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Waack N, Guirao T, Maquigussa E, Nishi E, Ormanji M, Ykuta O, Boim M. Stem cells prevent long-term deterioration of renal function after renal artery revascularization in a renovascular hypertension model in rats. Sci Rep 2025; 15:3397. [PMID: 39870783 PMCID: PMC11772754 DOI: 10.1038/s41598-025-87451-4] [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: 08/08/2024] [Accepted: 01/20/2025] [Indexed: 01/29/2025] Open
Abstract
Partial stenosis of the renal artery causes renovascular hypertension (RVH) and is accompanied by chronic renal ischemia, resulting in irreversible kidney damage. Revascularization constitutes the most efficient therapy for normalizing blood pressure (BP) and has significant benefits for renal function; however, the tissue damage caused by chronic hypoxia is not fully reversed. Mesenchymal stem cells (MSCs) have produced discrete results in minimizing RVH and renal tissue and functional improvements since the obstruction persists. This study aimed to evaluate the effects of administration of MSCs in combination with renal artery revascularization in rats subjected to RVH. The following groups were evaluated: control (SHAM), hypertensive (2K-1C), hypertensive treated with MSCs (MSC), hypertensive subjected to revascularization (REV), and hypertensive subjected to revascularization and treatment with MSCs (REV + MSC). The animals were followed up for 10 weeks. The animals in the MSC group received cell infusions at the 3rd, 5th, 7th and 9th weeks. In the REV and REV + MSC groups, the clip was removed by the 6th week (revascularization), and in the REV + MSC group, MSCs infusion was performed at the 6th and 8th weeks. Tail systolic blood pressure (SBP) was measured weekly, and histological parameters and renal function were evaluated at the end of the protocol. The clipped animals developed RVH, deterioration of total renal function (50% decrease in creatinine clearance), and significant proteinuria (15x increase). Treatment with MSCs had no detectable beneficial effects on kidney function or SBP. REV resulted in normalization of BP and a significant but partial reduction in proteinuria (80% vs. 2K-1C), but areas with renal fibrosis persisted. The combination of the two treatments was effective at normalizing all renal parameters as well as reversing proteinuria, reducing the number of ischemic glomeruli and atrophic tubules, indicating an improvement of the renal parenchyma. The results suggest that therapy with MSCs associated with revascularization can potentially help in the full recovery of renal function in the long term in patients with RVH.
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Affiliation(s)
- Nikolas Waack
- Renal Division, Department of Medicine, Universidade Federal de São Paulo, Rua Pedro de Toledo, 781, São Paulo, SP, 04039-032, Brazil
| | - Tatiana Guirao
- Renal Division, Department of Medicine, Universidade Federal de São Paulo, Rua Pedro de Toledo, 781, São Paulo, SP, 04039-032, Brazil
| | - Edgar Maquigussa
- Renal Division, Department of Medicine, Universidade Federal de São Paulo, Rua Pedro de Toledo, 781, São Paulo, SP, 04039-032, Brazil
| | - Erika Nishi
- Cardiovascular Physiology Division, Department of Medicine, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Milene Ormanji
- Renal Division, Department of Medicine, Universidade Federal de São Paulo, Rua Pedro de Toledo, 781, São Paulo, SP, 04039-032, Brazil
| | - Olinda Ykuta
- Renal Division, Department of Medicine, Universidade Federal de São Paulo, Rua Pedro de Toledo, 781, São Paulo, SP, 04039-032, Brazil
| | - Mirian Boim
- Renal Division, Department of Medicine, Universidade Federal de São Paulo, Rua Pedro de Toledo, 781, São Paulo, SP, 04039-032, Brazil.
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Song A, Wang M, Xie K, Lu J, Zhao B, Wu W, Qian C, Hong W, Gu L. Exosomal let-7b-5p deriving from parietal epithelial cells attenuate renal fibrosis through suppression of TGFβR1 and ARID3a in obstructive kidney disease. FASEB J 2024; 38:e70085. [PMID: 39352691 DOI: 10.1096/fj.202400802rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 09/10/2024] [Accepted: 09/20/2024] [Indexed: 11/13/2024]
Abstract
As renal progenitor cells, parietal epithelial cells (PECs) have demonstrated multilineage differentiation potential in response to kidney injury. However, the function of exosomes derived from PECs has not been extensively explored. Immunofluorescent staining of Claudin-1 was used to identify primary PECs isolated from mouse glomeruli. Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of PECs-derived exosomes (PEC-Exo). The therapeutic role of PEC-Exo in tubulointerstitial fibrosis was investigated in the unilateral ureteral obstruction (UUO) mouse model and TGF-β1-stimulated HK-2 cells. High-throughput miRNA sequencing was employed to profile PEC-Exo miRNAs. One of the most enriched miRNAs in PEC-Exo was knocked down by transfecting miRNA inhibitor, and then we investigated whether this candidate miRNA was involved in PEC-Exo-mediated tubular repair. The primary PECs expressed Claudin-1, PEC-Exo was homing to obstructed kidney, and TGF-β1 induced HK-2 cells. PEC-Exo significantly alleviated renal inflammation and ameliorated tubular fibrosis both in vivo and in vitro. Mechanistically, let-7b-5p, highly enriched in PEC-Exo, downregulated the protein levels of transforming growth factor beta receptor 1(TGFβR1) and AT-Rich Interaction Domain 3A(ARID3a) in tubular epithelial cells (TECs), leading to the inhibition of p21 and p27 to restoring cell cycle. Furthermore, administration of let-7b-5p agomir mitigated renal fibrosis in vivo. Our findings demonstrated that PEC-derived exosomes significantly repressed the expression of TGFβR1 and ARID3a by delivering let-7b-5p, thereby alleviating renal fibrosis. This study provides novel insights into the role of PEC-Exo in the repair of kidney injury and new ideas for renal fibrosis intervention.
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Affiliation(s)
- Ahui Song
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minzhou Wang
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kewei Xie
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayue Lu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bingru Zhao
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wangshu Wu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cheng Qian
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenkai Hong
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Leyi Gu
- Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Uremia Diagnosis and Treatment Center, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Lahane GP, Dhar A, Bhat A. Therapeutic approaches and novel antifibrotic agents in renal fibrosis: A comprehensive review. J Biochem Mol Toxicol 2024; 38:e23795. [PMID: 39132761 DOI: 10.1002/jbt.23795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 06/20/2024] [Accepted: 07/24/2024] [Indexed: 08/13/2024]
Abstract
Renal fibrosis (RF) is one of the underlying pathological conditions leading to progressive loss of renal function and end-stage renal disease (ESRD). Over the years, various therapeutic approaches have been explored to combat RF and prevent ESRD. Despite significant advances in understanding the underlying molecular mechanism(s), effective therapeutic interventions for RF are limited. Current therapeutic strategies primarily target these underlying mechanisms to halt or reverse fibrotic progression. Inhibition of transforming growth factor-β (TGF-β) signaling, a pivotal mediator of RF has emerged as a central strategy to manage RF. Small molecules, peptides, and monoclonal antibodies that target TGF-β receptors or downstream effectors have demonstrated potential in preclinical models. Modulating the renin-angiotensin system and targeting the endothelin system also provide established approaches for controlling fibrosis-related hemodynamic changes. Complementary to pharmacological strategies, lifestyle modifications, and dietary interventions contribute to holistic management. This comprehensive review aims to summarize the underlying mechanisms of RF and provide an overview of the therapeutic strategies and novel antifibrotic agents that hold promise in its treatment.
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Affiliation(s)
- Ganesh Panditrao Lahane
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad, Telangana, India
| | - Arti Dhar
- Department of Pharmacy, Birla Institute of Technology and Sciences (BITS) Pilani, Hyderabad, Telangana, India
| | - Audesh Bhat
- Centre for Molecular Biology, Central University of Jammu, Samba, Jammu and Kashmir, India
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Taherian M, Bayati P, Mojtabavi N. Stem cell-based therapy for fibrotic diseases: mechanisms and pathways. Stem Cell Res Ther 2024; 15:170. [PMID: 38886859 PMCID: PMC11184790 DOI: 10.1186/s13287-024-03782-5] [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: 01/29/2024] [Accepted: 06/04/2024] [Indexed: 06/20/2024] Open
Abstract
Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.
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Affiliation(s)
- Marjan Taherian
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Paria Bayati
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Mojtabavi
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran.
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Niu X, Xu X, Xu C, Cheuk YC, Rong R. Recent Advances of MSCs in Renal IRI: From Injury to Renal Fibrosis. Bioengineering (Basel) 2024; 11:432. [PMID: 38790298 PMCID: PMC11117619 DOI: 10.3390/bioengineering11050432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/21/2024] [Accepted: 04/23/2024] [Indexed: 05/26/2024] Open
Abstract
Renal fibrosis is a pathological endpoint of maladaptation after ischemia-reperfusion injury (IRI), and despite many attempts, no good treatment has been achieved so far. At the core of renal fibrosis is the differentiation of various types of cells into myofibroblasts. MSCs were once thought to play a protective role after renal IRI. However, growing evidence suggests that MSCs have a two-sided nature. In spite of their protective role, in maladaptive situations, MSCs start to differentiate towards myofibroblasts, increasing the myofibroblast pool and promoting renal fibrosis. Following renal IRI, it has been observed that Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs) and Renal Resident Mesenchymal Stem Cells (RR-MSCs) play important roles. This review presents evidence supporting their involvement, discusses their potential mechanisms of action, and suggests several new targets for future research.
