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Zeinhom A, Fadallah SA, Mahmoud M. Human mesenchymal stem/stromal cell based-therapy in diabetes mellitus: experimental and clinical perspectives. Stem Cell Res Ther 2024; 15:384. [PMID: 39468609 PMCID: PMC11520428 DOI: 10.1186/s13287-024-03974-z] [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: 09/02/2024] [Accepted: 10/04/2024] [Indexed: 10/30/2024] Open
Abstract
Diabetes mellitus (DM), a chronic metabolic disease, poses a significant global health challenge, with current treatments often fail to prevent the long-term disease complications. Mesenchymal stem/stromal cells (MSCs) are, adult progenitors, able to repair injured tissues, exhibiting regenerative effects and immunoregulatory and anti-inflammatory responses, so they have been emerged as a promising therapeutic approach in many immune-related and inflammatory diseases. This review summarizes the therapeutic mechanisms and outcomes of MSCs, derived from different human tissue sources (hMSCs), in the context of DM type 1 and type 2. Animal model studies and clinical trials indicate that hMSCs can facilitate pleiotropic actions in the diabetic milieu for improved metabolic indices. In addition to modulating abnormally active immune system, hMSCs can ameliorate peripheral insulin resistance, halt beta-cell destruction, preserve residual beta-cell mass, promote beta-cell regeneration and insulin production, support islet grafts, and correct lipid metabolism. Moreover, hMSC-free derivatives, importantly extracellular vesicles, have shown potent experimental anti-diabetic efficacy. Moreover, the review discusses the diverse priming strategies that are introduced to enhance the preclinical anti-diabetic actions of hMSCs. Such strategies are recommended to restore the characteristics and functions of MSCs isolated from patients with DM for autologous implications. Finally, limitations and merits for the wide spread clinical applications of MSCs in DM such as the challenge of autologous versus allogeneic MSCs, the optimal MSC tissue source and administration route, the necessity of larger clinical trials for longer evaluation duration to assess safety concerns, are briefly presented.
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Affiliation(s)
- Alaa Zeinhom
- Biotechnology Department, Faculty of Science, Cairo University, Cairo Governorate, 12316, Egypt
| | - Sahar A Fadallah
- Biotechnology Department, Faculty of Science, Cairo University, Cairo Governorate, 12316, Egypt
| | - Marwa Mahmoud
- Human Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre (NRC), Cairo, 12622, Egypt.
- Stem Cell Research Unit, Medical Research Centre of Excellence, NRC, Cairo, Egypt.
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Kuang YH, Zhu W, Lin G, Cheng LM, Qin Q, Huang ZJ, Shi YL, Zhang CL, Xu JH, Yan KX, Lv CZ, Li W, Han Q, Stambler I, Lim LW, Chakrabarti S, Ulfhake B, Min KJ, Ellison-Hughes G, Cho WC, Jin K, Yao D, Lu C, Zhao RC, Chen X. Expert Consensus on the Application of Stem Cells in Psoriasis Research and Clinical Trials. Aging Dis 2024; 16:1363-1377. [PMID: 39012666 PMCID: PMC12096900 DOI: 10.14336/ad.2024.0012] [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: 01/03/2024] [Accepted: 06/04/2024] [Indexed: 07/17/2024] Open
Abstract
Psoriasis is an immune-mediated, chronic, relapsing, inflammatory, systemic disease induced by individual-environmental interactions, and is often lifelong because of the difficulty of treatment. In recent years, a variety of targeted therapies, including biologics, have improved the lesions and quality of life of most psoriasis patients, but they still do not address the problem of relapse and may be associated with decreased efficacy or adverse events such as infections over time. Therefore, there is an urgent need for breakthroughs in psoriasis treatment and in relapse-delaying and non-pharmacologic strategies, and stem cell therapy for psoriasis has emerged. In recent years, research on stem cell therapy for psoriasis has received a lot of attention, however, there is no reference standard as well as consensus in this field of research. Therefore, according to the latest consensus and guidelines, combined with relevant literature reports, clinical practice experience and the results of discussions with experts, this consensus specifies the types of stem cells commonly used in the treatment of psoriasis, the methods, dosages, and routes of stem cell therapy for psoriasis, as well as the clinical evaluations (efficacy and safety) of stem cell therapy for psoriasis. In addition, this consensus also provides normative standards for the processes of collection, preparation, preservation and quality control of stem cells and their related products, as well as recommendations for the management of stem cells during infusion for the treatment of psoriasis. This consensus provides the latest specific reference standards and practice guidelines for the field of stem cell therapy for psoriasis.
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Affiliation(s)
- Ye-Hong Kuang
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
- China Dermatologist Association, China.
- Chinese Society of Dermatology, China.
| | - Wu Zhu
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
- China Dermatologist Association, China.
- Chinese Society of Dermatology, China.
| | - Ge Lin
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China.
- National Engineering Research Center of Human Stem Cell, Changsha, China.
| | - La-Mei Cheng
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, China.
- National Engineering Research Center of Human Stem Cell, Changsha, China.
| | - Qun Qin
- The Office of Drug Clinical Trials Institution, Xiangya Hospital, Central South University, Changsha, China.
| | - Zhi-Jun Huang
- Center for Clinical Pharmacology, The Third Xiangya Hospital of Central South University, Changsha, China.
| | - Yu-Ling Shi
- Department of Dermatology, Shanghai Skin Disease Hospital, Institute of Psoriasis, School of Medicine, Tongji University, Shanghai, China.
- China Dermatologist Association, China.
- Chinese Society of Dermatology, China.
| | - Chun-Lei Zhang
- Department of Dermatology, Peking University Third Hospital, Beijing, China.
- China Dermatologist Association, China.
- Chinese Society of Dermatology, China.
| | - Jin-Hua Xu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
- China Dermatologist Association, China.
- Chinese Society of Dermatology, China.
| | - Ke-Xiang Yan
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
- China Dermatologist Association, China.
- Chinese Society of Dermatology, China.
| | - Cheng-Zhi Lv
- Department of Dermatology, Dalian Dermatosis Hospital, Dalian, China.
- China Dermatologist Association, China.
- Chinese Society of Dermatology, China.
| | - Wei Li
- Department of Dermatology, Rare Diseases Center, West China Hospital, Sichuan University, Chengdu, China.
- China Dermatologist Association, China.
- Chinese Society of Dermatology, China.
| | - Qin Han
- International Society on Aging and Disease, Fort Worth, TX, USA.
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
- Center for Excellence in Tissue Engineering, Chinese Academy of Medical Sciences, Beijing, China.
- Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, China.
| | - Ilia Stambler
- International Society on Aging and Disease, Fort Worth, TX, USA.
- Department of Science, Technology and Society, Bar Ilan University, Ramat Gan, Israel.
| | - Lee Wei Lim
- International Society on Aging and Disease, Fort Worth, TX, USA.
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China.
| | - Sasanka Chakrabarti
- International Society on Aging and Disease, Fort Worth, TX, USA.
- Maharishi Markandeshwar Deemed University, Mullana-Ambala, India.
| | - Brun Ulfhake
- International Society on Aging and Disease, Fort Worth, TX, USA.
- Karolinska University Hospital, Stockholm, Sweden.
| | - Kyung-Jin Min
- International Society on Aging and Disease, Fort Worth, TX, USA.
- Department of Biological Sciences, Inha University, Incheon, Republic of Korea.
| | - Georgina Ellison-Hughes
- International Society on Aging and Disease, Fort Worth, TX, USA.
