhinolaryngology Hospital, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Zhong-Quan Qi
- Organ Transplantation Institute, Medical College, Xiamen University, Xiamen, Fujian, People's Republic of China.,Fujian Key Laboratory of Organ and Tissue Regeneration, Xiamen, Fujian, People's Republic of China.,Xiamen Key Laboratory of Regenerative Medicine, Xiamen, Fujian, People's Republic of China
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30
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Mot YY, Othman I, Sharifah SH. Synergistic antibacterial effect of co-administering adipose-derived mesenchymal stromal cells and Ophiophagus hannah L-amino acid oxidase in a mouse model of methicillin-resistant Staphylococcus aureus-infected wounds. Stem Cell Res Ther 2017; 8:5. [PMID: 28114965 PMCID: PMC5259957 DOI: 10.1186/s13287-016-0457-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 12/09/2016] [Accepted: 12/14/2016] [Indexed: 01/08/2023] Open
Abstract
Background Mesenchymal stromal cells (MSCs) and Ophiophagus hannahl-amino acid oxidase (Oh-LAAO) have been reported to exhibit antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA). Published data have indicated that synergistic antibacterial effects could be achieved by co-administration of two or more antimicrobial agents. However, this hypothesis has not been proven in a cell- and protein-based combination. In this study, we investigate if co-administration of adipose-derived MSCs and Oh-LAAO into a mouse model of MRSA-infected wounds would be able to result in a synergistic antibacterial effect. Methods MSCs and Oh-LAAO were isolated and characterized by standard methodologies. The effects of the experimental therapies were evaluated in C57/BL6 mice. The animal study groups consisted of full-thickness uninfected and MRSA-infected wound models which received Oh-LAAO, MSCs, or both. Oh-LAAO was administered directly on the wound while MSCs were delivered via intradermal injections. The animals were housed individually with wound measurements taken on days 0, 3, and 7. Histological analyses and bacterial enumeration were performed on wound biopsies to determine the efficacy of each treatment. Results Immunophenotyping and differentiation assays conducted on isolated MSCs indicated expression of standard cell surface markers and plasticity which corresponds to published data. Characterization of Oh-LAAO by proteomics, enzymatic, and antibacterial assays confirmed the identity, purity, and functionality of the enzyme prior to use in our subsequent studies. Individual treatments with MSCs and Oh-LAAO in the infected model resulted in reduction of MRSA load by one order of magnitude to the approximate range of 6 log10 colony-forming units (CFU) compared to untreated controls (7.3 log10 CFU). Similar wound healing and improvements in histological parameters were observed between the two groups. Co-administration of MSCs and Oh-LAAO reduced bacterial burden by approximately two orders of magnitude to 5.1 log10 CFU. Wound closure measurements and histology analysis of biopsies obtained from the combinational therapy group indicated significant enhancement in the wound healing process compared to all other groups. Conclusions We demonstrated that co-administration of MSCs and Oh-LAAO into a mouse model of MRSA-infected wounds exhibited a synergistic antibacterial effect which significantly reduced the bacterial count and accelerated the wound healing process. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0457-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yee Yik Mot
- Jeffrey Cheah School of Medicine and Health Sciences and Tropical Medicine and Biology, Infectious Diseases and Health, Monash University Malaysia, Jalan Lagoon Selatan, Subang Jaya, 47500, Selangor, Malaysia
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences and Tropical Medicine and Biology, Infectious Diseases and Health, Monash University Malaysia, Jalan Lagoon Selatan, Subang Jaya, 47500, Selangor, Malaysia
| | - Syed Hassan Sharifah
- Jeffrey Cheah School of Medicine and Health Sciences and Tropical Medicine and Biology, Infectious Diseases and Health, Monash University Malaysia, Jalan Lagoon Selatan, Subang Jaya, 47500, Selangor, Malaysia.
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Takeshita N, Hasegawa M, Sasaki K, Seki D, Seiryu M, Miyashita S, Takano I, Oyanagi T, Miyajima Y, Takano-Yamamoto T. In vivo expression and regulation of genes associated with vascularization during early response of sutures to tensile force. J Bone Miner Metab 2017; 35:40-51. [PMID: 26825658 DOI: 10.1007/s00774-016-0737-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Accepted: 01/04/2016] [Indexed: 12/14/2022]
Abstract
Sutures are fibrous tissues that connect bones in craniofacial skeletal complexes. Cranio- and dentofacial skeletal deformities in infant and adolescent patients can be treated by applying tensile force to sutures to induce sutural bone formation. The early gene expression induced by mechanical stress is essential for bone formation in long bones; however, early gene expression during sutural bone formation induced by tensile force is poorly characterized. In vivo studies are essential to evaluate molecular responses to mechanical stresses in heterogeneous cell populations, such as sutures. In this paper we examined in vivo early gene expression and the underlying regulatory mechanism for this expression in tensile-force-applied cranial sutures, focusing on genes involved in vascularization. Tensile force upregulated expression of vascular factors, such as vascular endothelial growth factor (Vegf) and endothelial cell markers, in sutures within 3 h. The expression of connective tissue growth factor (Ctgf) and Rho-associated coiled-coil containing protein kinase 2 (Rock2) was also upregulated by tensile force. A CTGF-neutralizing antibody and the ROCK inhibitor, Y-27632, abolished tensile-force-induced Vegf expression. Moreover, tensile force activated extracellular signal-related kinase 1/2 (ERK1/2) signaling in sagittal sutures, and the ERK1/2 inhibitor, U0126, partially inhibited tensile-force-induced Ctgf expression. These results indicate that tensile force induces in vivo gene expression associated with vascularization early in tensile-force-induced sutural bone formation. Moreover, the early induction of Vegf gene expression is regulated by CTGF and ROCK2.