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Affiliation(s)
- Xinhao Niu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Xiaoqing Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Cuidi Xu
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Yin Celeste Cheuk
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
| | - Ruiming Rong
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Shanghai Key Laboratory of Organ Transplantation, Shanghai 200032, China
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Reiss AB, Jacob B, Zubair A, Srivastava A, Johnson M, De Leon J. Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets. J Clin Med 2024; 13:1881. [PMID: 38610646 PMCID: PMC11012936 DOI: 10.3390/jcm13071881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 03/18/2024] [Accepted: 03/20/2024] [Indexed: 04/14/2024] Open
Abstract
Chronic kidney disease (CKD) is a slowly progressive condition characterized by decreased kidney function, tubular injury, oxidative stress, and inflammation. CKD is a leading global health burden that is asymptomatic in early stages but can ultimately cause kidney failure. Its etiology is complex and involves dysregulated signaling pathways that lead to fibrosis. Transforming growth factor (TGF)-β is a central mediator in promoting transdifferentiation of polarized renal tubular epithelial cells into mesenchymal cells, resulting in irreversible kidney injury. While current therapies are limited, the search for more effective diagnostic and treatment modalities is intensive. Although biopsy with histology is the most accurate method of diagnosis and staging, imaging techniques such as diffusion-weighted magnetic resonance imaging and shear wave elastography ultrasound are less invasive ways to stage fibrosis. Current therapies such as renin-angiotensin blockers, mineralocorticoid receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay progression. Newer antifibrotic agents that suppress the downstream inflammatory mediators involved in the fibrotic process are in clinical trials, and potential therapeutic targets that interfere with TGF-β signaling are being explored. Small interfering RNAs and stem cell-based therapeutics are also being evaluated. Further research and clinical studies are necessary in order to avoid dialysis and kidney transplantation.
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Affiliation(s)
- Allison B. Reiss
- Department of Medicine and Biomedical Research Institute, NYU Grossman Long Island School of Medicine, Mineola, NY 11501, USA; (B.J.); (A.Z.); (A.S.); (M.J.); (J.D.L.)
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Kim Y, Kang D, Choi GE, Kim SD, Yang SJ, Kim H, You D, Kim CS, Suh N. Therapeutic potential of BMSC-conditioned medium in an in vitro model of renal fibrosis using the RPTEC/TERT1 cell line. BMB Rep 2024; 57:116-121. [PMID: 38303564 PMCID: PMC10910087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 12/27/2023] [Accepted: 01/15/2024] [Indexed: 02/03/2024] Open
Abstract
We investigated the therapeutic potential of bone marrow-derived mesenchymal stem cell-conditioned medium (BMSC-CM) on immortalized renal proximal tubule epithelial cells (RPTEC/ TERT1) in a fibrotic environment. To replicate the increased stiffness characteristic of kidneys in chronic kidney disease, we utilized polyacrylamide gel platforms. A stiff matrix was shown to increase α-smooth muscle actin (α-SMA) levels, indicating fibrogenic activation in RPTEC/TERT1 cells. Interestingly, treatment with BMSC-CM resulted in significant reductions in the levels of fibrotic markers (α-SMA and vimentin) and increases in the levels of the epithelial marker E-cadherin and aquaporin 7, particularly under stiff conditions. Furthermore, BMSC-CM modified microRNA (miRNA) expression and reduced oxidative stress levels in these cells. Our findings suggest that BMSC-CM can modulate cellular morphology, miRNA expression, and oxidative stress in RPTEC/TERT1 cells, highlighting its therapeutic potential in fibrotic kidney disease. [BMB Reports 2024; 57(2): 116-121].
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Affiliation(s)
- Yunji Kim
- Department of Medical Sciences, General Graduate School, Soonchunhyang University, Asan 31538, Korea
| | - Dayeon Kang
- Department of Medical Sciences, General Graduate School, Soonchunhyang University, Asan 31538, Korea
- Department of Pharmaceutical Engineering, College of Medical Sciences, Soonchunhyang University, Asan 31538, Korea
| | - Ga-eun Choi
- Department of Medical Sciences, General Graduate School, Soonchunhyang University, Asan 31538, Korea
| | - Sang Dae Kim
- Department of Medical Sciences, General Graduate School, Soonchunhyang University, Asan 31538, Korea
| | | | - Hyosang Kim
- Division of Nephrology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Dalsan You
- Department of Urology, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Choung Soo Kim
- Urology Institute, Ewha Womans University Mokdong Hospital, Seoul 07985, Korea
| | - Nayoung Suh
- Department of Medical Sciences, General Graduate School, Soonchunhyang University, Asan 31538, Korea
- Department of Pharmaceutical Engineering, College of Medical Sciences, Soonchunhyang University, Asan 31538, Korea
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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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Khamis T, Abdelkhalek A, Abdellatif H, Dwidar N, Said A, Ahmed R, Wagdy K, Elgarhy R, Eltahan R, Mohamed H, Said Amer E, Hanna M, Ragab T, Kishk A, Wael J, Sarhan E, Saweres L, Reda M, Elkomy S, Mohamed A, Samy A, Khafaga A, Shaker Y, Yehia H, Alanazi A, Alassiri M, Tîrziu E, Bucur IM, Arisha AH. BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways. Front Pharmacol 2023; 14:1265230. [PMID: 38044936 PMCID: PMC10690373 DOI: 10.3389/fphar.2023.1265230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 10/12/2023] [Indexed: 12/05/2023] Open
Abstract
Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.
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Affiliation(s)
- Tarek Khamis
- Department of Pharmacology and Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Adel Abdelkhalek
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Hussein Abdellatif
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
- Anatomy and Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Nourelden Dwidar
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Ahmed Said
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Rama Ahmed
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Kerolos Wagdy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Rowina Elgarhy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Rawan Eltahan
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Hisham Mohamed
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Eman Said Amer
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Maria Hanna
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Tarek Ragab
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Abdallah Kishk
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Judy Wael
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Eyad Sarhan
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Linda Saweres
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Mohamed Reda
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Sara Elkomy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Abdalah Mohamed
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Abdullah Samy
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Ateya Khafaga
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Youliana Shaker
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Hamdy Yehia
- Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
| | - Asma Alanazi
- College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
| | - Mohammed Alassiri
- King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
- Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia
- Department of Pathology and Laboratory Medicine, King Abdulaziz Medical City (KAMC), Ministry of the National Guard—Health Affairs, Riyadh, Saudi Arabia
| | - Emil Tîrziu
- Department of Animal Production and Veterinary Public Health, Faculty of Veterinary Medicine, University of Life Sciences, “King Mihai I” from Timisoara [ULST], Timisoara, Romania
| | - Iulia Maria Bucur
- Department of Animal Production and Veterinary Public Health, Faculty of Veterinary Medicine, University of Life Sciences, “King Mihai I” from Timisoara [ULST], Timisoara, Romania
| | - Ahmed Hamed Arisha
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University in Cairo, Badr, Egypt
- Department of Physiology, Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
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Shati AA, Alkabli J, Alfaifi MY, Elbehairi SEI, Elshaarawy RFM, Serag WM, Hassan YA. Comparison of the ameliorative roles of crab chitosan nanoparticles and mesenchymal stem cells against cisplatin-triggered nephrotoxicity. Int J Biol Macromol 2023:124985. [PMID: 37230447 DOI: 10.1016/j.ijbiomac.2023.124985] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 05/15/2023] [Accepted: 05/18/2023] [Indexed: 05/27/2023]
Abstract
AIM In the present investigation, we compared the effects of mesenchymal stem cells extracted from bone marrow (BMSCs) and crab chitosan nanoparticles (CCNPs) on renal fibrosis in cisplatin (CDDP)-induced kidney injury rats. MATERIAL AND METHODS 90 male Sprague-Dawley (SD) rats were divided into two equal groups and alienated. Group I was set into three subgroups: the control subgroup, the CDDP-infected subgroup (acute kidney injury), and the CCNPs-treated subgroup. Group II was also divided into three subgroups: the control subgroup, the CDDP-infected subgroup (chronic kidney disease), and the BMSCs-treated subgroup. Through biochemical analysis and immunohistochemical research, the protective effects of CCNPs and BMSCs on renal function have been identified. RESULTS CCNPs and BMSC treatment resulted in a substantial rise in GSH and albumin and a decrease in KIM-1, MDA, creatinine, urea, and caspase-3 when compared to the infected groups (p < 0.05). CONCLUSION According to the current research, chitosan nanoparticles and BMSCs may be able to reduce renal fibrosis in acute and chronic kidney diseases caused by CDDP administration, with more improvement of kidney damage resembling normal cells after CCNPs administration.
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Affiliation(s)
- Ali A Shati
- King Khalid University, Faculty of Science, Biology Department, Abha 9004, Saudi Arabia
| | - J Alkabli
- Department of Chemistry, College of Sciences and Arts - Alkamil, University of Jeddah, Jeddah 23218, Saudi Arabia
| | - Mohammad Y Alfaifi
- King Khalid University, Faculty of Science, Biology Department, Abha 9004, Saudi Arabia
| | - Serag Eldin I Elbehairi
- King Khalid University, Faculty of Science, Biology Department, Abha 9004, Saudi Arabia; Cell Culture Lab, Egyptian Organization for Biological Products and Vaccines (VACSERA Holding Company), 51 Wezaret El-Zeraa St., Agouza, Giza, Egypt
| | - Reda F M Elshaarawy
- Department of Chemistry, Faculty of Science, Suez University, 43533 Suez, Egypt; Institut für Anorganische Chemie und Strukturchemie, Heinrich-Heine Universität Düsseldorf, Düsseldorf, Germany.
| | - Waleed M Serag
- Department of Chemistry, Faculty of Science, Suez University, 43533 Suez, Egypt
| | - Yasser A Hassan
- Department of Pharmaceutics, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt
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11
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Tripathy S, Das SK. Strategies for organ preservation: Current prospective and challenges. Cell Biol Int 2023; 47:520-538. [PMID: 36626269 DOI: 10.1002/cbin.11984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 11/02/2022] [Accepted: 11/09/2022] [Indexed: 01/11/2023]
Abstract
In current therapeutic approaches, transplantation of organs provides the best available treatment for a myriad of end-stage organ failures. However, shortage of organ donors, lacunae in preservation methods, and lack of a suitable match are the major constraints in advocating this life-sustaining therapy. There has been continuous progress in the strategies for organ preservation since its inception. Current strategies for organ preservation are based on the University of Wisconsin (UW) solution using the machine perfusion technique, which allows successful preservation of intra-abdominal organs (kidney and liver) but not intra-thoracic organs (lungs and heart). However, novel concepts with a wide range of adapted preservation technologies that can increase the shelf life of retrieved organs are still under investigation. The therapeutic interventions of in vitro-cultured stem cells could provide novel strategies for replacement of nonfunctional cells of damaged organs with that of functional ones. This review describes existing strategies, highlights recent advances, discusses challenges and innovative approaches for effective organ preservation, and describes application of stem cells to restore the functional activity of damaged organs for future clinical practices.
