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Cunanan J, Zhang D, Peired AJ, Barua M. Podocytes in health and glomerular disease. Front Cell Dev Biol 2025; 13:1564847. [PMID: 40342933 PMCID: PMC12058676 DOI: 10.3389/fcell.2025.1564847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/08/2025] [Indexed: 05/11/2025] Open
Abstract
Podocytes are highly specialized, terminally differentiated cells in the glomerulus of the kidney and these cells play a central role in blood filtration. In this review, we comprehensively describe the cell biology of podocytes under healthy conditions and in glomerular disorders wherein podocyte injury is a major pathological mechanism. First, the molecular mechanisms that maintain podocyte actin cytoskeleton structure, permanent cell cycle exit, and metabolism under healthy conditions are described. Secondly, the mechanisms of podocyte injury, including genetic alterations and external insults that ultimately disrupt podocyte actin cytoskeleton dynamics or interrupt podocyte quiescence and mitochondrial metabolism are discussed. This understanding forms the basis of described potential therapeutic agents that act by modulating dysregulated podocyte cytoskeleton organization, prevent or reverse cell cycle re-entry, and re-establish normal mitochondrial energy production. Lastly, the application of modern techniques such as single cell RNA sequencing, super resolution microscopy, atomic force microscopy, and glomerular organoids is improving the resolution of mechanistic podocytopathy knowledge. Taken together, our review provides critical insights into the cellular and molecular mechanisms leading to podocyte loss, necessary for the advancement of therapeutic development in glomerular diseases.
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Affiliation(s)
- Joanna Cunanan
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Daniel Zhang
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
| | - Anna Julie Peired
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence (Università degli Studi di Firenze), Florence, Italy
| | - Moumita Barua
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
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Ghassemifard L, Hasanlu M, Parsamanesh N, Atkin SL, Almahmeed W, Sahebkar A. Cell Therapies and Gene Therapy for Diabetes: Current Progress. Curr Diabetes Rev 2025; 21:e130524229899. [PMID: 38747221 DOI: 10.2174/0115733998292392240425122326] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 03/07/2024] [Accepted: 03/21/2024] [Indexed: 04/23/2025]
Abstract
The epidemic of diabetes continues to be an increasing problem, and there is a need for new therapeutic strategies. There are several promising drugs and molecules in synthetic medicinal chemistry that are developing for diabetes. In addition to this approach, extensive studies with gene and cell therapies are being conducted. Gene therapy is an existing approach in treating several diseases, such as cancer, autoimmune diseases, heart disease and diabetes. Several reports have also suggested that stem cells have the differentiation capability to functional pancreatic beta cell development in vitro and in vivo, with the utility to treat diabetes and prevent the progression of diabetes-related complications. In this current review, we have focused on the different types of cell therapies and vector-based gene therapy in treating or preventing diabetes.
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Affiliation(s)
- Leila Ghassemifard
- Department of Physiology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
- Department of Persian Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Masumeh Hasanlu
- Department of Internal Medicine, Vali-e-Asr Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Negin Parsamanesh
- Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Stephen L Atkin
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Bahrain
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Barutta F, Corbetta B, Bellini S, Gambino R, Bruno S, Kimura S, Hase K, Ohno H, Gruden G. Protective effect of mesenchymal stromal cells in diabetic nephropathy: the In vitro and In vivo role of the M-Sec-tunneling nanotubes. Clin Sci (Lond) 2024; 138:1537-1559. [PMID: 39535903 DOI: 10.1042/cs20242064] [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: 09/19/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/16/2024]
Abstract
Mitochondrial dysfunction plays an important role in the development of podocyte injury in diabetic nephropathy (DN). Tunnelling nanotubes (TNTs) are long channels that connect cells and allow organelle exchange. Mesenchymal stromal cells (MSCs) can transfer mitochondria to other cells through the M-Sec-TNTs system. However, it remains unexplored whether MSCs can form heterotypic TNTs with podocytes, thereby enabling the replacement of diabetes-damaged mitochondria. In this study, we analysed TNT formation, mitochondrial transfer, and markers of cell injury in podocytes that were pre-exposed to diabetes-related insults and then co-cultured with diabetic or non-diabetic MSCs. Furthermore, to assess the in vivo relevance, we treated DN mice with exogenous MSCs, either expressing or lacking M-Sec, carrying fluorescent-tagged mitochondria. MSCs formed heterotypic TNTs with podocytes, allowing mitochondrial transfer, via a M-Sec-dependent mechanism. This ameliorated mitochondrial function, nephrin expression, and reduced apoptosis in recipient podocytes. However, MSCs isolated from diabetic mice failed to confer cytoprotection due to Miro-1 down-regulation. In experimental DN, treatment with exogenous MSCs significantly improved DN, but no benefit was observed in mice treated with MSCs lacking M-Sec. Mitochondrial transfer from exogenous MSCs to podocytes occurred in vivo in a M-Sec-dependent manner. These findings demonstrate that the M-Sec-TNT-mediated transfer of mitochondria from healthy MSCs to diabetes-injured podocytes can ameliorate podocyte damage. Moreover, M-Sec expression in exogenous MSCs is essential for providing renoprotection in vivo in experimental DN.
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Affiliation(s)
- Federica Barutta
- Department of Medical Sciences, University of Turin, Turin, Italy
| | | | - Stefania Bellini
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Roberto Gambino
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Stefania Bruno
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Shunsuke Kimura
- Division of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Koji Hase
- Division of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan
| | - Hiroshi Ohno
- Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Gabriella Gruden
- Department of Medical Sciences, University of Turin, Turin, Italy
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Habiba UE, Khan N, Greene DL, Shamim S, Umer A. The therapeutic effect of mesenchymal stem cells in diabetic kidney disease. J Mol Med (Berl) 2024; 102:537-570. [DOI: https:/doi.org/10.1007/s00109-024-02432-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 02/02/2024] [Accepted: 02/12/2024] [Indexed: 03/07/2024]
Abstract
Abstract
Diabetes mellitus (DM) often causes chronic kidney damage despite best medical practices. Diabetic kidney disease (DKD) arises from a complex interaction of factors within the kidney and the whole body. Targeting specific disease-causing agents using drugs has not been effective in treating DKD. However, stem cell therapies offer a promising alternative by addressing multiple disease pathways and promoting kidney regeneration. Mesenchymal stem cells (MSCs) offer great promise due to their superior accessibility ratio from adult tissues and remarkable modes of action, such as the production of paracrine anti-inflammatory and cytoprotective substances. This review critically evaluates the development of MSC treatment for DKD as it moves closer to clinical application. Results from animal models suggest that systemic MSC infusion may positively impact DKD progression. However, few registered and completed clinical trials exist, and whether the treatments are effective in humans is still being determined. Significant knowledge gaps and research opportunities exist, including establishing the ideal source, dose, and timing of MSC delivery, better understanding of in vivo mechanisms, and developing quantitative indicators to obtain a more significant therapeutic response. This paper reviews recent literature on using MSCs in preclinical and clinical trials in DKD. Potent biomarkers related to DKD are also highlighted, which may help better understand MSCs’ action in this disease progression.
Key messages
Mesenchymal stem cells have anti-inflammatory and paracrine effects in diabetic kidney disease.
Mesenchymal stem cells alleviate in animal models having diabetic kidney disease.
Mesenchymal stem cells possess promise for the treatment of diabetic kidney disease.
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Habiba UE, Khan N, Greene DL, Shamim S, Umer A. The therapeutic effect of mesenchymal stem cells in diabetic kidney disease. J Mol Med (Berl) 2024; 102:537-570. [PMID: 38418620 PMCID: PMC10963471 DOI: 10.1007/s00109-024-02432-w] [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: 05/02/2023] [Revised: 02/02/2024] [Accepted: 02/12/2024] [Indexed: 03/02/2024]
Abstract
Diabetes mellitus (DM) often causes chronic kidney damage despite best medical practices. Diabetic kidney disease (DKD) arises from a complex interaction of factors within the kidney and the whole body. Targeting specific disease-causing agents using drugs has not been effective in treating DKD. However, stem cell therapies offer a promising alternative by addressing multiple disease pathways and promoting kidney regeneration. Mesenchymal stem cells (MSCs) offer great promise due to their superior accessibility ratio from adult tissues and remarkable modes of action, such as the production of paracrine anti-inflammatory and cytoprotective substances. This review critically evaluates the development of MSC treatment for DKD as it moves closer to clinical application. Results from animal models suggest that systemic MSC infusion may positively impact DKD progression. However, few registered and completed clinical trials exist, and whether the treatments are effective in humans is still being determined. Significant knowledge gaps and research opportunities exist, including establishing the ideal source, dose, and timing of MSC delivery, better understanding of in vivo mechanisms, and developing quantitative indicators to obtain a more significant therapeutic response. This paper reviews recent literature on using MSCs in preclinical and clinical trials in DKD. Potent biomarkers related to DKD are also highlighted, which may help better understand MSCs' action in this disease progression. KEY MESSAGES: Mesenchymal stem cells have anti-inflammatory and paracrine effects in diabetic kidney disease. Mesenchymal stem cells alleviate in animal models having diabetic kidney disease. Mesenchymal stem cells possess promise for the treatment of diabetic kidney disease.
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Affiliation(s)
- Umm E Habiba
- Pak-American Hospital Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan.
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA.
| | - Nasar Khan
- Pak-American Hospital Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan.
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA.
- Bello Bio Labs and Therapeutics (SMC) Pvt. Ltd., Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan.
| | - David Lawrence Greene
- Pak-American Hospital Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA
- Bello Bio Labs and Therapeutics (SMC) Pvt. Ltd., Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan
| | - Sabiha Shamim
- Pak-American Hospital Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA
| | - Amna Umer
- Pak-American Hospital Pvt. Ltd, Jahangir Multiplex, Peshawar Road, Sector H-13, Islamabad, 44000, Pakistan
- R3 Medical Research LLC, 10045 East Dynamite Boulevard Suite 260, Scottsdale, AZ, 85262, USA
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Zou Y, Li S, Chen W, Xu J. Urine-derived stem cell therapy for diabetes mellitus and its complications: progress and challenges. Endocrine 2024; 83:270-284. [PMID: 37801228 DOI: 10.1007/s12020-023-03552-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Accepted: 09/24/2023] [Indexed: 10/07/2023]
Abstract
Diabetes mellitus (DM) is a chronic and relentlessly progressive metabolic disease characterized by a relative or absolute deficiency of insulin in the body, leading to increased production of advanced glycosylation end products that further enhance oxidative and nitrosative stresses, often leading to multiple macrovascular (cardiovascular disease) and microvascular (e.g., diabetic nephropathy, diabetic retinopathy, and neuropathy) complications, representing the ninth leading cause of death worldwide. Existing medical treatments do not provide a complete cure for DM; thus, stem cell transplantation therapy has become the focus of research on DM and its complications. Urine-derived stem cells (USCs), which are isolated from fresh urine and have biological properties similar to those of mesenchymal stem cells (MSCs), were demonstrated to exert antiapoptotic, antifibrotic, anti-inflammatory, and proangiogenic effects through direct differentiation or paracrine mechanisms and potentially treat patients with DM. USCs also have the advantages of simple noninvasive sample collection procedures, minimal ethical issues, low cost, and easy cell isolation methods and thus have received more attention in regenerative therapies in recent years. This review outlines the biological properties of USCs and the research progress and current limitations of their role in DM and related complications. In summary, USCs have shown good versatility in treating hyperglycemia-impaired target organs in preclinical models, and many challenges remain in translating USC therapies to the clinic.
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Affiliation(s)
- Yun Zou
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Shanshan Li
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wen Chen
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jixiong Xu
- Department of Endocrinology and Metabolism, First Affiliated Hospital of Nanchang University, Nanchang, China.
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Wang K, Liu T, Zhang Y, Lv H, Yao H, Zhao Y, Li J, Li X. Combined Placental Mesenchymal Stem Cells with Guided Nanoparticles Effective Against Diabetic Nephropathy in Mouse Model. Int J Nanomedicine 2024; 19:901-915. [PMID: 38293609 PMCID: PMC10826715 DOI: 10.2147/ijn.s446733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 01/13/2024] [Indexed: 02/01/2024] Open
Abstract
Background Diabetic nephropathy (DN) is a prevalent complication of diabetes mellitus and constitutes the primary cause of mortality in affected patients. Previous studies have shown that placental mesenchymal stem cells (PL-MSCs) can alleviate kidney dysfunction in animal models of DN. However, the limited ability of mesenchymal stem cells (MSCs) to home to damaged sites restricts their therapeutic potential. Enhancing the precision of PL-MSCs' homing to target tissues is therefore vital for the success of cell therapies in treating DN. Methods We developed Fe3O4 coated polydopamine nanoparticle (NP)-internalized MSCs and evaluated their therapeutic effectiveness in a mouse model of streptozotocin- and high-fat diet-induced DN, using an external magnetic field. Results Our study confirmed that NPs were effectively internalized into PL-MSCs without compromising their intrinsic stem cell properties. The magnetic targeting of PL-MSCs notably improved their homing to the kidney tissues in mice with DN, resulting in enhanced kidney function compared to the transplantation of PL-MSCs alone. Furthermore, the anti-inflammatory and antifibrotic attributes of PL-MSCs played a role in the recovery of kidney function and structure. Conclusion These results demonstrate that magnetically targeted therapy using PL-MSCs is a promising approach for treating diabetic nephropathy.