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Affiliation(s)
- Nobuo Takeshita
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Masakazu Hasegawa
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Kiyo Sasaki
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Daisuke Seki
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Masahiro Seiryu
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Shunro Miyashita
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Ikuko Takano
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Toshihito Oyanagi
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Yuki Miyajima
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Teruko Takano-Yamamoto
- Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
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Shi Y, Du L, Lin L, Wang Y. Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets. Nat Rev Drug Discov 2016; 16:35-52. [PMID: 27811929 DOI: 10.1038/nrd.2016.193] [Citation(s) in RCA: 340] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells, also known as mesenchymal stromal cells (MSCs), exist in many tissues and are known to actively migrate to sites of tissue injury, where they participate in wound repair. Tumours can be considered "wounds that never heal" and, in response to cues from a tumour, MSCs are continuously recruited to and become integral components of the tumour microenvironment. Recently, it has become apparent that such tumour-associated MSCs (TA-MSCs) have an active role in tumour initiation, promotion, progression and metastasis. In this Review, we discuss recent advances in our understanding of the pathogenic role of TA-MSCs in regulating the survival, proliferation, migration and drug resistance of tumour cells, as well as the influence of MSCs on the immune status of the tumour microenvironment. Moreover, we discuss therapeutic approaches that target TA-MSC upstream or downstream modulators or use MSCs as vehicles for the delivery of tumoricidal agents. It is anticipated that new insights into the functions of TA-MSCs will lead to the development of novel therapeutic strategies against tumours.
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Affiliation(s)
- Yufang Shi
- The First Affiliated Hospital of Soochow University and Jiangsu Engineering Research Center for Tumor Immunotherapy, Institutes for Translational Medicine and Suzhou Key Laboratory of Tumor Microenvironment and Pathology, Soochow University, 199 Renai Road, Suzhou, Jiangsu 215123, China.,Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.,Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China
| | - Liming Du
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China
| | - Liangyu Lin
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China.,Shanghai Jiao Tong University School of Medicine, 280 Chongqing Road, Shanghai 200025, China
| | - Ying Wang
- Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, 320 Yueyang Road, Shanghai 200031, China
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Hussein AM, Barakat N, Awadalla A, Gabr MM, Khater S, Harraz AM, Shokeir AA. Modulation of renal ischemia/reperfusion in rats by a combination of ischemic preconditioning and adipose-derived mesenchymal stem cells (ADMSCs). Can J Physiol Pharmacol 2016; 94:936-46. [PMID: 27411029 DOI: 10.1139/cjpp-2016-0018] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The present study investigated the effects of combination of ischemic preconditioning (Ipre) and adipose-derived mesenchymal stem cells (ADMSCs) on renal ischemia-reperfusion (I-R) injury in rats. 90 male Sprague Dawley rats were divided into 5 equal groups; sham operated, control (45 min left renal ischemia), Ipre group as control group with 3 cycles of Ipre just before renal ischemia, ADMSCs-treated group (as control with ADMSCs 10(6) cells in 0.1 mL via penile vein 60 min before ischemia time), and Ipre + ADMSCs group as ADMCs group with 3 cycles of Ipre. Ipre and ADMSCs groups showed significant decrease in serum creatinine and blood urea nitrogen (BUN) and caspase-3 and CD45 expression in kidney and significant increase in HIF-1α, SDF-1α, CD31, and Ki67 expressions in kidney compared with the control group (p < 0.05). Moreover, the Ipre + ADMSCs group showed significant decrease in serum BUN and caspase-3 and CD45 expression in kidney with significant increase in HIF-1α, SDF-1α, CD31, and Ki67 expression in kidney compared with the Ipre and ADMCs groups (p < 0.05). We concluded that Ipre potentiates the renoprotective effect of ADMSCs against renal I/R injury probably by upregulation of HIF-1α, SDF-1α, CD31, and Ki67 and downregulation of caspase-3 and CD45.
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Affiliation(s)
- Abdelaziz M Hussein
- a Physiology Department, Faculty of Medicine, Mansoura University, Mansoura, 35516, Egypt
| | - Nashwa Barakat
- b Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt
| | - Amira Awadalla
- b Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt
| | - Mahmoud M Gabr
- b Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt
| | - Sherry Khater
- b Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt
| | - Ahmed M Harraz
- b Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt
| | - Ahmed A Shokeir
- b Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt
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Monteiro Carvalho Mori da Cunha MG, Zia S, Oliveira Arcolino F, Carlon MS, Beckmann DV, Pippi NL, Luhers Graça D, Levtchenko E, Deprest J, Toelen J. Amniotic Fluid Derived Stem Cells with a Renal Progenitor Phenotype Inhibit Interstitial Fibrosis in Renal Ischemia and Reperfusion Injury in Rats. PLoS One 2015; 10:e0136145. [PMID: 26295710 PMCID: PMC4546614 DOI: 10.1371/journal.pone.0136145] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 07/31/2015] [Indexed: 12/19/2022] Open
Abstract
Objectives Mesenchymal stem cells derived from human amniotic fluid (hAFSCs) are a promising source for cellular therapy, especially for renal disorders, as a subpopulation is derived from the fetal urinary tract. The purpose of this study was to evaluate if hAFSCs with a renal progenitor phenotype demonstrate a nephroprotective effect in acute ischemia reperfusion (I/R) model and prevent late stage fibrosis. Methods A total of 45 male 12-wk-old Wistar rats were divided into three equal groups;: rats subjected to I/R injury and treated with Chang Medium, rats subjected to I/R injury and treated with hAFSCs and sham-operated animals. In the first part of this study, hAFSCs that highly expressed CD24, CD117, SIX2 and PAX2 were isolated and characterized. In the second part, renal I/R injury was induced in male rats and cellular treatment was performed 6 hours later via arterial injection. Functional and histological analyses were performed 24 hours, 48 hours and 2 months after treatment using serum creatinine, urine protein to creatinine ratio, inflammatory and regeneration markers and histomorphometric analysis of the kidney. Statistical analysis was performed by analysis of variance followed by the Tukey’s test for multiple comparisons or by nonparametric Kruskal-Wallis followed by Dunn. Statistical significance level was defined as p <0.05. Results hAFSCs treatment resulted in significantly reduced serum creatinine level at 24 hours, less tubular necrosis, less hyaline cast formation, higher proliferation index, less inflammatory cell infiltration and less myofibroblasts at 48h. The treated group had less fibrosis and proteinuria at 2 months after injury. Conclusion hAFSCs contain a renal progenitor cell subpopulation that has a nephroprotective effect when delivered intra-arterially in rats with renal I/R injury, and reduces interstitial fibrosis on long term follow-up.
