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Duan Y, Zhao LJ, Lu YT, Li J, Li SX. Crosstalk between kidney and bones: New perspective for modulating osteoporosis. Ageing Res Rev 2025; 109:102776. [PMID: 40389172 DOI: 10.1016/j.arr.2025.102776] [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: 12/27/2024] [Revised: 05/09/2025] [Accepted: 05/16/2025] [Indexed: 05/21/2025]
Abstract
Growing evidence indicates an interesting interplay between kidney and bone. The pathophysiological condition of the skeletal system is intricately associated with the normal functioning of the kidneys. This relationship is modulated by various factors, including calcium and phosphate, 1-α-hydroxylase, erythropoietin (EPO), klotho, fibroblast growth factor 23 (FGF23), bone morphogenetic protein-7 (BMP-7), and extracellular vesicles (EVs). These interactions are notably evident in conditions such as chronic kidney disease with bone mineral density (CKD-BMD), renal osteodystrophy (ROD), and osteoporosis (OP). Furthermore, innovative methodologies such as cell co-culture, organ-on-a-chip, single-cell sequencing, and spatial transcriptomics are highlighted as instrumental in advancing the study of inter-organ interactions. This review, grounded in the pathogenesis, diagnostic and therapeutic modalities, and pharmacological treatments of OP, synthesizes evidence from molecular biology to clinical perspectives. It aims to establish a foundation for the development of more complex and physiologically relevant in vitro models and to propose potential therapeutic strategies.
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Affiliation(s)
- Yan Duan
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan 410208, PR China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan 410208, PR China
| | - Li-Juan Zhao
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan 410208, PR China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan 410208, PR China; College of Biology and Food Engineering, Huai Hua University, Huaihua 418000, PR China
| | - Yu-Ting Lu
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan 410208, PR China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan 410208, PR China; Department of Medicine, Guangxi University of Science and Technology, Liuzhou 545005, PR China
| | - Juan Li
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan 410208, PR China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan 410208, PR China.
| | - Shun-Xiang Li
- School of Pharmacy, Hunan University of Chinese Medicine, Changsha, Hunan 410208, PR China; Hunan Engineering Technology Research Center for Bioactive Substance Discovery of Chinese Medicine, Changsha, Hunan 410208, PR China; Hunan Province Sino-US International Joint Research Center for Therapeutic Drugs of Senile Degenerative Diseases, Changsha, Hunan 410208, PR China.
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2
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Bejoy J, Welch RC, Qian ES, Williams FM, Gibson-Corley KN, Wilson MH, Paragas N, Woodard LE. Urine-derived stem cells display homing, incorporation, and regeneration in human organoid and mouse models of acute kidney injury. Mol Ther 2025:S1525-0016(25)00219-9. [PMID: 40158205 DOI: 10.1016/j.ymthe.2025.03.044] [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: 06/27/2024] [Revised: 11/03/2024] [Accepted: 03/25/2025] [Indexed: 04/02/2025] Open
Abstract
Urine-derived stem cells (USCs) are adult human stem cells that can be collected noninvasively from urine and cultured in vitro. Because of their renal origin and reported therapeutic effects, we hypothesized that USCs would home to the injured kidney in acute kidney injury (AKI) models. We used mouse models of glycerol-induced rhabdomyolysis or unilateral nephrectomy with clamping ischemia reperfusion injury to model AKI. To track USC homing by live animal imaging, we administered luciferase-expressing (Luc) USCs to mice by intraperitoneal injection. We observed USC localization to both the tubules and glomeruli of injured mice within 3 h by histology. We confirmed the presence of Luc-USCs in the kidney at 3 h, 24 h, and 48 h after the injection using biodistribution analysis of quantitative bioluminescence tomography imaging. We performed immunostaining for kidney injury molecule-1 (KIM-1/HAVCR1/TIM-1) for kidney injury and found reduced expression in USC-treated group at 24 h after injection. To evaluate the effects of the human USCs on injured human nephrons, we injured human kidney organoids with the nephrotoxin cisplatin (5 μM) followed by 5 × 104 USC treatment. USCs were incorporated and lowered expression of KIM-1 in the organoids. USCs home to injured nephrons and reduce measures of kidney injury.
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Affiliation(s)
- Julie Bejoy
- Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Richard C Welch
- Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Eddie S Qian
- Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Felisha M Williams
- Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Katherine N Gibson-Corley
- Department of Medicine, Division of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Comparative Pathology and Research Histology, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Matthew H Wilson
- Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Nashville, TN 37212, USA; Departments of Pharmacology and Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232, USA
| | - Neal Paragas
- Department of Radiology, University of Washington, Seattle, WA 98109, USA
| | - Lauren E Woodard
- Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Veterans Affairs, Nashville, TN 37212, USA; Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232, USA.
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3
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Wang JJ, Zheng Y, Li YL, Xiao Y, Ren YY, Tian YQ. Emerging role of mesenchymal stem cell-derived exosomes in the repair of acute kidney injury. World J Stem Cells 2025; 17:103360. [PMID: 40160687 PMCID: PMC11947899 DOI: 10.4252/wjsc.v17.i3.103360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/26/2024] [Accepted: 02/13/2025] [Indexed: 03/21/2025] Open
Abstract
Acute kidney injury (AKI) is a clinical syndrome characterized by a rapid deterioration in kidney function and has a significant impact on patient health and survival. Mesenchymal stem cells (MSCs) have the potential to enhance renal function by suppressing the expression of cell cycle inhibitors and reducing the expression of senescence markers and microRNAs via paracrine and endocrine mechanisms. MSC-derived exosomes can alleviate AKI symptoms by regulating DNA damage, apoptosis, and other related signaling pathways through the delivery of proteins, microRNAs, long-chain noncoding RNAs, and circular RNAs. This technique is both safe and effective. MSC-derived exosomes may have great application prospects in the treatment of AKI. Understanding the underlying mechanisms will foster the development of new and promising therapeutic strategies against AKI. This review focused on recent advancements in the role of MSCs in AKI repair as well as the mechanisms underlying the role of MSCs and their secreted exosomes. It is anticipated that novel and profound insights into the functionality of MSCs and their derived exosomes will emerge.
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Affiliation(s)
- Juan-Juan Wang
- Clinical Laboratory, The First People's Hospital of Yancheng, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng 224000, Jiangsu Province, China
| | - Yu Zheng
- Clinical Laboratory, The First People's Hospital of Yancheng, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng 224000, Jiangsu Province, China
| | - Yan-Lin Li
- Clinical Laboratory, The First People's Hospital of Yancheng, Yancheng First Hospital, Affiliated Hospital of Nanjing University Medical School, Yancheng 224000, Jiangsu Province, China
| | - Yin Xiao
- Department of Medical Imaging, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou 221000, Jiangsu Province, China
| | - Yang-Yang Ren
- Clinical Laboratory, Xinyi People's Hospital, Xuzhou 221000, Jiangsu Province, China
| | - Yi-Qing Tian
- Clinical Laboratory, Xuzhou Central Hospital, Xuzhou 221000, Jiangsu Province, China.
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4
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Li J, Wu M, He L. Immunomodulatory effects of mesenchymal stem cell therapy in chronic kidney disease: a literature review. BMC Nephrol 2025; 26:107. [PMID: 40033224 PMCID: PMC11874639 DOI: 10.1186/s12882-025-04029-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/19/2025] [Indexed: 03/05/2025] Open
Abstract
Chronic kidney disease (CKD) has been a growing public medical concern in recent years which calls for effective interventions. Mesenchymal stem cells (MSCs) have garnered increased interest in past decades due to their potential to repair and regenerate damaged tissues. Many clinical trials have highlighted the safety and effectiveness of kidney disease with this novel cell therapy. MSC infusion can improve renal function indices such as glomerular filtration rate, urine protein, serum creatinine, and blood urea nitrogen, while inhibiting immune response by increasing regulatory T cells. The therapeutic mechanisms may be primarily attributed to a function combined with immunomodulation, anti-inflammation, anti-fibrosis, promoting angiogenesis, anti-oxidation, anti-apoptosis, or tissue healing produced by cell secretsome. However, CKD is a broad concept due to many pathological etiologies including diabetes, hypertension, heart disease, immunological damage, a family history of renal failure, and so on. Furthermore, the therapeutic efficacy of MSCs may be influenced by different cell sources, injection methods, medication dosage, or homing proportion. As a result, it is timely and essential to access recent advancements in the MSC application on CKD.
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Affiliation(s)
- Jipeng Li
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China
| | - Mengting Wu
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China
| | - Lijie He
- Department of Nephrology, Xijing Hospital, Air Force Medical University, Xi'an, Shaan Xi, China.
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Keate RL, Bury MI, Mendez-Santos M, Gerena A, Goedegebuure M, Rivnay J, Sharma AK, Ameer GA. Cell-free biodegradable electroactive scaffold for urinary bladder tissue regeneration. Nat Commun 2025; 16:11. [PMID: 39746994 PMCID: PMC11697025 DOI: 10.1038/s41467-024-55401-9] [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: 01/23/2024] [Accepted: 12/10/2024] [Indexed: 01/04/2025] Open
Abstract
Tissue engineering heavily relies on cell-seeded scaffolds to support the complex biological and mechanical requirements of a target organ. However, in addition to safety and efficacy, translation of tissue engineering technology will depend on manufacturability, affordability, and ease of adoption. Therefore, there is a need to develop scalable biomaterial scaffolds with sufficient bioactivity to eliminate the need for exogenous cell seeding. Herein, we describe implementation of an electroactive biodegradable elastomer for urinary bladder tissue engineering. To create an electrically conductive and mechanically robust scaffold to support bladder tissue regeneration, we develop a functionalization method wherein the hydrophobic conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) is polymerized in situ within a similarly hydrophobic citrate-based elastomer poly(octamethylene-citrate-co-octanol) (POCO) film. We demonstrate the efficacy of this scaffold for bladder augmentation in primarily female athymic rats, comparing PEDOT-POCO scaffolds to mesenchymal stromal cell-seeded POCO scaffolds. PEDOT-POCO recovers bladder function and anatomical structure comparably to the cell-seeded POCO scaffolds and significantly better than non-cell-seeded POCO scaffolds. This manuscript reports a functionalization method that confers electroactivity to a biodegradable elastic scaffold, facilitating the successful restoration of anatomical and physiological function of an organ.
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Affiliation(s)
- Rebecca L Keate
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA
| | - Matthew I Bury
- Division of Pediatric Urology, Department of Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
- Stanley Manne Children's Research Institute, Louis A. Simpson and Kimberly K. Querrey Biomedical Research Center, Chicago, IL, USA
| | - Maria Mendez-Santos
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA
| | - Andres Gerena
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA
| | - Madeleine Goedegebuure
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA
| | - Jonathan Rivnay
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA
- Center for Regenerative Nanomedicine, Northwestern University, Chicago, IL, USA
- Department of Materials Science, Northwestern University, Evanston, IL, USA
- Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA
- Chemistry Life Processes Institute, Northwestern University, Evanston, IL, USA
- International Institute for Nanotechnology, Evanston, IL, USA
| | - Arun K Sharma
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA
- Division of Pediatric Urology, Department of Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA
- Stanley Manne Children's Research Institute, Louis A. Simpson and Kimberly K. Querrey Biomedical Research Center, Chicago, IL, USA
- Center for Regenerative Nanomedicine, Northwestern University, Chicago, IL, USA
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Guillermo A Ameer
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
- Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA.
- Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA.
- Chemistry Life Processes Institute, Northwestern University, Evanston, IL, USA.
- International Institute for Nanotechnology, Evanston, IL, USA.