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Affiliation(s)
- Seema Tripathy
- School of Biological Sciences, National Institute of Science Education and Research (NISER), Bhubaneshwar, India
| | - Saroj Kumar Das
- Neurobiology Laboratory, Centre for Biotechnology, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, India
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12
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Hu Q, Zhu B, Yang G, Jia J, Wang H, Tan R, Zhang Q, Wang L, Kantawong F. Calycosin pretreatment enhanced the therapeutic efficacy of mesenchymal stem cells to alleviate unilateral ureteral obstruction-induced renal fibrosis by inhibiting necroptosis. J Pharmacol Sci 2023; 151:72-83. [PMID: 36707181 DOI: 10.1016/j.jphs.2022.12.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 11/25/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022] Open
Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) show antifibrotic activity in various chronic kidney diseases. Here, we aimed to investigate whether Calycosin (CA), a phytoestrogen, could enhance the antifibrotic activity of MSCs in primary tubular epithelial cells (PTECs) induced by TGF-β1 and in a mouse model of unilateral ureteral obstruction (UUO). We found that MSCs treatment significantly inhibited fibrosis, and CA pretreatment enhanced the effects of MSCs on fibrosis in vitro. Consistent with the in vitro studies, MSCs alleviated tubular injury and renal fibrosis in mice after UUO, and CA-pretreated MSCs resulted in more significant improvements in tubular injury and renal fibrosis than MSCs after UUO. Moreover, MSCs treatment significantly inhibited necroptosis by repressing the elevation of MLKL, RIPK1, and RIPK3 in PTECs treated by TGF-β1and in mice after UUO, and CA-pretreated MSCs were superior to MSCs in alleviating necroptosis. MSCs significantly reduced TNF-α and TNFR1 expression induced by TGF-β1 in PTECs and inhibited TGF-β1, TNF-α, and TNFR1 expression induced by UUO in mice. These effects of MSCs were significantly enhanced after CA pretreatment. Therefore, our results suggest that CA pretreatment enhances the antifibrotic activity of MSCs by inhibiting TGF-β1/TNF-α/TNFR1 signaling-induced necroptosis.
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Affiliation(s)
- Qiongdan Hu
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Sichuan, China
| | - Bingwen Zhu
- Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China
| | - Guoqiang Yang
- Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China; Molecular Imaging and Therapy Research Unit, Department of Radiologic Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Sichuan, China
| | - Jian Jia
- Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China
| | - Honglian Wang
- Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China
| | - Ruizhi Tan
- Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China
| | - Qiong Zhang
- Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China
| | - Li Wang
- Research Center of Integrated Traditional Chinese and Western Medicine, Department of Nephrology, The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Sichuan, China; Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Sichuan, China.
| | - Fahsai Kantawong
- Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
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13
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Cheuk YC, Niu X, Mao Y, Li J, Wang J, Xu S, Luo Y, Wang W, Wang X, Zhang Y, Rong R. Integration of transcriptomics and metabolomics reveals pathways involved in MDSC supernatant attenuation of TGF-β1-induced myofibroblastic differentiation of mesenchymal stem cells. Cell Tissue Res 2022; 390:465-489. [PMID: 36098854 DOI: 10.1007/s00441-022-03681-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 08/23/2022] [Indexed: 12/13/2022]
Abstract
Overexposure to transforming growth factor b1 (TGF-β1) induces myofibroblastic differentiation of mesenchymal stem cells (MSCs), which could be attenuated by myeloid-derived suppressor cell (MDSC) supernatant. However, the promyofibroblastic effects of TGF-β1 and the antimyofibroblastic effects of MDSC supernatant in MSCs have not been fully elucidated. To further clarify the latent mechanism and identify underlying therapeutic targets, we used an integrative strategy combining transcriptomics and metabolomics. Bone marrow MSCs were collected 24 h following TGF-β1 and MDSC supernatant treatment for RNA sequencing and untargeted metabolomic analysis. The integrated data were then analyzed to identify significant gene-metabolite correlations. Differentially expressed genes (DEGs) and differentially expressed metabolites (DEMs) were assessed by Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for exploring the mechanisms of myofibroblastic differentiation of MSCs. The integration of transcriptomic and metabolomic data highlighted significantly coordinated changes in glycolysis/gluconeogenesis and purine metabolism following TGF-β1 and MDSC supernatant treatment. By combining transcriptomic and metabolomic analyses, this study showed that glycolysis/gluconeogenesis and purine metabolism were essential for the myofibroblastic differentiation of MSCs and may serve as promising targets for mechanistic research and clinical practice in the treatment of fibrosis by MDSC supernatant.
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Affiliation(s)
- Yin Celeste Cheuk
- Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200040, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xinhao Niu
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yongxin Mao
- Department of Urology, Huadong Hospital, Fudan University, Shanghai, 200040, China
| | - Jiawei Li
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jiyan Wang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Shihao Xu
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.,Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
| | - Yongsheng Luo
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China.,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Weixi Wang
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xuanchuan Wang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China. .,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Yi Zhang
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China. .,Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
| | - Ruiming Rong
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032, China. .,Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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14
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Xu S, Cheuk YC, Jia Y, Chen T, Chen J, Luo Y, Cao Y, Guo J, Dong L, Zhang Y, Shi Y, Rong R. Bone marrow mesenchymal stem cell-derived exosomal miR-21a-5p alleviates renal fibrosis by attenuating glycolysis by targeting PFKM. Cell Death Dis 2022; 13:876. [PMID: 36253358 PMCID: PMC9576726 DOI: 10.1038/s41419-022-05305-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 09/24/2022] [Accepted: 09/27/2022] [Indexed: 02/08/2023]
Abstract
Renal fibrosis is a common pathological feature and outcome of almost all chronic kidney diseases, and it is characterized by metabolic reprogramming toward aerobic glycolysis. Mesenchymal stem cell-derived exosomes (MSC-Exos) have been proposed as a promising therapeutic approach for renal fibrosis. In this study, we investigated the effect of MSC-Exos on glycolysis and the underlying mechanisms. We demonstrated that MSC-Exos significantly ameliorated unilateral ureter obstruction (UUO)-induced renal fibrosis by inhibiting glycolysis in tubular epithelial cells (TECs). miRNA sequencing showed that miR-21a-5p was highly enriched in MSC-Exos. Mechanistically, miR-21a-5p repressed the expression of phosphofructokinase muscle isoform (PFKM), a rate-limiting enzyme of glycolysis, thereby attenuating glycolysis in TECs. Additionally, knockdown of miR-21a-5p abolished the renoprotective effect of MSC-Exos. These findings revealed a novel role for MSC-Exos in the suppression of glycolysis, providing a new insight into the treatment of renal fibrosis.