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Affiliation(s)
- Marina Gabriela Monteiro Carvalho Mori da Cunha
- Department of Development and Regeneration, Organ System Cluster, Fetal therapy group, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
- Experimental Veterinary Surgery Laboratory, Universidade Federal de Santa Maria, Santa Maria, Brazil
| | - Silvia Zia
- Department of Development and Regeneration, Organ System Cluster, Fetal therapy group, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
| | - Fanny Oliveira Arcolino
- Department of Development and Regeneration, Organ System Cluster, Laboratory of Pediatric Nephrology, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
| | - Marianne Sylvia Carlon
- Department of Pharmaceutical and Pharmacological Sciences, Laboratory of Molecular Virology and Gene Therapy, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
| | - Diego Vilibaldo Beckmann
- Experimental Veterinary Surgery Laboratory, Universidade Federal de Santa Maria, Santa Maria, Brazil
| | - Ney Luis Pippi
- Experimental Veterinary Surgery Laboratory, Universidade Federal de Santa Maria, Santa Maria, Brazil
| | - Dominguita Luhers Graça
- Experimental Veterinary Surgery Laboratory, Universidade Federal de Santa Maria, Santa Maria, Brazil
| | - Elena Levtchenko
- Department of Development and Regeneration, Organ System Cluster, Laboratory of Pediatric Nephrology, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Jan Deprest
- Department of Development and Regeneration, Organ System Cluster, Fetal therapy group, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
- Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium
| | - Jaan Toelen
- Department of Development and Regeneration, Organ System Cluster, Fetal therapy group, Group Biomedical Sciences, KU Leuven, Leuven, Belgium
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
- * E-mail:
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D'souza N, Rossignoli F, Golinelli G, Grisendi G, Spano C, Candini O, Osturu S, Catani F, Paolucci P, Horwitz EM, Dominici M. Mesenchymal stem/stromal cells as a delivery platform in cell and gene therapies. BMC Med 2015; 13:186. [PMID: 26265166 PMCID: PMC4534031 DOI: 10.1186/s12916-015-0426-0] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 07/17/2015] [Indexed: 02/07/2023] Open
Abstract
Regenerative medicine relying on cell and gene therapies is one of the most promising approaches to repair tissues. Multipotent mesenchymal stem/stromal cells (MSC), a population of progenitors committing into mesoderm lineages, are progressively demonstrating therapeutic capabilities far beyond their differentiation capacities. The mechanisms by which MSC exert these actions include the release of biomolecules with anti-inflammatory, immunomodulating, anti-fibrogenic, and trophic functions. While we expect the spectra of these molecules with a therapeutic profile to progressively expand, several human pathological conditions have begun to benefit from these biomolecule-delivering properties. In addition, MSC have also been proposed to vehicle genes capable of further empowering these functions. This review deals with the therapeutic properties of MSC, focusing on their ability to secrete naturally produced or gene-induced factors that can be used in the treatment of kidney, lung, heart, liver, pancreas, nervous system, and skeletal diseases. We specifically focus on the different modalities by which MSC can exert these functions. We aim to provide an updated understanding of these paracrine mechanisms as a prerequisite to broadening the therapeutic potential and clinical impact of MSC.
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Affiliation(s)
- Naomi D'souza
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Filippo Rossignoli
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Giulia Golinelli
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Giulia Grisendi
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Carlotta Spano
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Olivia Candini
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Satoru Osturu
- The Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, Departments of Pediatrics and Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Fabio Catani
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Paolo Paolucci
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy
| | - Edwin M Horwitz
- The Division of Hematology/Oncology/BMT, Nationwide Children's Hospital, Departments of Pediatrics and Medicine, The Ohio State University College of Medicine, Columbus, Ohio, USA
| | - Massimo Dominici
- Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Via del Pozzo 71, 41124, Modena, Italy.
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Bussolati B, Camussi G. Therapeutic use of human renal progenitor cells for kidney regeneration. Nat Rev Nephrol 2015; 11:695-706. [PMID: 26241019 DOI: 10.1038/nrneph.2015.126] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The ability of the human kidney to repair itself is limited. Consequently, repeated injury can trigger a maladaptive response that is characterized by fibrosis and loss of renal function. The transcription patterns that characterize nephrogenesis in fetal renal progenitor cells (RPCs) are only partially activated during renal repair in adults. Nevertheless, evidence suggests that segment-restricted progenitor resident cells support renal healing in adults. In this Review, we discuss the evidence for the existence of functional human RPCs in adults and their role in renal repair, and consider the controversial issue of whether RPCs are a fixed population or arise through phenotypical plasticity of tubular cells that is mediated by the microenvironment. We also discuss the strategies for generating renal progenitor cells from pluripotent stem cells or differentiated cells and their use in therapy. Finally, we examine preclinical data on the therapeutic use of human fetal cells, adult progenitor cells and adult renal cells.