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
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Ohtake T, Sato T, Tsukiyama T, Muraoka S, Mitomo A, Maruyama H, Yamano M, Mochida Y, Ishioka K, Oka M, Moriya H, Hidaka S, Masuda H, Asahara T, Kobayashi S. Preliminary evidence of renal function improvement in chronic progressive kidney disease using autologous CD34 + cell therapy: A clinical trial. World J Stem Cells 2024; 16:1012-1021. [PMID: 39734483 PMCID: PMC11669983 DOI: 10.4252/wjsc.v16.i12.1012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 10/08/2024] [Accepted: 11/12/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND To date, no specific treatment has been established to reverse progressive chronic kidney disease (CKD). AIM To evaluate the safety and efficacy of autologous CD34+ cell transplantation in CKD patients who exhibited a progressive decline in renal function. METHODS The estimated glomerular filtration rate (eGFR) at the beginning of the study was 15.0-28.0 mL/minute/1.73 m2. After five days of treatment with the granulocyte colony-stimulating factor, mononuclear cells were harvested and CD34+ cells were magnetically collected. CD34+ cells were directly injected into the bilateral renal arteries twice (at 0 and 3 months), and their safety and efficacy were evaluated for 6 months. RESULTS Four patients were enrolled and completed the study. Three of four patients showed improvement in eGFR slope (eGFR slope > 0 mL/minute/1.73 m2), with the monthly slope of eGFR (delta eGFR) changing from -1.36 ± 1.1 (pretreatment) to +0.22 ± 0.71 (at 6 months) mL/minute/1.73 m2/month (P = 0.135) after cell therapy. Additionally, intrarenal resistive index (P = 0.004) and shear wave velocity (P = 0.04) were significantly improved after cell therapy. One patient experienced transient fever after cell therapy, and experienced bone pain during granulocyte colony-stimulating factor administration. However, no severe adverse events were reported. CONCLUSION In conclusion, our findings suggest that repetitive peripheral blood-derived autologous CD34+ cell transplantation into the renal arteries is safe, feasible, and may be effective for patients with progressive CKD. However, a large-scale clinical trial is warranted to validate the efficacy of repetitive regenerative cell therapy using autologous CD34+ cells in patients with progressive CKD.
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Affiliation(s)
- Takayasu Ohtake
- Regenerative Medicine, The Center for Cell Therapy & Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan.
| | - Tsutomu Sato
- Clinical Laboratory, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Toshitaka Tsukiyama
- Department of Radiology and Interventional Radiology, Shonan Kamakura General Hospital, Kamakura 247-8533, Japan
| | - Suguru Muraoka
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Ayaka Mitomo
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Haruka Maruyama
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Mizuki Yamano
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Yasuhiro Mochida
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Kunihiro Ishioka
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Machiko Oka
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Hidekazu Moriya
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Sumi Hidaka
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Haruchika Masuda
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Takayuki Asahara
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Shuzo Kobayashi
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
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7
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Hejazian SM, Hejazian SS, Mostafavi SM, Hosseiniyan SM, Montazersaheb S, Ardalan M, Zununi Vahed S, Barzegari A. Targeting cellular senescence in kidney diseases and aging: A focus on mesenchymal stem cells and their paracrine factors. Cell Commun Signal 2024; 22:609. [PMID: 39696575 DOI: 10.1186/s12964-024-01968-1] [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: 09/15/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024] Open
Abstract
Cellular senescence is a phenomenon distinguished by the halting of cellular division, typically triggered by DNA injury or numerous stress-inducing factors. Cellular senescence is implicated in various pathological and physiological processes and is a hallmark of aging. The presence of accumulated senescent cells, whether transiently (acute senescence) or persistently (chronic senescence) plays a dual role in various conditions such as natural kidney aging and different kidney disorders. Elevations in senescent cells and senescence-associated secretory phenotype (SASP) levels correlate with decreased kidney function, kidney ailments, and age-related conditions. Strategies involving senotherapeutic agents like senolytics, senomorphics, and senoinflammation have been devised to specifically target senescent cells. Mesenchymal stem cells (MSCs) and their secreted factors may also offer alternative approaches for anti-senescence interventions. The MSC-derived secretome compromises significant therapeutic benefits in kidney diseases by facilitating tissue repair via anti-inflammatory, anti-fibrosis, anti-apoptotic, and pro-angiogenesis effects, thereby improving kidney function and mitigating disease progression. Moreover, by promoting the clearance of senescent cells or modulating their secretory profiles, MSCs could potentially reverse some age-related declines in kidney function.This review article intends to shed light on the present discoveries concerning the role of cellular senescence in kidney aging and diseases. Furthermore, it outlines the role of senotherapeutics utilized to alleviate kidney damage and aging. It also highlights the possible impact of MSCs secretome on mitigating kidney injury and prolonging lifespan across various models of kidney diseases as a novel senotherapy.
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Affiliation(s)
| | - Seyyed Sina Hejazian
- Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Seyyedeh Mina Mostafavi
- Ayatollah Taleghani Hospital, Research Development Unit, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Soheila Montazersaheb
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Abolfazl Barzegari
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wang Y, Luo P, Wuren T. Narrative Review of Mesenchymal Stem Cell Therapy in Renal Diseases: Mechanisms, Clinical Applications, and Future Directions. Stem Cells Int 2024; 2024:8658246. [PMID: 39698513 PMCID: PMC11655143 DOI: 10.1155/sci/8658246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 11/27/2024] [Indexed: 12/20/2024] Open
Abstract
Renal diseases, particularly acute kidney injury (AKI) and chronic kidney disease (CKD), are significant global health challenges. These conditions impair kidney function and can lead to serious complications, including cardiovascular diseases, which further exacerbate the public health burden. Currently, the global AKI mortality rate is alarmingly high (20%-50%); CKD is projected to emerge as a major global health burden by 2040. Existing treatments such as hemodialysis and kidney transplantation have limited effectiveness and are often associated with adverse effects. Mesenchymal stem cells (MSCs) offer considerable potential for treating renal diseases owing to their regenerative and immunomodulatory properties. Thus, this review focuses on the application of MSCs in renal disease, discusses fundamental research findings, and evaluates their application in clinical trials. Moreover, we discuss the impact and safety of MSCs as a therapeutic option and highlight challenges and potential directions for their clinical application. We selected research articles from PubMed published within the last 5 years (from 2019), focusing on high-impact journals and clinical trial data, and included a few key studies predating 2019. Considerations included the novelty of the research, sample size, experimental design, and data reliability. With advancements in single-cell sequencing, CRISPR/Cas9 gene editing, and other cutting-edge technologies, future MSC research will explore combination therapies and personalized treatments to provide more promising, safer treatments with reduced adverse reactions and enhanced therapeutic outcomes. These advances will improve kidney disease treatment methods, enhance patient quality of life, and maximize the benefits of MSC therapies.
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Affiliation(s)
- Yanjun Wang
- Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China
- High-Altitude Medicine Key Laboratory of the Ministry of Education, Xining 810001, China
- Qinghai Provincial Key Laboratory for Application of High-Altitude Medicine (Qinghai-Utah Joint Key Laboratory for Plateau Medicine), Xining 810001, China
- Nephrology Department, Affiliated Hospital of Qinghai University, Xining 810001, China
| | - Pengli Luo
- Nephrology Department, Affiliated Hospital of Qinghai University, Xining 810001, China
| | - Tana Wuren
- Research Center for High Altitude Medicine, Qinghai University, Xining 810001, China
- High-Altitude Medicine Key Laboratory of the Ministry of Education, Xining 810001, China
- Qinghai Provincial Key Laboratory for Application of High-Altitude Medicine (Qinghai-Utah Joint Key Laboratory for Plateau Medicine), Xining 810001, China
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9
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Salybekov AA, Kinzhebay A, Kobayashi S. Cell therapy in kidney diseases: advancing treatments for renal regeneration. Front Cell Dev Biol 2024; 12:1505601. [PMID: 39723242 PMCID: PMC11669058 DOI: 10.3389/fcell.2024.1505601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 11/13/2024] [Indexed: 12/28/2024] Open
Abstract
Kidney diseases, including acute kidney injury (AKI) and chronic kidney disease (CKD), pose a significant global health challenge, with high morbidity and mortality rates driven by rising prevalence of risk factors such as diabetes and hypertension. Current therapeutic strategies are often limited, prompting the exploration of advanced cell therapies as potential solutions. This review provides a comprehensive overview of the state of cell therapies in kidney disease, tracing the progression from preclinical studies to clinical applications. Recent studies highlited that cell-based interventions offer kidney-protective properties through mechanisms such as paracrine signaling, immune modulation, and direct tissue integration, demonstrating potential in both AKI and CKD settings. Despite promising results, challenges remain in optimizing cell therapy protocols, including cell sourcing, delivery methods, and long-term outcomes. Finally, the review addresses on efforts to enhance cell function, optimize dosing, and refine delivery techniques to improve clinical outcomes in kidney disease management.
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Affiliation(s)
- Amankeldi A. Salybekov
- Qazaq Institute of Innovative Medicine, Regenerative Medicine Division, Cell and Gene Therapy Department, Astana, Kazakhstan
| | - Aiman Kinzhebay
- Qazaq Institute of Innovative Medicine, Regenerative Medicine Division, Cell and Gene Therapy Department, Astana, Kazakhstan
| | - Shuzo Kobayashi
- Kidney Diseases and Transplant Center, Shonan Kamakura General Hospital, Kamakura, Japan
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10
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Tanaka A, Furuhashi K, Fujieda K, Horinouchi A, Maeda K, Saito S, Mimura T, Saka Y, Naruse T, Ishimoto T, Kato N, Kosugi T, Kinoshita F, Kuwatsuka Y, Nakai Y, Maruyama S. Safety and Tolerability of Adipose-Derived Mesenchymal Stem Cell (ADR-001) Therapy for IgA Nephropathy. KIDNEY360 2024; 5:1692-1705. [PMID: 39186380 DOI: 10.34067/kid.0000000000000563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 08/20/2024] [Indexed: 08/28/2024]
Abstract
Key Points
IgA nephropathy often requires KRT.Mesenchymal stem cells offer clinical benefits.Adipose-derived mesenchymal stem cells are safe and tolerable.
Background
IgA nephropathy (IgAN) often requires KRT because of its refractoriness and because corticosteroids pose infection risks. However, mesenchymal stem cells offer clinical benefits because of their regenerative and immunomodulatory properties. This prospective clinical trial assessed the safety and tolerability of adipose-derived mesenchymal stem cell (ASC) therapy and evaluated its therapeutic efficacy.
Methods
This phase 1 study included adult patients with refractory IgAN that was difficult to treat with traditional therapies. ASC therapy comprising one intravenous dose of 1×108 cells was administered to three to six patients in Cohort 1. The same intravenous dose was administered twice with a 2-week interval to six patients in Cohort 2. Heparin was administered simultaneously. This study continued for 52 weeks, and the primary end points were safety and tolerability during the 6-week period after treatment administration. Secondary end points included adverse events and efficacy measures such as clinical remission, partial remission, urine protein remission, hematuria remission, time to remission, changes in the urine protein and hematuria levels, and changes in the eGFR.
Results
The three patients in Cohort 1 and six patients in Cohort 2 who received ASC therapy achieved the primary end points. No severe adverse clinical events were observed. Therefore, the safety and tolerability of ASCs were confirmed. Improvements, such as significantly decreased kidney damage markers and urinary protein levels, were observed immediately after ASC administration.
Conclusions
The safety and tolerability of ASCs are acceptable for patients with IgAN.
Clinical Trial registry name and registration number:
This trial was registered with the Japan Registry of Clinical Trials (jRCT2043200002; registration date: April 14, 2020) and ClinicalTrials.gov (NCT04342325; registration date: April 13, 2020).