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Affiliation(s)
- Ke Wang
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
- Gynecology and Obstetrics Department, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Te Liu
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Yucheng Zhang
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Huiying Lv
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Hua Yao
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Ye Zhao
- Dermatological Department, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Jing Li
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
| | - Xiuying Li
- Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China
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Pour-Reza-Gholi F, Assadiasl S. Immunological Approaches in the Treatment of Diabetic Nephropathy. Curr Diabetes Rev 2024; 21:e061123223172. [PMID: 37936470 DOI: 10.2174/0115733998267893231016062205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 08/23/2023] [Accepted: 08/31/2023] [Indexed: 11/09/2023]
Abstract
Diabetic nephropathy (DN), the leading cause of end-stage renal disease, has no definite treatment so far. In fact, a combination of metabolic, hemodynamic, and immunological factors are involved in the pathogenesis of DN; therefore, effective disease management requires a holistic approach to all predisposing contributors. Due to the recent findings about the role of inflammation in the initiation and progression of kidney injury in diabetic patients and considerable advances in immunotherapy methods, it might be useful to revise and reconsider the current knowledge of the potential of immunomodulation in preventing and attenuating DN. In this review, we have summarized the findings of add-on therapeutic methods that have concentrated on regulating inflammatory responses in diabetic nephropathy, including phosphodiesterase inhibitors, nuclear factor-kB inhibitors, Janus kinase inhibitors, chemokine inhibitors, anti-cytokine antibodies, cell therapy, and vaccination.
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Affiliation(s)
- Fatemeh Pour-Reza-Gholi
- Department of Nephrology, Labbafinezhad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sara Assadiasl
- Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Qian Q, Pan J, Yang J, Wang R, Luo K, Ma Z, Li M, Gao Y. Effect of different hypoxic and hypobaric interventions on blood gas and erythrocyte-related indicators in rats. Zhejiang Da Xue Xue Bao Yi Xue Ban 2023; 52:777-784. [PMID: 38105680 PMCID: PMC10764180 DOI: 10.3724/zdxbyxb-2023-0352] [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: 07/27/2023] [Accepted: 11/07/2023] [Indexed: 12/19/2023]
Abstract
OBJECTIVES To explore the effects of hypoxic and hypobaric conditions on blood gas and erythrocyte-related indicators in rats. METHODS SD male rats were exposed to low-pressure hypoxic conditions simulating an altitude of 6500 m in a small or a large experimental cabin. Abdominal aortic blood samples were collected and blood gas indicators, red blood cells (RBCs) count, and hemoglobin (Hb) content were measured. The effects of exposure to different hypoxia times, different hypoxia modes, normal oxygen recovery after hypoxia, and re-hypoxia after hypoxia preconditioning on blood gas indicators, RBCs count and Hb content were investigated. RESULTS The effect of blood gas indicators was correlated with the length of exposure time of hypoxia and the reoxygenation after leaving the cabin. Hypoxia caused acid-base imbalance and its severity was associated with the duration of hypoxia; hypoxia also led to an increase in RBCs count and Hb content, and the increase was also related to the time exposed to hypoxia. The effects of reoxygenation on acid-base imbalance in rats caged in a small animal cabin were more severe that those in a large experimental cabin. Acetazolamide alleviated the effects of reoxygenation after leaving the cabin. Different hypoxia modes and administration of acetazolamide had little effect on RBCs count and Hb content. Normal oxygen recovery can alleviate the reoxygenation and acid-base imbalance of hypoxic rats after leaving the cabin and improve the increase in red blood cell and hemoglobin content caused by hypoxia. The improvement of hypoxia preconditioning on post hypoxia reoxygenation is not significant, but it can alleviate the acid-base imbalance caused by hypoxia in rats and to some extent improve the increase in red blood cell and hemoglobin content caused by hypoxia. CONCLUSIONS Due to excessive ventilation and elevated RBCs count and Hb content after hypoxia reoxygenation, oxygen partial pressure and other oxygenation indicators in hypoxic rats are prone to become abnormal, while blood gas acid-base balance indicators are relatively stable, which are more suitable for evaluating the degree of hypoxia injury and related pharmacological effects in rats.
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Affiliation(s)
- Qingyuan Qian
- College of Pharmacy, Lanzhou University, Lanzhou 730000, China.
- Institute of Radiation Medicine Sciences, Academy of Military Medicine, Academy of Military Sciences, Beijing 100850, China.
| | - Jinchao Pan
- Institute of Radiation Medicine Sciences, Academy of Military Medicine, Academy of Military Sciences, Beijing 100850, China
| | - Jun Yang
- Institute of Radiation Medicine Sciences, Academy of Military Medicine, Academy of Military Sciences, Beijing 100850, China
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Renjie Wang
- Institute of Radiation Medicine Sciences, Academy of Military Medicine, Academy of Military Sciences, Beijing 100850, China
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Kai Luo
- Institute of Radiation Medicine Sciences, Academy of Military Medicine, Academy of Military Sciences, Beijing 100850, China
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China
| | - Zengchun Ma
- Institute of Radiation Medicine Sciences, Academy of Military Medicine, Academy of Military Sciences, Beijing 100850, China
| | - Maoxing Li
- College of Pharmacy, Lanzhou University, Lanzhou 730000, China.
- Institute of Radiation Medicine Sciences, Academy of Military Medicine, Academy of Military Sciences, Beijing 100850, China.
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou 730000, China.
| | - Yue Gao
- Institute of Radiation Medicine Sciences, Academy of Military Medicine, Academy of Military Sciences, Beijing 100850, China.
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Perico N, Remuzzi G, Griffin MD, Cockwell P, Maxwell AP, Casiraghi F, Rubis N, Peracchi T, Villa A, Todeschini M, Carrara F, Magee BA, Ruggenenti PL, Rota S, Cappelletti L, McInerney V, Griffin TP, Islam MN, Introna M, Pedrini O, Golay J, Finnerty AA, Smythe J, Fibbe WE, Elliman SJ, O'Brien T. Safety and Preliminary Efficacy of Mesenchymal Stromal Cell (ORBCEL-M) Therapy in Diabetic Kidney Disease: A Randomized Clinical Trial (NEPHSTROM). J Am Soc Nephrol 2023; 34:1733-1751. [PMID: 37560967 PMCID: PMC10561817 DOI: 10.1681/asn.0000000000000189] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/26/2023] [Indexed: 08/11/2023] Open
Abstract
SIGNIFICANCE STATEMENT Mesenchymal stromal cells (MSCs) may offer a novel therapy for diabetic kidney disease (DKD), although clinical translation of this approach has been limited. The authors present findings from the first, lowest dose cohort of 16 adults with type 2 diabetes and progressive DKD participating in a randomized, placebo-controlled, dose-escalation phase 1b/2a trial of next-generation bone marrow-derived, anti-CD362 antibody-selected allogeneic MSCs (ORBCEL-M). A single intravenous (iv) infusion of 80×10 6 cells was safe and well-tolerated, with one quickly resolved infusion reaction in the placebo group and no subsequent treatment-related serious adverse events (SAEs). Compared with placebo, the median annual rate of decline in eGFR was significantly lower with ORBCEL-M, although mGFR did not differ. The results support further investigation of ORBCEL-M in this patient population in an appropriately sized phase 2b study. BACKGROUND Systemic therapy with mesenchymal stromal cells may target maladaptive processes involved in diabetic kidney disease progression. However, clinical translation of this approach has been limited. METHODS The Novel Stromal Cell Therapy for Diabetic Kidney Disease (NEPHSTROM) study, a randomized, placebo-controlled phase 1b/2a trial, assesses safety, tolerability, and preliminary efficacy of next-generation bone marrow-derived, anti-CD362-selected, allogeneic mesenchymal stromal cells (ORBCEL-M) in adults with type 2 diabetes and progressive diabetic kidney disease. This first, lowest dose cohort of 16 participants at three European sites was randomized (3:1) to receive intravenous infusion of ORBCEL-M (80×10 6 cells, n =12) or placebo ( n =4) and was followed for 18 months. RESULTS At baseline, all participants were negative for anti-HLA antibodies and the measured GFR (mGFR) and estimated GFR were comparable between groups. The intervention was safe and well-tolerated. One placebo-treated participant had a quickly resolved infusion reaction (bronchospasm), with no subsequent treatment-related serious adverse events. Two ORBCEL-M recipients died during follow-up of causes deemed unrelated to the trial intervention; one recipient developed low-level anti-HLA antibodies. The median annual rate of kidney function decline after ORBCEL-M therapy compared with placebo did not differ by mGFR, but was significantly lower by eGFR estimated by the Chronic Kidney Disease Epidemiology Collaboration and Modification of Diet in Renal Disease equations. Immunologic profiling provided evidence of preservation of circulating regulatory T cells, lower natural killer T cells, and stabilization of inflammatory monocyte subsets in those receiving the cell therapy compared with placebo. CONCLUSIONS Findings indicate safety and tolerability of intravenous ORBCEL-M cell therapy in the trial's lowest dose cohort. The rate of decline in eGFR (but not mGFR) over 18 months was significantly lower among those receiving cell therapy compared with placebo. Further studies will be needed to determine the therapy's effect on CKD progression. CLINICAL TRIAL REGISTRATION NUMBER ClinicalTrial.gov NCT02585622 .
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Affiliation(s)
- Norberto Perico
- Centro di Ricerche Cliniche per le Malattie Rare “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Giuseppe Remuzzi
- Centro di Ricerche Cliniche per le Malattie Rare “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Matthew D. Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, University of Galway, Galway, Ireland
| | - Paul Cockwell
- Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
- Institute of Ageing and Immunity, University of Birmingham, Birmingham, United Kingdom
| | | | - Federica Casiraghi
- Centro di Ricerche Cliniche per le Malattie Rare “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Nadia Rubis
- Centro di Ricerche Cliniche per le Malattie Rare “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Tobia Peracchi
- Centro di Ricerche Cliniche per le Malattie Rare “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Alessandro Villa
- Centro di Ricerche Cliniche per le Malattie Rare “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Marta Todeschini
- Centro di Ricerche Cliniche per le Malattie Rare “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Fabiola Carrara
- Centro di Ricerche Cliniche per le Malattie Rare “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Bernadette A. Magee
- Northern Ireland Histocompatibility and Immunogenetics Laboratory, Belfast City Hospital, Belfast, Northern Ireland
| | - Piero L. Ruggenenti
- Centro di Ricerche Cliniche per le Malattie Rare “Aldo e Cele Daccò”, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
- Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Stefano Rota
- Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Laura Cappelletti
- Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Veronica McInerney
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, University of Galway, Galway, Ireland
- HRB Clinical Research Facility, University of Galway, Galway, Ireland
| | - Tomás P. Griffin
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, University of Galway, Galway, Ireland
| | - Md Nahidul Islam
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, University of Galway, Galway, Ireland
| | - Martino Introna
- Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Olga Pedrini
- Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
- Fondazione per la Ricerca Ospedale di Bergamo (FROM), Bergamo, Italy
| | - Josée Golay
- Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Andrew A. Finnerty
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, University of Galway, Galway, Ireland
- HRB Clinical Research Facility, University of Galway, Galway, Ireland
- Centre for Cell Manufacturing Ireland, University of Galway, Galway, Ireland
| | - Jon Smythe
- NHS Blood and Transplant Oxford Centre, John Radcliffe Hospital, Oxford, United Kingdom
| | | | | | - Timothy O'Brien
- Regenerative Medicine Institute (REMEDI) at CÚRAM SFI Research Centre for Medical Devices, School of Medicine, University of Galway, Galway, Ireland
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11
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Mohammadi Y, Zangooei M, Salmani F, Farimani AR. Effect of crocin and losartan on biochemical parameters and genes expression of FRMD3 and BMP7 in diabetic rats. Turk J Med Sci 2023; 53:10-18. [PMID: 36945919 PMCID: PMC10387854 DOI: 10.55730/1300-0144.5553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 09/13/2022] [Indexed: 02/26/2023] Open
Abstract
BACKGROUND Diabetes is a multifactorial and growing disease, one of the severe complications of which is diabetic nephropathy (DN), which is the most common cause of chronic renal failure. FERM domain containing 3 (FRMD3) is responsible for maintaining the shape and integrity of nephron cells, and bone morphogenetic protein 7 (BMP7) helps maintain function and reduce kidney damage. This study aimed to evaluate the effect of crocin and losartan on biochemical parameters and the expression of FRMD3 and BMP7 genes in streptozotocin (STZ)-induced diabetic rats. METHODS Forty male Wistar rats were randomly divided into five experimental groups as healthy, diabetic control (D), crocin, losartan, and diabetic rats treated with losartan-crocin (n = 8). A single dose of STZ (50 mg/kg intraperitoneally injection) was used to induce diabetes. Four weeks after induction of diabetes, rats received crocin (50 mg/kg) and losartan (25 mg/kg) daily for four weeks orally. Rats were sacrificed at the end of the intervention, and blood samples were taken to determine serum levels of glucose, urea, creatinine (Cr), malondialdehyde (MDA), and thiol. Real-time polymerase chain reaction (PCR) was used to assess the expression of the FRMD3 and BMP7 genes in the kidney samples. RESULTS Diabetes induction increased serum levels of glucose, Cr, urea, MDA, and thiol, but decreased BMP7 and FRMD3 genes expression. Treatment with crocin and losartan decreased these biochemical parameters and increased the expression of the BMP7 and FRMD3 genes. DISCUSSION Crocin may be a promising therapeutic agent for preventing and improving diabetes-related kidney disease due to its antidiabetic and antioxidant properties.
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Affiliation(s)
- Yaser Mohammadi
- Qaen School of Nursing and Midwifery, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammad Zangooei
- Department of Clinical Biochemistry, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | - Fatemeh Salmani
- Departments of Epidemiology and Biostatistics, School of Health Social Determinants of Health Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Azam Rezaei Farimani
- Department of Clinical Biochemistry, School of Medicine, Birjand University of Medical Sciences, Birjand, Iran ; Cardiovascular Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
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12
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Infante B, Conserva F, Pontrelli P, Leo S, Stasi A, Fiorentino M, Troise D, dello Strologo A, Alfieri C, Gesualdo L, Castellano G, Stallone G. Recent advances in molecular mechanisms of acute kidney injury in patients with diabetes mellitus. Front Endocrinol (Lausanne) 2023; 13:903970. [PMID: 36686462 PMCID: PMC9849571 DOI: 10.3389/fendo.2022.903970] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 12/14/2022] [Indexed: 01/06/2023] Open
Abstract
Several insults can lead to acute kidney injury (AKI) in native kidney and transplant patients, with diabetes critically contributing as pivotal risk factor. High glucose per se can disrupt several signaling pathways within the kidney that, if not restored, can favor the instauration of mechanisms of maladaptive repair, altering kidney homeostasis and proper function. Diabetic kidneys frequently show reduced oxygenation, vascular damage and enhanced inflammatory response, features that increase the kidney vulnerability to hypoxia. Importantly, epidemiologic data shows that previous episodes of AKI increase susceptibility to diabetic kidney disease (DKD), and that patients with DKD and history of AKI have a generally worse prognosis compared to DKD patients without AKI; it is therefore crucial to monitor diabetic patients for AKI. In the present review, we will describe the causes that contribute to increased susceptibility to AKI in diabetes, with focus on the molecular mechanisms that occur during hyperglycemia and how these mechanisms expose the different types of resident renal cells to be more vulnerable to maladaptive repair during AKI (contrast- and drug-induced AKI). Finally, we will review the list of the existing candidate biomarkers of diagnosis and prognosis of AKI in patients with diabetes.