- School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King’s College London, London, UK.
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China.
| | - Kunlin Jin
- International Society on Aging and Disease, Fort Worth, TX, USA.
- University of North Texas Health Science Center, Bryan, TX, USA.
| | - Danni Yao
- Department of Dermatology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
| | | | - Robert Chunhua Zhao
- International Society on Aging and Disease, Fort Worth, TX, USA.
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
- Center for Excellence in Tissue Engineering, Chinese Academy of Medical Sciences, Beijing, China.
- Beijing Key Laboratory of New Drug Development and Clinical Trial of Stem Cell Therapy (BZ0381), Beijing, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
- China Dermatologist Association, China.
- Chinese Society of Dermatology, China.
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Chu W, Zhang F, Zeng X, He F, Shang G, Guo T, Wang Q, Wu J, Li T, Zhong ZZ, Liang X, Hu J, Liu M. A GMP-compliant manufacturing method for Wharton's jelly-derived mesenchymal stromal cells. Stem Cell Res Ther 2024; 15:131. [PMID: 38702793 PMCID: PMC11069138 DOI: 10.1186/s13287-024-03725-0] [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: 09/05/2023] [Accepted: 04/10/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) hold great therapeutic potential in regenerative medicine. Therefore, it is crucial to establish a Good Manufacturing Practice (GMP)-compliant methodology for the isolation and culture of WJ-MSCs. Through comprehensive research, encompassing laboratory-scale experiments to pilot-scale studies, we aimed to develop standardized protocols ensuring the high yield and quality of WJ-MSCs manufacturing. METHODS Firstly, optimization of parameters for the enzymatic digestion method used to isolate WJ-MSCs was conducted. These parameters included enzyme concentrations, digestion times, seeding densities, and culture media. Additionally, a comparative analysis between the explant method and the enzymatic digestion method was performed. Subsequently, the consecutive passaging of WJ-MSCs, specifically up to passage 9, was evaluated using the optimized method. Finally, manufacturing processes were developed and scaled up, starting from laboratory-scale flask-based production and progressing to pilot-scale cell factory-based production. Furthermore, a stability study was carried out to assess the storage and use of drug products (DPs). RESULTS The optimal parameters for the enzymatic digestion method were a concentration of 0.4 PZ U/mL Collagenase NB6 and a digestion time of 3 h, resulting in a higher yield of P0 WJ-MSCs. In addition, a positive correlation between the weight of umbilical cord tissue and the quantities of P0 WJ-MSCs has been observed. Evaluation of different concentrations of human platelet lysate revealed that 2% and 5% concentrations resulted in similar levels of cell expansion. Comparative analysis revealed that the enzymatic digestion method exhibited faster outgrowth of WJ-MSCs compared to the explant method during the initial passage. Passages 2 to 5 exhibited higher viability and proliferation ability throughout consecutive passaging. Moreover, scalable manufacturing processes from the laboratory scale to the pilot scale were successfully developed, ensuring the production of high-quality WJ-MSCs. Multiple freeze-thaw cycles of the DPs led to reduced cell viability and viable cell concentration. Subsequent thawing and dilution of the DPs resulted in a significant decrease in both metrics, especially when stored at 20-27 °C. CONCLUSION This study offers valuable insights into optimizing the isolation and culture of WJ-MSCs. Our scalable manufacturing processes facilitate the large-scale production of high-quality WJ-MSCs. These findings contribute to the advancement of WJ-MSCs-based therapies in regenerative medicine.
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Affiliation(s)
- Wanglong Chu
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Fen Zhang
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Xiuping Zeng
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Fangtao He
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Guanyan Shang
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Tao Guo
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Qingfang Wang
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Jianfu Wu
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Tongjing Li
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Zhen Zhong Zhong
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Xiao Liang
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China
| | - Junyuan Hu
- Shenzhen Beike Biotechnology Co., Ltd, 518000, Shenzhen, Guangdong, People's Republic of China.
| | - Muyun Liu
- National Engineering Research Center of Foundational Technologies for CGT Industry, 518000, Shenzhen, Guangdong, People's Republic of China.
- Shenzhen Kenuo Medical Laboratory, 518000, Shenzhen, Guangdong, People's Republic of China.
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Li L, Li J, Guan H, Oishi H, Takahashi S, Zhang C. Human umbilical cord mesenchymal stem cells in diabetes mellitus and its complications: applications and research advances. Int J Med Sci 2023; 20:1492-1507. [PMID: 37790847 PMCID: PMC10542192 DOI: 10.7150/ijms.87472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 08/22/2023] [Indexed: 10/05/2023] Open
Abstract
Diabetes mellitus and its complications pose a major threat to global health and affect the quality of life and life expectancy of patients. Currently, the application of traditional therapeutic drugs for diabetes mellitus has great limitations and can only temporarily control blood glucose but not fundamentally cure it. Mesenchymal stem cells, as pluripotent stromal cells, have multidirectional differentiation potential, high self-renewal, immune regulation, and low immunogenicity, which provide a new idea and possible development direction for diabetes mellitus treatment. Regenerative medicine with mesenchymal stem cells treatment as the core treatment will become another treatment option for diabetes mellitus after traditional treatment. Recently, human umbilical cord mesenchymal stem cells have been widely used in basic and clinical research on diabetes mellitus and its complications because of their abundance, low ethical controversy, low risk of infection, and high proliferation and differentiation ability. This paper reviews the therapeutic role and mechanism of human umbilical cord mesenchymal stem cells in diabetes mellitus and its complications and highlights the challenges faced by the clinical application of human umbilical cord mesenchymal stem cells to provide a more theoretical basis for the application of human umbilical cord mesenchymal stem cells in diabetes mellitus patients.
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Affiliation(s)
- Luyao Li
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Jicui Li
- Department of Nephrology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Haifei Guan
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
| | - Hisashi Oishi
- Department of Comparative and Experimental Medicine, Nagoya City University Graduate 24 School of Medical Sciences, Aichi 467-8601, Nagoya, Japan
| | - Satoru Takahashi
- Institute of Basic Medical Sciences and Laboratory Animal Resource Center, University of Tsukuba, Ibaraki 305-8575, Tsukuba, Japan
| | - Chuan Zhang
- Department of Endocrinology, the Second Hospital of Jilin University, Changchun 130041, Jilin, P.R. China
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Drobiova H, Sindhu S, Ahmad R, Haddad D, Al-Mulla F, Al Madhoun A. Wharton's jelly mesenchymal stem cells: a concise review of their secretome and prospective clinical applications. Front Cell Dev Biol 2023; 11:1211217. [PMID: 37440921 PMCID: PMC10333601 DOI: 10.3389/fcell.2023.1211217] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/13/2023] [Indexed: 07/15/2023] Open
Abstract
Accumulating evidence indicates that most primary Wharton's jelly mesenchymal stem cells (WJ-MSCs) therapeutic potential is due to their paracrine activity, i.e., their ability to modulate their microenvironment by releasing bioactive molecules and factors collectively known as secretome. These bioactive molecules and factors can either be released directly into the surrounding microenvironment or can be embedded within the membrane-bound extracellular bioactive nano-sized (usually 30-150 nm) messenger particles or vesicles of endosomal origin with specific route of biogenesis, known as exosomes or carried by relatively larger particles (100 nm-1 μm) formed by outward blebbing of plasma membrane called microvesicles (MVs); exosomes and MVs are collectively known as extracellular vesicles (EVs). The bioactive molecules and factors found in secretome are of various types, including cytokines, chemokines, cytoskeletal proteins, integrins, growth factors, angiogenic mediators, hormones, metabolites, and regulatory nucleic acid molecules. As expected, the secretome performs different biological functions, such as immunomodulation, tissue replenishment, cellular homeostasis, besides possessing anti-inflammatory and anti-fibrotic effects. This review highlights the current advances in research on the WJ-MSCs' secretome and its prospective clinical applications.