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Affiliation(s)
- Akihito Tanaka
- Department of Nephrology, Nagoya University Hospital, Nagoya, Japan
| | | | - Kumiko Fujieda
- Department of Nephrology, Nagoya University Hospital, Nagoya, Japan
| | - Asuka Horinouchi
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kayaho Maeda
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Shoji Saito
- Department of Nephrology, Nagoya University Hospital, Nagoya, Japan
| | - Tetsushi Mimura
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Yosuke Saka
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Tomohiko Naruse
- Department of Nephrology, Kasugai Municipal Hospital, Kasugai, Japan
| | - Takuji Ishimoto
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Noritoshi Kato
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoki Kosugi
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Fumie Kinoshita
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Yachiyo Kuwatsuka
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Yasuhiro Nakai
- Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Nagoya, Japan
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11
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Rostami M, Farahani P, Esmaelian S, Bahman Z, Fadel Hussein A, A Alrikabi H, Hosseini Hooshiar M, Yasamineh S. The Role of Dental-derived Stem Cell-based Therapy and Their Derived Extracellular Vesicles in Post-COVID-19 Syndrome-induced Tissue Damage. Stem Cell Rev Rep 2024; 20:2062-2103. [PMID: 39150646 DOI: 10.1007/s12015-024-10770-y] [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] [Accepted: 08/02/2024] [Indexed: 08/17/2024]
Abstract
Long coronavirus disease 2019 (COVID-19) is linked to an increased risk of post-acute sequelae affecting the pulmonary and extrapulmonary organ systems. Up to 20% of COVID-19 patients may proceed to a more serious form, such as severe pneumonia, acute respiratory distress syndrome (ARDS), or pulmonary fibrosis. Still, the majority of patients may only have mild, self-limiting sickness. Of particular concern is the possibility of parenchymal fibrosis and lung dysfunction in long-term COVID-19 patients. Furthermore, it has been observed that up to 43% of individuals hospitalized with COVID-19 also had acute renal injury (AKI). Care for kidney, brain, lung, cardiovascular, liver, ocular, and tissue injuries should be included in post-acute COVID-19 treatment. As a powerful immunomodulatory tool in regenerative medicine, dental stem cells (DSCs) have drawn much interest. Numerous immune cells and cytokines are involved in the excessive inflammatory response, which also has a significant effect on tissue regeneration. A unique reservoir of stem cells (SCs) for treating acute lung injury (ALI), liver damage, neurological diseases, cardiovascular issues, and renal damage may be found in tooth tissue, according to much research. Moreover, a growing corpus of in vivo research is connecting DSC-derived extracellular vesicles (DSC-EVs), which are essential paracrine effectors, to the beneficial effects of DSCs. DSC-EVs, which contain bioactive components and therapeutic potential in certain disorders, have been shown as potentially effective therapies for tissue damage after COVID-19. Consequently, we explore the properties of DSCs in this work. Next, we'll look at how SARS-CoV-2 affects tissue damage. Lastly, we have looked at the use of DSCs and DSC-EVs in managing COVID-19 and chronic tissue damage, such as injury to the heart, brain, lung, and other tissues.
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Affiliation(s)
- Mitra Rostami
- School of Dentistry, Tehran University of Medical Sciences, Tehran, Iran
| | - Pouria Farahani
- Doctor of Dental Surgery, Faculty of Dentistry, Shahid Beheshti University of Medical Science, Tehran, Iran
| | - Samar Esmaelian
- Faculty of Dentistry, Islamic Azad University, Tehran Branch, Tehran, Iran
| | - Zahra Bahman
- Faculty of dentistry, Belarusian state medical university, Minsk, Belarus
| | | | - Hareth A Alrikabi
- Collage of Dentist, National University of Science and Technology, Dhi Qar, 64001, Iraq
| | | | - Saman Yasamineh
- Young Researchers and Elite Club, Tabriz Branch, Islamic Azad University, Tabriz, Iran.
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12
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Li Y, Hunter A, Wakeel MM, Sun G, Lau RWK, Broughton BRS, Pino IEO, Deng Z, Zhang T, Murthi P, Del Borgo MP, Widdop RE, Polo JM, Ricardo SD, Samuel CS. The renoprotective efficacy and safety of genetically-engineered human bone marrow-derived mesenchymal stromal cells expressing anti-fibrotic cargo. Stem Cell Res Ther 2024; 15:375. [PMID: 39443975 PMCID: PMC11515549 DOI: 10.1186/s13287-024-03992-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 10/09/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Kidney fibrosis is a hallmark of chronic kidney disease (CKD) and compromises the viability of transplanted human bone marrow-derived mesenchymal stromal cells (BM-MSCs). Hence, BM-MSCs were genetically-engineered to express the anti-fibrotic and renoprotective hormone, human relaxin-2 (RLX) and green fluorescent protein (BM-MSCs-eRLX + GFP), which enabled BM-MSCs-eRLX + GFP delivery via a single intravenous injection. METHODS BM-MSCs were lentiviral-transduced with human relaxin-2 cDNA and GFP, under a eukaryotic translation elongation factor-1α promoter (BM-MSCs-eRLX + GFP) or GFP alone (BM-MSCs-eGFP). The ability of BM-MSCs-eRLX + GFP to differentiate, proliferate, migrate, produce RLX and cytokines was evaluated in vitro, whilst BM-MSC-eRLX + GFP vs BM-MSCs-eGFP homing to the injured kidney and renoprotective effects were evaluated in preclinical models of ischemia reperfusion injury (IRI) and high salt (HS)-induced hypertensive CKD in vivo. The long-term safety of BM-MSCs-RLX + GFP was also determined 9-months after treatment cessation in vivo. RESULTS When cultured for 3- or 7-days in vitro, 1 × 106 BM-MSCs-eRLX + GFP produced therapeutic RLX levels, and secreted an enhanced but finely-tuned cytokine profile without compromising their proliferation or differentiation capacity compared to naïve BM-MSCs. BM-MSCs-eRLX + GFP were identified in the kidney 2-weeks post-administration and retained the therapeutic effects of RLX in vivo. 1-2 × 106 BM-MSCs-eRLX + GFP attenuated the IRI- or therapeutically abrogated the HS-induced tubular epithelial damage and interstitial fibrosis, and significantly reduced the HS-induced hypertension, glomerulosclerosis and proteinuria. This was to an equivalent extent as RLX and BM-MSCs administered separately but to a broader extent than BM-MSCs-eGFP or the angiotensin-converting enzyme inhibitor, perindopril. Additionally, these renoprotective effects of BM-MSCs-eRLX + GFP were maintained in the presence of perindopril co-treatment, highlighting their suitability as adjunct therapies to ACE inhibition. Importantly, no major long-term adverse effects of BM-MSCs-eRLX + GFP were observed. CONCLUSIONS BM-MSCs-eRLX + GFP produced greater renoprotective and therapeutic efficacy over that of BM-MSCs-eGFP or ACE inhibition, and may represent a novel and safe treatment option for acute kidney injury and hypertensive CKD.
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Affiliation(s)
- Yifang Li
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Alex Hunter
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Miqdad M Wakeel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Guizhi Sun
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia
| | - Ricky W K Lau
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Brad R S Broughton
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Ivan E Oyarce Pino
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Zihao Deng
- Department of Medicine (Alfred Hospital), Central Clinical School, Monash University, Melbourne, VIC, 3004, Australia
| | - Tingfang Zhang
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Padma Murthi
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Mark P Del Borgo
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Robert E Widdop
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia
| | - Jose M Polo
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia
- Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia
- Adelaide Centre for Epigenetics, School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia
- The South Australian Immunogenomics Cancer Institute, The University of Adelaide, Adelaide, SA, 5005, Australia
| | - Sharon D Ricardo
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.
| | - Chrishan S Samuel
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
- Development and Stem Cells Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia.
- Department of Pharmacology, Monash University, Clayton, VIC, 3800, Australia.
- Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC, 3010, Australia.
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Pharoun J, Berro J, Sobh J, Abou-Younes MM, Nasr L, Majed A, Khalil A, Joseph, Stephan, Faour WH. Mesenchymal stem cells biological and biotechnological advances: Implications for clinical applications. Eur J Pharmacol 2024; 977:176719. [PMID: 38849038 DOI: 10.1016/j.ejphar.2024.176719] [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: 01/30/2024] [Revised: 05/31/2024] [Accepted: 06/05/2024] [Indexed: 06/09/2024]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to differentiate into multiple lineages including bone, cartilage, muscle and fat. They hold immunomodulatory properties and therapeutic ability to treat multiple diseases, including autoimmune and chronic degenerative diseases. In this article, we reviewed the different biological properties, applications and clinical trials of MSCs. Also, we discussed the basics of manufacturing conditions, quality control, and challenges facing MSCs in the clinical setting. METHODS Extensive review of the literature was conducted through the databases PubMed, Google Scholar, and Cochrane. Papers published since 2015 and covering the clinical applications and research of MSC therapy were considered. Furthermore, older papers were considered when referring to pioneering studies in the field. RESULTS The most widely studied stem cells in cell therapy and tissue repair are bone marrow-derived mesenchymal stem cells. Adipose tissue-derived stem cells became more common and to a lesser extent other stem cell sources e.g., foreskin derived MSCs. MSCs therapy were also studied in the setting of COVID-19 infections, ischemic strokes, autoimmune diseases, tumor development and graft rejection. Multiple obstacles, still face the standardization and optimization of MSC therapy such as the survival and the immunophenotype and the efficiency of transplanted cells. MSCs used in clinical settings displayed heterogeneity in their function despite their extraction from healthy donors and expression of similar surface markers. CONCLUSION Mesenchymal stem cells offer a rising therapeutic promise in various diseases. However, their potential use in clinical applications requires further investigation.
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Affiliation(s)
- Jana Pharoun
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Jana Berro
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Jeanine Sobh
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | | | - Leah Nasr
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Ali Majed
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Alia Khalil
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Joseph
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Stephan
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36
| | - Wissam H Faour
- Gilbert & Rose-Marie Chagoury School of Medicine, LAU, Byblos, Lebanon, P.O. Box 36.
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14
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Gabr MM, El-Halawani SM, Refaie AF, Khater SM, Ismail AM, Karras MS, Magar RW, Sayed SE, Kloc M, Uosef A, Sabek OM, Ghoneim MA. Modulation of naïve mesenchymal stromal cells by extracellular vesicles derived from insulin-producing cells: an in vitro study. Sci Rep 2024; 14:17844. [PMID: 39090166 PMCID: PMC11294623 DOI: 10.1038/s41598-024-68104-4] [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: 05/11/2024] [Accepted: 07/19/2024] [Indexed: 08/04/2024] Open
Abstract
This study was to determine whether extracellular vesicles (EVs) derived from insulin-producing cells (IPCs) can modulate naïve mesenchymal stromal cells (MSCs) to become insulin-secreting. MSCs were isolated from human adipose tissue. The cells were then differentiated to generate IPCs by achemical-based induction protocol. EVs were retrieved from the conditioned media of undifferentiated (naïve) MSCs (uneducated EVs) and from that of MSC-derived IPCs (educated EVs) by sequential ultracentrifugation. The obtained EVs were co-cultured with naïve MSCs.The cocultured cells were evaluated by immunofluorescence, flow cytometry, C-peptide nanogold silver-enhanced immunostaining, relative gene expression and their response to a glucose challenge.Immunostaining for naïve MSCs cocultured with educated EVs was positive for insulin, C-peptide, and GAD65. By flow cytometry, the median percentages of insulin-andC-peptide-positive cells were 16.1% and 14.2% respectively. C-peptide nanogoldimmunostaining providedevidence for the intrinsic synthesis of C-peptide. These cells released increasing amounts of insulin and C-peptide in response to increasing glucose concentrations. Gene expression of relevant pancreatic endocrine genes, except for insulin, was modest. In contrast, the results of naïve MSCs co-cultured with uneducated exosomes were negative for insulin, C-peptide, and GAD65. These findings suggest that this approach may overcome the limitations of cell therapy.