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Affiliation(s)
- Barbara Infante
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Francesca Conserva
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Paola Pontrelli
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Serena Leo
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Alessandra Stasi
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Marco Fiorentino
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Dario Troise
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | | | - Carlo Alfieri
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Giovanni Stallone
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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13
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Gao WW, Chun SY, Kim BS, Ha YS, Lee JN, Lee EH, Kim IY, You S, Kwon TG. Locally transplanted human urine-induced nephron progenitor cells contribute to renal repair in mice kidney with diabetic nephropathy. Biochem Biophys Res Commun 2022; 629:128-134. [PMID: 36116375 DOI: 10.1016/j.bbrc.2022.09.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 09/02/2022] [Indexed: 11/29/2022]
Abstract
Chronic Kidney Disease (CKD) is increasingly recognized as a global public health issue. Diabetic nephropathy (DN), also known as diabetic kidney disease, is a leading cause of CKD. Regenerative medicine strategy employing nephron progenitor cells (NPCs) is worthy of consideration as an alternative to shortage of donor organs for kidney transplantation. In previous study, we successfully generated induced NPCs (iNPCs) from human urine-derived cells that resembled human embryonic stem cell-derived NPCs. Here, we aimed to investigate the therapeutic potential of iNPCs in DN animal model. The results revealed the therapeutic effect of iNPCs as follows: (1) diminished glomerular hypertrophy, (2) reduced tubulointerstitial fibrosis, (3) low blood urea nitrogen, serum creatinine and albuminuria value, (4) decreased inflammation/fibrosis, (5) enhanced renal regeneration and (6) confirmed safety. This study demonstrates that human iNPCs have a therapeutic potential as a cell source for transplantation in patients with kidney diseases.
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Affiliation(s)
- Wei-Wei Gao
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, South Korea; Institute of Future Medicine, STEMLAB, Inc., Seoul, 02841, South Korea
| | - So Young Chun
- BioMedical Research Institute, Kyungpook National University Hospital, Daegu, 41940, South Korea
| | - Bum Soo Kim
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, 41405, South Korea
| | - Yun-Sok Ha
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, 41405, South Korea
| | - Jun Nyung Lee
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, 41405, South Korea
| | - Eun Hye Lee
- Joint Institute for Regenerative Medicine, Kyungpook National University, Daegu, 41940, Republic of Korea
| | - In Yong Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, South Korea.
| | - Seungkwon You
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, South Korea.
| | - Tae Gyun Kwon
- Department of Urology, School of Medicine, Kyungpook National University, Daegu, 41405, South Korea.
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Abstract
Findings of preclinical studies and recent phase I/II clinical trials have shown that mesenchymal stem cells (MSCs) play a significant role in the development of diabetic kidney disease (DKD). Thus, MSCs have attracted increasing attention as a novel regenerative therapy for kidney diseases. This review summarizes recent literature on the roles and potential mechanisms, including hyperglycemia regulation, anti-inflammation, anti-fibrosis, pro-angiogenesis, and renal function protection, of MSC-based treatment methods for DKD. This review provides novel insights into understanding the pathogenesis of DKD and guiding the development of biological therapies.
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Affiliation(s)
- Ning Xu
- Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, 261053, China
| | - Jie Liu
- Affiliated Hospital of Weifang Medical University, School of Clinical Medicine, Weifang Medical University, Weifang, 261053, China
| | - Xiangling Li
- Department of Nephrology, Affiliated Hospital of Weifang Medical University, Weifang, 261031, China
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15
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Dosing Limitation for Intra-Renal Arterial Infusion of Mesenchymal Stromal Cells. Int J Mol Sci 2022; 23:ijms23158268. [PMID: 35955404 PMCID: PMC9368110 DOI: 10.3390/ijms23158268] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 07/22/2022] [Accepted: 07/24/2022] [Indexed: 02/01/2023] Open
Abstract
The immunomodulatory and regenerative properties of mesenchymal stromal cells (MSCs) make MSC therapy a promising therapeutic strategy in kidney disease. A targeted MSC administration via the renal artery offers an efficient delivery method with limited spillover to other organs. Although local administration alleviates safety issues with MSCs in systemic circulation, it introduces new safety concerns in the kidneys. In a porcine model, we employed intra-renal arterial infusion of ten million allogenic adipose tissue-derived MSCs. In order to trigger any potential adverse events, a higher dose (hundred million MSCs) was also included. The kidney function was studied by magnetic resonance imaging after the MSC infusion and again at two weeks post-treatment. The kidneys were assessed by single kidney glomerular filtration rate (skGFR) measurements, histology and inflammation, and fibrosis-related gene expression. None of the measured parameters were affected immediately after the administration of ten million MSCs, but the administration of one hundred million MSCs induced severe adverse events. Renal perfusion was reduced immediately after MSC administration which coincided with the presence of microthrombi in the glomeruli and signs of an instant blood-mediated inflammatory reaction. At two weeks post-treatment, the kidneys that were treated with one hundred million MSCs showed reduced skGFR, signs of tissue inflammation, and glomerular and tubular damage. In conclusions, the intra-renal administration of ten million MSCs is well-tolerated by the porcine kidney. However, higher concentrations (one hundred million MSCs) caused severe kidney damage, implying that very high doses of intra-renally administered MSCs should be undertaken with caution.
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16
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Rafiee Z, Orazizadeh M, Nejad Dehbashi F, Neisi N, Babaahmadi-Rezaei H, Mansouri E. Mesenchymal stem cells derived from the kidney can ameliorate diabetic nephropathy through the TGF-β/Smad signaling pathway. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:53212-53224. [PMID: 35278177 DOI: 10.1007/s11356-021-17954-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 12/01/2021] [Indexed: 06/14/2023]
Abstract
Diabetic nephropathy (DN) has been introduced as one of the main microvascular complications in diabetic patients, the most common cause of end-stage renal disease (ESRD). Based on the therapeutic potential of mesenchymal stem cells in tissue repair, we aimed to test the hypothesis that kidney stem cells (KSCs) might be effective in the kidney regeneration process. Stem cells from rat kidney were separated, and the surface stem cell markers were determined by flow cytometry analysis. Thirty-two Sprague Dawley rats were divided into four groups (control, control that received kidney stem cells, diabetic, diabetic treated with stem cells). To establish diabetic, model STZ (streptozotocin) (60 mg/kg) was used. The KSCs were injected into experimental groups via tail vein (2 × 106 cells/rat). In order to determine the impact of stem cells on the function and structure of the kidney, biochemical and histological parameters were measured. Further, the expression of miRNA-29a, miR-192, IL-1β, and TGF-β was determined through the real-time PCR technique. Phosphorylation of Smad2/3 was evaluated by using the standard western blotting. The KSCs significantly reduced blood nitrogen (BUN), serum creatinine (Scr), and 24-h urinary proteins in DN (P < 0.05). IL-1β and TGF-β significantly increased in the kidney of diabetic rats. In addition, the expression of miR-29a is significantly increased, whereas miR-192 decreased after treatment with KSCs (P < 0.05). Diabetic rats showed an increased level of phosphorylation of both Smad2 and Smad3 (P < 0.05). Periodic acid-Schiff (PAS) staining showed improved histopathological changes in the presence of KSCs. Stem cells derived from adult rat kidney may be an option for treating the early DN to improve the functions and structure of kidneys in rats with DN.
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Affiliation(s)
- Zeinab Rafiee
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran
| | - Mahmoud Orazizadeh
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran
| | - Fereshteh Nejad Dehbashi
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Niloofar Neisi
- Alimentary Tract Research Center, Imam Khomeini Hospital Clinical Research Development Unit, Infectious and Tropical Diseases Research Center, Department of Virology, the School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Babaahmadi-Rezaei
- Hyperlipidemia Research Center, Department of Clinical Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Esrafil Mansouri
- Medical Basic Sciences Research Institute, Cellular and Molecular Research Center, Department of Anatomical Sciences, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, 61335, Ahvaz, Iran.
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Quaglia M, Merlotti G, Fornara L, Colombatto A, Cantaluppi V. Extracellular Vesicles Released from Stem Cells as a New Therapeutic Strategy for Primary and Secondary Glomerulonephritis. Int J Mol Sci 2022; 23:ijms23105760. [PMID: 35628570 PMCID: PMC9142886 DOI: 10.3390/ijms23105760] [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: 04/23/2022] [Revised: 05/13/2022] [Accepted: 05/20/2022] [Indexed: 12/04/2022] Open
Abstract
Current treatment of primary and secondary glomerulopathies is hampered by many limits and a significant proportion of these disorders still evolves towards end-stage renal disease. A possible answer to this unmet challenge could be represented by therapies with stem cells, which include a variety of progenitor cell types derived from embryonic or adult tissues. Stem cell self-renewal and multi-lineage differentiation ability explain their potential to protect and regenerate injured cells, including kidney tubular cells, podocytes and endothelial cells. In addition, a broad spectrum of anti-inflammatory and immunomodulatory actions appears to interfere with the pathogenic mechanisms of glomerulonephritis. Of note, mesenchymal stromal cells have been particularly investigated as therapy for Lupus Nephritis and Diabetic Nephropathy, whereas initial evidence suggest their beneficial effects in primary glomerulopathies such as IgA nephritis. Extracellular vesicles mediate a complex intercellular communication network, shuttling proteins, nucleic acids and other bioactive molecules from origin to target cells to modulate their functions. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, reparative and immunomodulatory properties of parental cells and are increasingly recognized as a cell-free alternative to stem cell-based therapies for different diseases including glomerulonephritis, also considering the low risk for potential adverse effects such as maldifferentiation and tumorigenesis. We herein summarize the renoprotective potential of therapies with stem cells and extracellular vesicles derived from progenitor cells in glomerulonephritis, with a focus on their different mechanisms of actions. Technological progress and growing knowledge are paving the way for wider clinical application of regenerative medicine to primary and secondary glomerulonephritis: this multi-level, pleiotropic therapy may open new scenarios overcoming the limits and side effects of traditional treatments, although the promising results of experimental models need to be confirmed in the clinical setting.
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Zhu Y, Luo M, Bai X, Lou Y, Nie P, Jiang S, Li J, Li B, Luo P. Administration of mesenchymal stem cells in diabetic kidney disease: mechanisms, signaling pathways, and preclinical evidence. Mol Cell Biochem 2022; 477:2073-2092. [PMID: 35469057 DOI: 10.1007/s11010-022-04421-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/22/2022] [Indexed: 02/07/2023]
Abstract
Diabetic kidney disease (DKD) is a serious microvascular complication of diabetes. Currently, the prevalence and mortality of DKD are increasing annually. However, with no effective drugs to prevent its occurrence and development, the primary therapeutic option is to control blood sugar and blood pressure. Therefore, new and effective drugs/methods are imperative to prevent the development of DKD in patients with diabetes. Mesenchymal stem cells (MSCs) with multi-differentiation potential and paracrine function have received extensive attention as a new treatment option for DKD. However, their role and mechanism in the treatment of DKD remain unclear, and clinical applications are still being explored. Given this, we here provide an unbiased review of recent advances in MSCs for the treatment of DKD in the last decade from the perspectives of the pathogenesis of DKD, biological characteristics of MSCs, and different molecular and signaling pathways. Furthermore, we summarize information on combination therapy strategies using MSCs. Finally, we discuss the challenges and prospects for clinical application.
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Affiliation(s)
- Yuexin Zhu
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China
| | - Manyu Luo
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China
| | - Xue Bai
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China
| | - Yan Lou
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China
| | - Ping Nie
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China
| | - Shan Jiang
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China
| | - Jicui Li
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China
| | - Bing Li
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China.
| | - Ping Luo
- Department of Nephrology, The Second Hospital of Jilin University, 218 ZiQiang Street, Changchun, 130041, Jilin, People's Republic of China.
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Peng L, Chen Y, Shi S, Wen H. Stem cell-derived and circulating exosomal microRNAs as new potential tools for diabetic nephropathy management. Stem Cell Res Ther 2022; 13:25. [PMID: 35073973 PMCID: PMC8785577 DOI: 10.1186/s13287-021-02696-w] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Despite major advances in the treatment of diabetic nephropathy (DN) in recent years, it remains the most common cause of end-stage renal disease. An early diagnosis and therapy may slow down the DN progression. Numerous potential biomarkers are currently being researched. Circulating levels of the kidney-released exosomes and biological molecules, which reflect the DN pathology including glomerular and tubular dysfunction as well as mesangial expansion and fibrosis, have shown the potential for predicting the occurrence and progression of DN. Moreover, many experimental therapies are currently being investigated, including stem cell therapy and medications targeting inflammatory, oxidant, or pro-fibrotic pathways activated during the DN progression. The therapeutic potential of stem cells is partly depending on their secretory capacity, particularly exosomal microRNAs (Exo-miRs). In recent years, a growing line of research has shown the participation of Exo-miRs in the pathophysiological processes of DN, which may provide effective therapeutic and biomarker tools for DN treatment. METHODS A systematic literature search was performed in MEDLINE, Scopus, and Google Scholar to collect published findings regarding therapeutic stem cell-derived Exo-miRs for DN treatment as well as circulating Exo-miRs as potential DN-associated biomarkers. FINDINGS Glomerular mesangial cells and podocytes are the most important culprits in the pathogenesis of DN and, thus, can be considered valuable therapeutic targets. Preclinical investigations have shown that stem cell-derived exosomes can exert beneficial effects in DN by transferring renoprotective miRs to the injured mesangial cells and podocytes. Of note, renoprotective Exo-miR-125a secreted by adipose-derived mesenchymal stem cells can improve the injured mesangial cells, while renoprotective Exo-miRs secreted by adipose-derived stem cells (Exo-miR-486 and Exo-miR-215-5p), human urine-derived stem cells (Exo-miR-16-5p), and bone marrow-derived mesenchymal stem cells (Exo-miR-let-7a) can improve the injured podocytes. On the other hand, clinical investigations have indicated that circulating Exo-miRs isolated from urine or serum hold great potential as promising biomarkers in DN.