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Affiliation(s)
- Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, Torino 10126, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, Via Nizza 52, Torino 10126, Italy
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Sallustio F, Serino G, Schena FP. Potential Reparative Role of Resident Adult Renal Stem/Progenitor Cells in Acute Kidney Injury. Biores Open Access 2015; 4:326-33. [PMID: 26309808 PMCID: PMC4509615 DOI: 10.1089/biores.2015.0011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Human kidney is particularly susceptible to ischemia and toxins with consequential tubular necrosis and activation of inflammatory processes. This process can lead to the acute renal injury, and even if the kidney has a great capacity for regeneration after tubular damage, in several circumstances, the normal renal repair program may not be sufficient to achieve a successful regeneration. Resident adult renal stem/progenitor cells could participate in this repair process and have the potentiality to enhance the renal regenerative mechanism. This could be achieved both directly, by means of their capacity to differentiate and integrate into the renal tissues, and by means of paracrine factors able to induce or improve the renal repair or regeneration. Recent genetic fate-tracing studies indicated that tubular damage is instead repaired by proliferative duplication of epithelial cells, acquiring a transient progenitor phenotype and by fate-restricted clonal cell progeny emerging from different nephron segments. In this review, we discuss about the properties and the reparative characteristics of high regenerative CD133(+)/CD24(+) cells, with a view to a future application of these cells for the treatment of acute renal injury.
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Affiliation(s)
- Fabio Sallustio
- Department of Emergency and Organ Transplantation, University of Bari , Bari, Italy . ; C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3 , Valenzano, Italy . ; Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (DiSTeBA), Università del Salento , Lecce-Monteroni, Lecce, Italy
| | - Grazia Serino
- Department of Emergency and Organ Transplantation, University of Bari , Bari, Italy
| | - Francesco Paolo Schena
- C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3 , Valenzano, Italy . ; Schena Foundation, Research Center of Renal Diseases , Bari, Italy
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Unwrapping the origins and roles of the renal endothelium. Pediatr Nephrol 2015; 30:865-72. [PMID: 24633402 PMCID: PMC4164630 DOI: 10.1007/s00467-014-2798-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2013] [Revised: 02/18/2014] [Accepted: 02/21/2014] [Indexed: 10/25/2022]
Abstract
The renal vasculature, like all vessels, is lined by a thin layer of simple squamous epithelial cells called an endothelium. These endothelial-lined vessels can be subdivided into four major compartments: arteries, veins, capillaries and lymphatics. The renal vasculature is a highly integrated network that forms through the active processes of angiogenesis and vasculogenesis. Determination of the precise contribution of these two processes and of the molecular signaling that governs the differentiation, specification and maturation of these critical cell populations is the focus of an actively evolving field of research. Although much of the focus has concentrated on the origin of the glomerular capillaries, in this review we extend the investigation to the origins of the endothelial cells throughout the entire kidney and the signaling events that cause their distinct functional and molecular profiles. A thorough understanding of endothelial cell biology may play a critical role in a better understanding of renal vascular diseases.
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Gupta AK, Jadhav SH, Tripathy NK, Nityanand S. Fetal kidney stem cells ameliorate cisplatin induced acute renal failure and promote renal angiogenesis. World J Stem Cells 2015; 7:776-788. [PMID: 26029348 PMCID: PMC4444617 DOI: 10.4252/wjsc.v7.i4.776] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 02/05/2015] [Accepted: 03/05/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate whether fetal kidney stem cells (fKSC) ameliorate cisplatin induced acute renal failure (ARF) in rats and promote renal angiogenesis. METHODS The fKSC were isolated from rat fetuses of gestation day 16 and expanded in vitro up to 3(rd) passage. They were characterized for the expression of mesenchymal and renal progenitor markers by flow cytometry and immunocytochemistry, respectively. The in vitro differentiation of fKSC towards epithelial lineage was evaluated by the treatment with specific induction medium and their angiogenic potential by matrigel induced tube formation assay. To study the effect of fKSC in ARF, fKSC labeled with PKH26 were infused in rats with cisplatin induced ARF and, the blood and renal tissues of the rats were collected at different time points. Blood biochemical parameters were studied to evaluate renal function. Renal tissues were evaluated for renal architecture, renal cell proliferation and angiogenesis by immunohistochemistry, renal cell apoptosis by terminal deoxynucleotidyl transferase nick-end labeling assay and early expression of angiogenic molecules viz. vascular endothelial growth factor (VEGF), hypoxia-inducible factor (HIF)-1α and endothelial nitric oxide synthase (eNOS) by western blot. RESULTS The fKSC expressed mesenchymal markers viz. CD29, CD44, CD73, CD90 and CD105 as well as renal progenitor markers viz. Wt1, Pax2 and Six2. They exhibited a potential to form CD31 and Von Willebrand factor expressing capillary-like structures and could be differentiated into cytokeratin (CK)18 and CK19 positive epithelial cells. Administration of fKSC in rats with ARF as compared to administration of saline alone, resulted in a significant improvement in renal function and histology on day 3 (2.33 ± 0.33 vs 3.50 ± 0.34, P < 0.05) and on day 7 (0.83 ± 0.16 vs 2.00 ± 0.25, P < 0.05). The infused PKH26 labeled fKSC were observed to engraft in damaged renal tubules and showed increased proliferation and reduced apoptosis (P < 0.05) of renal cells. The kidneys of fKSC as compared to saline treated rats had a higher capillary density on day 3 [13.30 ± 1.54 vs 7.10 ± 1.29, capillaries/high-power fields (HPF), P < 0.05], and on day 7 (21.10 ± 1.46 vs 15.00 ± 1.30, capillaries/HPF, P < 0.05). In addition, kidneys of fKSC treated rats had an up-regulation of angiogenic proteins hypoxia-inducible factor-1α, VEGF and eNOS on day 3 (P < 0.05). CONCLUSION Our study shows that fKSC ameliorate cisplatin induced ARF in rats and promote renal angiogenesis, which may be an important therapeutic mechanism of these stem cells in the disease.