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Affiliation(s)
- Shihao Xu
- grid.8547.e0000 0001 0125 2443Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China ,grid.413087.90000 0004 1755 3939Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032 China
| | - Yin Celeste Cheuk
- grid.8547.e0000 0001 0125 2443Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200040 China
| | - Yichen Jia
- grid.8547.e0000 0001 0125 2443Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China ,grid.413087.90000 0004 1755 3939Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032 China
| | - Tian Chen
- grid.8547.e0000 0001 0125 2443Department of Urology, Huashan Hospital, Fudan University, Shanghai, 200040 China
| | - Juntao Chen
- grid.8547.e0000 0001 0125 2443Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China ,grid.413087.90000 0004 1755 3939Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032 China
| | - Yongsheng Luo
- grid.8547.e0000 0001 0125 2443Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China ,grid.413087.90000 0004 1755 3939Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032 China
| | - Yirui Cao
- grid.8547.e0000 0001 0125 2443Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China ,grid.413087.90000 0004 1755 3939Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032 China
| | - Jingjing Guo
- grid.8547.e0000 0001 0125 2443Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China ,grid.413087.90000 0004 1755 3939Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032 China
| | - Lijun Dong
- grid.24516.340000000123704535Operation Room, Shanghai Tenth People’s Hospital, Tongji University, Shanghai, 200072 China
| | - Yi Zhang
- grid.413087.90000 0004 1755 3939Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032 China ,grid.8547.e0000 0001 0125 2443Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Yi Shi
- grid.413087.90000 0004 1755 3939Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032 China ,grid.8547.e0000 0001 0125 2443Institute of Clinical Science, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
| | - Ruiming Rong
- grid.8547.e0000 0001 0125 2443Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032 China ,grid.413087.90000 0004 1755 3939Shanghai Key Laboratory of Organ Transplantation, Shanghai, 200032 China ,grid.8547.e0000 0001 0125 2443Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, 200032 China
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15
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Li YY, Tian ZH, Pan GH, Zhao P, Pan DJ, Zhang JQ, Ye LY, Zhang FR, Xu XD. Heidihuangwan alleviates renal fibrosis in rats with 5/6 nephrectomy by inhibiting autophagy. Front Pharmacol 2022; 13:977284. [PMID: 36160409 PMCID: PMC9503832 DOI: 10.3389/fphar.2022.977284] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 07/29/2022] [Indexed: 11/13/2022] Open
Abstract
Renal fibrosis is a common pathway for the progression of various chronic kidney diseases (CKD), and the formation and deterioration will eventually lead to end-stage renal failure, which brings a heavy medical burden to the world. HeidihuangWan (HDHW) is a herbal formulation with stable and reliable clinical efficacy in the treatment of renal fibrosis. However, the mechanism of HDHW in treating renal fibrosis is not clear. In this study, we aimed to investigate the mechanism of HDHW to improve renal fibrosis. Wistar rats were randomly divided into the normal control group, 5/6 Nephrectomy group, astragaloside IV (AS-IV) group, HDHW group, and HDHW + IGF-1R inhibitor (JB1) group. Except for the normal control group, the rat renal fibrosis model was established by 5/6 nephrectomy and intervened with drugs for 8 weeks. Blood samples were collected to evaluate renal function. Hematoxylin-Eosin (HE), Periodic Acid-Schiff (PAS), Modified Masson’s Trichrome (Masson) staining were used to evaluate the pathological renal injury, and immunohistochemistry and Western blotting were used to detect the protein expression of renal tissue. The results showed that HDHW was effective in improving renal function and reducing renal pathological damage. HDHW down-regulated the levels of fibrosis marker proteins, including α-smooth muscle actin (α-SMA), vimentin, and transforming growth factors–β(TGF-β), which in turn reduced renal fibrosis. Further studies showed that HDHW down-regulated the expression of autophagy-related proteins Beclin1 and LC3II, indicating that HDHW inhibited autophagy. In addition, we examined the activity of the class I phosphatidylinositol-3 kinase (PI3K)/serine-threonine kinase (Akt)/mTOR pathway, an important signaling pathway regulating autophagy, and the level of insulin-like growth factor 1 (IGF-1), an upstream activator of PI3K/Akt/mTOR. HDHW upregulated the expression of IGF-1 and activated the PI3K/Akt/mTOR pathway, which may be a vital pathway for its inhibition of autophagy. Application of insulin-like growth factor 1 receptor (IGF-1R) inhibitor further confirmed that the regulation of autophagy and renal fibrosis by HDHW was associated with IGF-1-mediated activation of the PI3K/Akt/mTOR pathway. In conclusion, our study showed that HDHW inhibited autophagy by upregulating IGF-1 expression, promoting the binding of IGF-1 to IGF-1R, and activating the PI3K/Akt/mTOR signaling pathway, thereby reducing renal fibrosis and protecting renal function. This study provides support for the application and further study of HDHW.
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Affiliation(s)
- Ying-Ying Li
- College of First Clinical Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zeng-Hui Tian
- College of First Clinical Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Guang-Hui Pan
- Department of Nephrology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ping Zhao
- Department of Nephrology, Tai’an City Hospital of Traditional Chinese Medicine, Tai’an, China
| | - De-Jun Pan
- Department of Clinical Laboratory, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jun-Qing Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Li-Ying Ye
- College of First Clinical Medical, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fa-Rong Zhang
- Department of Nephrology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- *Correspondence: Fa-Rong Zhang, ; Xiang-Dong Xu,
| | - Xiang-Dong Xu
- Experimental Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
- *Correspondence: Fa-Rong Zhang, ; Xiang-Dong Xu,
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16
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Alasmari WA, Abdelfattah-Hassan A, El-Ghazali HM, Abdo SA, Ibrahim D, ElSawy NA, El-Shetry ES, Saleh AA, Abourehab MAS, Mahfouz H. Exosomes Derived from BM-MSCs Mitigate the Development of Chronic Kidney Damage Post-Menopause via Interfering with Fibrosis and Apoptosis. Biomolecules 2022; 12:biom12050663. [PMID: 35625591 PMCID: PMC9138582 DOI: 10.3390/biom12050663] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/13/2022] [Accepted: 04/22/2022] [Indexed: 02/07/2023] Open
Abstract
The rate of chronic kidney disease (CKD) is increasing globally, and it is caused by continuous damage to kidney tissue. With time the renal damage becomes irreversible, leading to CKD development. In females, post-menopause lack of estrogen supply has been described as a risk factor for CKD development, and studies targeting post-menopause CKD are scarce. In the present study, we used exosomes isolated from bone marrow mesenchymal stem/stromal cells (BM-MSCs) to test their therapeutic potential against the development of CKD. At first, the menopause model was achieved by surgical bilateral ovariectomy in female albino rats. After that, 100 µg of exosomes was given to ovariectomized rats, and the study continued for 2 months. Changes in urine volume, urine protein content, kidney function biochemical parameters (creatinine and BUN), kidney antioxidant parameters (SOD, GPx and CAT), histological changes, immunohistochemical levels of caspase 3, and the gene expression of NGAL (related to kidney damage), TGFβ1 and αSMA (related to fibrosis and EMT), and caspase 3 (related to apoptosis) were studied. After the ovariectomy, the occurrence of CKD was confirmed in the rats by the drastic reduction of serum estrogen and progesterone levels, reduced urine output, increased urinary protein excretion, elevated serum creatinine and BUN, reduced GPx SOD, and CAT in kidney tissue, degenerative and fibrotic lesions in the histopathological examination, higher immunohistochemical expression of caspase 3 and increased expression of all studied genes. After exosomes administration, the entire chronic inflammatory picture in the kidney was corrected, and a near-normal kidney structure and function were attained. This study shows for the first time that BM-MSCs exosomes are potent for reducing apoptosis and fibrosis levels and, thus, can reduce the chronic damage of the kidneys in females that are in their menopause period. Therefore, MSCs-derived exosomes should be considered a valuable therapy for preserving postmenopausal kidney structure and function and, subsequently, could improve the quality of females’ life during menopause.
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Affiliation(s)
- Wardah A. Alasmari
- Department of Anatomy, Faculty of Medicine, Umm Al-Qura University, Makkah 24230, Saudi Arabia
- Correspondence: (W.A.A.); or (A.A.-H.)
| | - Ahmed Abdelfattah-Hassan
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt;
- Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza 12578, Egypt
- Correspondence: (W.A.A.); or (A.A.-H.)
| | - Hanaa M. El-Ghazali
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt;
| | - Samar A. Abdo
- Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt;
| | - Doaa Ibrahim
- Department of Nutrition and Clinical Nutrition, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt;
| | - Naser A. ElSawy
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig 44511, Egypt; (N.A.E.); (E.S.E.-S.)
| | - Eman S. El-Shetry
- Department of Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, Zagazig 44511, Egypt; (N.A.E.); (E.S.E.-S.)
| | - Ayman A. Saleh
- Department of Animal Wealth Development, Genetics & Genetic Engineering, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44519, Egypt;
| | - Mohammed A. S. Abourehab
- Department of Pharmaceutics, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia;
| | - Hala Mahfouz
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
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17
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Zhao Y, Guo C, Zeng L, Li J, Liu X, Wang Y, Zhao K, Chen B. Mesenchymal Stem Cells Ameliorate Fibrosis by Enhancing Autophagy via Inhibiting Galectin-3/Akt/mTOR Pathway and by Alleviating the EMT via Inhibiting Galectin-3/Akt/GSK3β/Snail Pathway in NRK-52E Fibrosis. Int J Stem Cells 2022; 16:52-65. [PMID: 35483714 PMCID: PMC9978829 DOI: 10.15283/ijsc22014] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 11/09/2022] Open
Abstract
Background and Objectives Epithelial-Mesenchymal transition (EMT) is one of the origins of myofibroblasts in renal interstitial fibrosis. Mesenchymal stem cells (MSCs) alleviating EMT has been proved, but the concrete mechanism is unclear. To explore the mechanism, serum-free MSCs conditioned medium (SF-MSCs-CM) was used to treat rat renal tubular epithelial cells (NRK-52E) fibrosis induced by transforming growth factor-β1 (TGF-β1) which ameliorated EMT. Methods and Results Galectin-3 knockdown (Gal-3 KD) and overexpression (Gal-3 OE) lentiviral vectors were established and transfected into NRK-52E. NRK-52E fibrosis model was induced by TGF-β1 and treated with the SF-MSCs-CM for 24 h after modelling. Fibrosis and autophagy related indexes were detected by western blot and immunocytochemistry. In model group, the expressions of α-smooth muscle actin (α-SMA), fibronectin (FN), Galectin-3, Snail, Kim-1, and the ratios of P-Akt/Akt, P-GSK3β/GSK3β, P-PI3K/PI3K, P-mTOR/mTOR, TIMP1/MMP9, and LC3B-II/I were obviously increased, and E-Cadherin (E-cad) and P62 decreased significantly compared with control group. SF-MSCs-CM showed an opposite trend after treatment compared with model group. Whether in Gal-3 KD or Gal-3 OE NRK-52E cells, SF-MSCs-CM also showed similar trends. However, the effects of anti-fibrosis and enhanced autophagy in Gal-3 KD cells were more obvious than those in Gal-3 OE cells. Conclusions SF-MSCs-CM probably alleviated the EMT via inhibiting Galectin-3/Akt/GSK3β/Snail pathway. Meanwhile, Gal-3 KD possibly enhanced autophagy via inhibiting Galectin-3/Akt/mTOR pathway, which synergistically ameliorated renal fibrosis. Targeting galectin-3 may be a potential target for the treatment of renal fibrosis.