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Affiliation(s)
- Lei Peng
- Department of Nephrology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, 610072, China
| | - Yu Chen
- Department of Cardiology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, 610072, China
| | - Shaoqing Shi
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
| | - Heling Wen
- Department of Cardiology, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, 610072, China.
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Nie P, Bai X, Lou Y, Zhu Y, Jiang S, Zhang L, Tian N, Luo P, Li B. Human umbilical cord mesenchymal stem cells reduce oxidative damage and apoptosis in diabetic nephropathy by activating Nrf2. Stem Cell Res Ther 2021; 12:450. [PMID: 34380544 PMCID: PMC8356418 DOI: 10.1186/s13287-021-02447-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 06/07/2021] [Indexed: 12/31/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have a therapeutic effect on diabetic nephropathy (DN) but the underlying mechanism remains unclear. This study was conducted to investigate whether human umbilical cord-MSCs (hUCMSCs) can induce oxidative damage and apoptosis by activating Nrf2. Methods We used a type 2 diabetic rat model and a high-glucose and fat-stimulated human glomerular mesangial cell (hGMC) model. Western blotting, RT-qPCR, and TUNEL staining were performed on animal tissues and cultured cells. Nuclear expression of Nrf2 was detected in the renal tissue. Furthermore, Nrf2 siRNA was used to examine the effects of hUCMSCs on hGMCs. Finally, the effect of hUCMSCs on the Nrf2 upstream signalling pathway was investigated. Results After treatment with hUCMSCs, Nrf2 showed increased expression and nuclear translocation. After Nrf2-specific knockout in hGMCs, the protective effect of hUCMSCs on apoptosis induced by high-glucose and fat conditions was reduced. Activation of the PI3K signalling pathway may be helpful for ameliorating DN using hUCMSCs. Conclusions hUCMSCs attenuated renal oxidative damage and apoptosis in type 2 diabetes mellitus and Nrf2 activation is one of the important mechanisms of this effect. hUCMSCs show potential as drug targets for DN. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02447-x.
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Affiliation(s)
- Ping Nie
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Xue Bai
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yan Lou
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Yuexin Zhu
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Shan Jiang
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Lina Zhang
- Research and Development Department, Jilin Tuohua Biotechnology Co., Ltd., Changchun, Jilin Province, China
| | - Na Tian
- Research and Development Department, Jilin Tuohua Biotechnology Co., Ltd., Changchun, Jilin Province, China
| | - Ping Luo
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, China.
| | - Bing Li
- Department of Nephropathy, The Second Hospital of Jilin University, Changchun, Jilin Province, China.
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21
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Hickson LJ, Abedalqader T, Ben-Bernard G, Mondy JM, Bian X, Conley SM, Zhu X, Herrmann SM, Kukla A, Lorenz EC, Kim SR, Thorsteinsdottir B, Lerman LO, Murad MH. A systematic review and meta-analysis of cell-based interventions in experimental diabetic kidney disease. Stem Cells Transl Med 2021; 10:1304-1319. [PMID: 34106528 PMCID: PMC8380442 DOI: 10.1002/sctm.19-0419] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 02/24/2021] [Accepted: 03/04/2021] [Indexed: 02/06/2023] Open
Abstract
Regenerative, cell‐based therapy is a promising treatment option for diabetic kidney disease (DKD), which has no cure. To prepare for clinical translation, this systematic review and meta‐analysis summarized the effect of cell‐based interventions in DKD animal models and treatment‐related factors modifying outcomes. Electronic databases were searched for original investigations applying cell‐based therapy in diabetic animals with kidney endpoints (January 1998‐May 2019). Weighted or standardized mean differences were estimated for kidney outcomes and pooled using random‐effects models. Subgroup analyses tested treatment‐related factor effects for outcomes (creatinine, urea, urine protein, fibrosis, and inflammation). In 40 studies (992 diabetic rodents), therapy included mesenchymal stem/stromal cells (MSC; 61%), umbilical cord/amniotic fluid cells (UC/AF; 15%), non‐MSC (15%), and cell‐derived products (13%). Tissue sources included bone marrow (BM; 65%), UC/AF (15%), adipose (9%), and others (11%). Cell‐based therapy significantly improved kidney function while reducing injury markers (proteinuria, histology, fibrosis, inflammation, apoptosis, epithelial‐mesenchymal‐transition, oxidative stress). Preconditioning, xenotransplantation, and disease‐source approaches were effective. MSC and UC/AF cells had greater effect on kidney function while cell products improved fibrosis. BM and UC/AF tissue sources more effectively improved kidney function and proteinuria vs adipose or other tissues. Cell dose, frequency, and administration route also imparted different benefits. In conclusion, cell‐based interventions in diabetic animals improved kidney function and reduced injury with treatment‐related factors modifying these effects. These findings may aid in development of optimal repair strategies through selective use of cells/products, tissue sources, and dose administrations to allow for successful adaptation of this novel therapeutic in human DKD.
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Affiliation(s)
- LaTonya J Hickson
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, Florida, USA.,Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Kern Center Affiliate, Mayo Clinic, Rochester, Minnesota, USA
| | - Tala Abedalqader
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Gift Ben-Bernard
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Jayla M Mondy
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Xiaohui Bian
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, Florida, USA
| | - Sabena M Conley
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, Florida, USA
| | - Xiangyang Zhu
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Sandra M Herrmann
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Aleksandra Kukla
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Elizabeth C Lorenz
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Kern Center Affiliate, Mayo Clinic, Rochester, Minnesota, USA
| | - Seo Rin Kim
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Bjorg Thorsteinsdottir
- Kern Center Affiliate, Mayo Clinic, Rochester, Minnesota, USA.,Division of Preventative Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Lilach O Lerman
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - M Hassan Murad
- Kern Center Affiliate, Mayo Clinic, Rochester, Minnesota, USA.,Division of Preventative Medicine, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
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22
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Wu Y, Zhang C, Guo R, Wu D, Shi J, Li L, Chu Y, Yuan X, Gao J. Mesenchymal Stem Cells: An Overview of Their Potential in Cell-Based Therapy for Diabetic Nephropathy. Stem Cells Int 2021; 2021:6620811. [PMID: 33815509 PMCID: PMC7990550 DOI: 10.1155/2021/6620811] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/11/2021] [Accepted: 02/18/2021] [Indexed: 12/13/2022] Open
Abstract
Diabetic nephropathy (DN) is a devastating complication associated with diabetes mellitus, and it is the leading cause of end-stage renal diseases (ESRD). Over the last few decades, numerous studies have reported the beneficial effects of stem cell administration, specifically mesenchymal stem or stromal cells (MSCs), on tissue repair and regeneration. MSC therapy has been considered a promising strategy for ameliorating the progression of DN largely based on results obtained from several preclinical studies and recent Phase I/II clinical trials. This paper will review the recent literature on MSC treatment in DN. In addition, the roles and potential mechanisms involved in MSC treatment of DN will be summarized, which may present much needed new drug targets for this disease. Moreover, the potential benefits and related risks associated with the therapeutic action of MSCs are elucidated and may help in achieving a better understanding of MSCs.
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Affiliation(s)
- Yan Wu
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Chunlei Zhang
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Ran Guo
- Department of Physiology, Mudanjiang Medical University, Mudanjiang, China
| | - Dan Wu
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Jiayi Shi
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Luxin Li
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Yanhui Chu
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Xiaohuan Yuan
- Heilongjiang Key Laboratory of Antifibrosis Biotherapy, Mudanjiang Medical University, Mudanjiang, China
| | - Jie Gao
- Institute of Translational Medicine, Shanghai University, Shanghai, China
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23
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Wang Y, Liu J, Zhang Q, Wang W, Liu Q, Liu S, Song Y, Wang X, Zhang Y, Li S, Yang X, Lv S, Liu G. Human umbilical cord mesenchymal stem cells attenuate podocyte injury under high glucose via TLR2 and TLR4 signaling. Diabetes Res Clin Pract 2021; 173:108702. [PMID: 33609619 DOI: 10.1016/j.diabres.2021.108702] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 01/07/2021] [Accepted: 02/04/2021] [Indexed: 11/26/2022]
Abstract
AIMS This research aimed to investigate the effects of high glucose (HG) on the innate immunity of podocytes and diabetic nephropathy (DN) mice via Toll like receptor (TLR) signaling, and explore the protective effectsof human umbilical cord mesenchymal stem cells (HUC-MSCs) on this process. METHODS HUC-MSCs obtained from human umbilical cord were cocultured with podocytes and transplanted into DN mice. Flow cytometry, CCK-8assay, ELISA, western blot analysis, periodicacid-schiff, masson, immunohistochemistry and immunofluorescence staining was used to detect the inflammation, TLR signaling, physical, biochemical and morphological parameters in podocytes and DN mice. RESULTS HG reduced the viability of podocytes, activated TLR2 and TLR4 signaling pathway and increased the expression of inflammatory cytokines such as IL-6, IL-1β, TNF-α, and MCP-1 in podocytes and DN mice. However, HUC-MSCs decreased the inflammation and restrained the TLR signaling pathway caused by HG in vitro and in vivo. Furthermore the rhHGF decreased the expression of TLR2 and TLR4 while the blockade of HGF increased the expression of TLR2 and TLR4 in podocytes. CONCLUSIONS HUC-MSCs have benefits to the podocytes under HG and the progression of DN by inhibiting TLR signaling pathway and depressing the inflammation. HUC-MSCs may be a therapeutic strategy for treating patients with DN.
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Affiliation(s)
- Yinghui Wang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China; Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong 250012, China
| | - Jiaxi Liu
- Graduate School of Arts and Sciences, Columbia University, USA
| | - Qingqing Zhang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China; Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong 250012, China
| | | | - Qingzhen Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China
| | - Shanshan Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China
| | - Yan Song
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China
| | - Xueling Wang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China
| | - Yaping Zhang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China
| | - Shan Li
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China; Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong 250012, China
| | - Xue Yang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China; Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong 250012, China
| | - Shasha Lv
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China.
| | - Gang Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong 250033, China; Key laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, Shandong 250012, China.
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24
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Abstract
PURPOSE OF REVIEW Nephrology lacks effective therapeutics for many of the presentations and diseases seen in clinical practice. In recent decades, we have come to understand the central place of inflammation in initiating and propagating kidney disease, and, research in more recent years has established that the resolution of inflammation is a highly regulated and active process. With this, has evolved an appreciation that this aspect of the host inflammatory response is defective in kidney disease and led to consideration of a therapeutic paradigm aiming to harness the activity of the molecular drivers of the resolution phase of inflammation. Fatty-acid-derived Specialized pro-resolving mediators (SPMs), partly responsible for resolution of inflammation have gained traction as potential therapeutics. RECENT FINDINGS We describe our current understanding of SPMs for this purpose in acute and chronic kidney disease. These studies cement the place of inflammation and its defective resolution in the pathogenesis of kidney disease, and highlight new avenues for therapy. SUMMARY Targeting resolution of inflammation is a viable approach to treating kidney disease. We optimistically look forward to translating these experimental advances into tractable therapeutics to treat kidney disease.
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25
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Akan E, Cetinkaya B, Kipmen-Korgun D, Ozmen A, Koksoy S, Mendilcioğlu İ, Sakinci M, Suleymanlar G, Korgun ET. Effects of amnion derived mesenchymal stem cells on fibrosis in a 5/6 nephrectomy model in rats. Biotech Histochem 2021; 96:594-607. [PMID: 33522283 DOI: 10.1080/10520295.2021.1875502] [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: 01/13/2023] Open
Abstract
Chronic kidney disease (CKD) is characterized by disruption of the glomerulus, tubule and vascular structures by renal fibrosis. Mesenchymal stem cells (MSC) ameliorate CKD. We investigated the effects of human amnion derived MSC (hAMSC) on fibrosis using expression of transforming growth factor beta (TGF-β), collagen type I (COL-1) and bone morphogenetic protein (BMP-7). We also investigated levels of urinary creatinine and nitrogen in CKD. We used a 5/6 nephrectomy (5/6 Nx) induced CKD model. We used 36 rats in six groups of six animals: sham group, 5/6 Nx group, 15 days after 5/6 Nx (5/6 Nx + 15) group, 30 days after 5/6 Nx (5/6 Nx + 30) group, transfer of hAMSC 15 days after 5/6 Nx (5/6 Nx + hAMSC + 15) group and transfer of hAMSC 30 days after 5/6 Nx (5/6 Nx + hAMSC + 30) group. We isolated 106 hAMSC from the amnion and transplanted them via the rat tail vein into the 5/6 Nx + hAMSC + 15 and 5/6 Nx + hAMSC + 30 groups. We measured the expression of BMP-7, COL-1 and TGF-β using western blot and immunohistochemistry, and their gene expressions were analyzed by quantitative real time PCR. TGF-β and COL-1 protein, and gene expressions were increased in the 5/6 Nx +30 group compared to the 5/6 Nx + hAMSC + 30 group. Conversely, both protein and gene expression of BMP-7 was increased in 5/6 Nx + hAMSC + 30 group compared to the 5/6 Nx groups. Increased TGF-β together with decreased BMP-7 expression may cause fibrosis by epithelial-mesenchymal transition due to chronic renal injury. Increased COL-1 levels cause accumulation of extracellular matrix in CKD. Levels of urea, creatinine and nitrogen were increased significantly in 5/6 Nx + 15 and 5/6 Nx + 30 groups compared to the hAMSC groups. We found that hAMSC ameliorate CKD.