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Affiliation(s)
- Hana Drobiova
- Human Genetics Unit, Department of Pathology, College of Medicine, Kuwait University, Jabriya, Kuwait
| | - Sardar Sindhu
- Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman, Kuwait
- Department of Immunology and Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Rasheed Ahmad
- Department of Immunology and Microbiology, Dasman Diabetes Institute, Dasman, Kuwait
| | - Dania Haddad
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
| | - Fahd Al-Mulla
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
| | - Ashraf Al Madhoun
- Animal and Imaging Core Facilities, Dasman Diabetes Institute, Dasman, Kuwait
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman, Kuwait
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Russo E, Corrao S, Di Gaudio F, Alberti G, Caprnda M, Kubatka P, Kruzliak P, Miceli V, Conaldi PG, Borlongan CV, La Rocca G. Facing the Challenges in the COVID-19 Pandemic Era: From Standard Treatments to the Umbilical Cord-Derived Mesenchymal Stromal Cells as a New Therapeutic Strategy. Cells 2023; 12:1664. [PMID: 37371134 PMCID: PMC10297457 DOI: 10.3390/cells12121664] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/10/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which counts more than 650 million cases and more than 6.6 million of deaths worldwide, affects the respiratory system with typical symptoms such as fever, cough, sore throat, acute respiratory distress syndrome (ARDS), and fatigue. Other nonpulmonary manifestations are related with abnormal inflammatory response, the "cytokine storm", that could lead to a multiorgan disease and to death. Evolution of effective vaccines against SARS-CoV-2 provided multiple options to prevent the infection, but the treatment of the severe forms remains difficult to manage. The cytokine storm is usually counteracted with standard medical care and anti-inflammatory drugs, but researchers moved forward their studies on new strategies based on cell therapy approaches. The perinatal tissues, such as placental membranes, amniotic fluid, and umbilical cord derivatives, are enriched in mesenchymal stromal cells (MSCs) that exert a well-known anti-inflammatory role, immune response modulation, and tissue repair. In this review, we focused on umbilical-cord-derived MSCs (UC-MSCs) used in in vitro and in vivo studies in order to evaluate the weakening of the severe symptoms, and on recent clinical trials from different databases, supporting the favorable potential of UC-MSCs as therapeutic strategy.
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Affiliation(s)
- Eleonora Russo
- Section of Histology and Embryology, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
| | - Simona Corrao
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per per i Trapianti e Terapie Ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | | | - Giusi Alberti
- Section of Histology and Embryology, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
| | - Martin Caprnda
- 1st Department of Internal Medicine, Faculty of Medicine, Comenius University, University Hospital Bratislava, 81499 Bratislava, Slovakia;
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 03649 Martin, Slovakia;
| | - Peter Kruzliak
- Research and Development Services, Pradlacka 18, 61300 Brno, Czech Republic;
| | - Vitale Miceli
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per per i Trapianti e Terapie Ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | - Pier Giulio Conaldi
- Research Department, IRCCS ISMETT (Istituto Mediterraneo per per i Trapianti e Terapie Ad Alta Specializzazione), 90127 Palermo, Italy; (S.C.); (V.M.); (P.G.C.)
| | - Cesario Venturina Borlongan
- Department of Neurosurgery and Brain Repair, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Giampiero La Rocca
- Section of Histology and Embryology, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90127 Palermo, Italy; (E.R.); (G.A.)
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Zhang M, He Y, Zhang X, Gan S, Xie X, Zheng Z, Liao J, Chen W. Engineered cell-overexpression of circular RNA hybrid hydrogels promotes healing of calvarial defects. Biomater Sci 2023; 11:1665-1676. [PMID: 36472132 DOI: 10.1039/d2bm01472f] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Craniomaxillofacial bone defects seriously affect the physical and mental health of patients. Bone marrow mesenchymal stem cells (BMSCs) are "gold standard" cells used for bone repair. However, the collection of BMSCs is invasive, and the osteogenic capacity is limited with age. Human umbilical cord mesenchymal stem cells (hUCMSCs) are promising alternative seed cells for bone tissue engineering. Our group previously used high-throughput sequencing technology and bioinformatics methods to detect circ-CTTN (hsa-circ_0003376) molecules, which may play an essential role in the osteogenic differentiation of hUCMSCs. In this study, osteogenic induction in vitro showed that the overexpressing circ-CTTN (OE group) exhibits a more pronounced osteogenic phenotype. The levels of osteogenesis-related genes in the OE group were highly expressed. The gelatin-methacrylate (GelMA) hydrogel possessed excellent biocompatibility and was used to load hUCMSCs. In the rat calvarial defect, the OE group presented a larger bone healing volume and denser bone trabecular distribution than other groups. So far, the overexpression of circ-CTTN could enhance the osteogenic differentiation of hUCMSCs and accelerate bone reconstruction. Our research could provide a new strategy and a strong theoretical basis for promoting hUCMSC clinical application in bone tissue engineering.
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Affiliation(s)
- Min Zhang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Med-X Center for Materials, West China Hospital of Stomatology, Sichuan University, China. .,Department of Oral Prosthodontics & Jinjiang out-patient section, West China Hospital of Stomatology, Sichuan University, China
| | - Yanjing He
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Med-X Center for Materials, West China Hospital of Stomatology, Sichuan University, China. .,Department of Oral Prosthodontics & Jinjiang out-patient section, West China Hospital of Stomatology, Sichuan University, China
| | - Xu Zhang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Med-X Center for Materials, West China Hospital of Stomatology, Sichuan University, China.
| | - Shuaiqi Gan
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Med-X Center for Materials, West China Hospital of Stomatology, Sichuan University, China. .,Department of Oral Prosthodontics & Jinjiang out-patient section, West China Hospital of Stomatology, Sichuan University, China
| | - Xi Xie
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Med-X Center for Materials, West China Hospital of Stomatology, Sichuan University, China.
| | - Zheng Zheng
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Med-X Center for Materials, West China Hospital of Stomatology, Sichuan University, China. .,Department of Oral Prosthodontics & Jinjiang out-patient section, West China Hospital of Stomatology, Sichuan University, China
| | - Jinfeng Liao
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Med-X Center for Materials, West China Hospital of Stomatology, Sichuan University, China.
| | - Wenchuan Chen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Med-X Center for Materials, West China Hospital of Stomatology, Sichuan University, China. .,Department of Oral Prosthodontics & Jinjiang out-patient section, West China Hospital of Stomatology, Sichuan University, China
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8
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Khaing ZZ, Chen JY, Safarians G, Ezubeik S, Pedroncelli N, Duquette RD, Prasse T, Seidlits SK. Clinical Trials Targeting Secondary Damage after Traumatic Spinal Cord Injury. Int J Mol Sci 2023; 24:3824. [PMID: 36835233 PMCID: PMC9960771 DOI: 10.3390/ijms24043824] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/06/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
Spinal cord injury (SCI) often causes loss of sensory and motor function resulting in a significant reduction in quality of life for patients. Currently, no therapies are available that can repair spinal cord tissue. After the primary SCI, an acute inflammatory response induces further tissue damage in a process known as secondary injury. Targeting secondary injury to prevent additional tissue damage during the acute and subacute phases of SCI represents a promising strategy to improve patient outcomes. Here, we review clinical trials of neuroprotective therapeutics expected to mitigate secondary injury, focusing primarily on those in the last decade. The strategies discussed are broadly categorized as acute-phase procedural/surgical interventions, systemically delivered pharmacological agents, and cell-based therapies. In addition, we summarize the potential for combinatorial therapies and considerations.