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Affiliation(s)
- Yu Zhao
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China,Department of Otorhinolaryngology Head and Neck Surgery, Chongqing University Fuling Hospital, Chongqing, China
| | - Chuan Guo
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Lianlin Zeng
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Jialing Li
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Xia Liu
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Yiwei Wang
- Department of Chemistry, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Kun Zhao
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Bo Chen
- Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China,Correspondence to Bo Chen, Department of Human Anatomy and Histoembryology, School of Basic Medical Sciences, Southwest Medical University, No.1, Section 1, Lingxiang Road, Matan Long District, Luzhou, Sichuan 646000, China, Tel: +86-08303160545, E-mail: ,
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18
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Gutierrez AM, Frazar EM, X Klaus MV, Paul P, Hilt JZ. Hydrogels and Hydrogel Nanocomposites: Enhancing Healthcare through Human and Environmental Treatment. Adv Healthc Mater 2022; 11:e2101820. [PMID: 34811960 PMCID: PMC8986592 DOI: 10.1002/adhm.202101820] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/08/2021] [Indexed: 12/11/2022]
Abstract
Humans are constantly exposed to exogenous chemicals throughout their life, which can lead to a multitude of negative health impacts. Advanced materials can play a key role in preventing or mitigating these impacts through a wide variety of applications. The tunable properties of hydrogels and hydrogel nanocomposites (e.g., swelling behavior, biocompatibility, stimuli responsiveness, functionality, etc.) have deemed them ideal platforms for removal of environmental contaminants, detoxification, and reduction of body burden from exogenous chemical exposures for prevention of disease initiation, and advanced treatment of chronic diseases, including cancer, diabetes, and cardiovascular disease. In this review, three main junctures where the use of hydrogel and hydrogel nanocomposite materials can intervene to positively impact human health are highlighted: 1) preventing exposures to environmental contaminants, 2) prophylactic treatments to prevent chronic disease initiation, and 3) treating chronic diseases after they have developed.
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Affiliation(s)
- Angela M Gutierrez
- Department of Chemical and Materials Engineering, University of Kentucky, 177 F Paul Anderson Tower, Lexington, KY, 40506, USA
- Superfund Research Center, University of Kentucky, Lexington, KY, 40506, USA
| | - Erin Molly Frazar
- Department of Chemical and Materials Engineering, University of Kentucky, 177 F Paul Anderson Tower, Lexington, KY, 40506, USA
- Superfund Research Center, University of Kentucky, Lexington, KY, 40506, USA
| | - Maria Victoria X Klaus
- Department of Chemical and Materials Engineering, University of Kentucky, 177 F Paul Anderson Tower, Lexington, KY, 40506, USA
- Superfund Research Center, University of Kentucky, Lexington, KY, 40506, USA
| | - Pranto Paul
- Department of Chemical and Materials Engineering, University of Kentucky, 177 F Paul Anderson Tower, Lexington, KY, 40506, USA
- Superfund Research Center, University of Kentucky, Lexington, KY, 40506, USA
| | - J Zach Hilt
- Department of Chemical and Materials Engineering, University of Kentucky, 177 F Paul Anderson Tower, Lexington, KY, 40506, USA
- Superfund Research Center, University of Kentucky, Lexington, KY, 40506, USA
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19
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Serag WM, Barakat N, Elshehabi ME, Hafez HS, Zahran F. Renoprotective effect of bone marrow mesenchymal stem cells with hyaluronic acid against adriamycin- induced kidney fibrosis via inhibition of Wnt/β-catenin pathway. Int J Biol Macromol 2022; 207:741-749. [PMID: 35354071 DOI: 10.1016/j.ijbiomac.2022.03.156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 03/21/2022] [Accepted: 03/24/2022] [Indexed: 11/05/2022]
Abstract
AIM The current study aimed to explore the pretreatment of bone marrow mesenchymal stem cells (BMSCs) with hyaluronic acid (HA) on renal fibrosis in Adriamycin- induced CKD in rats. MATERIAL AND METHODS Sixty male SD rats were alienated into 4 equal groups; The control group: rats received two saline injections at 1 and 14 days, adriamycin (ADR) group: rats were injected i.v. twice via tail vein at day one and after 2 weeks, BMSCs group; rats were injected i.v. twice after 5 days of each ADR injection, and HA+BMSCs; rats were i.v. injected twice with BMSCs pretreated with 1 mg/ml HA after 5 days of each ADR injection. Protective role of BMSCs on renal function and morphology was detected using biochemical analysis, molecular studies, histopathological, and immunohistohemical investigations. RESULTS Pretreatment of BMSCs with HA showed significant decrease in KIM-1, and increase in serum albumin compared to CKD group (p <0.05). Moreover, it reduced the expression of the apoptotic marker Caspase-3, the inflammatory markers TNF and IL-6, and the fibrotic markers Wnt7a, β-catenin, and fibronectin1 than the CKD group (p < 0.05). CONCLUSION The current outcomes suggested that BMSCs preconditioned with HA could attenuate the renal fibrosis in adriamycin- induced CKD.
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Affiliation(s)
- Waleed M Serag
- Chemistry Department, Faculty of Science, Suez University, Suez, Egypt
| | - Nashwa Barakat
- Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
| | | | - Hani S Hafez
- Zoology Department, Faculty of Science, Suez University, Suez, Egypt
| | - Faten Zahran
- Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt
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20
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Liao C, Chen G, Yang Q, Liu Y, Zhou T. Potential Therapeutic Effect and Mechanisms of Mesenchymal Stem Cells-Extracellular Vesicles in Renal Fibrosis. Front Cell Dev Biol 2022; 10:824752. [PMID: 35359447 PMCID: PMC8961868 DOI: 10.3389/fcell.2022.824752] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 02/14/2022] [Indexed: 02/05/2023] Open
Abstract
Renal fibrosis (RF) is central pathological pathway for kidney diseases, with the main pathological features being the aberrant accumulation of myofibroblasts that produce accumulation of extracellular matrix in the renal interstitium and glomeruli. Acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with RF. Current treatment strategies for RF are ineffective. Mesenchymal stem cells (MSCs) have been found to be able to treat organ fibrosis including RF, but they have some safety problems, such as cell rejection, carcinogenicity, and virus contamination, which limit the application of MSCs. However, current studies have found that MSCs may exert their therapeutic effect by releasing extracellular vesicles (EVs). MSC-EVs can transfer functional proteins and genetic material directly to the recipient cells. As non-cell membrane structures, MSC-EVs have the advantages of low immunogenicity, easy preservation, and artificial modification, but do not have the characteristics of self-replication and ectopic differentiation. Therefore, EVs are safer than MSCs for treatment, but might be less effective than MSCs. Recent studies have also found that MSC-EVs can improve renal function and pathological changes of RF. Thus, this review summarizes the therapeutic effect of MSC-EVs on RF and the mechanisms that have been discovered so far, so as to provide a theoretical basis for the further study of the role of MSC-EVs in treating RF diseases.
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Affiliation(s)
- Chunling Liao
- Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | | | | | | | - Tianbiao Zhou
- Department of Nephrology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China
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21
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Li X, Zhang Q, Wang Z, Zhuang Q, Zhao M. Immune and Metabolic Alterations in Liver Fibrosis: A Disruption of Oxygen Homeostasis? Front Mol Biosci 2022; 8:802251. [PMID: 35187072 PMCID: PMC8850363 DOI: 10.3389/fmolb.2021.802251] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/17/2021] [Indexed: 12/06/2022] Open
Abstract
According to the WHO, “cirrhosis of the liver” was the 11th leading cause of death globally in 2019. Many kinds of liver diseases can develop into liver cirrhosis, and liver fibrosis is the main pathological presentation of different aetiologies, including toxic damage, viral infection, and metabolic and genetic diseases. It is characterized by excessive synthesis and decreased decomposition of extracellular matrix (ECM). Hepatocyte cell death, hepatic stellate cell (HSC) activation, and inflammation are crucial incidences of liver fibrosis. The process of fibrosis is also closely related to metabolic and immune disorders, which are usually induced by the destruction of oxygen homeostasis, including mitochondrial dysfunction, oxidative stress, and hypoxia pathway activation. Mitochondria are important organelles in energy generation and metabolism. Hypoxia-inducible factors (HIFs) are key factors activated when hypoxia occurs. Both are considered essential factors of liver fibrosis. In this review, the authors highlight the impact of oxygen imbalance on metabolism and immunity in liver fibrosis as well as potential novel targets for antifibrotic therapies.
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Affiliation(s)
- Xinyu Li
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Quyan Zhang
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Zeyu Wang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - Quan Zhuang
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Quan Zhuang, ; Mingyi Zhao,
| | - Mingyi Zhao
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Quan Zhuang, ; Mingyi Zhao,
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22
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Burk J, Sassmann A, Kasper C, Nimptsch A, Schubert S. Extracellular Matrix Synthesis and Remodeling by Mesenchymal Stromal Cells Is Context-Sensitive. Int J Mol Sci 2022; 23:ijms23031758. [PMID: 35163683 PMCID: PMC8836208 DOI: 10.3390/ijms23031758] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/25/2022] [Accepted: 01/29/2022] [Indexed: 12/17/2022] Open
Abstract
Matrix remodeling could be an important mode of action of multipotent mesenchymal stromal cells (MSC) in extracellular matrix (ECM) disease, but knowledge is limited in this respect. As MSC are well-known to adapt their behavior to their environment, we aimed to investigate if their mode of action would change in response to healthy versus pathologically altered ECM. Human MSC-derived ECM was produced under different culture conditions, including standard culture, culture on Matrigel-coated dishes, and stimulation with the pro-fibrotic transforming growth factor-β1 (TGFβ1). The MSC-ECM was decellularized, characterized by histochemistry, and used as MSC culture substrate reflecting different ECM conditions. MSC were cultured on the different ECM substrates or in control conditions for 2 days. Culture on ECM increased the presence of surface molecules with ECM receptor function in the MSC, demonstrating an interaction between MSC and ECM. In MSC cultured on Matrigel-ECM and TGFβ1-ECM, which displayed a fibrosis-like morphology, gene expression of collagens and decorin, as well as total matrix metalloproteinase (MMP) activity in the supernatant were decreased as compared with control conditions. These results demonstrated that MSC adapt to their ECM environment, which may include pathological adaptations that could compromise therapeutic efficacy.