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Affiliation(s)
- Ezgi Akan
- Department of Medical Biochemistry, Akdeniz University Medical School, Antalya, Turkey
| | - Busra Cetinkaya
- Department of Histology and Embryology, Akdeniz University, Medical School, Antalya, Turkey.,Department of Histology and Embryology, Medical Faculty, Bulent Ecevit University, Zonguldak, Turkey
| | - Dijle Kipmen-Korgun
- Department of Medical Biochemistry, Akdeniz University Medical School, Antalya, Turkey
| | - Aslı Ozmen
- Department of Histology and Embryology, Akdeniz University, Medical School, Antalya, Turkey
| | - Sadi Koksoy
- Department of Medical Microbiology and Immunology, Akdeniz University Medical School, Antalya, Turkey
| | - İnanc Mendilcioğlu
- Department of Obstetrics and Gynecology, Akdeniz University Medical School, Antalya, Turkey
| | - Mehmet Sakinci
- Department of Obstetrics and Gynecology, Akdeniz University Medical School, Antalya, Turkey
| | - Gultekin Suleymanlar
- Division of Nephrology, Department of Internal Medicine, Medical Faculty, Akdeniz University, Antalya, Turkey
| | - Emin Turkay Korgun
- Department of Histology and Embryology, Akdeniz University, Medical School, Antalya, Turkey
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26
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Lin W, Li HY, Yang Q, Chen G, Lin S, Liao C, Zhou T. Administration of mesenchymal stem cells in diabetic kidney disease: a systematic review and meta-analysis. Stem Cell Res Ther 2021; 12:43. [PMID: 33413678 PMCID: PMC7792034 DOI: 10.1186/s13287-020-02108-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/17/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC) therapy shows great promise for diabetic kidney disease (DKD) patients. Research has been carried out on this topic in recent years. The main goals of this paper are to evaluate the therapeutic effects of MSCs on DKD through a meta-analysis and address the mechanism through a systematic review of the literature. METHOD An electronic search of the Embase, Cochrane Library, ISI Web of Science, PubMed, and US National Library of Medicine (NLM) databases was performed for all articles about MSC therapy for DKD, without species limitations, up to January 2020. Data were pooled for analysis with Stata SE 12. RESULT The MSC-treated group showed a large and statistically significant hypoglycemic effect at 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, and 6 months. Total hypoglycemic effect was observed (SMD = - 1.954, 95%CI - 2.389 to - 1.519, p < 0.001; I2 = 85.1%). The overall effects on serum creatinine (SCr) and blood urea nitrogen (BUN) were analyzed, suggesting that MSC decreased SCr and BUN and mitigated the impairment of renal function (SCr: SMD = - 4.838, 95%CI - 6.789 to - 2.887, p < 0.001; I2 = 90.8%; BUN: SMD = - 4.912, 95%CI - 6.402 to - 3.422, p < 0.001; I2 = 89.3%). Furthermore, MSC therapy decreased the excretion of urinary albumin. Fibrosis indicators were assessed, and the results showed that transforming growth factor-β, collagen I, fibronectin, and α-smooth muscle actin were significantly decreased in the MSC-treated group compared to the control group. CONCLUSION MSCs might improve glycemic control and reduce SCr, BUN, and urinary protein. MSCs can also alleviate renal fibrosis. MSC therapy might be a potential treatment for DKD.
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Affiliation(s)
- Wenshan Lin
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Hong-Yan Li
- Department of Nephrology, Huadu District People's Hospital of Guangzhou, Southern Medical University, Guangzhou, China
| | - Qian Yang
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Guangyong Chen
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Shujun Lin
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Chunling Liao
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China
| | - Tianbiao Zhou
- Department of Nephrology, the Second Affiliated Hospital of Shantou University Medical College, No. 69 Dongsha Road, Shantou, 515041, China.
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27
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Wang Y, Shan SK, Guo B, Li F, Zheng MH, Lei LM, Xu QS, Ullah MHE, Xu F, Lin X, Yuan LQ. The Multi-Therapeutic Role of MSCs in Diabetic Nephropathy. Front Endocrinol (Lausanne) 2021; 12:671566. [PMID: 34163437 PMCID: PMC8216044 DOI: 10.3389/fendo.2021.671566] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Accepted: 05/20/2021] [Indexed: 12/16/2022] Open
Abstract
Diabetic nephropathy (DN) is one of the most common diabetes mellitus (DM) microvascular complications, which always ends with end-stage renal disease (ESRD). Up to now, as the treatment of DN in clinic is still complicated, ESRD has become the main cause of death in diabetic patients. Mesenchymal stem cells (MSCs), with multi-differentiation potential and paracrine function, have attracted considerable attention in cell therapy recently. Increasing studies concerning the mechanisms and therapeutic effect of MSCs in DN emerged. This review summarizes several mechanisms of MSCs, especially MSCs derived exosomes in DN therapy, including hyperglycemia regulation, anti-inflammatory, anti-fibrosis, pro-angiogenesis, and renal function protection. We also emphasize the limitation of MSCs application in the clinic and the enhanced therapeutic role of pre-treated MSCs in the DN therapy. This review provides balanced and impartial views for MSC therapy as a promising strategy in diabetic kidney disease amelioration.
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Affiliation(s)
- Yi Wang
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Su-Kang Shan
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Bei Guo
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Fuxingzi Li
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Ming-Hui Zheng
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Li-Min Lei
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Qiu-Shuang Xu
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Muhammad Hasnain Ehsan Ullah
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Feng Xu
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiao Lin
- Department of Radiology, the Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling-Qing Yuan
- Department of Metabolism and Endocrinology, National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory of Metabolic Bone Diseases, the Second Xiangya Hospital, Central South University, Changsha, China
- *Correspondence: Ling-Qing Yuan,
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28
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Liu D, Zheng W, Pan S, Liu Z. Concise review: current trends on applications of stem cells in diabetic nephropathy. Cell Death Dis 2020; 11:1000. [PMID: 33221823 PMCID: PMC7680458 DOI: 10.1038/s41419-020-03206-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 10/27/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022]
Abstract
Diabetic nephropathy, with high prevalence, is the main cause of renal failure in diabetic patients. The strategies for treating DN are limited with not only high cost but an unsatisfied effect. Therefore, the effective treatment of DN needs to be explored urgently. In recent years, due to their self-renewal ability and multi-directional differentiation potential, stem cells have exerted therapeutic effects in many diseases, such as graft-versus-host disease, autoimmune diseases, pancreatic diseases, and even acute kidney injury. With the development of stem cell technology, stem cell-based regenerative medicine has been tried to be applied to the treatment of DN. Related stem cells include embryonic stem cells, induced pluripotent stem cells, mesenchymal cells, and endothelial progenitor cells. Undoubtedly, stem cell transplantation has achieved certain results in the treatment of DN animal models. However, stem cell therapy still remains certain thorny issues during treatment. For instance, poor engraftment and limited differentiation of stem cells caused by the diabetic microenvironment, differentiation into unwanted cell lineages, and malignant transformation or genetic aberrations of stem cells. At present, various researches on the therapeutic effects of stem cells in DN with different opinions are reported and the specific mechanism of stem cells is still unclear. We review here the potential mechanism of stem cells as new therapeutic agents in the treatment of DN. Also, we review recent findings and updated information about not only the utilization of stem cells on DN in both preclinical and clinical trials but limitations and future expectations of stem cell-based therapy for DN.
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Affiliation(s)
- Dongwei Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China
| | - Wen Zheng
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China
| | - Shaokang Pan
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China.,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China.,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China.,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China
| | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, P.R. China. .,Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, P.R. China. .,Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, P.R. China. .,Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, P.R. China.
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29
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Sávio-Silva C, Beyerstedt S, Soinski-Sousa PE, Casaro EB, Balby-Rocha MTA, Simplício-Filho A, Alves-Silva J, Rangel ÉB. Mesenchymal Stem Cell Therapy for Diabetic Kidney Disease: A Review of the Studies Using Syngeneic, Autologous, Allogeneic, and Xenogeneic Cells. Stem Cells Int 2020; 2020:8833725. [PMID: 33505469 PMCID: PMC7812547 DOI: 10.1155/2020/8833725] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 10/31/2020] [Accepted: 11/03/2020] [Indexed: 12/18/2022] Open
Abstract
Diabetic kidney disease (DKD) is a microvascular complication of diabetes mellitus (DM) and comprises multifactorial pathophysiologic mechanisms. Despite current treatment, around 30-40% of individuals with type 1 and type 2 DM (DM1 and DM2) have progressive DKD, which is the most common cause of end-stage chronic kidney disease worldwide. Mesenchymal stem cell- (MSC-) based therapy has important biological and therapeutic implications for curtailing DKD progression. As a chronic disease, DM may impair MSC microenvironment, but there is compelling evidence that MSC derived from DM1 individuals maintain their cardinal properties, such as potency, secretion of trophic factors, and modulation of immune cells, so that both autologous and allogeneic MSCs are safe and effective. Conversely, MSCs derived from DM2 individuals are usually dysfunctional, exhibiting higher rates of senescence and apoptosis and a decrease in clonogenicity, proliferation, and angiogenesis potential. Therefore, more studies in humans are needed to reach a conclusion if autologous MSCs from DM2 individuals are effective for treatment of DM-related complications. Importantly, the bench to bedside pathway has been constructed in the last decade for assessing the therapeutic potential of MSCs in the DM setting. Laboratory research set the basis for establishing further translation research including preclinical development and proof of concept in model systems. Phase I clinical trials have evaluated the safety profile of MSC-based therapy in humans, and phase II clinical trials (proof of concept in trial participants) still need to answer important questions for treating DKD, yet metabolic control has already been documented. Therefore, randomized and controlled trials considering the source, optimal cell number, and route of delivery in DM patients are further required to advance MSC-based therapy. Future directions include strategies to reduce MSC heterogeneity, standardized protocols for isolation and expansion of those cells, and the development of well-designed large-scale trials to show significant efficacy during a long follow-up, mainly in individuals with DKD.
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Affiliation(s)
- Christian Sávio-Silva
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Stephany Beyerstedt
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Poliana E. Soinski-Sousa
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Expedito B. Casaro
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | | | - Antônio Simplício-Filho
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Jamille Alves-Silva
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Érika B. Rangel
- Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
- Nephrology Division, Federal University of São Paulo, São Paulo, SP, Brazil
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Aslam R, Hussain A, Cheng K, Kumar V, Malhotra A, Gupta S, Singhal PC. Transplantation of mesenchymal stem cells preserves podocyte homeostasis through modulation of parietal epithelial cell activation in adriamycin-induced mouse kidney injury model. Histol Histopathol 2020; 35:1483-1492. [PMID: 33124682 DOI: 10.14670/hh-18-276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
To determine the role of the transplantation of bone marrow-derived mesenchymal stem cells (MSCs) in podocyte renewal, we studied BALB/C mice with or without adriamycin-induced acute kidney injury. MSCs were transplanted ectopically under the capsule of the left kidney or into the peritoneal cavity after the onset of kidney injury to test testing their local or systemic paracrine effects, respectively. Adriamycin produced increases in urine protein: creatinine ratios, blood urea nitrogen, and blood pressure, which improved after both renal subcapsular and intraperitoneal MSCs transplants. The histological changes of adriamycin kidney changes regressed in both kidneys and in only the ipsilateral kidney after intraperitoneal or renal subcapsular transplants indicating that the benefits of transplanted MSCs were related to the extent of paracrine factor distribution. Analysis of kidney tissues for p57-positive parietal epithelial cells (PECs) showed that MSC transplants restored adriamycin-induced decreases in the abundance of these cells to normal levels, although after renal subcapsular transplants these changes did not extend to contralateral kidneys. Moreover, adriamycin caused inflammatory activation of PECs with coexpression of CD44 and phospho-ERK, which was normalized in both or only ipsilateral kidneys depending on whether MSCs were transplanted in the peritoneal cavity or subcapsular space, respectively.
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Affiliation(s)
- Rukhsana Aslam
- Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA
| | - Ali Hussain
- Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA
| | - Kang Cheng
- Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA
| | - Vinod Kumar
- Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA
| | - Ashwani Malhotra
- Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA
| | - Sanjeev Gupta
- Department of Medicine, Department of Pathology, Marion Bessin Liver Research Center, Diabetes Center, The Irwin S. and Sylvia Chanin Institute for Cancer Research, and Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, USA
| | - Pravin C Singhal
- Department of Medicine, Hofstra Northwell School of Medicine, Hempstead, New York, USA.
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Takemura S, Shimizu T, Oka M, Sekiya S, Babazono T. Transplantation of adipose-derived mesenchymal stem cell sheets directly into the kidney suppresses the progression of renal injury in a diabetic nephropathy rat model. J Diabetes Investig 2020; 11:545-553. [PMID: 31622047 PMCID: PMC7232293 DOI: 10.1111/jdi.13164] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 09/15/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023] Open
Abstract
AIMS/INTRODUCTION Adipose-derived mesenchymal stem cell (ASC) transplantation is a promising therapy for diabetic nephropathy (DN). However, intravascular administration of ASCs is associated with low engraftment in target organs. Therefore, we considered applying the cell sheet technology to ASCs. In this study, ASC sheets were directly transplanted into the kidneys of a DN rat model, and therapeutic consequences were analyzed. MATERIALS AND METHODS Adipose-derived mesenchymal stem cells were isolated from adipose tissues of 7-week-old enhanced green fluorescent protein rats, and ASC sheets were prepared using a temperature-responsive culture dish. A DN rat model was established from 5-week-old Spontaneously Diabetic Torii fatty rats. Seven-week-old DN rats (n = 21) were assigned to one of the following groups: sham-operated (n = 6); ASC suspension (6.0 × 106 cells/mL) administered intravenously (n = 7); six ASC sheets transplanted directly into the kidney (n = 8). The therapeutic effect of the cell sheets was determined based on urinary biomarker expression and histological analyses. RESULTS The ASC sheets survived under the kidney capsule of the DN rat model for 14 days after transplantation. Furthermore, albuminuria and urinary tumor necrosis factor-α levels were significantly lower in the ASC sheets transplanted directly into the kidney group than in the sham-operated and ASC suspension administered intravenously groups (P < 0.05). Histologically, the ASC sheets transplanted directly into the kidney group presented mild atrophy of the proximal tubule and maintained the renal tubular structure. CONCLUSIONS Transplantation of ASC sheets directly into the kidney improved transplantation efficiency and suppressed renal injury progression. Therefore, the ASC sheet technology might be a promising novel treatment for DN.