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Affiliation(s)
- Mahmoud M Gabr
- Biotechnology Department, Urology and Nephrology Center, Mansoura, Egypt
| | | | - Ayman F Refaie
- Nephrology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Sherry M Khater
- Pathology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Amani M Ismail
- Immunology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Mary S Karras
- Immunology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Raghda W Magar
- Immunology Department, Urology and Nephrology Center, Mansoura, Egypt
| | - Shorouk El Sayed
- Microbiology Department, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Malgorzata Kloc
- The Houston Methodist Research Institute, Houston, TX, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
- Department of Genetics, MD Anderson Cancer Center, University of Texas, Houston, TX, USA
| | - Ahmed Uosef
- The Houston Methodist Research Institute, Houston, TX, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - Omaima M Sabek
- The Houston Methodist Research Institute, Houston, TX, USA
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
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Slaats GG, Chen J, Levtchenko E, Verhaar MC, Arcolino FO. Advances and potential of regenerative medicine in pediatric nephrology. Pediatr Nephrol 2024; 39:383-395. [PMID: 37400705 PMCID: PMC10728238 DOI: 10.1007/s00467-023-06039-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/28/2023] [Accepted: 05/04/2023] [Indexed: 07/05/2023]
Abstract
The endogenous capacity of the kidney to repair is limited, and generation of new nephrons after injury for adequate function recovery remains a need. Discovery of factors that promote the endogenous regenerative capacity of the injured kidney or generation of transplantable kidney tissue represent promising therapeutic strategies. While several encouraging results are obtained after administration of stem or progenitor cells, stem cell secretome, or extracellular vesicles in experimental kidney injury models, very little data exist in the clinical setting to make conclusions about their efficacy. In this review, we provide an overview of the cutting-edge knowledge on kidney regeneration, including pre-clinical methodologies used to elucidate regenerative pathways and describe the perspectives of regenerative medicine for kidney patients.
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Affiliation(s)
- Gisela G Slaats
- Department of Nephrology and Hypertension, Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Junyu Chen
- Department of Development and Regeneration, Cluster Woman and Child, Laboratory of Pediatric Nephrology, KU Leuven, Leuven, Belgium
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Elena Levtchenko
- Department of Development and Regeneration, Cluster Woman and Child, Laboratory of Pediatric Nephrology, KU Leuven, Leuven, Belgium
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, Regenerative Medicine Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Fanny Oliveira Arcolino
- Department of Development and Regeneration, Cluster Woman and Child, Laboratory of Pediatric Nephrology, KU Leuven, Leuven, Belgium.
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands.
- Emma Center for Personalized Medicine, Amsterdam University Medical Centers, 1105 AZ, Amsterdam, The Netherlands.
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Ameer G, Keate R, Bury M, Mendez-Santos M, Gerena A, Goedegebuure M, Rivnay J, Sharma A. Cell-free biodegradable electroactive scaffold for urinary bladder regeneration. RESEARCH SQUARE 2024:rs.3.rs-3817836. [PMID: 38352487 PMCID: PMC10862962 DOI: 10.21203/rs.3.rs-3817836/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/21/2024]
Abstract
Tissue engineering heavily relies on cell-seeded scaffolds to support the complex biological and mechanical requirements of a target organ. However, in addition to safety and efficacy, translation of tissue engineering technology will depend on manufacturability, affordability, and ease of adoption. Therefore, there is a need to develop scalable biomaterial scaffolds with sufficient bioactivity to eliminate the need for exogenous cell seeding. Herein, we describe synthesis, characterization, and implementation of an electroactive biodegradable elastomer for urinary bladder tissue engineering. To create an electrically conductive and mechanically robust scaffold to support bladder tissue regeneration, we developed a phase-compatible functionalization method wherein the hydrophobic conductive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) was polymerized in situ within a similarly hydrophobic citrate-based elastomer poly(octamethylene-citrate-co-octanol) (POCO) film. We demonstrate the efficacy of this film as a scaffold for bladder augmentation in athymic rats, comparing PEDOT-POCO scaffolds to mesenchymal stromal cell-seeded POCO scaffolds. PEDOT-POCO recovered bladder function and anatomical structure comparably to the cell-seeded POCO scaffolds and significantly better than non-cell seeded POCO scaffolds. This manuscript reports: (1) a new phase-compatible functionalization method that confers electroactivity to a biodegradable elastic scaffold, and (2) the successful restoration of the anatomy and function of an organ using a cell-free electroactive scaffold.
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17
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Lindoso RS, Collino F, Kasai-Brunswick TH, Costa MR, Verdoorn KS, Einicker-Lamas M, Vieira-Beiral HJ, Wessely O, Vieyra A. Resident Stem Cells in Kidney Tissue. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:159-203. [DOI: 10.1016/b978-0-443-15289-4.00009-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Wang Y, Gao T, Wang B. Application of mesenchymal stem cells for anti-senescence and clinical challenges. Stem Cell Res Ther 2023; 14:260. [PMID: 37726805 PMCID: PMC10510299 DOI: 10.1186/s13287-023-03497-z] [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: 07/25/2023] [Accepted: 09/13/2023] [Indexed: 09/21/2023] Open
Abstract
Senescence is a hot topic nowadays, which shows the accumulation of senescent cells and inflammatory factors, leading to the occurrence of various senescence-related diseases. Although some methods have been identified to partly delay senescence, such as strengthening exercise, restricting diet, and some drugs, these only slow down the process of senescence and cannot fundamentally delay or even reverse senescence. Stem cell-based therapy is expected to be a potential effective way to alleviate or cure senescence-related disorders in the coming future. Mesenchymal stromal cells (MSCs) are the most widely used cell type in treating various diseases due to their potentials of self-replication and multidirectional differentiation, paracrine action, and immunoregulatory effects. Some biological characteristics of MSCs can be well targeted at the pathological features of aging. Therefore, MSC-based therapy is also a promising strategy to combat senescence-related diseases. Here we review the recent progresses of MSC-based therapies in the research of age-related diseases and the challenges in clinical application, proving further insight and reference for broad application prospects of MSCs in effectively combating senesce in the future.
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Affiliation(s)
- Yaping Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
- Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China
| | - Tianyun Gao
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People's Republic of China.
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Ohtake T, Itaba S, Salybekov AA, Sheng Y, Sato T, Yanai M, Imagawa M, Fujii S, Kumagai H, Harata M, Asahara T, Kobayashi S. Repetitive administration of cultured human CD34+ cells improve adenine-induced kidney injury in mice. World J Stem Cells 2023; 15:268-280. [PMID: 37181001 PMCID: PMC10173816 DOI: 10.4252/wjsc.v15.i4.268] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/24/2023] [Accepted: 03/21/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease (CKD).
AIM To examine the efficacy of cultured human CD34+ cells with enhanced proliferating potential in kidney injury in mice.
METHODS Human umbilical cord blood (UCB)-derived CD34+ cells were incubated for one week in vasculogenic conditioning medium. Vasculogenic culture significantly increased the number of CD34+ cells and their ability to form endothelial progenitor cell colony-forming units. Adenine-induced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice, and cultured human UCB-CD34+ cells were administered at a dose of 1 × 106/mouse on days 7, 14, and 21 after the start of adenine diet.
RESULTS Repetitive administration of cultured UCB-CD34+ cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group. Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group (P < 0.01). Microvasculature integrity was significantly preserved (P < 0.01) and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group (P < 0.001).
CONCLUSION Early intervention using human cultured CD34+ cells significantly improved the progression of tubulointerstitial kidney injury. Repetitive administration of cultured human UCB-CD34+ cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.
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Affiliation(s)
- Takayasu Ohtake
- Regenerative Medicine, The Center for Cell Therapy & Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Kidney Disease and Transplant center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Shoichi Itaba
- Kamakura Techno-science Inc., Kamakura 248-0036, Japan
| | - Amankeldi A Salybekov
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Yin Sheng
- Advanced Medicine Science, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Tsutomu Sato
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
| | - Mitsuru Yanai
- Department of Pathology, Sapporo Tokushukai Hospital, Sapporo 004-0041, Japan
| | - Makoto Imagawa
- Department of Pathology, Sapporo Medical Center, Sapporo 004-0041, Japan
| | - Shigeo Fujii
- Kamakura Techno-science Inc., Kamakura 248-0036, Japan
| | | | | | - Takayuki Asahara
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
- Cell Processing and Cell/Genome Analysis Center, The Center for Cell Therapy & Regenerative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanagawa, Japan
| | - Shuzo Kobayashi
- Regenerative Medicine, Shonan Research Institute of Innovative Medicine, Kamakura 247-8533, Kanagawa, Japan
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, Kamakura 247-8533, Kanazawa, Japan
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20
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Oka M, Kameishi S, Cho YK, Song SU, Grainger DW, Okano T. Clinically Relevant Mesenchymal Stem/Stromal Cell Sheet Transplantation Method for Kidney Disease. Tissue Eng Part C Methods 2023; 29:54-62. [PMID: 36719774 DOI: 10.1089/ten.tec.2022.0200] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Chronic kidney disease (CKD) is the irreversible loss of nephron function, leading to a build-up of toxins, prolonged inflammation, and ultimately fibrosis. Currently, no effective therapies exist to treat CKD due to its complex pathophysiology. Mesenchymal stem/stromal cell (MSC) transplantation is a promising strategy to treat kidney diseases, and multiple clinical trials are currently ongoing. We previously demonstrated that rat bone marrow-derived MSC (BMSC) sheets transplanted onto surgically decapsulated kidney exert therapeutic effects that suppressed renal fibrosis progression based on enhanced vascularization. However, there are clinical concerns about kidney decapsulation such as impaired glomerular filtration rate and Na+ ion and H2O excretion, leading to kidney dysfunction. Therefore, for transitioning from basic research to translational research using cell sheet therapy for kidney disease, it is essential to develop a new cell sheet transplantation strategy without kidney decapsulation. Significantly, we employed cell sheets engineered from clinical-grade human clonal BMSC (cBMSC) and transplanted these onto intact renal capsule to evaluate their therapeutic ability in the rat ischemia-reperfusion injury (IRI) model. Histological analysis 1-day postsurgery showed that cBMSC sheets engrafted well onto intact renal capsule. Interestingly, some grafted cBMSCs migrated into the renal parenchyma. At 1-3 days postsurgery (acute stage), grafted cBMSC sheets prevented tubular epithelial cell injury. At 28 days postsurgery (chronic phase), we observed that grafted cBMSC sheets suppressed renal fibrosis in the rat IRI model. Taken together, engineered cBMSC sheet transplantation onto intact renal capsule suppresses tubular epithelial cell injury and renal fibrosis, supporting further development as a possible clinically relevant strategy. Impact statement Chronic kidney disease (CKD) produces irreversible loss of nephron function, leading to toxemia, prolonged inflammation, and ultimately kidney fibrosis. Currently, no therapies exist to effectively treat CKD due to its complex pathophysiology. Mesenchymal stem/stromal cells (MSCs) are widely known to secret therapeutic paracrine factors, which is expected to provide a new effective therapy for unmet medical needs. However, unsatisfied MSC quality and administration methods to patients limit their therapeutic effects. In this study, we engineered clonal bone marrow-derived MSC sheets and established clinically relevant cell sheet transplantation strategy to treat renal fibrosis, which would improve MSC treatment for kidney disease.