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Affiliation(s)
- Zin Z. Khaing
- Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA
| | - Jessica Y. Chen
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Gevick Safarians
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Sohib Ezubeik
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Nicolas Pedroncelli
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
| | - Rebecca D. Duquette
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Tobias Prasse
- Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA
- Department of Orthopedics and Trauma Surgery, University of Cologne, 50931 Cologne, Germany
| | - Stephanie K. Seidlits
- Department of Bioengineering, University of California Los Angeles, Los Angeles, CA 90095, USA
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
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Perinatal Stem Cell Therapy to Treat Type 1 Diabetes Mellitus: A Never-Say-Die Story of Differentiation and Immunomodulation. Int J Mol Sci 2022; 23:ijms232314597. [PMID: 36498923 PMCID: PMC9738084 DOI: 10.3390/ijms232314597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/14/2022] [Accepted: 11/18/2022] [Indexed: 11/24/2022] Open
Abstract
Human term placenta and other postpartum-derived biological tissues are promising sources of perinatal cells with unique stem cell properties. Among the massive current research on stem cells, one medical focus on easily available stem cells is to exploit them in the design of immunotherapy protocols, in particular for the treatment of chronic non-curable human diseases. Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells and perinatal cells can be harnessed both to generate insulin-producing cells for beta cell replenishment and to regulate autoimmune mechanisms via immunomodulation capacity. In this study, the strong points of cells derived from amniotic epithelial cells and from umbilical cord matrix are outlined and their potential for supporting cell therapy development. From a basic research and expert stem cell point of view, the aim of this review is to summarize information regarding the regenerative medicine field, as well as describe the state of the art on possible cell therapy approaches for diabetes.
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10
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Papait A, Silini AR, Gazouli M, Malvicini R, Muraca M, O’Driscoll L, Pacienza N, Toh WS, Yannarelli G, Ponsaerts P, Parolini O, Eissner G, Pozzobon M, Lim SK, Giebel B. Perinatal derivatives: How to best validate their immunomodulatory functions. Front Bioeng Biotechnol 2022; 10:981061. [PMID: 36185431 PMCID: PMC9518643 DOI: 10.3389/fbioe.2022.981061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/12/2022] [Indexed: 11/27/2022] Open
Abstract
Perinatal tissues, mainly the placenta and umbilical cord, contain a variety of different somatic stem and progenitor cell types, including those of the hematopoietic system, multipotent mesenchymal stromal cells (MSCs), epithelial cells and amnion epithelial cells. Several of these perinatal derivatives (PnDs), as well as their secreted products, have been reported to exert immunomodulatory therapeutic and regenerative functions in a variety of pre-clinical disease models. Following experience with MSCs and their extracellular vesicle (EV) products, successful clinical translation of PnDs will require robust functional assays that are predictive for the relevant therapeutic potency. Using the examples of T cell and monocyte/macrophage assays, we here discuss several assay relevant parameters for assessing the immunomodulatory activities of PnDs. Furthermore, we highlight the need to correlate the in vitro assay results with preclinical or clinical outcomes in order to ensure valid predictions about the in vivo potency of therapeutic PnD cells/products in individual disease settings.
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Affiliation(s)
- Andrea Papait
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
| | - Antonietta Rosa Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Maria Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Ricardo Malvicini
- Department of Women and Children Health, University of Padova, Padova, Italy
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina
| | - Maurizio Muraca
- Department of Women and Children Health, University of Padova, Padova, Italy
| | - Lorraine O’Driscoll
- School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland
- Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Trinity St. James’s Cancer Institute, Trinity College Dublin, Dublin, Ireland
| | - Natalia Pacienza
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina
| | - Wei Seong Toh
- Department of Orthopaedic Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Gustavo Yannarelli
- Laboratorio de Regulación Génica y Células Madre, Instituto de Medicina Traslacional, Trasplante y Bioingeniería (IMeTTyB), Universidad Favaloro-CONICET, Buenos Aires, Argentina
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
| | - Günther Eissner
- Systems Biology Ireland, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Michela Pozzobon
- Department of Women and Children Health, University of Padova, Padova, Italy
| | - Sai Kiang Lim
- Institute of Medical Biology and Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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11
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Padovano M, Scopetti M, Manetti F, Morena D, Radaelli D, D'Errico S, Di Fazio N, Frati P, Fineschi V. Pancreatic transplant surgery and stem cell therapy: Finding the balance between therapeutic advances and ethical principles. World J Stem Cells 2022; 14:577-586. [PMID: 36157914 PMCID: PMC9453273 DOI: 10.4252/wjsc.v14.i8.577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/24/2022] [Accepted: 08/01/2022] [Indexed: 02/07/2023] Open
Abstract
The latest achievements in the field of pancreas transplantation and stem cell therapy require an effort by the scientific community to clarify the ethical implications of pioneering treatments, often characterized by high complexity from a surgical point of view, due to transplantation of multiple organs at the same time or at different times, and from an immunological point of view for stem cell therapy. The fundamental value in the field of organ transplants is, of course, a solidarity principle, namely that of protecting the health and life of people for whom transplantation is a condition of functional recovery, or even of survival. The nature of this value is that of a concept to which the legal discipline of transplants entrusts its own ethical dignity and for which it has ensured a constitutional recognition in different systems. The general principle of respect for human life, both of the donor and of the recipient, evokes the need not to put oneself and one's neighbor in dangerous conditions. The present ethical reflection aims to find a balance between the latest therapeutic advances and several concepts including the idea of the person, the respect due to the dead, the voluntary nature of the donation and the consent to the same, the gratuitousness of the donation, the scientific progress and the development of surgical techniques, and the policies of health promotion.
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Affiliation(s)
- Martina Padovano
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy
| | - Matteo Scopetti
- Department of Medical Surgical Sciences and Translational Medicine, Sapienza University of Rome, Rome 00189, Italy
| | - Federico Manetti
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy
| | - Donato Morena
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy
| | - Davide Radaelli
- Department of Medicine, Surgery and Health, University of Trieste, Trieste 34149, Italy
| | - Stefano D'Errico
- Department of Medicine, Surgery and Health, University of Trieste, Trieste 34149, Italy
| | - Nicola Di Fazio
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy
| | - Paola Frati
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy
| | - Vittorio Fineschi
- Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Rome 00185, Italy.