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Affiliation(s)
- Shunsuke Takemura
- Department of MedicineDiabetes CenterSchool of MedicineTokyo Women’s Medical UniversityTokyoJapan
- Institute of Advanced Biomedical Engineering and ScienceTokyo Women’s Medical UniversityTokyoJapan
| | - Tatsuya Shimizu
- Institute of Advanced Biomedical Engineering and ScienceTokyo Women’s Medical UniversityTokyoJapan
| | - Masatoshi Oka
- Department of MedicineKidney CenterTokyo Women’s Medical UniversityTokyoJapan
| | - Sachiko Sekiya
- Institute of Advanced Biomedical Engineering and ScienceTokyo Women’s Medical UniversityTokyoJapan
| | - Tetsuya Babazono
- Department of MedicineDiabetes CenterSchool of MedicineTokyo Women’s Medical UniversityTokyoJapan
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Hashemi SM, Hassan ZM, Hossein-Khannazer N, Pourfathollah AA, Soudi S. Investigating the route of administration and efficacy of adipose tissue-derived mesenchymal stem cells and conditioned medium in type 1 diabetic mice. Inflammopharmacology 2020; 28:585-601. [PMID: 31741175 DOI: 10.1007/s10787-019-00661-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/29/2019] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease destroying the insulin-producing beta cells. Recently, stem cell therapy has been tested to treat T1D. In the present study, we aim to investigate the effects of intraperitoneal and intravenous infusion of multipotent mesenchymal stem/stromal cells (MSCs) and MSC-conditioned medium (MSC-CM) in an experimental model of diabetes, induced by multiple injections of Streptozotocin (STZ). The adipose tissue-derived MSC and MSC-CM were isolated from C57Bl/6 male mice and characterized. Later, MSC and MSC-CM were injected intraperitoneally or intravenously into mice. The blood glucose, urinary glucose, and body weight were measured, and the percentages of CD4+ CD25+ FOXP3+ T cells as well as the levels of IFN-γ, TGF-β, IL-4, IL-17, and IL-10 were evaluated. Our results showed that both intraperitoneal and intravenous infusions of MSC and MSC-CM could decrease the blood glucose, recover pancreatic islets, and increase the levels of insulin-producing cells. Furthermore, the percentage of CD4+ CD25+ FOXP3+ T cells was increased after intraperitoneal injection of MSC or MSC-CM and intravenous injection of MSCs. After intraperitoneal injection of the MSC and MSC-CM, the levels of inflammatory cytokines reduced, while the levels of anti-inflammatory cytokines increased. Together current data showed that although both intraperitoneal and intravenous administration had beneficial effects on T1D animal model, but intraperitoneal injection of AD-MSC and AD-MSC-CM was more effective than systemic administration.
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Affiliation(s)
- Seyed Mahmoud Hashemi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Zuhair Mohammad Hassan
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Nikoo Hossein-Khannazer
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Pourfathollah
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Liu Q, Lv S, Liu J, Liu S, Wang Y, Liu G. Mesenchymal stem cells modified with angiotensin-converting enzyme 2 are superior for amelioration of glomerular fibrosis in diabetic nephropathy. Diabetes Res Clin Pract 2020; 162:108093. [PMID: 32109518 DOI: 10.1016/j.diabres.2020.108093] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Revised: 02/14/2020] [Accepted: 02/24/2020] [Indexed: 01/06/2023]
Abstract
AIMS This study aimed to detect the effect of angiotensin-converting enzyme (ACE) 2-modified mesenchymal stem cells (MSCs) on glomerular fibrosis in vitro and in vivo and investigate the underlying molecular mechanism. METHODS MSCs transduced with the ACE2 gene (MSCs-ACE2) were cocultured with glomerular mesangial cells (GMCs) following Ang II stimulation. MSCs-ACE2 were transplanted into streptozotocin-induced diabetic rats. Physical, biochemical and morphological parameters were measured, and fibrotic indicators and renin-angiotensin system (RAS) components in GMCs and kidney tissues were assessed. RESULTS The transduction efficiency of MSCs was as high as 85%. The modified MSCs secreted soluble ACE2 protein into the culture medium. After transplantation into rats with diabetes, MSCs-ACE2 targeted injured kidneys and enhanced local expression of ACE2. Compared with MSC treatment alone, MSC-ACE2 treatment was superior in reducing albuminuria and improving glomerulosclerosis. In vitro and in vivo, MSCs-ACE2 were more beneficial than MSCs alone in decreasing Ang II and increasing Ang1-7, thereby inhibiting the detrimental effects of Ang II accumulation by downregulating collagen I and fibronectin (FN) expression and inhibiting the transforming growth factor (TGF-β)/Smad pathway. CONCLUSIONS MSCs modified with ACE2 therapy have additional benefits to the progression of diabetic nephropathy (DN) by inhibiting renal RAS activation and reducing glomerular fibrosis.
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Affiliation(s)
- Qingzhen Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Shasha Lv
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Jiaxi Liu
- College of Liberal Arts, University of Minnesota, USA
| | - Shanshan Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Yinghui Wang
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China
| | - Gang Liu
- Nephrology Research Institute of Shandong University, The Second Hospital of Shandong University, Shandong University, Jinan, Shandong, China.
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The future of diabetic kidney disease management: what to expect from the experimental studies? J Nephrol 2020; 33:1151-1161. [PMID: 32221858 DOI: 10.1007/s40620-020-00724-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 03/12/2020] [Indexed: 12/18/2022]
Abstract
Diabetic kidney disease (DKD) is a major cause of end-stage renal disease. Intensive blood glucose and blood pressure control, particularly using inhibitors of the renin-angiotensin system, have long been mainstays of therapy in patients with DKD. Moreover, new anti-hyperglycemic drugs have recently shown renoprotective effects and this represents a major progress in the management of DKD. However, the risk of progression is still substantial and additional drugs are required. Recent preclinical studies have identified novel therapeutic targets that may optimize renoprotection in the near future. Besides strategies aimed to reduce oxidative stress and inflammation in the kidney, novel extra-renal approaches targeting stem cells, extracellular vesicles, and the microbiota are on the horizon with promising preclinical data. Herein, we will review these lines of research and discuss potential clinical applications. Given the poor yield of experimental studies in DKD in the past years, we will also discuss strategies to improve translation of preclinical research to humans.
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Chen L, Xiang E, Li C, Han B, Zhang Q, Rao W, Xiao C, Wu D. Umbilical Cord-Derived Mesenchymal Stem Cells Ameliorate Nephrocyte Injury and Proteinuria in a Diabetic Nephropathy Rat Model. J Diabetes Res 2020; 2020:8035853. [PMID: 32405507 PMCID: PMC7206880 DOI: 10.1155/2020/8035853] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 03/30/2020] [Indexed: 12/21/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are shown to alleviate renal injury of diabetic nephropathy (DN) in rats. However, the underlying mechanism of this beneficial effect is not fully understood. The aims of this study are to evaluate effects of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on renal cell apoptosis in streptozotocin- (STZ-) induced diabetic rats and explore the underlying mechanisms. Characteristics of UC-MSCs were identified by flow cytometry and differentiation capability. Six weeks after DN induction by STZ injection in Sprague-Dawley rats, the DN rats received UC-MSCs once a week for consecutive two weeks. DN-related physical and biochemical parameters were measured at 2 weeks after UC-MSC infusion. Renal histological changes were also assessed. Moreover, the apoptosis of renal cells and expression of apoptosis-related proteins were evaluated. Compared with DN rats, rats treated with UC-MSCs showed suppressed increase in 24-hour urinary total protein, urinary albumin to creatinine ratio, serum creatinine, and blood urea nitrogen. UC-MSC treatment ameliorated pathological abnormalities in the kidney of DN rats as evidenced by H&E, PAS, and Masson Trichrome staining. Furthermore, UC-MSC treatment reduced apoptosis of renal cells in DN rats. UC-MSCs promoted expression of antiapoptosis protein Bcl-xl and suppressed expression of high mobility group protein B1 (HMGB1) in the kidney of DN rats. Most importantly, UC-MSCs suppressed upregulation of thioredoxin-interacting protein (TXNIP), downregulation of thioredoxin 1 (TRX1), and activation of apoptosis signal-regulating kinase 1 (ASK1) and P38 MAPK in the kidney of DN rats. Our results suggest that UC-MSCs could alleviate nephrocyte injury and albuminuria of DN rats through their antiapoptotic property. The protective effects of UC-MSCs may be mediated by inhibiting TXNIP upregulation in part.
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Affiliation(s)
- Lian Chen
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - E. Xiang
- Wuhan Hamilton Biotechnology Co., Ltd., Wuhan, China
| | - Changyong Li
- Department of Physiology, Wuhan University School of Basic Medical Sciences, Wuhan, China
| | - Bing Han
- Wuhan Hamilton Biotechnology Co., Ltd., Wuhan, China
| | - Quan Zhang
- Wuhan Hamilton Biotechnology Co., Ltd., Wuhan, China
| | - Wei Rao
- Wuhan Hamilton Biotechnology Co., Ltd., Wuhan, China
| | - Cuihong Xiao
- Wuhan Hamilton Biotechnology Co., Ltd., Wuhan, China
| | - Dongcheng Wu
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical Sciences, Wuhan, China
- Wuhan Hamilton Biotechnology Co., Ltd., Wuhan, China
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36
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An X, Liao G, Chen Y, Luo A, Liu J, Yuan Y, Li L, Yang L, Wang H, Liu F, Yang G, Yi S, Li Y, Cheng J, Lu Y. Intervention for early diabetic nephropathy by mesenchymal stem cells in a preclinical nonhuman primate model. Stem Cell Res Ther 2019; 10:363. [PMID: 31791397 PMCID: PMC6889652 DOI: 10.1186/s13287-019-1401-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 08/27/2019] [Accepted: 08/29/2019] [Indexed: 02/05/2023] Open
Abstract
Background Diabetic nephropathy (DN) is one of the most severe chronic diabetic complications and the main cause of end-stage renal disease. Chronic inflammation plays a key role in the development of DN. However, few treatment strategies are available; therefore, new and effective strategies to ameliorate DN at the early stage must be identified. Methods Mesenchymal stem cells (MSCs) are characterized by anti-inflammatory and immune regulatory abilities. We developed a rhesus macaque model of DN and administered MSCs four times over 2 months. We measured blood glucose level, HbA1c, and levels of renal function parameters in the blood and urine, and cytokine levels in the kidney and blood circulatory system of rhesus macaques. Also, we analyzed the renal pathological changes of rhesus macaques. In vitro, we treated tubular epithelial cells (HK2) with 30 mmol/L glucose and 10 ng/mL human recombinant TNF-alpha (rhTNF-α) and explored the effects of MSCs on inflammation and Na+-glucose cotransporter 2 (SGLT2) expression in HK2. Results We found that MSCs decreased the blood glucose level and daily insulin requirement of DN rhesus macaques. Furthermore, MSCs had a dominant function in improving renal function and decreasing SGLT2 expression on renal tubular epithelial cells. Also, renal pathological changes were ameliorated after MSC treatment. Moreover, MSCs powerfully reduced inflammation, especially decreased the level of pro-inflammatory cytokine interleukin-16 (IL-16), in the kidney and blood circulatory system. Conclusions Our study is an important step to explore the mechanism of MSCs in ameliorating the early stage of DN, potentially through influencing SGLT2 expression and resulting in improved glycemic control and anti-inflammation. We hope these findings would provide insights for the clinical application of MSCs in DN. Electronic supplementary material The online version of this article (10.1186/s13287-019-1401-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xingxing An
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, Chengdu, China
| | - Guangneng Liao
- Animal Center, West China Hospital, Sichuan University, Chengdu, China
| | - Younan Chen
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, Chengdu, China
| | - Ai Luo
- Sichuan Neo-Life Stem Cell Biotech Inc., Chengdu, China
| | - Jingping Liu
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, Chengdu, China
| | - Yujia Yuan
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, Chengdu, China
| | - Lan Li
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, Chengdu, China
| | - Lichuan Yang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Hong Wang
- Department of Ultrasound, West China Hospital, Sichuan University, Chengdu, China
| | - Fang Liu
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China
| | - Guang Yang
- Animal Center, West China Hospital, Sichuan University, Chengdu, China
| | - Shounan Yi
- Center for Transplant and Renal Research, Westmead Institute for Medical Research, The University of Sydney, Camperdown, NSW, Australia
| | - Yuanmin Li
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, Chengdu, China
| | - Jingqiu Cheng
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, Chengdu, China.
| | - Yanrong Lu
- Key Laboratory of Transplant Engineering and Immunology, NHFPC, West China Hospital, Sichuan University, Chengdu, China.