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Affiliation(s)
- Masatoshi Oka
- Cell Sheet Tissue Engineering Center (CSTEC), University of Utah, Salt Lake City, Utah, USA.,Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah, USA.,Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Sumako Kameishi
- Cell Sheet Tissue Engineering Center (CSTEC), University of Utah, Salt Lake City, Utah, USA.,Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah, USA
| | - Yun-Kyoung Cho
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - Sun U Song
- Department of Nephrology, Tokyo Women's Medical University, Tokyo, Japan
| | - David W Grainger
- Cell Sheet Tissue Engineering Center (CSTEC), University of Utah, Salt Lake City, Utah, USA.,SCM Lifescience Co., Ltd., Republic of Korea
| | - Teruo Okano
- Cell Sheet Tissue Engineering Center (CSTEC), University of Utah, Salt Lake City, Utah, USA.,Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah, USA.,Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah, USA
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21
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Yang P, Zhang S, Yan T, Li F, Zhang S. The Therapeutic Application of Stem Cells and Their Derived Exosomes in the Treatment of Radiation-Induced Skin Injury. Radiat Res 2023; 199:182-201. [PMID: 36630584 DOI: 10.1667/rade-22-00023.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 12/05/2022] [Indexed: 01/13/2023]
Abstract
Radiation-induced skin injury (RISI) is a serious concern for nuclear accidents and cancer radiotherapy, which seriously affects the quality of life of patients. This injury differs from traditional wounds due to impaired healing and the propensity to recurrence and is divided into acute and chronic phases on the basis of the injury time. Unfortunately, there are few effective therapies for preventing or mitigating this injury. Over the last few decades, various studies have focused on the effects of stem cell-based therapies to address the tissue repair and regeneration of irradiated skin. These stem cells modulate inflammation and instigate tissue repair by differentiating into specific kinds of cells or releasing paracrine factors. Stem cell-based therapies, including bone marrow-derived stem cells (BMSCs), adipose-derived stem cells (ADSCs) and stromal vascular fraction (SVF), have been reported to facilitate wound healing after radiation exposure. Moreover, stem cell-derived exosomes have recently been suggested as an effective and cell-free approach to support skin regeneration, circumventing the concerns respecting direct application of stem cells. Based on the literature on stem cell-based therapies for radiation-induced skin injury, we summarize the characteristics of different stem cells and describe their latest animal and clinical applications, as well as potential mechanisms. The promise of stem-cell based therapies against radiation-induced skin injury contribute to our response to nuclear events and smooth progress of cancer radiotherapy.
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Affiliation(s)
- Ping Yang
- Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China.,Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China
| | - Shuaijun Zhang
- Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China
| | - Tao Yan
- Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China.,Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610051, China
| | - Fengsheng Li
- PLA Rocket Rorce Characteristic Medical Center, Beijing 100088, China
| | - Shuyu Zhang
- Laboratory of Radiation Medicine, West China Second University Hospital, Sichuan University, Chengdu 610041, China.,Laboratory of Radiation Medicine, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu 610041, China.,Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610051, China.,NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Mianyang 621099, China
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22
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Botelho BF, Barreira AL, Leite M, Morales MM. Chronic Kidney Disease: Challenges in Translational Medicine. Methods Mol Biol 2023; 2575:61-75. [PMID: 36301471 DOI: 10.1007/978-1-0716-2716-7_4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Chronic kidney disease (CKD) has long been recognized as a state of progressive decline in renal function. Morbidity and mortality are well correlated to the stage of renal function decline. Approximately one million deaths are estimated to be related to CKD worldwide. They are mostly associated with cardiovascular disease as a result of concurrent hypertension, accelerated atherosclerosis, and volume overload. Even with the best current treatment, disease progression is the general rule with a small fraction who reach CKD stage 5 requiring kidney transplantation or dialysis. Transplant patients show substantial reductions in mortality and cardiovascular events, as well as improvements in quality of life. However, the capacity of health systems to deliver kidney transplantation varies worldwide with worse indicators in low-income countries. Consequently, exploring novel and better therapeutic options for CKD is mandatory. Cell-based therapy is a promising strategy for treating CKD in preclinical models, and several clinical trials involving kidney disease exhibit a favorable safety profile. This chapter aims to provide an overview of CKD and the recent results of clinical trials of cell therapy in kidney diseases.
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Affiliation(s)
- Bruno Freire Botelho
- Department of Nephrology, School of Medicine, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, Brazil
- Hospital Universitário Clementino Fraga Filho Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ, Brazil
| | - André Luis Barreira
- Department of Nephrology, School of Medicine, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, Brazil
- Hospital Universitário Clementino Fraga Filho Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ, Brazil
| | - Maurilo Leite
- Department of Nephrology, School of Medicine, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, Brazil
- Hospital Universitário Clementino Fraga Filho Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ, Brazil
| | - Marcelo Marcos Morales
- Laboratory of Cellular and Molecular Physiology, Instituto de Biofísica Carlos Chagas Filho, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Ilha do Fundão, Rio de Janeiro, RJ, Brazil.
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23
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Extracellular Vesicles and Cellular Ageing. Subcell Biochem 2023; 102:271-311. [PMID: 36600137 DOI: 10.1007/978-3-031-21410-3_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Ageing is a complex process characterized by deteriorated performance at multiple levels, starting from cellular dysfunction to organ degeneration. Stem cell-based therapies aim to administrate stem cells that eventually migrate to the injured site to replenish the damaged tissue and recover tissue functionality. Stem cells can be easily obtained and cultured in vitro, and display several qualities such as self-renewal, differentiation, and immunomodulation that make them suitable candidates for stem cell-based therapies. Current animal studies and clinical trials are being performed to assess the safety and beneficial effects of stem cell engraftments for regenerative medicine in ageing and age-related diseases.Since alterations in cell-cell communication have been associated with the development of pathophysiological processes, new research is focusing on the modulation of the microenvironment. Recent research has highlighted the important role of some microenvironment components that modulate cell-cell communication, thus spreading signals from damaged ageing cells to neighbor healthy cells, thereby promoting systemic ageing. Extracellular vesicles (EVs) are small-rounded vesicles released by almost every cell type. EVs cargo includes several bioactive molecules, such as lipids, proteins, and genetic material. Once internalized by target cells, their specific cargo can induce epigenetic modifications and alter the fate of the recipient cells. Also, EV's content is dependent on the releasing cells, thus, EVs can be used as biomarkers for several diseases. Moreover, EVs have been proposed to be used as cell-free therapies that focus on their administration to slow or even reverse some hallmarks of physiological ageing. It is not surprising that EVs are also under study as next-generation therapies for age-related diseases.
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24
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Margiana R, Markov A, Zekiy AO, Hamza MU, Al-Dabbagh KA, Al-Zubaidi SH, Hameed NM, Ahmad I, Sivaraman R, Kzar HH, Al-Gazally ME, Mustafa YF, Siahmansouri H. Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review. Stem Cell Res Ther 2022; 13:366. [PMID: 35902958 PMCID: PMC9330677 DOI: 10.1186/s13287-022-03054-0] [Citation(s) in RCA: 183] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/18/2022] [Indexed: 12/16/2022] Open
Abstract
The multipotency property of mesenchymal stem cells (MSCs) has attained worldwide consideration because of their immense potential for immunomodulation and their therapeutic function in tissue regeneration. MSCs can migrate to tissue injury areas to contribute to immune modulation, secrete anti-inflammatory cytokines and hide themselves from the immune system. Certainly, various investigations have revealed anti-inflammatory, anti-aging, reconstruction, and wound healing potentials of MSCs in many in vitro and in vivo models. Moreover, current progresses in the field of MSCs biology have facilitated the progress of particular guidelines and quality control approaches, which eventually lead to clinical application of MSCs. In this literature, we provided a brief overview of immunoregulatory characteristics and immunosuppressive activities of MSCs. In addition, we discussed the enhancement, utilization, and therapeutic responses of MSCs in neural, liver, kidney, bone, heart diseases, and wound healing.
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Affiliation(s)
- Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Alexander Markov
- Tyumen State Medical University, Tyumen, Russian Federation.,Tyumen Industrial University, Tyumen, Russian Federation
| | - Angelina O Zekiy
- Department of Prosthetic Dentistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | | | | | | | - Noora M Hameed
- Anesthesia Techniques, Al-Nisour University College, Baghdad, Iraq
| | - Irshad Ahmad
- Department of Medical Rehabilitation Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - R Sivaraman
- Department of Mathematics, Dwaraka Doss Goverdhan Doss Vaishnav College, Arumbakkam, University of Madras, Chennai, India
| | - Hamzah H Kzar
- Veterinary Medicine College, Al-Qasim Green University, Al-Qasim, Iraq
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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25
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Li Y, Ricardo SD, Samuel CS. Enhancing the Therapeutic Potential of Mesenchymal Stromal Cell-Based Therapies with an Anti-Fibrotic Agent for the Treatment of Chronic Kidney Disease. Int J Mol Sci 2022; 23:ijms23116035. [PMID: 35682717 PMCID: PMC9181689 DOI: 10.3390/ijms23116035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/24/2022] [Accepted: 05/26/2022] [Indexed: 01/02/2023] Open
Abstract
Chronic kidney disease (CKD) affects 1 in 10 members of the general population, placing these patients at an increasingly high risk of kidney failure. Despite the significant burden of CKD on various healthcare systems, there are no effective cures that reverse or even halt its progression. In recent years, human bone-marrow-derived mesenchymal stromal cells (BM-MSCs) have been recognised as a novel therapy for CKDs, owing to their well-established immunomodulatory and tissue-reparative properties in preclinical settings, and their promising safety profile that has been demonstrated in patients with CKDs from several clinical trials. However, renal fibrosis (scarring), a hallmark of CKD, has been shown to impair the viability and functionality of BM-MSCs post-transplantation. This has suggested that BM-MSCs might require a pre-treatment or adjunct therapy that can enhance the viability and therapeutic efficacy of these stromal cells in chronic disease settings. To address this, recent studies that have combined BM-MSCs with the anti-fibrotic drug serelaxin (RLX), have demonstrated the enhanced therapeutic potential of this combination therapy in normotensive and hypertensive preclinical models of CKD. In this review, a critical appraisal of the preclinical data available on the anti-fibrotic and renoprotective actions of BM-MSCs or RLX alone and when combined, as a treatment option for normotensive vs. hypertensive CKD, is discussed.
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Affiliation(s)
- Yifang Li
- Cardiovascular Disease Program, Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia;
| | - Sharon D. Ricardo
- Development and Stem Cells Program, Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
- Correspondence: (S.D.R.); (C.S.S.)
| | - Chrishan S. Samuel
- Cardiovascular Disease Program, Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia;
- Development and Stem Cells Program, Department of Pharmacology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC 3800, Australia
- Department of Biochemistry and Molecular Biology, The University of Melbourne, Melbourne, VIC 3010, Australia
- Correspondence: (S.D.R.); (C.S.S.)
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26
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Khodayari S, Khodayari H, Ebrahimi-Barough S, Khanmohammadi M, Islam MS, Vesovic M, Goodarzi A, Mahmoodzadeh H, Nayernia K, Aghdami N, Ai J. Stem Cell Therapy in Limb Ischemia: State-of-Art, Perspective, and Possible Impacts of Endometrial-Derived Stem Cells. Front Cell Dev Biol 2022; 10:834754. [PMID: 35676930 PMCID: PMC9168222 DOI: 10.3389/fcell.2022.834754] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 04/11/2022] [Indexed: 11/13/2022] Open
Abstract
As an evidence-based performance, the rising incidence of various ischemic disorders has been observed across many nations. As a result, there is a growing need for the development of more effective regenerative approaches that could serve as main therapeutic strategies for the treatment of these diseases. From a cellular perspective, promoted complex inflammatory mechanisms, after inhibition of organ blood flow, can lead to cell death in all tissue types. In this case, using the stem cell technology provides a safe and regenerative approach for ischemic tissue revascularization and functional cell formation. Limb ischemia (LI) is one of the most frequent ischemic disease types and has been shown to have a promising regenerative response through stem cell therapy based on several clinical trials. Bone marrow-derived mononuclear cells (BM-MNCs), peripheral blood CD34-positive mononuclear cells (CD34+ PB-MNCs), mesenchymal stem cells (MSCs), and endothelial stem/progenitor cells (ESPCs) are the main, well-examined stem cell types in these studies. Additionally, our investigations reveal that endometrial tissue can be considered a suitable candidate for isolating new safe, effective, and feasible multipotent stem cells for limb regeneration. In addition to other teams’ results, our in-depth studies on endometrial-derived stem cells (EnSCs) have shown that these cells have translational potential for limb ischemia treatment. The EnSCs are able to generate diverse types of cells which are essential for limb reconstruction, including endothelial cells, smooth muscle cells, muscle cells, and even peripheral nervous system populations. Hence, the main object of this review is to present stem cell technology and evaluate its method of regeneration in ischemic limb tissue.