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Affiliation(s)
- Ashwani Kumar Gupta
- Ashwani Kumar Gupta, Sachin H Jadhav, Naresh Kumar Tripathy, Soniya Nityanand, Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Sachin H Jadhav
- Ashwani Kumar Gupta, Sachin H Jadhav, Naresh Kumar Tripathy, Soniya Nityanand, Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Naresh Kumar Tripathy
- Ashwani Kumar Gupta, Sachin H Jadhav, Naresh Kumar Tripathy, Soniya Nityanand, Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow 226014, India
| | - Soniya Nityanand
- Ashwani Kumar Gupta, Sachin H Jadhav, Naresh Kumar Tripathy, Soniya Nityanand, Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Lucknow 226014, India
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Zullo JA, Nadel EP, Rabadi MM, Baskind MJ, Rajdev MA, Demaree CM, Vasko R, Chugh SS, Lamba R, Goligorsky MS, Ratliff BB. The Secretome of Hydrogel-Coembedded Endothelial Progenitor Cells and Mesenchymal Stem Cells Instructs Macrophage Polarization in Endotoxemia. Stem Cells Transl Med 2015; 4:852-61. [PMID: 25947337 DOI: 10.5966/sctm.2014-0111] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Accepted: 03/16/2015] [Indexed: 01/27/2023] Open
Abstract
UNLABELLED : We previously reported the delivery of endothelial progenitor cells (EPCs) embedded in hyaluronic acid-based (HA)-hydrogels protects renal function during acute kidney injury (AKI) and promotes angiogenesis. We attempted to further ameliorate renal dysfunction by coembedding EPCs with renal mesenchymal stem cells (MSCs), while examining their paracrine influence on cytokine/chemokine release and proinflammatory macrophages. A live/dead assay determined whether EPC-MSC coculturing improved viability during lipopolysaccharide (LPS) treatment, and HA-hydrogel-embedded delivery of cells to LPS-induced AKI mice was assessed for effects on mean arterial pressure (MAP), renal blood flow (RBF), circulating cytokines/chemokines, serum creatinine, proteinuria, and angiogenesis (femoral ligation). Cytokine/chemokine release from embedded stem cells was examined, including effects on macrophage polarization and release of proinflammatory molecules. EPC-MSC coculturing improved stem cell viability during LPS exposure, an effect augmented by MSC hypoxic preconditioning. The delivery of coembedded EPCs with hypoxic preconditioned MSCs to AKI mice demonstrated additive improvement (compared with EPC delivery alone) in medullary RBF and proteinuria, with comparable effects on serum creatinine, MAP, and angiogenesis. Exposure of proinflammatory M1 macrophages to EPC-MSC conditioned medium changed their polarization to anti-inflammatory M2. Incubation of coembedded EPCs-MSCs with macrophages altered their release of cytokines/chemokines, including enhanced release of anti-inflammatory interleukin (IL)-4 and IL-10. EPC-MSC delivery to endotoxemic mice elevated the levels of circulating M2 macrophages and reduced the circulating cytokines/chemokines. In conclusion, coembedding EPCs-MSCs improved their resistance to stress, impelled macrophage polarization from M1 to M2 while altering their cytokine/chemokines release, reduced circulating cytokines/chemokines, and improved renal and vascular function when MSCs were hypoxically preconditioned. SIGNIFICANCE This report provides insight into a new therapeutic approach for treatment of sepsis and provides a new and improved strategy using hydrogels for the delivery of stem cells to treat sepsis and, potentially, other injuries and/or diseases. The delivery of two different stem cell lines (endothelial progenitor cells and mesenchymal stem cells; delivered alone and together) embedded in a protective bioengineered scaffolding (hydrogel) offers many therapeutic benefits for the treatment of sepsis. This study shows how hydrogel-delivered stem cells elicit their effects and how hydrogel embedding enhances the therapeutic efficacy of delivered stem cells. Hydrogel-delivered stem cells influence the components of the overactive immune system during sepsis and work to counterbalance the release of many proinflammatory and prodamage substances from immune cells, thereby improving the associated vascular and kidney damage.
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Affiliation(s)
- Joseph A Zullo
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - Ellen P Nadel
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - May M Rabadi
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - Matthew J Baskind
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - Maharshi A Rajdev
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - Cameron M Demaree
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - Radovan Vasko
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - Savneek S Chugh
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - Rajat Lamba
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - Michael S Goligorsky
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
| | - Brian B Ratliff
- Departments of Medicine, Pharmacology, and Physiology, Renal Research Institute, New York Medical College, Valhalla, New York, USA; Department of Nephrology and Rheumatology, University Medical Center Goettingen, Goettingen, Germany
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Mesenchymal stem cell-derived microparticles ameliorate peritubular capillary rarefaction via inhibition of endothelial-mesenchymal transition and decrease tubulointerstitial fibrosis in unilateral ureteral obstruction. Stem Cell Res Ther 2015; 6:18. [PMID: 25889661 PMCID: PMC4393614 DOI: 10.1186/s13287-015-0012-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2014] [Revised: 02/19/2015] [Accepted: 02/19/2015] [Indexed: 01/05/2023] Open
Abstract
Introduction Microparticles (MPs) derived from kidney-derived mesenchymal stem cells (KMSCs) have recently been reported to ameliorate rarefaction of peritubular capillaries (PTC) in ischemic kidneys via delivery of proangiogenic effectors. This study aimed to investigate whether KMSC-derived MPs show anti-fibrotic effects by ameliorating endothelial-to-mesenchymal transition (EndoMT) in human umbilical vein endothelial cells (HUVEC) in vitro and by preserving PTC in kidneys with unilateral ureteral obstruction (UUO) in vivo. Methods MPs isolated from the supernatants of KMSC were co-cultured with HUVEC to assess their in vitro biologic effects on endothelial cells. Mice were treated with MPs via the tail vein after UUO injury to assess their anti-fibrotic and PTC sparing effects. Renal tubulointerstitial damage and inflammatory cell infiltration were examined with Masson’s trichrome, F4/80 and α-smooth muscle actin (α-SMA) staining and PTC rarefaction index was determined by CD31 staining. Results KMSC-derived MPs significantly ameliorated EndoMT and improved in vitro proliferation of TGF-β1 treated HUVEC. In vivo administration of KMSC-derived MPs significantly inhibited EndoMT of PTC endothelial cells and improved PTC rarefaction in UUO kidneys. Furthermore, administration of KMSC-derived MPs inhibited inflammatory cell infiltration as well as tubulointerstitial fibrosis in UUO mice as demonstrated by decreased F4/80 and α-SMA-positive cells and Masson’s trichrome staining, respectively. Conclusions Our results suggest that KMSC-derived MPs ameliorate PTC rarefaction via inhibition of EndoMT and protect against progression of renal damage by inhibiting tubulointerstitial fibrosis.