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Affiliation(s)
- Janina Burk
- Equine Clinic (Surgery, Orthopedics), Justus-Liebig-University Giessen, 35392 Giessen, Germany
- Institute for Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), 1190 Vienna, Austria; (A.S.); (C.K.)
- Correspondence:
| | - Anna Sassmann
- Institute for Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), 1190 Vienna, Austria; (A.S.); (C.K.)
| | - Cornelia Kasper
- Institute for Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), 1190 Vienna, Austria; (A.S.); (C.K.)
| | - Ariane Nimptsch
- Institute for Medical Physics and Biophysics, University of Leipzig, 04107 Leipzig, Germany;
| | - Susanna Schubert
- Institute of Human Genetics, University of Leipzig, 04103 Leipzig, Germany;
- Saxon Incubator for Clinical Translation, University of Leipzig, 04103 Leipzig, Germany
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23
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Bilgiç T, İnce Ü, Narter F. Autologous omentum transposition for regeneration of a renal injury model in rats. Mil Med Res 2022; 9:1. [PMID: 34983664 PMCID: PMC8725455 DOI: 10.1186/s40779-021-00361-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 12/08/2021] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND After renal trauma, surgical treatment is vital, but sometimes there may be loss of function due to fibrosis. This study aimed to evaluate the effect of autologous omentum flaps on injured renal tissues in a rat model. METHODS A total of 30 Wistar albino rats were included and randomly divided equally into a control group and four intervention groups. Iatrogenic renal injuries were repaired using a surgical technique (primary repair 1 group and primary repair 2 group) or transposition of the autologous omentum (omentum repair 1 group and omentum repair 2 group). Blood samples were taken preoperatively and on the 1st and 7th postoperative days in all groups and on the 18th postoperative day in the control and two intervention groups. All rats were sacrificed on the 7th or 18th day postoperatively, and their right kidneys were taken for histopathological evaluation. RESULTS The mean urea level significantly decreased from day 1 to day 7 and from day 1 to day 18 in the omentum repair 2 group (P = 0.005 and P = 0.004, respectively). There were no other significant changes in urea or creatinine levels within the intervention groups (P > 0.05). There was no significant correlation between the urea and creatinine levels and the histological scores (P > 0.05). The primary repair 1 and 2 groups had significantly higher median granulation and inflammation scores in the kidney specimen than the control and omentum repair groups (P < 0.05). The omentum repair 2 group had significantly lower median granulation and inflammation scores in the surrounding tissues than the primary repair 2 group (P < 0.05). The completion score for the healing process in the kidney specimen was significantly higher in the omentum repair groups than in the primary repair groups (P < 0.05). The omentum repair 2 group had significantly lower median granulation and inflammation scores in the surrounding tissues than the primary repair 2 group (P < 0.05). Granulation degree in the kidney specimen was strongly and positively correlated with the inflammation degree (r = 0.824, P < 0.001) and foreign body reaction in the kidney specimen (r = 0.872, P < 0.001) and a strong and negative correlation with the healing process completion score in the kidney (r = - 0.627, P = 0.001). Inflammation degree in the kidney specimen was strongly and positively correlated with the foreign body reaction in the kidney specimen (r = 0.731, P = 0.001) and strongly and negatively correlated with the healing process completion score in the kidney specimen (r = - 0.608, P = 0.002). CONCLUSION Autologous omentum tissue for kidney injury repair attenuated inflammation and granulation. Additionally, the use of omental tissue to facilitate healing of kidney injury may theoretically lead to a more effective healing process and reduced fibrosis and tissue and function loss.
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Affiliation(s)
- Tayfun Bilgiç
- Acıbadem Kadıkoy Hospital of General Surgery, Istanbul, 34718 Turkey
| | - Ümit İnce
- Department of Pathology, Acıbadem Mehmet Ali Aydınlar University, Istanbul, 34684 Turkey
| | - Fehmi Narter
- Department of Urology, Acıbadem Mehmet Ali Aydınlar University, Istanbul, 34684 Turkey
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Exosomes derived from mesenchymal stem cells ameliorate renal fibrosis via delivery of miR-186-5p. Hum Cell 2021; 35:83-97. [PMID: 34585365 DOI: 10.1007/s13577-021-00617-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/16/2021] [Indexed: 01/08/2023]
Abstract
Evidence has shown that mesenchymal stem cells' (MSCs) therapy has potential application in treating chronic kidney disease (CKD). In addition, MSCs-derived exosomes can improve the renal function and prevent the progression of CKD. However, the mechanisms by which MSCs-derived exosomes (MSCs-Exo) ameliorate renal fibrosis in CKD remain largely unclear. To mimic an in vitro model of renal fibrosis, rat kidney tubular epithelial cells (NRK52E) were stimulated with transforming growth factor (TGF)-β1. In addition, we established an in vivo model of unilateral ureteric obstruction (UUO)-induced renal fibrosis. Meanwhile, we exploited exosomes derived from MSCs for delivering miR-186-5p agomir into NRK52E cells or kidneys in vitro and in vivo. In this study, we found that level of miR-186-5p was significantly downregulated in TGF-β1-stimulated NRK52E cells and the obstructed kidneys of UUO mice. In addition, miR-186-5p can be transferred from MSCs to NRK52E cells via exosomes. MSCs-delivered miR-186-5p markedly reduced the accumulation of extracellular matrix (ECM) protein, and inhibited epithelial-to-mesenchymal transition (EMT) and apoptosis in TGF-β1-stimulated NRK52E cells. Moreover, exosomal miR-186-5p from MSCs attenuated kidney injury and fibrosis in a UUO mouse model via inhibition of the ECM protein accumulation and EMT process. Meanwhile, dual-luciferase assay showed that miR-186-5p downregulated Smad5 expression via direct binding with the 3'-UTR of Smad5. Collectively then, these findings indicated that exosomal miR-186-5p derived from MSCs could attenuate renal fibrosis in vitro and in vivo by downregulation of Smad5. These findings may help to understand the role of MSCs' exosomes in alleviating renal fibrosis in CKD.
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25
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Wong CY. Current advances of stem cell-based therapy for kidney diseases. World J Stem Cells 2021; 13:914-933. [PMID: 34367484 PMCID: PMC8316868 DOI: 10.4252/wjsc.v13.i7.914] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Revised: 04/10/2021] [Accepted: 07/12/2021] [Indexed: 02/06/2023] Open
Abstract
Kidney diseases are a prevalent health problem around the world. Multidrug therapy used in the current routine treatment for kidney diseases can only delay disease progression. None of these drugs or treatments can reverse the progression to an end-stage of the disease. Therefore, it is crucial to explore novel therapeutics to improve patients’ quality of life and possibly cure, reverse, or alleviate the kidney disease. Stem cells have promising potentials as a form of regenerative medicine for kidney diseases due to their unlimited replication and their ability to differentiate into kidney cells in vitro. Mounting evidences from the administration of stem cells in an experimental kidney disease model suggested that stem cell-based therapy has therapeutic or renoprotective effects to attenuate kidney damage while improving the function and structure of both glomerular and tubular compartments. This review summarises the current stem cell-based therapeutic approaches to treat kidney diseases, including the various cell sources, animal models or in vitro studies. The challenges of progressing from proof-of-principle in the laboratory to widespread clinical application and the human clinical trial outcomes reported to date are also highlighted. The success of cell-based therapy could widen the scope of regenerative medicine in the future.
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Affiliation(s)
- Chee-Yin Wong
- Faculty of Medicine and Health Sciences, Universiti Tunku Abdul Rahman, Kajang 43000, Selangor, Malaysia
- Research Department, Cytopeutics, Cyberjaya 63000, Selangor, Malaysia
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26
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Gao M, Wang J, Zang J, An Y, Dong Y. The Mechanism of CD8 + T Cells for Reducing Myofibroblasts Accumulation during Renal Fibrosis. Biomolecules 2021; 11:biom11070990. [PMID: 34356613 PMCID: PMC8301885 DOI: 10.3390/biom11070990] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 07/02/2021] [Accepted: 07/03/2021] [Indexed: 02/07/2023] Open
Abstract
Renal fibrosis is a hallmark of chronic kidney disease (CKD) and a common manifestation of end-stage renal disease that is associated with multiple types of renal insults and functional loss of the kidney. Unresolved renal inflammation triggers fibrotic processes by promoting the activation and expansion of extracellular matrix-producing fibroblasts and myofibroblasts. Growing evidence now indicates that diverse T cells and macrophage subpopulations play central roles in the inflammatory microenvironment and fibrotic process. The present review aims to elucidate the role of CD8+ T cells in renal fibrosis, and identify its possible mechanisms in the inflammatory microenvironment.