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Affiliation(s)
- Saeed Khodayari
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
- Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
- International Center for Personalized Medicine (P7MEDICINE), Düsseldorf, Germany
| | - Hamid Khodayari
- Breast Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
- International Center for Personalized Medicine (P7MEDICINE), Düsseldorf, Germany
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Somayeh Ebrahimi-Barough
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Mehdi Khanmohammadi
- Skull Base Research Center, The Five Senses Institute, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Md Shahidul Islam
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
| | - Miko Vesovic
- Department of Mathematics, Statistics, and Computer Science, University of Illinois at Chicago, Chicago, IL, United States
| | - Arash Goodarzi
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
| | | | - Karim Nayernia
- International Center for Personalized Medicine (P7MEDICINE), Düsseldorf, Germany
| | - Nasser Aghdami
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Infectious Diseases and Tropical Medicines, Tehran University of Medical Sciences, Tehran, Iran
- *Correspondence: Jafar Ai, ; Nasser Aghdami,
| | - Jafar Ai
- Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Science, Tehran, Iran
- *Correspondence: Jafar Ai, ; Nasser Aghdami,
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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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Regenerative Medicine Application of Mesenchymal Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1387:25-42. [DOI: 10.1007/5584_2022_713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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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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Tang H, Zhang P, Zeng L, Zhao Y, Xie L, Chen B. Mesenchymal stem cells ameliorate renal fibrosis by galectin-3/Akt/GSK3β/Snail signaling pathway in adenine-induced nephropathy rat. Stem Cell Res Ther 2021; 12:409. [PMID: 34271976 PMCID: PMC8283866 DOI: 10.1186/s13287-021-02429-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 06/03/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Tubulointerstitial fibrosis (TIF) is one of the main pathological features of various progressive renal damages and chronic kidney diseases. Mesenchymal stromal cells (MSCs) have been verified with significant improvement in the therapy of fibrosis diseases, but the mechanism is still unclear. We attempted to explore the new mechanism and therapeutic target of MSCs against renal fibrosis based on renal proteomics. METHODS TIF model was induced by adenine gavage. Bone marrow-derived MSCs was injected by tail vein after modeling. Renal function and fibrosis related parameters were assessed by Masson, Sirius red, immunohistochemistry, and western blot. Renal proteomics was analyzed using iTRAQ-based mass spectrometry. Further possible mechanism was explored by transfected galectin-3 gene for knockdown (Gal-3 KD) and overexpression (Gal-3 OE) in HK-2 cells with lentiviral vector. RESULTS MSCs treatment clearly decreased the expression of α-SMA, collagen type I, II, III, TGF-β1, Kim-1, p-Smad2/3, IL-6, IL-1β, and TNFα compared with model rats, while p38 MAPK increased. Proteomics showed that only 40 proteins exhibited significant differences (30 upregulated, 10 downregulated) compared MSCs group with the model group. Galectin-3 was downregulated significantly in renal tissues and TGF-β1-induced rat tubular epithelial cells and interstitial fibroblasts, consistent with the iTRAQ results. Gal-3 KD notably inhibited the expression of p-Akt, p-GSK3β and snail in TGF-β1-induced HK-2 cells fibrosis. On the contrary, Gal-3 OE obviously increased the expression of p-Akt, p-GSK3β and snail. CONCLUSION The mechanism of MSCs anti-renal fibrosis was probably mediated by galectin-3/Akt/GSK3β/Snail signaling pathway. Galectin-3 may be a valuable target for treating renal fibrosis.
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Affiliation(s)
- Huajun Tang
- Department of Human Anatomy, School of Basic Medical Sciences, Southwest Medical University, No.1, Section 1, Lingxiang Road, Matan Long District, Luzhou, Sichuan, People's Republic of China, 646000
| | - Peiyue Zhang
- Department of Human Anatomy, School of Basic Medical Sciences, Southwest Medical University, No.1, Section 1, Lingxiang Road, Matan Long District, Luzhou, Sichuan, People's Republic of China, 646000
| | - Lianlin Zeng
- Department of Human Anatomy, School of Basic Medical Sciences, Southwest Medical University, No.1, Section 1, Lingxiang Road, Matan Long District, Luzhou, Sichuan, People's Republic of China, 646000
| | - Yu Zhao
- Department of Human Anatomy, School of Basic Medical Sciences, Southwest Medical University, No.1, Section 1, Lingxiang Road, Matan Long District, Luzhou, Sichuan, People's Republic of China, 646000
| | - Libo Xie
- Department of Urology, Sichuan Clinical Research Center for Nephropathy, the Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou, Sichuan, 646000, People's Republic of China.
| | - Bo Chen
- Department of Human Anatomy, School of Basic Medical Sciences, Southwest Medical University, No.1, Section 1, Lingxiang Road, Matan Long District, Luzhou, Sichuan, People's Republic of China, 646000.
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31
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Aitong W, Leisheng Z, Hao Y. Visualized analyses of investigations upon mesenchymal stem/stromal cell-based cytotherapy and underlying mechanisms for COVID-19 associated ARDS. Curr Stem Cell Res Ther 2021; 17:2-12. [PMID: 34254927 DOI: 10.2174/1574888x16666210712212421] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 11/22/2022]
Abstract
The outbreak of coronavirus disease 2019 (COVID-19) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a widespread pandemic globally and seriously threatened the public health. Patients with COVID-19 infection, and in particular, those with severe pneumonia-associated acute respiratory distress syndrome (ARDS) manifested rapid disease progression and the resultant high mortality and morbidity. Advances in fundamental and clinical studies have suggested the feasibility of mesenchymal stem/stromal cell (MSC)-based therapy as an inspiring alternative for ARDS administration. However, the systematic characteristics of the MSC-based cytotherapy and underlying mechanism for COVID-19 associated ARDS by bibliometric analyses are still unknowable. Herein, we took advantage of visual analyses to reveal the overview of ARDS-associated updates, core authors and focused issues, as well as to summarize the comprehensive knowledge of the keywords, authors, institutions with the aid of indicated software. Meanwhile, we have provided a brief overview on the molecular mechanisms and discussed the safety and efficacy of MSC-based therapy for ARDS on the basis of clinical trials.
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Affiliation(s)
- Wang Aitong
- National Engineering Research Center of Cell Products, AmCellGene Engineering Co., Ltd, Tianjin 300457, China
| | - Zhang Leisheng
- Institute of Stem Cells, Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd., Tianjin, 301700, China
| | - Yu Hao
- The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin, 300071, China
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32
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McKenna DH, Stroncek DF. Cellular Engineering. Transfus Med 2021. [DOI: 10.1002/9781119599586.ch19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Khoshdel-Rad N, Zahmatkesh E, Moeinvaziri F, Haghparast N, Baharvand H, Aghdami N, Moghadasali R. Promoting Maturation of Human Pluripotent Stem Cell-Derived Renal Microtissue by Incorporation of Endothelial and Mesenchymal Cells. Stem Cells Dev 2021; 30:428-440. [PMID: 33787359 DOI: 10.1089/scd.2020.0189] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Directed differentiation of human pluripotent stem cells (hPSCs) uses a growing number of small molecules and growth factors required for in vitro generation of renal lineage cells. Although current protocols are relatively inefficient or expensive. The first objective of the present work was to establish a new differentiation protocol for generating renal precursors. We sought to determine if inducer of definitive endoderm 1 (IDE1), a cost-effective small molecule, can be used to replace activin A. Gene expression data showed significantly increased expressions of nephrogenic markers in cells differentiated with 20 nM IDE1 compared with cells differentiated with activin A. Thus, renal lineage cells could be generated by this alternative approach. Afterward, we determined whether coculture of endothelial and mesenchymal cells could increase the maturation of three-dimensional (3D) renal structures. For this purpose, we employed a 3D coculture system in which hPSC-derived kidney precursors were cocultured with endothelial cells (ECs) and mesenchymal stem cells (MSCs), hereafter named RMEM (renal microtissue derived from coculture of renal precursors with endothelial and mesenchymal stem cells). hPSC-derived kidney precursors were cultured either alone [renal microtissue (RM)] or in coculture with human umbilical vein endothelial cells and human bone marrow-derived mesenchymal stem cells at an approximate ratio of 10:7:2, respectively. Immunofluorescent staining showed expressions of kidney-specific markers synaptopodin, LTL, and E-cadherin, as well as CD31+ ECs that were distributed throughout the RMEMs. Quantitative real-time polymerase chain reaction analysis confirmed a significant increase in gene expressions of the renal-specific markers in RMEMs compared with RMs. These findings demonstrated that renal precursors cocultured with endothelial and MSCs showed greater maturity compared with RMs. Moreover, ex ovo transplantation induced further maturation in the RMEM constructs. Our novel approach enabled the generation of RMEM that could potentially be used in high-throughput drug screening and nephrotoxicology studies.
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Affiliation(s)
- Niloofar Khoshdel-Rad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Ensieh Zahmatkesh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Farideh Moeinvaziri
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Newsha Haghparast
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Developmental Biology, University of Science and Culture, Tehran, Iran
| | - Nasser Aghdami
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Reza Moghadasali
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Developmental Biology, University of Science and Culture, Tehran, Iran
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34
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Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases. Stem Cell Res Ther 2021; 12:219. [PMID: 33789750 PMCID: PMC8011150 DOI: 10.1186/s13287-021-02289-7] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 03/15/2021] [Indexed: 12/14/2022] Open
Abstract
Kidney diseases pose a threat to human health due to their rising incidence and fatality rate. In preclinical and clinical studies, it has been acknowledged that mesenchymal stem cells (MSCs) are effective and safe when used to treat kidney diseases. MSCs play their role mainly by secreting trophic factors and delivering extracellular vesicles (EVs). The genetic materials and proteins contained in the MSC-derived EVs (MSC-EVs), as an important means of cellular communication, have become a research focus for targeted therapy of kidney diseases. At present, MSC-EVs have shown evident therapeutic effects on acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy (DN), and atherosclerotic renovascular disease (ARVD); however, their roles in the transplanted kidney remain controversial. This review summarises the mechanisms by which MSC-EVs treat these diseases in animal models and proposes certain problems, expecting to facilitate corresponding future clinical practice.
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35
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Concentrated exosomes from menstrual blood-derived stromal cells improves ovarian activity in a rat model of premature ovarian insufficiency. Stem Cell Res Ther 2021; 12:178. [PMID: 33712079 PMCID: PMC7953711 DOI: 10.1186/s13287-021-02255-3] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/01/2021] [Indexed: 12/15/2022] Open
Abstract
Background Premature ovarian insufficiency (POI) is one of the major causes of infertility. We previously demonstrated that transplantation of menstrual blood-derived stromal cells (MenSCs) effectively improved ovarian function in a murine model of POI. Recent studies indicated that mesenchymal stem cell-derived exosomes were important components in tissue repair. In this study, we investigated the therapeutic effects of MenSCs-derived exosomes (MenSCs-Exos) in a rat model of POI and its mechanism in restoring ovulation. Methods Ovaries of 4.5-day-old Sprague Dawley rats (SD rats) were cultured in vitro to evaluate the effects of MenSCs-Exos exposure on early follicle development. Furthermore, POI in rats was induced by intraperitoneal administration of 4-vinylcyclohexene diepoxide (VCD). Forty-eight POI rats were randomly assigned to four groups, each receiving a different treatment: PBS, MenSCs, MenSCs-Exos, and Exo-free culture supernatant of MenSCs. Estrous cyclicity, ovarian morphology, follicle dynamics, serum hormones, pregnancy outcomes, and molecular changes were investigated. Results Exposure to MenSCs-Exos promoted the proliferation of granulosa cells in primordial and primary follicles in vitro and increased the expression of early follicle markers Deleted In Azoospermia Like (DAZL) and Forkhead Box L2 (FOXL2) while inhibiting follicle apoptosis. In vivo, MenSCs-Exos transplantation effectively promoted follicle development in the rat model of POI and restored the estrous cyclicity and serum sex hormone levels, followed by improving the live birth outcome. In addition, transplantation of MenSCs-Exos regulated the composition of the ovarian extracellular matrix and accelerated the recruitment of dormant follicles in the ovarian cortex and increased proliferation of granulosa cells in these follicles. Conclusion MenSCs-Exos markedly promoted follicle development in vitro and in vivo and restored fertility in POI rats, suggesting a restorative effect on ovarian functions. The therapeutic effect of MenSCs-Exos transplantation was sustainable, consistent with that of MenSCs transplantation. Our results suggested that MenSCs-Exos transplantation may be a promising cell-free bioresource in the treatment of POI.