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Ahmadi A, Moghadasali R, Ezzatizadeh V, Taghizadeh Z, Nassiri SM, Asghari-Vostikolaee MH, Alikhani M, Hadi F, Rahbarghazi R, Yazdi RS, Baharvand H, Aghdami N. Transplantation of Mouse Induced Pluripotent Stem Cell-Derived Podocytes in a Mouse Model of Membranous Nephropathy Attenuates Proteinuria. Sci Rep 2019; 9:15467. [PMID: 31664077 PMCID: PMC6820764 DOI: 10.1038/s41598-019-51770-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 09/26/2019] [Indexed: 12/31/2022] Open
Abstract
Injury to podocytes is a principle cause of initiation and progression of both immune and non-immune mediated glomerular diseases that result in proteinuria and decreased function of the kidney. Current advances in regenerative medicine shed light on the therapeutic potential of cell-based strategies for treatment of such disorders. Thus, there is hope that generation and transplantation of podocytes from induced pluripotent stem cells (iPSCs), could potentially be used as a curative treatment for glomerulonephritis caused by podocytes injury and loss. Despite several reports on the generation of iPSC-derived podocytes, there are rare reports about successful use of these cells in animal models. In this study, we first generated a model of anti-podocyte antibody-induced heavy proteinuria that resembled human membranous nephropathy and was characterized by the presence of sub-epithelial immune deposits and podocytes loss. Thereafter, we showed that transplantation of functional iPSC-derived podocytes following podocytes depletion results in recruitment of iPSC-derived podocytes within the damaged glomerulus, and leads to attenuation of proteinuria and histological alterations. These results provided evidence that application of iPSCs-derived renal cells could be a possible therapeutic strategy to favorably influence glomerular diseases outcomes.
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Affiliation(s)
- Amin Ahmadi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Reza Moghadasali
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Vahid Ezzatizadeh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Medical Genetics Department, Medical Laboratory Center, Royesh Medical Group, Tehran, Iran
| | - Zeinab Taghizadeh
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Seyed Mahdi Nassiri
- Department of Clinical Pathology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | | | - Mehdi Alikhani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Fatemeh Hadi
- Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Reza Rahbarghazi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Salman Yazdi
- Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, 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 Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
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Kim HS, Lee JS, Lee HK, Park EJ, Jeon HW, Kang YJ, Lee TY, Kim KS, Bae SC, Park JH, Han SB. Mesenchymal Stem Cells Ameliorate Renal Inflammation in Adriamycin-induced Nephropathy. Immune Netw 2019; 19:e36. [PMID: 31720047 PMCID: PMC6829076 DOI: 10.4110/in.2019.19.e36] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 09/27/2019] [Accepted: 10/02/2019] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal stem cells (MSCs) ameliorate the renal injury in Adriamycin (ADR)-induced nephropathy, but the mechanisms underlying their efficacy remain incompletely understood. In this study, we demonstrated that MSCs increased the survival, recovered body weight loss, and decreased proteinuria and serum creatinine levels in ADR-treated mice. MSCs also prevented podocyte damage and renal fibrosis by decreasing the expression of fibronectin, collagen 1α1, and α-smooth muscle actin. From a mechanistic perspective, MSCs inhibited renal inflammation by lowering the expression of CCL4, CCL7, CCL19, IFN-α/β, TGF-β, TNF-α, and chitinase 3-like 1. In summary, our data demonstrate that MSCs improve renal functions by inhibiting renal inflammation in ADR-induced nephropathy.
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Affiliation(s)
- Hyung Sook Kim
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea
| | - Jae Seob Lee
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea
| | - Hong Kyung Lee
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea
| | - Eun Jae Park
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea
| | - Hye Won Jeon
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea
| | - Yu Jeong Kang
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea
| | - Tae Yong Lee
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea
- Bioengineering Institute, Corestem Inc., Seoul 04763, Korea
| | - Kyung Suk Kim
- Bioengineering Institute, Corestem Inc., Seoul 04763, Korea
| | - Sang-Cheol Bae
- Hanyang University Hospital for Rheumatic Diseases, Seoul 04763, Korea
| | - Ji Hyun Park
- College of Pharmacy, Korea University, Sejong 30019, Korea
| | - Sang-Bae Han
- College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea
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Duan YR, Chen BP, Chen F, Yang SX, Zhu CY, Ma YL, Li Y, Shi J. Exosomal microRNA-16-5p from human urine-derived stem cells ameliorates diabetic nephropathy through protection of podocyte. J Cell Mol Med 2019; 25:10798-10813. [PMID: 31568645 PMCID: PMC8642687 DOI: 10.1111/jcmm.14558] [Citation(s) in RCA: 92] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 05/30/2019] [Accepted: 07/05/2019] [Indexed: 01/19/2023] Open
Abstract
Diabetic nephropathy (DN) remains one of the severe complications associated with diabetes mellitus. It is worthwhile to uncover the underlying mechanisms of clinical benefits of human urine‐derived stem cells (hUSCs) in the treatment of DN. At present, the clinical benefits associated with hUSCs in the treatment of DN remains unclear. Hence, our study aims to investigate protective effect of hUSC exosome along with microRNA‐16‐5p (miR‐16‐5p) on podocytes in DN via vascular endothelial growth factor A (VEGFA). Initially, miR‐16‐5p was predicated to target VEGFA based on data retrieved from several bioinformatics databases. Notably, dual‐luciferase report gene assay provided further verification confirming the prediction. Moreover, our results demonstrated that high glucose (HG) stimulation could inhibit miR‐16‐5p and promote VEGFA in human podocytes (HPDCs). miR‐16‐5p in hUSCs was transferred through the exosome pathway to HG‐treated HPDCs. The viability and apoptosis rate of podocytes after HG treatment together with expression of the related factors were subsequently determined. The results indicated that miR‐16‐5p secreted by hUSCs could improve podocyte injury induced by HG. In addition, VEGA silencing could also ameliorate HG‐induced podocyte injury. Finally, hUSC exosomes containing overexpressed miR‐16‐5p were injected into diabetic rats via tail vein, followed by qualification of miR‐16‐5p and observation on the changes of podocytes, which revealed that overexpressed miR‐16‐5p in hUSCs conferred protective effects on HPDCs in diabetic rats. Taken together, the present study revealed that overexpressed miR‐16‐5p in hUSC exosomes could protect HPDCs induced by HG and suppress VEGFA expression and podocytic apoptosis, providing fresh insights for novel treatment of DN.
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Affiliation(s)
- Yu-Rui Duan
- Department of Nephrology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Bao-Ping Chen
- Department of Nephrology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Fang Chen
- Department of Nephrology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Su-Xia Yang
- Department of Nephrology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Chao-Yang Zhu
- Department of Nephrology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Ya-Li Ma
- Department of Nephrology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Yang Li
- Department of Urology, Huaihe Hospital of Henan University, Kaifeng, China
| | - Jun Shi
- Department of Nephrology, Huaihe Hospital of Henan University, Kaifeng, China
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Cai X, Wang L, Wang X, Hou F. miR-124a enhances therapeutic effects of bone marrow stromal cells transplant on diabetic nephropathy-related epithelial-to-mesenchymal transition and fibrosis. J Cell Biochem 2019; 121:299-312. [PMID: 31190436 DOI: 10.1002/jcb.29170] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 05/20/2019] [Accepted: 05/23/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Epithelial-to-mesenchymal transition (EMT) has been gradually considered as one of the major pathways that causes the production of interstitial myofibroblasts in diseased kidneys. MATERIALS AND METHODS The study was done to investigate the effect of a bone marrow stromal cell (BMSCs) transplant on rat podocytes and diabetic nephropathy (DN) rats in high-glucose concentration, and to explore the effect of miR-124a on BMSC therapy. High glucose-injured podocytes and streptozotocin-induced DN rats have been respectively used as injury models in in vitro and in vivo studies. Podocyte viability was measured using the Cell Counting Kit-8 assay. Renal pathological examination was observed by HE staining and Masson staining. The messenger RNA and protein levels were determined via real-time polymerase chain reaction and Western blotting, respectively. RESULTS By mediating the activation of caveolin-1 (cav-1) and β-catenin and affecting the expression levels of EMT biomarkers including p-cadherin, synaptopodin, fibroblast-specific protein-1, α-smooth muscle actin and snail, our in vitro study confirmed that miR-124a played a significant role in the treatment of high glucose-induced podocyte injury by BMSCs. The therapeutic effects of the BMSC transplant on DN rats were also proved to be further enhanced by miR-124a overexpression in BMSCs, and such a phenomenon was accompanied by the improvement of renal fibrosis and mitigation of DN-related kidney impairment. Regulation of fibronectin, collagen1, and EMT-related proteins was closely implicated with the mechanism, and the activation of cav-1 and β-catenin was also possibly involved. CONCLUSION The study demonstrated the pivotal effect of miR-124a on BMSC therapy for DN rats via mitigating EMT and fibrosis. Our results provide a novel insight into how therapeutic effects of BMSCs can be improved at the posttranscriptional level.
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Affiliation(s)
- Xiaojun Cai
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang, China
| | - Lei Wang
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang, China
| | - Xuling Wang
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang, China
| | - Fengyan Hou
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang, China
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Gan J, Wang Y, Zhou X. Stem cell transplantation for the treatment of patients with type 1 diabetes mellitus: A meta-analysis. Exp Ther Med 2018; 16:4479-4492. [PMID: 30542397 PMCID: PMC6257425 DOI: 10.3892/etm.2018.6769] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Accepted: 08/31/2018] [Indexed: 12/28/2022] Open
Abstract
The efficacy of stem cell (SC) transplantation in patients with type 1 diabetes mellitus (T1DM) has remained to be fully elucidated. In the present study, a systematic review and meta-analysis was performed to determine the clinical outcomes. Electronic databases, including PubMed, MEDLINE, WanFang and the Cochrane Library were screened for relevant studies published until January 13, 2018. The references of retrieved papers, systematic reviews and trial registries were manually screened for additional papers. Two authors were involved in screening the titles in order to select eligible studies, extract data and assess the risk of bias. Studies were pooled using a random-effects model as well as the Begg's funnel plot and subgroup analysis was performed using Stata 14.0 software. A total of 47 studies were retrieved for detailed evaluation, of which 22 met the inclusion criteria. No substantial publication bias was identified. The meta-analysis revealed that SC therapy increased C-peptide levels when compared with placebo treatment in randomized-controlled trials [RCT; standardized mean difference (SMD), 0.93; 95% confidence interval (CI) 0.23-1.63] and self-controlled trials (SMD, 0.66; 95% CI, -0.22 to 1.54). An analysis demonstrated that SC therapy was more efficient at reducing the glycated hemoglobin level compared with the control group in RCTs (SMD, 0.56; 95% CI; 0.06-1.06; and SMD, 1.63; 95% CI, 0.92-2.34, respectively). The graphs demonstrated that SC transplantation resulted in a reduction of insulin requirement. Furthermore, subgroup analyses revealed that patient age, medical history and the SC injection dose may be sources of the heterogeneity observed. The greatest benefit of SC transplantation was seen in patients aged ≥18 years or a medical history of <3 months. In addition, the SC injection dose of ≥107 IU/kg/day was more effective than <107 IU/kg/day when the cellular composition included mesenchymal SCs and hematopoietic SCs. In conclusion, SC therapy represents an efficient option for patients with T1DM. This systematic review was registered at the International prospective register of systematic reviews (no. 42018093930).
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Affiliation(s)
- Jiadi Gan
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Department of Clinical Medicine, The First Clinical Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yingjin Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
- Department of Clinical Medicine, The Second Clinical Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xiaodong Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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Gaipov A, Taubaldiyeva Z, Askarov M, Turebekov Z, Kozina L, Myngbay A, Ulyanova O, Tuganbekova S. Infusion of autologous bone marrow derived mononuclear stem cells potentially reduces urinary markers in diabetic nephropathy. J Nephrol 2018; 32:65-73. [PMID: 30406605 DOI: 10.1007/s40620-018-0548-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Accepted: 10/11/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Previous studies demonstrated safety and efficacy of autologous bone marrow-derived mononuclear cells (ABM-MNCs) in induced type-1 diabetes mellitus (T1DM) rats. However, the effect of ABM-MNCs on urinary markers of DN in humans is not well studied. We evaluated the therapeutic effect of ABM-MNCs on the urinary markers microalbuminuria (MAU), urinary type-IV collagen and urinary neutrophil gelatinase-associated lipocalin (uNGAL) in T1DM patients with and without nephropathy. METHODS This prospective open-label pilot study included 15 patients with T1DM, who had completed 2 visits within 6 months. Patients were divided into two groups according to the presence (DN, n = 7) and absence of nephropathy (T1DM, n = 8). ABM-MNCs were injected at each visit as per study protocol. Routine laboratory data, diabetes tests (fasting serum C-peptide and insulin, glycated hemoglobin, fasting and postprandial glucose), 24-h MAU and urinary type-IV collagen were measured at each visit. uNGAL levels were studied before and after 3 days of ABM-MNCs infusion at each visit. RESULTS Mean age of patients was 29.2 ± 10.4 years, 33% were male, and 27% of the overall group had hypertension. MAU was significantly reduced in the overall group (- 26.0%, p = 0.037), including in DN (- 83.2%, p = 0.021). A short-term significant reduction of uNGAL levels was observed 3 days after ABM-MNCs administration during the both the 1st visit (median 13.4 vs. 9.5 ng/ml, p = 0.027) and 2nd visit (median 8.8 vs. 6.4 ng/ml, p = 0.042) in both groups. However this reduction did not remain significant at the 6-month follow-up. Urinary type-IV collagen did not respond significantly to ABM-MNCs infusion. CONCLUSION Infusion of autologous bone marrow-derived mononuclear cells significantly reduced levels of MAU in DN patients. Further studies with larger sample size are needed to confirm these observations.
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Affiliation(s)
- Abduzhappar Gaipov
- Department of Extracorporeal Hemocorrection, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009.
| | - Zhannat Taubaldiyeva
- Department of Endocrinology, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| | - Manarbek Askarov
- Department of Stem Cell Technology, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| | - Zaiyrkhan Turebekov
- Department of Internal Medicine, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| | - Larisa Kozina
- Department of Biochemistry, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| | - Askhat Myngbay
- Private Institution "National Laboratory Astana", Nazarbayev University, Astana, Kazakhstan
| | - Olga Ulyanova
- Department of Endocrinology, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
| | - Saltanat Tuganbekova
- Department of Internal Medicine, JSC National Scientific Medical Research Center, Avenue Abylai-Khan #42, Astana, Kazakhstan, 010009
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Li H, Rong P, Ma X, Nie W, Chen C, Yang C, Zhang J, Dong Q, Wang W. Paracrine effect of mesenchymal stem cell as a novel therapeutic strategy for diabetic nephropathy. Life Sci 2018; 215:113-118. [PMID: 30399376 DOI: 10.1016/j.lfs.2018.11.001] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 10/25/2018] [Accepted: 11/01/2018] [Indexed: 12/14/2022]
Abstract
Diabetic nephropathy (DN) is a microvascular complication of diabetes mellitus (DM) and the main reason for end-stage renal diseases (ESRD). Based on the role of mesenchymal stem cells (MSCs) in regenerative medicine, the MSC therapy has been considered a promising strategy to ameliorate the progression of DN. In this article, we review the therapeutic potential of MSCs in DN, mainly involving MSC paracrine mechanism based on trophic factors and extracellular vesicles. Knowledge of mechanism underlying the therapeutic action of MSCs on DN can provide much needed new drug targets for this disease.