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Xavier S, Vasko R, Matsumoto K, Zullo JA, Chen R, Maizel J, Chander PN, Goligorsky MS. Curtailing endothelial TGF-β signaling is sufficient to reduce endothelial-mesenchymal transition and fibrosis in CKD. J Am Soc Nephrol 2014; 26:817-29. [PMID: 25535303 DOI: 10.1681/asn.2013101137] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Excessive TGF-β signaling in epithelial cells, pericytes, or fibroblasts has been implicated in CKD. This list has recently been joined by endothelial cells (ECs) undergoing mesenchymal transition. Although several studies focused on the effects of ablating epithelial or fibroblast TGF-β signaling on development of fibrosis, there is a lack of information on ablating TGF-β signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-β receptor knockout (TβRII(endo+/-)) mice to explore whether curtailed TGF-β signaling significantly modifies nephrosclerosis. These mice developed normally, but showed enhanced angiogenic potential compared with TβRII(endo+/+) mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, TβRII(endo+/-) mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than TβRII(endo+/+) counterparts. In addition, partial deletion of TβRII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-β-induced canonical Smad2 signaling was reduced in TβRII(+/-) ECs; however, activin receptor-like kinase 1 (ALK1)-mediated Smad1/5 phosphorylation in TβRII(+/-) ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in TβRII(+/-) ECs compared with TβRII(+/+) ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-β signals favors Smad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-β signaling and EndoMT in regulating angiogenic and fibrotic responses to injury.
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Affiliation(s)
- Sandhya Xavier
- Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and
| | - Radovan Vasko
- Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and Department of Nephrology and Rheumatology, University Medical Center, Goettingen, Germany
| | - Kei Matsumoto
- Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and
| | - Joseph A Zullo
- Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and
| | - Robert Chen
- Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and
| | - Julien Maizel
- Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and
| | | | - Michael S Goligorsky
- Departments of Medicine, Pharmacology, Physiology, and Renal Research Institute, New York Medical College, Valhalla, New York; and
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Bruno S, Chiabotto G, Camussi G. Concise review: different mesenchymal stromal/stem cell populations reside in the adult kidney. Stem Cells Transl Med 2014; 3:1451-5. [PMID: 25355731 DOI: 10.5966/sctm.2014-0142] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
During fetal life, mesenchymal stromal/stem cells (MSCs) surround glomeruli and tubules and contribute to the development of the renal interstitium by secretion of growth factors that drive nephron differentiation. In the adult, an MSC-like population has been demonstrated in different compartments of human and murine nephrons. After injury, these cells might provide support for kidney regeneration by recapitulating the role they have in embryonic life. In this short review, we discuss the evidence of an MSC presence within the adult kidney and their potential contribution to the turnover of renal cells and injury repair.
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Affiliation(s)
- Stefania Bruno
- Departments of Molecular Biotechnology and Health Science and Medical Sciences, University of Torino, Torino, Italy
| | - Giulia Chiabotto
- Departments of Molecular Biotechnology and Health Science and Medical Sciences, University of Torino, Torino, Italy
| | - Giovanni Camussi
- Departments of Molecular Biotechnology and Health Science and Medical Sciences, University of Torino, Torino, Italy
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White SM, North LM, Haines E, Goldberg M, Sullivan LM, Pressly JD, Weber DS, Park F, Regner KR. G-protein βγ subunit dimers modulate kidney repair after ischemia-reperfusion injury in rats. Mol Pharmacol 2014; 86:369-77. [PMID: 25028481 PMCID: PMC4164983 DOI: 10.1124/mol.114.092346] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 07/15/2014] [Indexed: 12/23/2022] Open
Abstract
Heterotrimeric G-proteins play a crucial role in the control of renal epithelial cell function during homeostasis and in response to injury. In this report, G-protein βγ subunit (Gβγ) dimer activity was evaluated during the process of tubular repair after renal ischemia-reperfusion injury (IRI) in male Sprague Dawley rats. Rats were treated with a small molecule inhibitor of Gβγ activity, gallein (30 or 100 mg/kg), 1 hour after reperfusion and every 24 hours for 3 additional days. After IRI, renal dysfunction was prolonged after the high-dose gallein treatment in comparison with vehicle treatment during the 7-day recovery period. Renal tubular repair in the outer medulla 7 days after IRI was significantly (P < 0.001) attenuated after treatment with high-dose gallein (100 mg/kg) in comparison with low-dose gallein (30 mg/kg), or the vehicle and fluorescein control groups. Gallein treatment significantly reduced (P < 0.05) the number of proliferating cell nuclear antigen-positive tubular epithelial cells at 24 hours after the ischemia-reperfusion phase in vivo. In vitro application of gallein on normal rat kidney (NRK-52E) proximal tubule cells significantly reduced (P < 0.05) S-phase cell cycle entry compared with vehicle-treated cells as determined by 5'-bromo-2'-deoxyuridine incorporation. Taken together, these data suggest that Gβγ signaling contributes to the maintenance and repair of renal tubular epithelium and may be a novel therapeutic target for the development of drugs to treat acute kidney injury.