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Jin J, Qian F, Zheng D, He W, Gong J, He Q. Mesenchymal Stem Cells Attenuate Renal Fibrosis via Exosomes-Mediated Delivery of microRNA Let-7i-5p Antagomir. Int J Nanomedicine 2021; 16:3565-3578. [PMID: 34079249 PMCID: PMC8164705 DOI: 10.2147/ijn.s299969] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 04/30/2021] [Indexed: 01/17/2023] Open
Abstract
Background Renal fibrosis is a chronic and progressive process affecting kidneys in chronic kidney disease (CKD). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been shown to alleviate renal fibrosis and injury, but the mechanism of MSCs-Exo-induced renal protection remains unknown. Methods In this study, MSCs were transfected with let-7i-5p antagomir (anti-let-7i-5p), and then exosomes were isolated from the transfected MSCs to deliver anti-let-7i-5p oligonucleotides to inhibit the level of let-7i-5p in kidney tubular epithelial cells (NRK-52E). Results In both NRK-52E cells stimulated by TGF-β1 and the mouse kidneys after unilateral ureteral obstruction (UUO), we demonstrated increased level of let-7i-5p. In addition, MSCs-Exo can deliver anti-let-7i-5p to reduce the level of let-7i-5p in NRK-52E cells and increase the expression of its target gene TSC1. Moreover, exosomal anti-let-7i-5p reduced extracellular matrix (ECM) deposition and attenuated epithelial-mesenchymal transition (EMT) process in transforming growth factor beta 1 (TGF-β1)-stimulated NRK-52E cells and in the kidneys of UUO-treated mice. Meanwhile, mice received exosomal anti-let-7i-5p displayed reduced renal fibrosis and improved kidney function when challenged with UUO. Furthermore, exosomal anti-let-7i-5p promoted the activation the tuberous sclerosis complex subunit 1/mammalian target of rapamycin (TSC1/mTOR) signaling pathway in vivo and in vitro. Conclusion In conclusion, exosomal anti-let-7i-5p from MSCs exerts anti-fibrotic effects in TGF-β1-induced fibrogenic responses in NRK52E cells in vitro as well as in UUO-induced renal fibrosis model in vivo. These results provided a novel perspective on improving renal fibrosis by MSCs-Exo.
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Affiliation(s)
- Juan Jin
- Department of Nephrology, Zhejiang Provincial People's Hospital and Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China
| | - Fengmei Qian
- Department of Nephrology, Zhejiang Provincial People's Hospital and Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China
| | - Danna Zheng
- Department of Nephrology, Zhejiang Provincial People's Hospital and Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China
| | - Wenfang He
- Department of Nephrology, Zhejiang Provincial People's Hospital and Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China
| | - Jianguang Gong
- Department of Nephrology, Zhejiang Provincial People's Hospital and Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China
| | - Qiang He
- Department of Nephrology, Zhejiang Provincial People's Hospital and Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, 310014, People's Republic of China
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Zhao Y, Zhu XY, Song T, Zhang L, Eirin A, Conley S, Tang H, Saadiq I, Jordan K, Lerman A, Lerman LO. Mesenchymal stem cells protect renal tubular cells via TSG-6 regulating macrophage function and phenotype switching. Am J Physiol Renal Physiol 2021; 320:F454-F463. [PMID: 33554782 DOI: 10.1152/ajprenal.00426.2020] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Tumor necrosis factor (TNF)-α-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of mesenchymal stem cells (MSCs), but its ability to protect the ischemic kidney is unknown. In a swine model of renal artery stenosis (RAS) and metabolic syndrome (MetS), we assessed the contribution of TSG-6 produced by MSCs to their immunomodulatory properties. Pigs were studied after 16 wk of diet-induced MetS and unilateral RAS and were either untreated or treated 4 wk earlier with intrarenal autologous adipose tissue-derived MSCs (n = 6 each). Lean, MetS, and RAS sham animals served as controls. We studied renal function in vivo (using computed tomography) and kidney histopathology and macrophage phenotype ex vivo. In vitro, TSG-6 levels were also measured in conditioned media of human MSCs incubated with TNF-α and levels of the tubular injury marker lactate dehydrogenase in conditioned media after coculturing macrophages with injured human kidney 2 (HK-2) cells with or without TSG-6. The effects of TSG-6 on macrophage phenotype (M1/M2), adhesion, and migration were also determined. MetS + RAS showed increased M1 macrophages and renal vein TNF-α levels. After MSC delivery, renal vein TSG-6 increased and TNF-α decreased, the M1-to-M2 ratio decreased, renal function improved, and fibrosis was alleviated. In vitro, TNF-α increased TSG-6 secretion by human MSCs. TSG-6 decreased lactate dehydrogenase release from injured HK-2 cells, increased expression of macrophage M2 markers, and reduced M1 macrophage adhesion and migration. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype. These observations suggest that TSG-6 is endowed with renoprotective properties.NEW & NOTEWORTHY Tumor necrosis factor-α-induced gene/protein (TSG)-6 regulates the immunomodulatory properties of MSCs, but its ability to protect the ischemic kidney is unknown. In pigs with renal artery stenosis, we show that MSC delivery increased renal vein TSG-6, decreased kidney inflammatory macrophages, and improved renal function. In vitro, TSG-6 decreased inflammatory macrophages and tubular cell injury. Therefore, TSG-6 released from MSCs may decrease renal tubular cell injury, which is associated with regulating macrophage function and phenotype.
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Affiliation(s)
- Yu Zhao
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.,Institute of Nephrology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, China
| | - Xiang-Yang Zhu
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Turun Song
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Lei Zhang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota.,Institute of Urology, Zhong Da Hospital, Southeast University, School of Medicine, Nanjing, Jiangsu, China
| | - Alfonso Eirin
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Sabena Conley
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Hui Tang
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Ishran Saadiq
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Kyra Jordan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota
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Kan XL, Pan XH, Zhao J, He J, Cai XM, Pang RQ, Zhu XQ, Cao XB, Ruan GP. Effect and mechanism of human umbilical cord mesenchymal stem cells in treating allergic rhinitis in mice. Sci Rep 2020; 10:19295. [PMID: 33168885 PMCID: PMC7652838 DOI: 10.1038/s41598-020-76343-4] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 10/27/2020] [Indexed: 12/17/2022] Open
Abstract
A model of allergic rhinitis (AR) in BALB/c mice was established and evaluated to provide experimental subjects for further research. Preparation of human umbilical cord mesenchymal stem cells (hUCMSCs), including isolation, expansion culture, passaging, cryopreservation, and preparation of cell suspensions, provided materials for experimental research and clinical treatment. The mouse AR model was established by ovalbumin (OVA) intraperitoneal injection and the nasal stimulation induction method, and the model had a good effect and high repeatability. GFP-labeled hUCMSCs had good effects and were stable cells that could be used for tracking in animals. Transplantation of hUCMSCs by intraperitoneal and tail vein injections had a specific effect on the AR model of mice, and tail vein injection had a better effect. Tracking of hUCMSCs in vivo showed that the three groups of mice had the greatest number of hUCMSCs in the nose at week 2. The mouse AR model was used to evaluate the efficacy of hUCMSC transplantation via multiple methods for AR. The distribution of hUCMSCs in vivo was tracked by detecting green fluorescent protein (GFP), and the treatment mechanism of hUCMSCs was elucidated. This study provides technical methods and a theoretical basis for the clinical application of hUCMSCs.
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Affiliation(s)
- Xiao-Li Kan
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Xing-Hua Pan
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Jing Zhao
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Jie He
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Xue-Min Cai
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Rong-Qing Pang
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Xiang-Qing Zhu
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China.,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China.,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China
| | - Xian-Bao Cao
- Department of Otorhinolaryngology, Kunming First People's Hospital, Kunming, Yunnan, China.
| | - Guang-Ping Ruan
- Kunming Key Laboratory of Stem Cell and Regenerative Medicine, 920th Hospital of the PLA Joint Logistics Support Force, Kunming, 650032, Yunnan, China. .,Stem Cell and Immune Cell Biomedical Techniques and Integrated Engineering Laboratory of State and Regions, Kunming, Yunnan, China. .,Cell Therapy Technology Transfer Medical Key Laboratory of Yunnan Province, Kunming, Yunnan, China.
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Radmanesh F, Mahmoudi M, Yazdanpanah E, Keyvani V, Kia N, Nikpoor AR, Zafari P, Esmaeili SA. The immunomodulatory effects of mesenchymal stromal cell-based therapy in human and animal models of systemic lupus erythematosus. IUBMB Life 2020; 72:2366-2381. [PMID: 33006813 DOI: 10.1002/iub.2387] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 09/11/2020] [Accepted: 09/12/2020] [Indexed: 12/17/2022]
Abstract
Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune inflammatory disease with no absolute cure. Although the exact etiopathogenesis of SLE is still enigmatic, it has been well demonstrated that a combination of genetic predisposition and environmental factors trigger a disturbance in immune responses and thereby participate in the development of this condition. Almost all available therapeutic strategies in SLE are primarily based on the administration of immunosuppressive drugs and are not curative. Mesenchymal stromal cells (MSCs) are a subset of non-hematopoietic adult stem cells that can be isolated from many adult tissues and are increasingly recognized as immune response modulating agents. MSC-mediated inhibition of immune responses is a complex mechanism that involves almost every aspect of the immune response. MSCs suppress the maturation of antigen-presenting cells (DC and MQ), proliferation of T cells (Th1, T17, and Th2), proliferation and immunoglobulin production of B cells, the cytotoxic activity of CTL and NK cells in addition to increasing regulatory cytokines (TGF-β and IL10), and decreasing inflammatory cytokines (IL17, INF-ϒ, TNF-α, and IL12) levels. MSCs have shown encouraging results in the treatment of several autoimmune diseases, in particular SLE. This report aims to review the beneficial and therapeutic properties of MSCs; it also focuses on the results of animal model studies, preclinical studies, and clinical trials of MSC therapy in SLE from the immunoregulatory aspect.