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36
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Zilberman-Itskovich S, Efrati S. Mesenchymal Stromal Cell Uses for Acute Kidney Injury-Current Available Data and Future Perspectives: A Mini-Review. Front Immunol 2020; 11:1369. [PMID: 32793191 PMCID: PMC7385060 DOI: 10.3389/fimmu.2020.01369] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 05/28/2020] [Indexed: 12/22/2022] Open
Abstract
There is growing evidence concerning the potential use of mesenchymal stromal cells (MSCs) for different tissue injuries. Initially, the intended physiological use of MSCs was due to their ability to differentiate and replace damaged cells. However, MSCs have multiple effects, including being able to significantly modulate immunological responses. MSCs are currently being tested for neurodegenerative diseases, graft vs. host disease, kidney injury, and other chronic unremitting tissue damage. Using MSCs in acute tissue damage is only now being studied. Acute kidney injury (AKI) is a common cause of morbidity and mortality. After the primary insult, overactivation of the immune system culminates in additional secondary potentially permanent kidney damage. MSCs have the potential to ameliorate the secondary damage, and recent studies have shed important light on their mechanisms of action. This article summarizes the basics of MSCs therapy, the newly discovered mechanisms of action, and their potential application in the setting of AKI.
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Affiliation(s)
- Shani Zilberman-Itskovich
- Nephrology Division, Assaf-Harofeh (Shamir) Medical Center, Be'er Ya'akov, Israel.,Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Shai Efrati
- Nephrology Division, Assaf-Harofeh (Shamir) Medical Center, Be'er Ya'akov, Israel.,Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
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37
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Liu D, Cheng F, Pan S, Liu Z. Stem cells: a potential treatment option for kidney diseases. Stem Cell Res Ther 2020; 11:249. [PMID: 32586408 PMCID: PMC7318741 DOI: 10.1186/s13287-020-01751-2] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 05/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
The prevalence of kidney diseases is emerging as a public health problem. Stem cells (SCs), currently considered as a promising tool for therapeutic application, have aroused considerable interest and expectations. With self-renewal capabilities and great potential for proliferation and differentiation, stem cell therapy opens new avenues for the development of renal function and structural repair in kidney diseases. Mounting evidence suggests that stem cells exert a therapeutic effect mainly by replacing damaged tissues and paracrine pathways. The benefits of various types of SCs in acute kidney disease and chronic kidney disease have been demonstrated in preclinical studies, and preliminary results of clinical trials present its safety and tolerability. This review will focus on the stem cell-based therapy approaches for the treatment of kidney diseases, including various cell sources used, possible mechanisms involved, and outcomes that are generated so far, along with prospects and challenges in clinical application.
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Affiliation(s)
- Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Fei Cheng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Shaokang Pan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
- Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
- Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People's Republic of China.
- Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People's Republic of China.
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38
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Kidney Regenerative Medicine: Promises and Limitations. CURRENT TRANSPLANTATION REPORTS 2020. [DOI: 10.1007/s40472-020-00273-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Tavakoli S, Ghaderi Jafarbeigloo HR, Shariati A, Jahangiryan A, Jadidi F, Jadidi Kouhbanani MA, Hassanzadeh A, Zamani M, Javidi K, Naimi A. Mesenchymal stromal cells; a new horizon in regenerative medicine. J Cell Physiol 2020; 235:9185-9210. [PMID: 32452052 DOI: 10.1002/jcp.29803] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/03/2020] [Accepted: 05/07/2020] [Indexed: 12/11/2022]
Abstract
In recent decades, mesenchymal stromal cells (MSCs) biomedical utilizing has attracted worldwide growing attention. After the first report of the human MSCs obtaining from the bone marrow (BM) tissue, these cells were isolated from wide types of the other tissues, ranging from adipose tissue to dental pulp. Their specific characteristics, comprising self-renewality, multipotency, and availability accompanied by their immunomodulatory properties and little ethical concern denote their importance in the context of regenerative medicine. Considering preclinical studies, MSCs can modify immune reactions during tissue repair and restoration, providing suitable milieu for tissue recovery; on the other hand, they can be differentiated into comprehensive types of the body cells, such as osteoblast, chondrocyte, hepatocyte, cardiomyocyte, fibroblast, and neural cells. Though a large number of studies have investigated MSCs capacities in regenerative medicine in varied animal models, the oncogenic capability of unregulated MSCs differentiation must be more assessed to enable their application in the clinic. In the current review, we provide a brief overview of MSCs sources, isolation, and expansion as well as immunomodulatory activities. More important, we try to collect and discuss recent preclinical and clinical research and evaluate current challenges in the context of the MSC-based cell therapy for regenerative medicine.
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Affiliation(s)
- Shirin Tavakoli
- Department of Toxicology and Pharmacology, Mazandaran University of Medical Sciences, Sari, Iran.,Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Ali Shariati
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Afsaneh Jahangiryan
- Immunology Department, Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine (IBTO), Tehran, Iran
| | - Faezeh Jadidi
- Student Research Committee, Zarand School of Nursing, Kerman University of Medical Sciences, Kerman, Iran
| | - Mohammd Amin Jadidi Kouhbanani
- Department of Medical Nanotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Hassanzadeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Zamani
- Department of Medical Laboratory Sciences, Faculty of Allied Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Kamran Javidi
- School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Adel Naimi
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
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Abstract
IMPACT STATEMENT Stem cells hold great promise in regenerative medicine. Pluripotent stem cells have been differentiated into kidney organoids to understand human kidney development and to dissect renal disease mechanisms. Meanwhile, recent studies have explored the treatment of kidney diseases using a variety of cells, including mesenchymal stem cells and renal derivatives. This mini-review discusses the diverse mechanisms underlying current renal disease treatment via stem cell therapy. We postulate that clinical applications of stem cell therapy for kidney diseases can be readily achieved in the near future.
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Affiliation(s)
- Binbin Pan
- Department of Nephrology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210029, China.,Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, CA 90095, USA
| | - Guoping Fan
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, CA 90095, USA
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41
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Sun DZ, Abelson B, Babbar P, Damaser MS. Harnessing the mesenchymal stem cell secretome for regenerative urology. Nat Rev Urol 2020; 16:363-375. [PMID: 30923338 DOI: 10.1038/s41585-019-0169-3] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The extensive arsenal of bioactive molecules secreted by mesenchymal stem cells (MSCs), known as the secretome, has demonstrated considerable therapeutic benefit in regenerative medicine. Investigation into the therapeutic potential of the secretome has enabled researchers to replicate the anti-inflammatory, pro-angiogenic and trophic effects of stem cells without the need for the cells themselves. Furthermore, treatment with the MSC secretome could circumvent hurdles associated with cellular therapy, including oncogenic transformation, immunoreactivity and cost. Thus, a clear rationale exists for investigating the therapeutic potential of the MSC secretome in regenerative urology. Indeed, preclinical studies have demonstrated the therapeutic benefits of the MSC secretome in models of stress urinary incontinence, renal disease, bladder dysfunction and erectile dysfunction. However, the specific mechanisms underpinning therapeutic activity are unclear and require further research before clinical translation. Improvements in current proteomic methods used to characterize the secretome will be necessary to provide further insight into stem cells and their secretome in regenerative urology.
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Affiliation(s)
- Daniel Z Sun
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA. .,Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA. .,Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
| | - Benjamin Abelson
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.,Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Paurush Babbar
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.,Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Margot S Damaser
- Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.,Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, OH, USA.,Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.,Advanced Platform Technology Center, Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA
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42
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Zhang C, George SK, Wu R, Thakker PU, Abolbashari M, Kim TH, Ko IK, Zhang Y, Sun Y, Jackson J, Lee SJ, Yoo JJ, Atala A. Reno-protection of Urine-derived Stem Cells in A Chronic Kidney Disease Rat Model Induced by Renal Ischemia and Nephrotoxicity. Int J Biol Sci 2020; 16:435-446. [PMID: 32015680 PMCID: PMC6990904 DOI: 10.7150/ijbs.37550] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 09/30/2019] [Indexed: 12/12/2022] Open
Abstract
Purpose: Drug-induced nephrotoxicity can occur in patients with pre-existing renal dysfunction or renal ischemia, potentially leading to chronic kidney disease (CKD) and end-stage renal disease (ESRD). Prompt treatment of CKD and the related side effects is critical in preventing progression to ESRD. The goal of this study was to demonstrate the therapeutic potential of urine-derived stem cells (USC) to treat chronic kidney disease-induced by nephrotoxic drugs and renal ischemia. Materials and methods: Human USC were collected, expanded and characterized by flow cytometry. A CKD model was induced by creating an ischemia-reperfusion injury and gentamicin administration. Twenty-eight adult immunodeficient rats were divided into three groups: PBS-treated group (n=9), USC-treated group (n=9), and sham group with age-matched control animals (n=10). Cell suspension of USC (5 x 106 / 100µl / kidney) or PBS was injected bilaterally into the renal parenchyma 9 weeks after CKD model creation. Renal function was evaluated by collection blood and urine samples to measure serum creatinine and glomerulus filtration rate. The kidneys were harvested 12 weeks after cell injection. Histologically, the extent of glomerulosclerosis and tubular atrophy, the amount of collagen deposition, interstitial fibrosis, inflammatory monocyte infiltration, and expression of transforming growth factor beta 1 (TGF-ß1), and superoxide dismutase 1 (SOD-1) were examined. Results: USC expressed renal parietal epithelial cells (CD24, CD29 and CD44). Renal function, measured by GFR and serum Cr in USC-treated group were significantly improved compared to PBS-treated animals (p<0.05). The degree of glomerular sclerosis and atrophic renal tubules, the amount of fibrosis, and monocyte infiltration significantly decreased in USC-treated group compared to the PBS group (p<0.05). The level of TGF-ß1 expression in renal tissues was also significantly lower in the PBS group, while the level of SOD-1 expression was significantly elevated in the USC group, compared to PBS group (p<0.05). Conclusions: The present study demonstrates the nephron-protective effect of USC on renal function via anti-inflammatory, anti-oxidative stress, and anti-fibrotic activity in a dual-injury CKD rat model. This provides an alternative treatment for CKD in certain clinical situations, such as instances where CKD is due to drug-induced nephrotoxicity and renal ischemia.
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Affiliation(s)
- Chao Zhang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.,Department of Urology, Changhai Hospital, the Second Military Medical University, 168 Changhai Road, Shanghai, People's Republic of China
| | - Sunil K George
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Rongpei Wu
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.,Department of Urology, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guang Dong, People's Republic of China
| | - Parth Udayan Thakker
- Department of Urology, Wake Forest Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Mehran Abolbashari
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Tae-Hyoung Kim
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA.,Department of Urology, College of Medicine, Chung-Ang University, Seoul, South Korea
| | - In Kap Ko
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Yuanyuan Zhang
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Yinghao Sun
- Department of Urology, Changhai Hospital, the Second Military Medical University, 168 Changhai Road, Shanghai, People's Republic of China
| | - John Jackson
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Sang Jin Lee
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - James J Yoo
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
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Rockel JS, Rabani R, Viswanathan S. Anti-fibrotic mechanisms of exogenously-expanded mesenchymal stromal cells for fibrotic diseases. Semin Cell Dev Biol 2019; 101:87-103. [PMID: 31757583 DOI: 10.1016/j.semcdb.2019.10.014] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 10/11/2019] [Accepted: 10/30/2019] [Indexed: 12/17/2022]
Abstract
Most chronic diseases involving inflammation have a fibrotic component that involves remodeling and excess accumulation of extracellular matrix components. Left unchecked, fibrosis leads to organ failure and death. Mesenchymal stromal cells (MSCs) are emerging as a potent cell-based therapy for a wide spectrum of fibrotic conditions due to their immunomodulatory, anti-inflammatory and anti-fibrotic properties. This review provides an overview of known mechanisms by which MSCs mediate their anti-fibrotic actions and in relation to animal models of pulmonary, liver, renal and cardiac fibrosis. Recent MSC clinical trials results in liver, lung, skin, kidney and hearts are discussed and next steps for future MSC-based therapies including pre-activated or genetically-modified cells, or extracellular vesicles are also considered.