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12
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Human umbilical cord-derived mesenchymal stem cells ameliorate psoriasis-like dermatitis by suppressing IL-17-producing γδ T cells. Cell Tissue Res 2022; 388:549-563. [DOI: 10.1007/s00441-022-03616-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 03/10/2022] [Indexed: 12/14/2022]
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13
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Cells to the Rescue: Emerging Cell-Based Treatment Approaches for NMOSD and MOGAD. Int J Mol Sci 2021; 22:ijms22157925. [PMID: 34360690 PMCID: PMC8347572 DOI: 10.3390/ijms22157925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/04/2021] [Accepted: 07/15/2021] [Indexed: 12/12/2022] Open
Abstract
Cell-based therapies are gaining momentum as promising treatments for rare neurological autoimmune diseases, including neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease. The development of targeted cell therapies is hampered by the lack of adequate animal models that mirror the human disease. Most cell-based treatments, including HSCT, CAR-T cell, tolerogenic dendritic cell and mesenchymal stem cell treatment have entered early stage clinical trials or have been used as rescue treatment in treatment-refractory cases. The development of antigen-specific cell-based immunotherapies for autoimmune diseases is slowed down by the rarity of the diseases, the lack of surrogate outcomes and biomarkers that are able to predict long-term outcomes and/or therapy effectiveness as well as challenges in the manufacturing of cellular products. These challenges are likely to be overcome by future research.
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14
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Shang Y, Guan H, Zhou F. Biological Characteristics of Umbilical Cord Mesenchymal Stem Cells and Its Therapeutic Potential for Hematological Disorders. Front Cell Dev Biol 2021; 9:570179. [PMID: 34012958 PMCID: PMC8126649 DOI: 10.3389/fcell.2021.570179] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 04/08/2021] [Indexed: 01/14/2023] Open
Abstract
Umbilical cord mesenchymal stem cells (UC-MSCs) are a class of multifunctional stem cells isolated and cultured from umbilical cord. They possessed the characteristics of highly self-renewal, multi-directional differentiation potential and low immunogenicity. Its application in the field of tissue engineering and gene therapy has achieved a series of results. Recent studies have confirmed their characteristics of inhibiting tumor cell proliferation and migration to nest of cancer. The ability of UC-MSCs to support hematopoietic microenvironment and suppress immune system suggests that they can improve engraftment after hematopoietic stem cell transplantation, which shows great potential in treatment of hematologic diseases. This review will focus on the latest advances in biological characteristics and mechanism of UC-MSCs in treatment of hematological diseases.
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Affiliation(s)
- Yufeng Shang
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Haotong Guan
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Fuling Zhou
- Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, China
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15
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Magatti M, Masserdotti A, Cargnoni A, Papait A, Stefani FR, Silini AR, Parolini O. The Role of B Cells in PE Pathophysiology: A Potential Target for Perinatal Cell-Based Therapy? Int J Mol Sci 2021; 22:3405. [PMID: 33810280 PMCID: PMC8037408 DOI: 10.3390/ijms22073405] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/19/2021] [Accepted: 03/24/2021] [Indexed: 12/16/2022] Open
Abstract
The pathophysiology of preeclampsia (PE) is poorly understood; however, there is a large body of evidence that suggests a role of immune cells in the development of PE. Amongst these, B cells are a dominant element in the pathogenesis of PE, and they have been shown to play an important role in various immune-mediated diseases, both as pro-inflammatory and regulatory cells. Perinatal cells are defined as cells from birth-associated tissues isolated from term placentas and fetal annexes and more specifically from the amniotic membrane, chorionic membrane, chorionic villi, umbilical cord (including Wharton's jelly), the basal plate, and the amniotic fluid. They have drawn particular attention in recent years due to their ability to modulate several aspects of immunity, making them promising candidates for the prevention and treatment of various immune-mediated diseases. In this review we describe main findings regarding the multifaceted in vitro and in vivo immunomodulatory properties of perinatal cells, with a focus on B lymphocytes. Indeed, we discuss evidence on the ability of perinatal cells to inhibit B cell proliferation, impair B cell differentiation, and promote regulatory B cell formation. Therefore, the findings discussed herein unveil the possibility to modulate B cell activation and function by exploiting perinatal immunomodulatory properties, thus possibly representing a novel therapeutic strategy in PE.
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Affiliation(s)
- Marta Magatti
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (A.C.); (A.P.); (F.R.S.); (A.R.S.)
| | - Alice Masserdotti
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, 00168 Roma, Italy;
| | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (A.C.); (A.P.); (F.R.S.); (A.R.S.)
| | - Andrea Papait
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (A.C.); (A.P.); (F.R.S.); (A.R.S.)
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, 00168 Roma, Italy;
| | - Francesca Romana Stefani
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (A.C.); (A.P.); (F.R.S.); (A.R.S.)
| | - Antonietta Rosa Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (A.C.); (A.P.); (F.R.S.); (A.R.S.)
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, 00168 Roma, Italy;
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Roma, Italy
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16
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Cargnoni A, Papait A, Masserdotti A, Pasotti A, Stefani FR, Silini AR, Parolini O. Extracellular Vesicles From Perinatal Cells for Anti-inflammatory Therapy. Front Bioeng Biotechnol 2021; 9:637737. [PMID: 33614619 PMCID: PMC7892960 DOI: 10.3389/fbioe.2021.637737] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/19/2021] [Indexed: 01/08/2023] Open
Abstract
Perinatal cells, including cells from placenta, fetal annexes (amniotic and chorionic membranes), umbilical cord, and amniotic fluid display intrinsic immunological properties which very likely contribute to the development and growth of a semiallogeneic fetus during pregnancy. Many studies have shown that perinatal cells can inhibit the activation and modulate the functions of various inflammatory cells of the innate and adaptive immune systems, including macrophages, neutrophils, natural killer cells, dendritic cells, and T and B lymphocytes. These immunological properties, along with their easy availability and lack of ethical concerns, make perinatal cells very useful/promising in regenerative medicine. In recent years, extracellular vesicles (EVs) have gained great interest as a new therapeutic tool in regenerative medicine being a cell-free product potentially capable, thanks to the growth factors, miRNA and other bioactive molecules they convey, of modulating the inflammatory microenvironment thus favoring tissue regeneration. The immunomodulatory actions of perinatal cells have been suggested to be mediated by still not fully identified factors (secretoma) secreted either as soluble proteins/cytokines or entrapped in EVs. In this review, we will discuss how perinatal derived EVs may contribute toward the modulation of the immune response in various inflammatory pathologies (acute and chronic) by directly targeting different elements of the inflammatory microenvironment, ultimately leading to the repair and regeneration of damaged tissues.
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Affiliation(s)
- Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Andrea Papait
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alice Masserdotti
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Anna Pasotti
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | | | - Antonietta Rosa Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
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17
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Papait A, Cargnoni A, Sheleg M, Silini AR, Kunis G, Ofir R, Parolini O. Perinatal Cells: A Promising COVID-19 Therapy? Front Bioeng Biotechnol 2021; 8:619980. [PMID: 33520970 PMCID: PMC7841388 DOI: 10.3389/fbioe.2020.619980] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 12/08/2020] [Indexed: 01/08/2023] Open
Abstract
The COVID-19 pandemic has become a priority in the health systems of all nations worldwide. In fact, there are currently no specific drugs or preventive treatments such as vaccines. The numerous therapies available today aim to counteract the symptoms caused by the viral infection that in some subjects can evolve causing acute respiratory distress syndromes (ARDS) with consequent admission to intensive care unit. The exacerbated response of the immune system, through cytokine storm, causes extensive damage to the lung tissue, with the formation of edema, fibrotic tissues and susceptibility to opportunistic infections. The inflammatory picture is also aggravated by disseminated intravascular coagulation which worsens the damage not only to the respiratory system, but also to other organs. In this context, perinatal cells represent a valid strategy thanks to their strong immunomodulatory potential, their safety profile, the ability to reduce fibrosis and stimulate reparative processes. Furthermore, perinatal cells exert antibacterial and antiviral actions. This review therefore provides an overview of the characteristics of perinatal cells with a particular focus on the beneficial effects that they could have in patients with COVID-19, and more specifically for their potential use in the treatment of ARDS and sepsis.