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Affiliation(s)
- Sarah M White
- Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.)
| | - Lauren M North
- Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.)
| | - Emily Haines
- Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.)
| | - Megan Goldberg
- Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.)
| | - Lydia M Sullivan
- Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.)
| | - Jeffrey D Pressly
- Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.)
| | - David S Weber
- Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.)
| | - Frank Park
- Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.)
| | - Kevin R Regner
- Department of Medicine, Division of Nephrology (S.M.W., L.M.N., E.H., M.G., K.R.R.), Cardiovascular Research Center (K.R.R.), Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Pharmaceutical Sciences, University of Tennessee Health Sciences Center, Memphis, Tennessee (J.D.P., F.P.); and Department of Physiology, University of South Alabama, Mobile, Alabama (L.M.S., D.S.W.)
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Abstract
Renal pericytes have been neglected for many years, but recently they have become an intensively studied cell population in renal biology and pathophysiology. Pericytes are stromal cells that support vasculature, and a subset of pericytes are mesenchymal stem cells. In kidney, pericytes have been reported to play critical roles in angiogenesis, regulation of renal medullary and cortical blood flow, and serve as progenitors of interstitial myofibroblasts in renal fibrogenesis. They interact with endothelial cells through distinct signaling pathways and their activation and detachment from capillaries after acute or chronic kidney injury may be critical for driving chronic kidney disease progression. By contrast, during kidney homeostasis it is likely that pericytes serve as a local stem cell population that replenishes differentiated interstitial and vascular cells lost during aging. This review describes both the regenerative properties of pericytes as well as involvement in pathophysiologic conditions such as fibrogenesis.
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Affiliation(s)
- Rafael Kramann
- Brigham and Women's Hospital, Renal Division, Department of Medicine, Boston, MA; Harvard Medical School, Boston, MA; Division of Nephrology, Rheinisch-Westfaelische Technische Hochschule Aachen University, Aachen, Germany
| | - Benjamin D Humphreys
- Brigham and Women's Hospital, Renal Division, Department of Medicine, Boston, MA; Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Cambridge, MA.
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Fine LG. Restoring the function of a diseased kidney via its microvasculature. Nephron Clin Pract 2014; 126:82. [PMID: 24854646 DOI: 10.1159/000360672] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Based upon observations which indicate that chronic intrarenal hypoxia and microvascular obliteration play an important role in the pathogenesis of renal scarring and loss of function, the idea is presented that restoration of kidney structure and function by arresting microvascular drop-out and restoring the interstitial capillary network could be a feasible approach to regeneration of a diseased kidney. This paper addresses the reasoning behind this possibility. SUMMARY A 'unifying vasculogenic hypothesis' is discussed which proposes that, in hypoxic nephrons which retain poorly functioning vascular and epithelial elements, the disease process can be slowed or arrested, and nephrons regenerated, by adoptive transfer of endothelial progenitor cells to restore interstitial and glomerular vascular integrity. It is suggested that no other cell types are required to achieve this end. Improved differentiation, proliferation, and function of surviving nephrons could be achieved by restoring adequate oxygen delivery via this approach. KEY MESSAGES It is hypothesized that, to regenerate the function of a chronically diseased kidney, it is not plausible to create new nephrons. Restoration of function of surviving nephrons could be achieved by regeneration of the renal microvasculature alone. Based upon observations that have demonstrated the feasibility of adoptive endothelial progenitor cell transfer into the kidney, this hypothesis is worthy of being tested.
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Affiliation(s)
- Leon G Fine
- Cedars-Sinai Medical Center and University of California at Los Angeles, Los Angeles, Calif., USA
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Choi HY, Moon SJ, Ratliff BB, Ahn SH, Jung A, Lee M, Lee S, Lim BJ, Kim BS, Plotkin MD, Ha SK, Park HC. Microparticles from kidney-derived mesenchymal stem cells act as carriers of proangiogenic signals and contribute to recovery from acute kidney injury. PLoS One 2014; 9:e87853. [PMID: 24504266 PMCID: PMC3913695 DOI: 10.1371/journal.pone.0087853] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Accepted: 01/01/2014] [Indexed: 12/20/2022] Open
Abstract
We recently demonstrated the use of in vitro expanded kidney-derived mesenchymal stem cells (KMSC) protected peritubular capillary endothelial cells in acute renal ischemia-reperfusion injury. Herein, we isolated and characterized microparticles (MPs) from KMSC. We investigated their in vitro biologic effects on human endothelial cells and in vivo renoprotective effects in acute ischemia-reperfusion renal injury. MPs were isolated from the supernatants of KMSC cultured in anoxic conditions in serum-deprived media for 24 hours. KMSC-derived MPs demonstrated the presence of several adhesion molecules normally expressed on KMSC membranes, such as CD29, CD44, CD73, α4, 5, and 6 integrins. Quantitative real time PCR confirmed the presence of 3 splicing variants of VEGF-A (120, 164, 188), bFGF and IGF-1 in isolated MPs. MPs labeled with PKH26 red fluorescence dye were incorporated by cultured human umbilical vein endothelial cells (HUVEC) via surface molecules such as CD44, CD29, and α4, 5, and 6 integrins. MP dose dependently improved in vitro HUVEC proliferation and promoted endothelial tube formation on growth factor reduced Matrigel. Moreover, apoptosis of human microvascular endothelial cell was inhibited by MPs. Administration of KMSC-derived MPs into mice with acute renal ischemia was followed by selective engraftment in ischemic kidneys and significant improvement in renal function. This was achieved by improving proliferation, of peritubular capillary endothelial cell and amelioration of peritubular microvascular rarefaction. Our results support the hypothesis that KMSC-derived MPs may act as a source of proangiogenic signals and confer renoprotective effects in ischemic kidneys.