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Affiliation(s)
- Hongde Li
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Pengfei Rong
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiaoqian Ma
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Wei Nie
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Cheng Chen
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Cejun Yang
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Juan Zhang
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Qiong Dong
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Wei Wang
- Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China.
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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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Abstract
Diabetic nephropathy (DN) is currently the leading cause of end-stage renal disease globally. Given the increasing incidence of diabetes, many experts hold the view that DN will eventually progress toward pandemic proportions. Whilst hyperglycaemia-induced vascular dysfunction is the primary initiating mechanism in DN, its progression is also driven by a heterogeneous set of pathological mechanisms, including oxidative stress, inflammation and fibrosis. Current treatment strategies for DN are targeted against the fundamental dysregulation of glycaemia and hypertension. Unfortunately, these standards of care can delay but do not prevent disease progression or the significant emotional, physical and financial costs associated with this disease. As such, there is a pressing need to develop novel therapeutics that are both effective and safe. Set against the genomic era, numerous potential target pathways in DN have been identified. However, the clinical translation of basic DN research has been met with a number of challenges. Moreover, the notion of DN as a purely vascular disease is outdated and it has become clear that DN is a multi-dimensional, multi-cellular condition. The review will highlight the current therapeutic approaches for DN and provide an insight into how the inherent complexity of DN is shaping the research pathways toward the development and clinical translation of novel therapeutic strategies.
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Torres Crigna A, Daniele C, Gamez C, Medina Balbuena S, Pastene DO, Nardozi D, Brenna C, Yard B, Gretz N, Bieback K. Stem/Stromal Cells for Treatment of Kidney Injuries With Focus on Preclinical Models. Front Med (Lausanne) 2018; 5:179. [PMID: 29963554 PMCID: PMC6013716 DOI: 10.3389/fmed.2018.00179] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 05/24/2018] [Indexed: 12/18/2022] Open
Abstract
Within the last years, the use of stem cells (embryonic, induced pluripotent stem cells, or hematopoietic stem cells), Progenitor cells (e.g., endothelial progenitor cells), and most intensely mesenchymal stromal cells (MSC) has emerged as a promising cell-based therapy for several diseases including nephropathy. For patients with end-stage renal disease (ESRD), dialysis or finally organ transplantation are the only therapeutic modalities available. Since ESRD is associated with a high healthcare expenditure, MSC therapy represents an innovative approach. In a variety of preclinical and clinical studies, MSC have shown to exert renoprotective properties, mediated mainly by paracrine effects, immunomodulation, regulation of inflammation, secretion of several trophic factors, and possibly differentiation to renal precursors. However, studies are highly diverse; thus, knowledge is still limited regarding the exact mode of action, source of MSC in comparison to other stem cell types, administration route and dose, tracking of cells and documentation of therapeutic efficacy by new imaging techniques and tissue visualization. The aim of this review is to provide a summary of published studies of stem cell therapy in acute and chronic kidney injury, diabetic nephropathy, polycystic kidney disease, and kidney transplantation. Preclinical studies with allogeneic or xenogeneic cell therapy were first addressed, followed by a summary of clinical trials carried out with autologous or allogeneic hMSC. Studies were analyzed with respect to source of cell type, mechanism of action etc.
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Affiliation(s)
- Adriana Torres Crigna
- Medical Faculty Mannheim, Institute of Transfusion Medicine and Immunology, University of Heidelberg, German Red Cross Blood Service Baden-Württemberg-Hessen, Mannheim, Germany
| | - Cristina Daniele
- Medical Faculty Mannheim, Medical Research Centre, University of Heidelberg, Mannheim, Germany
| | - Carolina Gamez
- Department for Experimental Orthopaedics and Trauma Surgery, Medical Faculty Mannheim, Orthopaedic and Trauma Surgery Centre (OUZ), Heidelberg University, Mannheim, Germany
| | - Sara Medina Balbuena
- Department of Medicine (Nephrology/Endrocrinology/Rheumathology), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
| | - Diego O. Pastene
- Department of Medicine (Nephrology/Endrocrinology/Rheumathology), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
| | - Daniela Nardozi
- Medical Faculty Mannheim, Medical Research Centre, University of Heidelberg, Mannheim, Germany
| | - Cinzia Brenna
- Medical Faculty Mannheim, Medical Research Centre, University of Heidelberg, Mannheim, Germany
| | - Benito Yard
- Department of Medicine (Nephrology/Endrocrinology/Rheumathology), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
| | - Norbert Gretz
- Medical Faculty Mannheim, Medical Research Centre, University of Heidelberg, Mannheim, Germany
| | - Karen Bieback
- Medical Faculty Mannheim, Institute of Transfusion Medicine and Immunology, University of Heidelberg, German Red Cross Blood Service Baden-Württemberg-Hessen, Mannheim, Germany
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Cai X, Wang L, Wang X, Hou F. Silence of IGFBP7 suppresses apoptosis and epithelial mesenchymal transformation of high glucose induced-podocytes. Exp Ther Med 2018; 16:1095-1102. [PMID: 30112052 PMCID: PMC6090473 DOI: 10.3892/etm.2018.6298] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 02/16/2018] [Indexed: 12/15/2022] Open
Abstract
Insulin-like growth factor-binding protein 7 (IGFBP7) has been identified as a secreted protein associated with a number of cellular processes. However, the specific regulatory mechanisms of IGFBP7 on podocytes of diabetic nephropathy (DN) are yet to be elucidated. In the present study, podocytes were identified initially via an immunofluorescence assay using an anti-synaptopodin antibody. It was subsequently demonstrated that glucose promoted podocyte proliferation in a time- and dose-dependent manner via MTT assay. In addition, IGFBP7 expression was silenced in podocytes via siRNA, the effects of which were evaluated using western blotting and reverse transcription-quantitative polymerase chain reaction. It was demonstrated that silencing IGFBP7 inhibited apoptosis and epithelial mesenchymal transformation (EMT) of podocytes mediated by high glucose (HG). Transforming growth factor (TGF)-β1/mothers against decapentaplegic homolog (Smad) signaling was associated with proliferation, apoptotic activities and EMT. Therefore, the expression levels of TGF-β1/Smad pathway were detected, and it was observed that silencing IGFBP7 suppressed the TGF-β1/Smad pathway in podocytes induced by HG. These findings suggested that IGFBP7 may serve as a potential therapeutic target for DN.
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Affiliation(s)
- Xiaojun Cai
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang 150036, P.R. China
| | - Lei Wang
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang 150036, P.R. China
| | - Xuling Wang
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang 150036, P.R. China
| | - Fengyan Hou
- Department of Endocrinology, Heilongjiang Provincial Academy of Chinese Medical Science, Harbin, Heilongjiang 150036, P.R. China
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Li Y, Liu J, Liao G, Zhang J, Chen Y, Li L, Li L, Liu F, Chen B, Guo G, Wang C, Yang L, Cheng J, Lu Y. Early intervention with mesenchymal stem cells prevents nephropathy in diabetic rats by ameliorating the inflammatory microenvironment. Int J Mol Med 2018; 41:2629-2639. [PMID: 29484379 PMCID: PMC5846648 DOI: 10.3892/ijmm.2018.3501] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 09/01/2017] [Indexed: 02/05/2023] Open
Abstract
Diabetic nephropathy (DN) is a major complication of diabetes and represents the leading cause of end-stage renal disease. Mesenchymal stem cell (MSC) treatment has been demonstrated to be effective in DN models by reducing albuminuria and attenuating glomerular injury; however, limited in-depth understanding of the underlying mechanism and a lack of clinical trials hinders its clinical use. Additionally, most of these experimental studies were conducted on the advanced stage of nephropathy, which is difficult to reverse and consequently showed limited therapeutic efficacy. We sought to evaluate whether early intervention by MSCs has the potential to prevent DN onset and progression as well as protect kidney function when intravenously administered to rats with diabetes. Diabetes was induced in adult male SD rats by streptozotocin (STZ) injection (55 mg/kg, i.p.). The diabetic rats were injected with or without bone marrow-derived MSCs (5×106 per rat), via tail vein at 2, 4, 5 and 7 weeks after diabetes onset. Fasting blood glucose (FBG), blood urea nitrogen (BUN) and serum creatinine (Scr) levels in serum samples and glycosuria (GLU), microalbumin (MAU), and albumin to creatinine ratio (ACR) in urine samples were determined. Renal pathology and immunohistochemistry (IHC) for CD68, MCP-1, fibronectin (FN), transforming growth factor-β (TGF-β) and pro-inflammatory cytokines were also performed. Expression levels of the above factors as well as interleukin-10 (IL-10), and epidermal growth factor (EGF) were assessed by qPCR and multiplex bead-based suspension array system, respectively. Additionally, MSC tracing in vivo was performed. Ex vivo, peritoneal macrophages were co-cultured with MSCs, and expression of inflammatory cytokines was detected as well. MSC treatment profoundly suppressed renal macrophage infiltration and inflammatory cytokine secretion in diabetic rats, resulting in prominently improved kidney histology, systemic homeostasis, and animal survival, although no significant effect on hyperglycemia was observed. Engrafted MSCs were primarily localized in deteriorated areas of the kidney and immune organs 48 h after infusion. MSC treatment upregulated serum anti-inflammatory cytokines IL-10 and EGF. Ex vivo, MSCs inhibited lipopolysaccharide (LPS)-stimulated rat peritoneal macrophage activation via the downregulation of inflammatory-related cytokines such as IL-6, MCP-1, tumor necrosis factor-α (TNF-α) and IL-1β. Our results demonstrated that early intervention with MSCs prevented renal injury via immune regulation in diabetic rats, which restored the homeostasis of the immune microenvironment, contributing to the prevention of kidney dysfunction and glomerulosclerosis.
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Affiliation(s)
- Yuanmin Li
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jingping Liu
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Guangneng Liao
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jie Zhang
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Younan Chen
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lan Li
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Li Li
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Fang Liu
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Bo Chen
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Gang Guo
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Chengshi Wang
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lichuan Yang
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jingqiu Cheng
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yangrong Lu
- Key Laboratory of Transplant Engineering and Immunology, National Health and Family Planning Commission (NHFPC), West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Sunitha MM, Srikanth L, Kumar PS, Chandrasekhar C, Sarma PVGK. Down-regulation of PAX2 promotes in vitro differentiation of podocytes from human CD34+ cells. Cell Tissue Res 2017; 370:477-488. [DOI: 10.1007/s00441-017-2680-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 08/07/2017] [Indexed: 12/16/2022]
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Nagaishi K, Mizue Y, Chikenji T, Otani M, Nakano M, Saijo Y, Tsuchida H, Ishioka S, Nishikawa A, Saito T, Fujimiya M. Umbilical cord extracts improve diabetic abnormalities in bone marrow-derived mesenchymal stem cells and increase their therapeutic effects on diabetic nephropathy. Sci Rep 2017; 7:8484. [PMID: 28814814 PMCID: PMC5559488 DOI: 10.1038/s41598-017-08921-y] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 07/20/2017] [Indexed: 01/04/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSC) has been applied as the most valuable source of autologous cell transplantation for various diseases including diabetic complications. However, hyperglycemia may cause abnormalities in intrinsic BM-MSC which might lose sufficient therapeutic effects in diabetic patients. We demonstrated the functional abnormalities in BM-MSC derived from both type 1 and type 2 diabetes models in vitro, which resulted in loss of therapeutic effects in vivo in diabetic nephropathy (DN). Then, we developed a novel method to improve abnormalities in BM-MSC using human umbilical cord extracts, namely Wharton’s jelly extract supernatant (WJs). WJs is a cocktail of growth factors, extracellular matrixes and exosomes, which ameliorates proliferative capacity, motility, mitochondrial degeneration, endoplasmic reticular functions and exosome secretions in both type 1 and type 2 diabetes-derived BM-MSC (DM-MSC). Exosomes contained in WJs were a key factor for this activation, which exerted similar effects to complete WJs. DM-MSC activated by WJs ameliorated renal injury in both type 1 and type 2 DN. In this study, we developed a novel activating method using WJs to significantly increase the therapeutic effect of BM-MSC, which may allow effective autologous cell transplantation.
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Affiliation(s)
- Kanna Nagaishi
- Second Department of Anatomy, Sapporo Medical University, Sapporo, Japan. .,Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Sapporo, Japan.
| | - Yuka Mizue
- Second Department of Anatomy, Sapporo Medical University, Sapporo, Japan.,Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Sapporo, Japan
| | - Takako Chikenji
- Second Department of Anatomy, Sapporo Medical University, Sapporo, Japan.,Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Sapporo, Japan
| | - Miho Otani
- Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Sapporo, Japan
| | - Masako Nakano
- Second Department of Anatomy, Sapporo Medical University, Sapporo, Japan
| | - Yusaku Saijo
- Second Department of Anatomy, Sapporo Medical University, Sapporo, Japan
| | - Hikaru Tsuchida
- Second Department of Anatomy, Sapporo Medical University, Sapporo, Japan
| | - Shinichi Ishioka
- Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo, Japan
| | - Akira Nishikawa
- Department of Gynecology and Obstetrics, NTT Sapporo Hospital, Sapporo, Japan
| | - Tsuyoshi Saito
- Department of Obstetrics and Gynecology, Sapporo Medical University, Sapporo, Japan
| | - Mineko Fujimiya
- Second Department of Anatomy, Sapporo Medical University, Sapporo, Japan.,Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Sapporo, Japan
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