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Affiliation(s)
- Andrea Papait
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy
| | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy
| | | | - Antonietta R. Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza-Istituto Ospedaliero, Brescia, Italy
| | | | | | - Ornella Parolini
- Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, Rome, Italy
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18
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Intranasal administration of Cytoglobin modifies human umbilical cord‑derived mesenchymal stem cells and improves hypoxic‑ischemia brain damage in neonatal rats by modulating p38 MAPK signaling‑mediated apoptosis. Mol Med Rep 2020; 22:3493-3503. [PMID: 32945464 PMCID: PMC7453519 DOI: 10.3892/mmr.2020.11436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 07/17/2020] [Indexed: 12/21/2022] Open
Abstract
Neonatal hypoxic‑ischemic brain damage (HIBD) is a common clinical syndrome in newborns. Hypothermia is the only approved therapy for the clinical treatment; however, the therapeutic window of hypothermia is confined to 6 h after birth and even then, >40% of the infants either die or survive with various impairments, including cerebral palsy, seizure disorder and intellectual disability following hypothermic treatment. The aim of the present study was to determine whether nasal transplantation of Cytoglobin (CYGB) genetically modified human umbilical cord‑derived mesenchymal stem cells (CYGB‑HuMSCs) exhibited protective effects in neonatal rats with HIBD compared with those treated without genetically modified CYGB. A total of 120 neonatal Sprague‑Dawley rats (postnatal day 7) were assigned to either a Sham, HIBD, HuMSCs or CYGB‑HuMSCs group (n = 30 rats/group). For HIBD modeling, rats underwent left carotid artery ligation and were exposed to 8% oxygen for 2.5 h. A total of 30 min after HI, HuMSCs (or CYGB‑HuMSCs) labeled with enhanced‑green fluorescent protein (eGFP) were intranasally administered. After modeling for 3, 14 and 29 days, five randomly selected rats were sacrificed in each group, and the expression levels of CYGB, ERK, JNK and p38 in brain tissues were determined. Nissl staining of the cortex and hippocampal Cornu Ammonis 1 area of rats in each group were compared after 3 days of modeling. TUNEL assay and immunofluorescence were performed 3 days after modeling. Long term memory in rats was assessed using a Morris‑water maze 29 days after modeling. The HIBD group demonstrated significant deficiencies compared with the Sham group based on Nissl staining, TUNEL assay and the Morris‑water maze test. HuMSC treated rats exhibited improvement on in all the tests, and CYGB‑HuMSCs treatment resulted in further improvements. PCR and western blotting results indicated that the CYGB mRNA and protein levels were increased from day 3 to day 29 after transplantation of CYGB‑HuMSCs. Furthermore, it was identified that CYGB‑HuMSC transplantation suppressed p38 signaling at all experimental time points. Immunofluorescence indicated the scattered presence of HuMSCs or CYGB‑HuMSCs in damaged brain tissue. No eGFP and glial fibrillary acidic protein or eGFP and neuron‑specific enolase double‑stained positive cells were found in the brain tissues. Therefore, CYGB‑HuMSCs may serve as a gene transporter, as well as exert a neuroprotective and antiapoptotic effect in HIBD, potentially via the p38 mitogen‑activated protein kinase signaling pathway.
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Black L, Zorina T. Cell-based immunomodulatory therapy approaches for type 1 diabetes mellitus. Drug Discov Today 2020; 25:380-391. [DOI: 10.1016/j.drudis.2019.11.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/11/2019] [Accepted: 11/30/2019] [Indexed: 12/14/2022]
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Magatti M, Stefani FR, Papait A, Cargnoni A, Masserdotti A, Silini AR, Parolini O. Perinatal Mesenchymal Stromal Cells and Their Possible Contribution to Fetal-Maternal Tolerance. Cells 2019; 8:E1401. [PMID: 31703272 PMCID: PMC6912620 DOI: 10.3390/cells8111401] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 10/31/2019] [Accepted: 11/03/2019] [Indexed: 12/11/2022] Open
Abstract
During pregnancy, a successful coexistence between the mother and the semi-allogenic fetus occurs which requires a dynamic immune system to guarantee an efficient immune protection against possible infections and tolerance toward fetal antigens. The mechanism of fetal-maternal tolerance is still an open question. There is growing in vitro and in vivo evidence that mesenchymal stromal cells (MSC) which are present in perinatal tissues have a prominent role in generating a functional microenvironment critical to a successful pregnancy. This review highlights the immunomodulatory properties of perinatal MSC and their impact on the major immune cell subsets present in the uterus during pregnancy, such as natural killer cells, antigen-presenting cells (macrophages and dendritic cells), and T cells. Here, we discuss the current understanding and the possible contribution of perinatal MSC in the establishment of fetal-maternal tolerance, providing a new perspective on the physiology of gestation.
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Affiliation(s)
- Marta Magatti
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (F.R.S.); (A.P.); (A.C.); (A.R.S.)
| | - Francesca Romana Stefani
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (F.R.S.); (A.P.); (A.C.); (A.R.S.)
| | - Andrea Papait
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (F.R.S.); (A.P.); (A.C.); (A.R.S.)
| | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (F.R.S.); (A.P.); (A.C.); (A.R.S.)
| | - Alice Masserdotti
- Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Roma, Italy;
| | - Antonietta Rosa Silini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (F.R.S.); (A.P.); (A.C.); (A.R.S.)
| | - Ornella Parolini
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy; (M.M.); (F.R.S.); (A.P.); (A.C.); (A.R.S.)
- Istituto di Anatomia Umana e Biologia Cellulare, Università Cattolica del Sacro Cuore, 00168 Roma, Italy;
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21
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Ma Y, Dong L, Zhou D, Li L, Zhang W, Zhen Y, Wang T, Su J, Chen D, Mao C, Wang X. Extracellular vesicles from human umbilical cord mesenchymal stem cells improve nerve regeneration after sciatic nerve transection in rats. J Cell Mol Med 2019; 23:2822-2835. [PMID: 30772948 PMCID: PMC6433678 DOI: 10.1111/jcmm.14190] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 12/21/2018] [Accepted: 01/10/2019] [Indexed: 01/03/2023] Open
Abstract
Peripheral nerve injury results in limited nerve regeneration and severe functional impairment. Mesenchymal stem cells (MSCs) are a remarkable tool for peripheral nerve regeneration. The involvement of human umbilical cord MSC-derived extracellular vesicles (hUCMSC-EVs) in peripheral nerve regeneration, however, remains unknown. In this study, we evaluated functional recovery and nerve regeneration in rats that received hUCMSC-EV treatment after nerve transection. We observed that hUCMSC-EV treatment promoted the recovery of motor function and the regeneration of axons; increased the sciatic functional index; resulted in the generation of numerous axons and of several Schwann cells that surrounded individual axons; and attenuated the atrophy of the gastrocnemius muscle. hUCMSC-EVs aggregated to rat nerve defects, down-regulated interleukin (IL)-6 and IL-1β, up-regulated IL-10 and modulated inflammation in the injured nerve. These effects likely contributed to the promotion of nerve regeneration. Our findings indicate that hUCMSC-EVs can improve functional recovery and nerve regeneration by providing a favourable microenvironment for nerve regeneration. Thus, hUCMSC-EVs have considerable potential for application in the treatment of peripheral nerve injury.