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Affiliation(s)
- Jason S Rockel
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
| | - Razieh Rabani
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Sowmya Viswanathan
- Arthritis Program, University Health Network, Toronto, ON, Canada; Division of Genetics and Development, Krembil Research Institute, University Health Network, Toronto, ON, Canada; Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada; Division of Hematology, Department of Medicine, University of Toronto, Toronto, Canada
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44
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Villanueva S, González F, Lorca E, Tapia A, Valentina López G, Strodthoff R, Fajre F, Carreño JE, Valjalo R, Vergara C, Lecanda M, Bartolucci J, Figueroa FE, Khoury M. Adipose tissue-derived mesenchymal stromal cells for treating chronic kidney disease: A pilot study assessing safety and clinical feasibility. Kidney Res Clin Pract 2019; 38:176-185. [PMID: 31189223 PMCID: PMC6577210 DOI: 10.23876/j.krcp.18.0139] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/25/2019] [Accepted: 02/18/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a growing public health concern, and available treatments are insufficient in limiting disease progression. New strategies, including regenerative cell-based therapies, have emerged as therapeutic alternatives. Results from several groups, including our own, have reported evidence of a supportive role for mesenchymal stromal cells (MSCs) in functional recovery and prevention of tissue damage in murine models of CKD. Prompted by these data, an open pilot study was conducted to assess the safety and efficacy of a single injection of autologous adipose tissue-derived MSCs (AT-MSCs) for treatment of CKD. METHODS AT-MSCs were infused intravenously into six CKD patients at a dose of 1 million cells/kg. Patients were stabilized and followed for one year prior to MSC infusion and one year following infusion. RESULTS No patients presented with adverse effects. Statistically significant improvement in urinary protein excretion was observed in AT-MSCs transplanted patients, from a median of 0.75 g/day (range, 0.15-9.57) at baseline to 0.54 g/day (range, 0.01-2.66) at month 12 (P = 0.046). The glomerular filtration rate was not significantly decreased post-infusion of AT-MSCs. CONCLUSION Findings from this pilot study demonstrate that intravenous infusion of autologous expanded AT-MSCs into CKD patients was not associated with adverse effects and could benefit patients already undergoing standard medical treatment.
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Affiliation(s)
- Sandra Villanueva
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | | | - Eduardo Lorca
- Department of Nephrology, Hospital Salvador, Santiago,
Chile
| | - Andrés Tapia
- Laboratory of Nano-regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - G Valentina López
- Cells for Cells, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Rocío Strodthoff
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Francisca Fajre
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Juan E. Carreño
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Ricardo Valjalo
- Department of Nephrology, Hospital Salvador, Santiago,
Chile
| | - César Vergara
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Manuel Lecanda
- Laboratory of Molecular and Integrative Physiology, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Jorge Bartolucci
- Cells for Cells, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Fernando E. Figueroa
- Laboratory of Nano-regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
- Program for Translational Research in Cell Therapy, Universidad de Los Andes, Santiago,
Chile
- Consorcio Regenero, the Chilean Consortium for Regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
| | - Maroun Khoury
- Laboratory of Nano-regenerative Medicine, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
- Cells for Cells, Faculty of Medicine, Universidad de Los Andes, Santiago,
Chile
- Program for Translational Research in Cell Therapy, Universidad de Los Andes, Santiago,
Chile
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45
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Chung BH. Use of mesenchymal stem cells for chronic kidney disease. Kidney Res Clin Pract 2019; 38:131-134. [PMID: 31189218 PMCID: PMC6577207 DOI: 10.23876/j.krcp.19.051] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 05/26/2019] [Accepted: 05/27/2019] [Indexed: 12/19/2022] Open
Affiliation(s)
- Byung Ha Chung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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46
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Regmi S, Pathak S, Kim JO, Yong CS, Jeong JH. Mesenchymal stem cell therapy for the treatment of inflammatory diseases: Challenges, opportunities, and future perspectives. Eur J Cell Biol 2019; 98:151041. [PMID: 31023504 DOI: 10.1016/j.ejcb.2019.04.002] [Citation(s) in RCA: 188] [Impact Index Per Article: 31.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/01/2019] [Accepted: 04/09/2019] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are promising alternative agents for the treatment of inflammatory disorders due to their immunomodulatory functions, and several clinical trials on MSC-based products are currently being conducted. In this review, we discuss recent progress made on the use of MSCs as immunomodulatory agents, developmental challenges posed by MSC-based therapy, and the strategies being used to overcome these challenges. In this context, current understanding of the mechanisms responsible for MSC interactions with the immune system and the molecular responses of MSCs to inflammatory signals are discussed. The immunosuppressive activities of MSCs are initiated by cell-to-cell contact and the release of immuno-regulatory molecules. By doing so, MSCs can inhibit the proliferation and function of T cells, natural killer cells, B cells, and dendritic cells, and can also increase the proliferation of regulatory T cells. However, various problems, such as low transplanted cell viability, poor homing and engraftment into injured tissues, MSC heterogeneity, and lack of adequate information on optimum MSC doses impede clinical applications. On the other hand, it has been shown that the immunomodulatory activities and viabilities of MSCs might be enhanced by 3D-cultured systems, genetic modifications, preconditioning, and targeted-delivery.
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Affiliation(s)
- Shobha Regmi
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Shiva Pathak
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Jong Oh Kim
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Chul Soon Yong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
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Oliveira M, Lira R, Freire T, Luna C, Martins M, Almeida A, Carvalho S, Cortez E, Stumbo AC, Thole A, Carvalho L. Bone marrow mononuclear cell transplantation rescues the glomerular filtration barrier and epithelial cellular junctions in a renovascular hypertension model. Exp Physiol 2019; 104:740-754. [DOI: 10.1113/ep087330] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 02/19/2019] [Indexed: 12/13/2022]
Affiliation(s)
- Mariana Oliveira
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Rafaelle Lira
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Thiago Freire
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Camila Luna
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Marcela Martins
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Aline Almeida
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Simone Carvalho
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Erika Cortez
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Ana Carolina Stumbo
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Alessandra Thole
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Lais Carvalho
- Laboratory of Stem Cell ResearchHistology and Embryology DepartmentBiology InstituteState University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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Malekshahabi T, Khoshdel Rad N, Serra AL, Moghadasali R. Autosomal dominant polycystic kidney disease: Disrupted pathways and potential therapeutic interventions. J Cell Physiol 2019; 234:12451-12470. [PMID: 30644092 DOI: 10.1002/jcp.28094] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 12/07/2018] [Indexed: 12/18/2022]
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic inherited renal cystic disease that occurs in different races worldwide. It is characterized by the development of a multitude of renal cysts, which leads to massive enlargement of the kidney and often to renal failure in adulthood. ADPKD is caused by a mutation in PKD1 or PKD2 genes encoding the proteins polycystin-1 and polycystin-2, respectively. Recent studies showed that cyst formation and growth result from deregulation of multiple cellular pathways like proliferation, apoptosis, metabolic processes, cell polarity, and immune defense. In ADPKD, intracellular cyclic adenosine monophosphate (cAMP) promotes cyst enlargement by stimulating cell proliferation and transepithelial fluid secretion. Several interventions affecting many of these defective signaling pathways have been effective in animal models and some are currently being tested in clinical trials. Moreover, the stem cell therapy can improve nephropathies and according to studies were done in this field, can be considered as a hopeful therapeutic approach in future for PKD. This study provides an in-depth review of the relevant molecular pathways associated with the pathogenesis of ADPKD and their implications in development of potential therapeutic strategies.
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Affiliation(s)
- Talieh Malekshahabi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Khoshdel Rad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Andreas L Serra
- Department of Internal Medicine and Nephrology, Klinik Hirslanden, Zurich, Switzerland
| | - Reza Moghadasali
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Marcheque J, Bussolati B, Csete M, Perin L. Concise Reviews: Stem Cells and Kidney Regeneration: An Update. Stem Cells Transl Med 2018; 8:82-92. [PMID: 30302937 PMCID: PMC6312445 DOI: 10.1002/sctm.18-0115] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 08/03/2018] [Indexed: 02/06/2023] Open
Abstract
Significant progress has been made to advance stem cell products as potential therapies for kidney diseases: various kinds of stem cells can restore renal function in preclinical models of acute and chronic kidney injury. Nonetheless this literature contains contradictory results, and for this reason, we focus this review on reasons for apparent discrepancies in the literature, because they contribute to difficulty in translating renal regenerative therapies. Differences in methodologies used to derive and culture stem cells, even those from the same source, in addition to the lack of standardized renal disease animal models (both acute and chronic), are important considerations underlying contradictory results in the literature. We propose that harmonized rigorous protocols for characterization, handling, and delivery of stem cells in vivo could significantly advance the field, and present details of some suggested approaches to foster translation in the field of renal regeneration. Our goal is to encourage coordination of methodologies (standardization) and long‐lasting collaborations to improve protocols and models to lead to reproducible, interpretable, high‐quality preclinical data. This approach will certainly increase our chance to 1 day offer stem cell therapeutic options for patients with all‐too‐common renal diseases. Stem Cells Translational Medicine2019;8:82–92
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Affiliation(s)
- Julia Marcheque
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Children's Hospital Los Angeles, Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, California
| | - Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
| | - Marie Csete
- Medical Engineering, California Institute of Technology, Los Angeles, California.,Department of Anesthesiology, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Laura Perin
- GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics, Children's Hospital Los Angeles, Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, California
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50
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MSC exosome works through a protein-based mechanism of action. Biochem Soc Trans 2018; 46:843-853. [PMID: 29986939 PMCID: PMC6103455 DOI: 10.1042/bst20180079] [Citation(s) in RCA: 276] [Impact Index Per Article: 39.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 05/24/2018] [Accepted: 05/29/2018] [Indexed: 02/07/2023]
Abstract
Mesenchymal stem cell (MSC) exosome specifically defines the 50–200 nm vesicles that are secreted into the extracellular space when multivesicular bodies in the MSC fuse with the plasma membrane. However, the exosome is just one of several 50–200 nm extracellular vesicles (EVs) known to be secreted by cells. Nevertheless, the term ‘MSC exosome’ is often used to describe populations of 50–200 nm EVs that are prepared from culture medium conditioned by MSCs on the basis that these populations collectively exhibited typical exosome-associated proteins such as endosomal proteins, TSG101 and Alix, and tetraspanin proteins, CD9, CD63 and CD81. They also carry a rich diverse RNA cargo. MSC exosomes are increasingly implicated as the mediator of many of the MSC-associated therapeutic potencies. They elicit therapeutic activity by delivering their cargo of potentially therapeutic proteins and RNAs to the recipient cells. The therapeutic potency of MSC exosomes is usually rationalized on the presence of a biologically relevant protein or RNA in the MSC exosome. In the present paper, we expanded this rationale beyond a physical presence to include biologically relevant concentration, biochemical functionality and the potential to elicit an appropriate timely biochemical response. Based on these, we propose that MSC exosomes most probably work through the protein rather than the RNA.
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