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Affiliation(s)
| | - Mahmoud Mahmoudi
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Esmaeil Yazdanpanah
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahideh Keyvani
- Molecular Genetics, Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | - Nadia Kia
- Skin Cancer Prevention Research Center, Torvergata University of Medical Sciences, Rome, Italy
| | - Amin Reza Nikpoor
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Parisa Zafari
- Department of Immunology, School of Medicine, Mazandaran University of Medical Science, Sari, Iran.,Student Research Committee, Mazandaran University of Medical Science, Sari, Iran
| | - Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Abstract
Organ fibrosis is defined as a deregulated wound-healing process characterized by a progressive accumulation of fibrous tissue and by reduced remodeling that can lead to the loss of functionality of the affected organ. This pathological process is quite common in several parenchymal organs such as kidneys, liver, and lungs and represents a real health emergency in developed western countries since a real anti-fibrotic therapy is not yet available in most cases. Heparanase (HPSE), which is the enzyme that cuts off the side chains of heparan sulfate (HS) proteoglycan, appears to be involved in the aetiopathogenesis of fibrosis in all these organs, even if with different mechanisms. Here we discuss how the interplay between HPSE and components of the immune and inflammatory responses can activate recruitment, proliferation, and activation of myofibroblasts which represent the main cell type responsible for the deposition of fibrous matrix. Finally, bearing in mind that once the activity of HPSE is inhibited no other molecule is able to perform the same function, it is desirable that this enzyme could prove to be a suitable pharmacological target in anti-fibrotic therapy.
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Tang PCT, Zhang YY, Chan MKK, Lam WWY, Chung JYF, Kang W, To KF, Lan HY, Tang PMK. The Emerging Role of Innate Immunity in Chronic Kidney Diseases. Int J Mol Sci 2020; 21:ijms21114018. [PMID: 32512831 PMCID: PMC7312694 DOI: 10.3390/ijms21114018] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/28/2020] [Accepted: 06/02/2020] [Indexed: 12/12/2022] Open
Abstract
Renal fibrosis is a common fate of chronic kidney diseases. Emerging studies suggest that unsolved inflammation will progressively transit into tissue fibrosis that finally results in an irreversible end-stage renal disease (ESRD). Renal inflammation recruits and activates immunocytes, which largely promotes tissue scarring of the diseased kidney. Importantly, studies have suggested a crucial role of innate immunity in the pathologic basis of kidney diseases. This review provides an update of both clinical and experimental information, focused on how innate immune signaling contributes to renal fibrogenesis. A better understanding of the underlying mechanisms may uncover a novel therapeutic strategy for ESRD.
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Affiliation(s)
- Philip Chiu-Tsun Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China; (P.C.-T.T.); (M.K.-K.C.); (J.Y.-F.C.); (W.W.-Y.L.); (W.K.); (K.-F.T.)
| | - Ying-Ying Zhang
- Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China;
| | - Max Kam-Kwan Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China; (P.C.-T.T.); (M.K.-K.C.); (J.Y.-F.C.); (W.W.-Y.L.); (W.K.); (K.-F.T.)
| | - Winson Wing-Yin Lam
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China; (P.C.-T.T.); (M.K.-K.C.); (J.Y.-F.C.); (W.W.-Y.L.); (W.K.); (K.-F.T.)
| | - Jeff Yat-Fai Chung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China; (P.C.-T.T.); (M.K.-K.C.); (J.Y.-F.C.); (W.W.-Y.L.); (W.K.); (K.-F.T.)
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China; (P.C.-T.T.); (M.K.-K.C.); (J.Y.-F.C.); (W.W.-Y.L.); (W.K.); (K.-F.T.)
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China; (P.C.-T.T.); (M.K.-K.C.); (J.Y.-F.C.); (W.W.-Y.L.); (W.K.); (K.-F.T.)
| | - Hui-Yao Lan
- Li Ka Shing Institute of Health Sciences, and Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Hong Kong 999077, China;
| | - Patrick Ming-Kuen Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China; (P.C.-T.T.); (M.K.-K.C.); (J.Y.-F.C.); (W.W.-Y.L.); (W.K.); (K.-F.T.)
- Correspondence:
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Chang SH, Kim HJ, Park CG. Allogeneic ADSCs Induce the Production of Alloreactive Memory-CD8 T Cells through HLA-ABC Antigens. Cells 2020; 9:cells9051246. [PMID: 32443511 PMCID: PMC7290988 DOI: 10.3390/cells9051246] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/13/2020] [Accepted: 05/16/2020] [Indexed: 12/11/2022] Open
Abstract
We investigated the immunogenicity of allogeneic human adipose-derived mesenchymal stem cells (ADSCs) through the production of alloreactive-CD8 T and -memory CD8 T cells, based on their human leukocyte antigen (HLA) expression. In surface antigen analysis, ADSCs do not express co-stimulatory molecules, but expresses HLA-ABC, which is further increased by exposure to the pro-inflammatory cytokines as well as IFN-γ alone. For immunogenicity analysis, allogeneic ADSCs cultured in xenofree medium (XF-ADSCs) were incubated with the recipient immune cells for allogeneic-antigen stimulation. As a result, XF-ADSCs induced IFN-γ and IL-17A release by alloreactive-CD8 T cells and the production of alloreactive-CD8 T cell through a direct pathway, although they have immunomodulatory activity. In the analysis of alloreactive memory CD8 T cells, XF-ADSCs also significantly induced the production of CFSE-low-CD8 TEM and -CD8 TCM cells. However, HLA-blocking antibodies significantly inhibited the production of CFSE-low memory-CD8 T cells, indicating that HLAs are the main antigens responsible for the development of allogeneic ADSCs' immunogenicity. These results suggested that HLA surface antigens expressed in allogeneic MSCs should be solved in order to address concerns related to the immunogenicity problem.
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Affiliation(s)
- Sung-Ho Chang
- Departments of Oral Microbiology and Immunology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Korea;
| | - Hyun Je Kim
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea;
- Department of Dermatology, Samsung Medical Center, Seoul 06351, Korea
| | - Chung-Gyu Park
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Korea;
- Institute of Endemic Diseases, Medical Research center, Seoul National University College of Medicine, Seoul 03080, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea
- Correspondence: ; Tel.: +82-2-740-8308
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Wang H, Zhong J, Zhang C, Chai Z, Cao H, Wang J, Zhu J, Wang J, Ji Q. The whole-transcriptome landscape of muscle and adipose tissues reveals the ceRNA regulation network related to intramuscular fat deposition in yak. BMC Genomics 2020; 21:347. [PMID: 32381004 PMCID: PMC7203869 DOI: 10.1186/s12864-020-6757-z] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
Background The Intramuscular fat (IMF) content in meat products, which is positively correlated with meat quality, is an important trait considered by consumers. The regulation of IMF deposition is species specific. However, the IMF-deposition-related mRNA and non-coding RNA and their regulatory network in yak (Bos grunniens) remain unknown. High-throughput sequencing technology provides a powerful approach for analyzing the association between transcriptome-related differences and specific traits in animals. Thus, the whole transcriptomes of yak muscle and adipose tissues were screened and analyzed to elucidate the IMF deposition-related genes. The muscle tissues were used for IMF content measurements. Results Significant differences were observed between the 0.5- and 2.5-year-old yaks. Several mRNAs, miRNAs, lncRNAs and circRNAs were generally expressed in both muscle and adipose tissues. Between the 0.5- and 2.5-year-old yaks, 149 mRNAs, 62 miRNAs, 4 lncRNAs, and 223 circRNAs were differentially expressed in muscle tissue, and 72 mRNAs, 15 miRNAs, 9 lncRNAs, and 211 circRNAs were differentially expressed in adipose tissue. KEGG annotation revelved that these differentially expressed genes were related to pathways that maintain normal biological functions of muscle and adipose tissues. Moreover, 16 mRNAs, 5 miRNAs, 3 lncRNAs, and 5 circRNAs were co-differentially expressed in both types of tissue. We suspected that these co-differentially expressed genes were involved in IMF-deposition in the yak. Additionally, LPL, ACADL, SCD, and FASN, which were previously shown to be associated with the IMF content, were identified in the competing endogenous RNA (ceRNA) regulatory network that was constructed on the basis of the IMF deposition-related genes. Three ceRNA subnetworks also revealed that TCONS-00016416 and its target SIRT1 “talk” to each other through the same miR-381-y and miR-208 response elements, whereas TCONS-00061798 and its target PRKCA, and TCONS-00084092 and its target LPL “talk” to each other through miR-122-x and miR-499-y response elements, respectively. Conclusion Taken together, our results reveal the potential mRNA and noncoding RNAs involved in IMF deposition in the yak, providing a useful resource for further research on IMF deposition in this animal species.
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Affiliation(s)
- Hui Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province and Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China.,Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China
| | - Jincheng Zhong
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province and Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China. .,Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China.
| | - Chengfu Zhang
- State Key Laboratory of Hulless Barley and Yak Germplasm Resources and Genetic Improvement, the Tibet Academy of Agricultural and Animal Husbandry Science , Lhasa, Tibet, 850000, People's Republic of China
| | - Zhixin Chai
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province and Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China.,Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China
| | - Hanwen Cao
- State Key Laboratory of Hulless Barley and Yak Germplasm Resources and Genetic Improvement, the Tibet Academy of Agricultural and Animal Husbandry Science , Lhasa, Tibet, 850000, People's Republic of China
| | - Jikun Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province and Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China.,Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China
| | - Jiangjiang Zhu
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province and Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China.,Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China
| | - Jiabo Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Sichuan Province and Ministry of Education, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China.,Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Key Laboratory of Sichuan Province, Southwest Minzu University, Chengdu, Sichuan, 610041, People's Republic of China
| | - Qiumei Ji
- State Key Laboratory of Hulless Barley and Yak Germplasm Resources and Genetic Improvement, the Tibet Academy of Agricultural and Animal Husbandry Science , Lhasa, Tibet, 850000, People's Republic of China.
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Endometrial Mesenchymal Stem Cell-Derived Exosome Promote Endothelial Cell Angiogenesis in a Dose Dependent Manner: A New Perspective on Regenerative Medicine and Cell-Free Therapy. ARCHIVES OF NEUROSCIENCE 2019. [DOI: 10.5812/ans.94041] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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