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Affiliation(s)
- Yongbin Ma
- Department of Central LaboratoryThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
- Department of Neurology LaboratoryJintan Hospital, Jiangsu UniversityJintanChina
| | - Liyang Dong
- Department of Nuclear Medicine and Institute of OncologyThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
| | - Dan Zhou
- Department of Neurology LaboratoryJintan Hospital, Jiangsu UniversityJintanChina
| | - Li Li
- Department of Central LaboratoryThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
| | - Wenzhe Zhang
- Department of Central LaboratoryThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
| | - Yu Zhen
- Department of Central LaboratoryThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
| | - Ting Wang
- Department of Central LaboratoryThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
| | - Jianhua Su
- Department of Neurology LaboratoryJintan Hospital, Jiangsu UniversityJintanChina
| | - Deyu Chen
- Department of Nuclear Medicine and Institute of OncologyThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
| | - Chaoming Mao
- Department of Nuclear Medicine and Institute of OncologyThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
| | - Xuefeng Wang
- Department of Central LaboratoryThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
- Department of Neurology LaboratoryJintan Hospital, Jiangsu UniversityJintanChina
- Department of Nuclear Medicine and Institute of OncologyThe Affiliated Hospital of Jiangsu UniversityZhenjiangChina
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22
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Barrachina L, Remacha AR, Romero A, Zaragoza P, Vázquez FJ, Rodellar C. Differentiation of equine bone marrow derived mesenchymal stem cells increases the expression of immunogenic genes. Vet Immunol Immunopathol 2018; 200:1-6. [DOI: 10.1016/j.vetimm.2018.04.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 03/14/2018] [Accepted: 04/09/2018] [Indexed: 12/27/2022]
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23
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Moroncini G, Paolini C, Orlando F, Capelli C, Grieco A, Tonnini C, Agarbati S, Mondini E, Saccomanno S, Goteri G, Svegliati Baroni S, Provinciali M, Introna M, Del Papa N, Gabrielli A. Mesenchymal stromal cells from human umbilical cord prevent the development of lung fibrosis in immunocompetent mice. PLoS One 2018; 13:e0196048. [PMID: 29856737 PMCID: PMC5983506 DOI: 10.1371/journal.pone.0196048] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 02/28/2018] [Indexed: 12/14/2022] Open
Abstract
Lung fibrosis is a severe condition resulting from several interstial lung diseases (ILD) with different etiologies. Current therapy of ILD, especially those associated with connective tissue diseases, is rather limited and new anti-fibrotic strategies are needed. In this study, we investigated the anti-fibrotic activity in vivo of human mesenchymal stromal cells obtained from whole umbilical cord (hUC-MSC). Adult immunocompetent C57BL/6 mice (n. = 8 for each experimental condition) were injected intravenously with hUC-MSC (n. = 2.5 × 105) twice, 24 hours and 7 days after endotracheal injection of bleomycin. Upon sacrifice at days 8, 14, 21, collagen content, inflammatory cytokine profile, and hUC-MSC presence in explanted lung tissue were analyzed. Systemic administration of a double dose of hUC-MSC significantly reduced bleomycin-induced lung injury (inflammation and fibrosis) in mice through a selective inhibition of the IL6-IL10-TGFβ axis involving lung M2 macrophages. Only few hUC-MSC were detected from explanted lungs, suggesting a “hit and run” mechanism of action of this cellular therapy. Our data indicate that hUC-MSC possess strong in vivo anti-fibrotic activity in a mouse model resembling an immunocompetent human subject affected by inflammatory ILD, providing proof of concept for ad-hoc clinical trials.
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Affiliation(s)
- Gianluca Moroncini
- Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
- * E-mail:
| | - Chiara Paolini
- Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
| | - Fiorenza Orlando
- Centro di Tecnologie Avanzate nell’Invecchiamento, IRCCS-INRCA, Ancona, Italy
| | - Chiara Capelli
- UOS Centro di Terapia Cellulare "G. Lanzani", A.S.S.T. Papa Giovanni XXIII, Bergamo, Italy
| | - Antonella Grieco
- Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
| | - Cecilia Tonnini
- Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
| | - Silvia Agarbati
- Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
| | - Eleonora Mondini
- Dipartimento di Medicina Sperimentale e Clinica, Università Politecnica delle Marche, Ancona, Italy
| | - Stefania Saccomanno
- AnatomiaPatologica, Dipartimento di Scienze Biomediche s e Sanità Pubblica, Università Politecnica delle Marche, Ancona, Italy
| | - Gaia Goteri
- AnatomiaPatologica, Dipartimento di Scienze Biomediche s e Sanità Pubblica, Università Politecnica delle Marche, Ancona, Italy
| | - Silvia Svegliati Baroni
- Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
| | - Mauro Provinciali
- Centro di Tecnologie Avanzate nell’Invecchiamento, IRCCS-INRCA, Ancona, Italy
| | - Martino Introna
- UOS Centro di Terapia Cellulare "G. Lanzani", A.S.S.T. Papa Giovanni XXIII, Bergamo, Italy
| | - Nicoletta Del Papa
- UOC Day Hospital di Reumatologia, Dipartimento di Reumatologia, ASST G. Pini-CTO, Milano, Italy
| | - Armando Gabrielli
- Dipartimento di Scienze Cliniche e Molecolari, Università Politecnica delle Marche, Ancona, Italy
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24
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Cui Y, Yao Y, Zhao Y, Xiao Z, Cao Z, Han S, Li X, Huan Y, Pan J, Dai J. Functional collagen conduits combined with human mesenchymal stem cells promote regeneration after sciatic nerve transection in dogs. J Tissue Eng Regen Med 2018; 12:1285-1296. [PMID: 29499096 DOI: 10.1002/term.2660] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 01/08/2018] [Accepted: 02/17/2018] [Indexed: 12/20/2022]
Abstract
Numerous studies have focused on the development of novel and innovative approaches for the treatment of peripheral nerve injury using artificial nerve guide conduits. In this study, we attempted to bridge 3.5-cm defects of the sciatic nerve with a longitudinally oriented collagen conduit (LOCC) loaded with human umbilical cord mesenchymal stem cells (hUC-MSCs). The LOCC contains a bundle of longitudinally aligned collagenous fibres enclosed in a hollow collagen tube. Our previous studies showed that an LOCC combined with neurotrophic factors enhances peripheral nerve regeneration. However, it remained unknown whether an LOCC seeded with hUC-MSCs could also promote regeneration. In this study, using various histological and electrophysiological analyses, we found that an LOCC provides mechanical support to newly growing nerves and functions as a structural scaffold for cells, thereby stimulating sciatic nerve regeneration. The LOCC and hUC-MSCs synergistically promoted regeneration and improved the functional recovery in a dog model of sciatic nerve injury. Therefore, the combined use of an LOCC and hUC-MSCs might have therapeutic potential for the treatment of peripheral nerve injury.