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Affiliation(s)
- Hoon Young Choi
- Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Seoul, Korea
- Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea
| | - Sung Jin Moon
- Department of Internal Medicine, Kwandong University College of Medicine, Gangneung, Korea
| | - Brian B. Ratliff
- Departments of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York, United States of America
| | - Sun Hee Ahn
- Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Ara Jung
- Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Mirae Lee
- Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Seol Lee
- Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Beom Jin Lim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Beom Seok Kim
- Division of Nephrology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Matthew D. Plotkin
- Departments of Medicine, Pharmacology and Physiology, New York Medical College, Valhalla, New York, United States of America
| | - Sung Kyu Ha
- Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Seoul, Korea
| | - Hyeong Cheon Park
- Division of Nephrology, Department of Internal Medicine, Gangnam Severance Hospital, Seoul, Korea
- Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea
- * E-mail:
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Kalbasi Anaraki P, Patecki M, Larmann J, Tkachuk S, Jurk K, Haller H, Theilmeier G, Dumler I. Urokinase receptor mediates osteogenic differentiation of mesenchymal stem cells and vascular calcification via the complement C5a receptor. Stem Cells Dev 2013; 23:352-62. [PMID: 24192237 DOI: 10.1089/scd.2013.0318] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Vascular calcification is a severe consequence of several pathological processes with a lack of effective therapy. Recent studies suggest that circulating and resident mesenchymal stem cells (MSC) contribute to the osteogenic program of vascular calcification. Molecular mechanisms underlying MSC osteogenic potential and differentiation remain, however, sparsely explored. We investigated a role for the complement receptor C5aR in these processes. We found that expression of C5aR was upregulated upon differentiation of human MSC to osteoblasts. C5aR inhibition by silencing and specific antagonist impaired osteogenic differentiation. We demonstrate that C5aR expression upon MSC differentiation was regulated by the multifunctional urokinase receptor (uPAR). uPAR targeting by siRNA resulted in complete abrogation of C5aR expression and consequently in the inhibition of MSC-osteoblast differentiation. We elucidated the NFκB pathway as the mechanism utilized by the uPAR-C5aR axis. MSC treatment with the NFκB inhibitor completely blocked the differentiation process. Nuclear translocation of the p65 RelA component of the NFκB complex was induced under osteogenic conditions and impaired by the inhibition of uPAR or C5aR. Dual-luciferase reporter assays demonstrated enhanced NFκB signaling upon MSC differentiation, whereas uPAR and C5aR downregulation lead to inhibition of the NFκB activity. We show involvement of the Erk1/2 kinase in this cascade. In vivo studies in a uPAR/LDLR double knockout mouse model of diet-induced atherosclerosis revealed impaired C5aR expression and calcification in aortic sinus plaques in uPAR(-/-)/LDLR(-/-) versus uPAR(+/+)/LDLR(-/-) control animals. These results suggest that uPAR-C5aR axis via the underlying NFκB transcriptional program controls osteogenic differentiation with functional impact on vascular calcification in vivo.
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Herrera M, Mirotsou M. Stem cells: potential and challenges for kidney repair. Am J Physiol Renal Physiol 2013; 306:F12-23. [PMID: 24197069 DOI: 10.1152/ajprenal.00238.2013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Renal damage resulting from acute and chronic kidney injury poses an important problem to public health. Currently, patients with end-stage renal disease rely solely on kidney transplantation or dialysis for survival. Emerging therapies aiming to prevent and reverse kidney damage are thus in urgent need. Although the kidney was initially thought to lack the capacity for self-repair, several studies have indicated that this might not be the case; progenitor and stem cells appear to play important roles in kidney repair under various pathological conditions. In this review, we summarize recent findings on the role of progenitor/stem cells on kidney repair as well as discuss their potential as a therapeutic approach for kidney diseases.
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Affiliation(s)
- Marcela Herrera
- Division of Cardiology, Genome Research Bldg. II, Rm. 4022, 210 Research Drive, Duke Univ. Medical Center, Durham, NC 27710.
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de Almeida DC, Donizetti-Oliveira C, Barbosa-Costa P, Origassa CST, Câmara NOS. In search of mechanisms associated with mesenchymal stem cell-based therapies for acute kidney injury. Clin Biochem Rev 2013; 34:131-144. [PMID: 24353358 PMCID: PMC3866950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Acute kidney injury (AKI) is classically described as a rapid loss of kidney function. AKI affects more than 15% of all hospital admissions and is associated with elevated mortality rates. Although many advances have occurred, intermittent or continuous renal replacement therapies are still considered the best options for reversing mild and severe AKI syndrome. For this reason, it is essential that innovative and effective therapies, without side effects and complications, be developed to treat AKI and the end-stages of renal disease. Mesenchymal stem cell (MSC) based therapies have numerous advantages in helping to repair inflamed and damaged tissues and are being considered as a new alternative for treating kidney injuries. Numerous experimental models have shown that MSCs can act via differentiation-independent mechanisms to help renal recovery. Essentially, MSCs can secrete a pool of cytokines, growth factors and chemokines, express enzymes, interact via cell-to-cell contacts and release bioagents such as microvesicles to orchestrate renal protection. In this review, we propose seven distinct properties of MSCs which explain how renoprotection may be conferred: 1) anti-inflammatory; 2) pro-angiogenic; 3) stimulation of endogenous progenitor cells; 4) anti-apoptotic; 5) anti-fibrotic; 6) anti-oxidant; and 7) promotion of cellular reprogramming. In this context, these mechanisms, either individually or synergically, could induce renal protection and functional recovery. This review summarises the most important effects and benefits associated with MSC-based therapies in experimental renal disease models and attempts to clarify the mechanisms behind the MSC-related renoprotection. MSCs may prove to be an effective, innovative and affordable treatment for moderate and severe AKI. However, more studies need to be performed to provide a more comprehensive global understanding of MSC-related therapies and to ensure their safety for future clinical applications.
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Affiliation(s)
- Danilo C de Almeida
- Department of Medicine, Division of Nephrology, Universidade Federal de São Paulo, Brazil
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Science IV, Universidade de São Paulo, Brazil
| | | | | | - Clarice ST Origassa
- Department of Medicine, Division of Nephrology, Universidade Federal de São Paulo, Brazil
| | - Niels OS Câmara
- Department of Medicine, Division of Nephrology, Universidade Federal de São Paulo, Brazil
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Science IV, Universidade de São Paulo, Brazil
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