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Affiliation(s)
- Yi Cui
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China.,Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yao Yao
- Department of Prosthodontics, School of Stomatology, Capital Medical University, Beijing, China
| | - Yannan Zhao
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Zhifeng Xiao
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Zongfu Cao
- Reproductive and Genetic Center of National Research Institute for Family Planning, Beijing, China
| | - Sufang Han
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Xing Li
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Yong Huan
- State Key Laboratory of Nonlinear Mechanics (LNM), Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
| | - Juli Pan
- Department of Prosthodontics, School of Stomatology, Capital Medical University, Beijing, China
| | - Jianwu Dai
- Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
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25
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Zhang C, Zhou G, Chen Y, Liu S, Chen F, Xie L, Wang W, Zhang Y, Wang T, Lai X, Ma L. Human umbilical cord mesenchymal stem cells alleviate interstitial fibrosis and cardiac dysfunction in a dilated cardiomyopathy rat model by inhibiting TNF‑α and TGF‑β1/ERK1/2 signaling pathways. Mol Med Rep 2018; 17:71-78. [PMID: 29115435 PMCID: PMC5780147 DOI: 10.3892/mmr.2017.7882] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 08/18/2017] [Indexed: 02/05/2023] Open
Abstract
Dilated cardiomyopathy (DCM) is a disease of the heart characterized by pathological remodeling, including patchy interstitial fibrosis and degeneration of cardiomyocytes. In the present study, the beneficial role of human umbilical cord‑derived mesenchymal stem cells (HuMSCs) derived from Wharton's jelly was evaluated in the myosin‑induced rat model of DCM. Male Lewis rats (aged 8‑weeks) were injected with porcine myosin to induce DCM. Cultured HuMSCs (1x106 cells/rat) were intravenously injected 28 days after myosin injection and the effects on myocardial fibrosis and the underlying signaling pathways were investigated and compared with vehicle‑injected and negative control rats. Myosin injections in rats (vehicle group and experimental group) for 28 days led to severe fibrosis and significant deterioration of cardiac function indicative of DCM. HuMSC treatment reduced fibrosis as determined by Masson's staining of collagen deposits, as well as quantification of molecular markers of myocardial fibrosis such as collagen I/III, profibrotic factors transforming growth factor‑β1 (TGF‑β1), tumor necrosis factor‑α (TNF‑α), and connective tissue growth factor (CTGF). HuMSC treatment restored cardiac function as observed using echocardiography. In addition, western blot analysis indicated that HuMSC injections in DCM rats inhibited the expression of TNF‑α, extracellular‑signal regulated kinase 1/2 (ERK1/2) and TGF‑β1, which is a master switch for inducing myocardial fibrosis. These findings suggested that HuMSC injections attenuated myocardial fibrosis and dysfunction in a rat model of DCM, likely by inhibiting TNF‑α and the TGF‑β1/ERK1/2 fibrosis pathways. Therefore, HuMSC treatment may represent a potential therapeutic method for treatment of DCM.
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Affiliation(s)
- Changyi Zhang
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Guichi Zhou
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Yezeng Chen
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Sizheng Liu
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Fen Chen
- Department of Pediatrics, Maternal and Child Health Care Hospital of Pingshan District, Shenzhen, Guangdong 518000, P.R. China
- Department of Pediatrics, Beijing Children's Hospital, Capital Medical Hospital, Beijing 100032, P.R. China
| | - Lichun Xie
- Department of Pediatrics, Maternal and Child Health Care Hospital of Pingshan District, Shenzhen, Guangdong 518000, P.R. China
- Department of Pediatrics, Beijing Children's Hospital, Capital Medical Hospital, Beijing 100032, P.R. China
| | - Wei Wang
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Yonggang Zhang
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
| | - Tianyou Wang
- Department of Pediatrics, Beijing Children's Hospital, Capital Medical Hospital, Beijing 100032, P.R. China
| | - Xiulan Lai
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Dr Xiulan Lai, Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, 69 North DongXia Road, Shantou, Guangdong 515041, P.R. China, E-mail:
| | - Lian Ma
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong 515041, P.R. China
- Department of Pediatrics, Maternal and Child Health Care Hospital of Pingshan District, Shenzhen, Guangdong 518000, P.R. China
- Department of Pediatrics, Maternal and Child Health Care Hospital of Shenzhen University, Guangdong 518000, P.R. China
- Correspondence to: Professor Lian Ma, Department of Pediatrics, Maternal and Child Health Care Hospital of Shenzhen University, 6 South LongXing Road, Shenzhen, Guangdong 518000, P.R. China, E-mail:
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26
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Wu D, Zou S, Chen H, Li X, Xu Y, Zuo Q, Pan Y, Jiang SW, Huang H, Sun L. Transplantation routes affect the efficacy of human umbilical cord mesenchymal stem cells in a rat GDM model. Clin Chim Acta 2017; 475:137-146. [PMID: 29050787 DOI: 10.1016/j.cca.2017.10.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 10/15/2017] [Accepted: 10/15/2017] [Indexed: 02/05/2023]
Abstract
Gestational diabetes mellitus (GDM) is harmful to both the mother and fetus. Although transplantation of human umbilical cord mesenchymal stem cells (HUMSCs) could be a useful therapy for GDM, the influences of different transplantation routes on the therapeutic effects remain unclear. In this study, we isolated and cultured the HUMSCs for transplantation, and the biological activity of HUMSCs was verified by flow cytometric analysis (the positive markers, CD44, CD73, CD105 and CD90, the negative markers, CD45, CD34, CD19, HLA-DR, and CD11b) and potency of osteogenic, adipogenic and chondrogenic differentiation. Streptozotocin (STZ)-induced diabetes mellitus (DM)/GDM rats were transplanted with HUMSCs by different routes: single or multiple tail vein injection, liver parenchyma, and renal capsule transplantation. These were compared to positive controls (STZ-induced, untreated) and negative controls (non-induced, untreated) to determine the effect of the transplant on the control of DM/GDM. The blood glucose level and body weight of rats in each group were determined and showed different effects. Transplantation of HUMSCs to GDM rats can increase the number of offspring in comparison to the negative controls. The weight of the offspring in the transplantation groups also increased due to the therapeutic effect of HUMSCs. Based on results, we concluded that transplanting HUMSCs could effectively alleviate the symptoms of elevated blood glucose and weight loss and improve the body weight and survival rate of offspring. Injections of HUMSCs were required to persistently decrease the blood glucose of DM and GDM rats. Transplanting HUMSCs into the liver or renal capsule of GDM rats led to a similar efficiency of controlling blood glucose and compensation for body weight. HUMSCs therapy increased the number and body weight of offspring and improved their activity. In summary, this study has enabled progress toward determining the optimal route for GDM therapy.
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MESH Headings
- Animals
- Antigens, CD/genetics
- Antigens, CD/metabolism
- Biomarkers/metabolism
- Blood Glucose/metabolism
- Body Weight
- Cell Differentiation
- Cord Blood Stem Cell Transplantation/methods
- Diabetes, Gestational/chemically induced
- Diabetes, Gestational/metabolism
- Diabetes, Gestational/pathology
- Diabetes, Gestational/therapy
- Disease Models, Animal
- Female
- Gene Expression
- HLA-DR Antigens/genetics
- HLA-DR Antigens/metabolism
- Humans
- Infusions, Intravenous
- Kidney
- Litter Size
- Liver
- Mesenchymal Stem Cells/cytology
- Mesenchymal Stem Cells/physiology
- Pregnancy
- Primary Cell Culture
- Rats
- Rats, Sprague-Dawley
- Streptozocin
- Transplantation, Heterologous/methods
- Transplantation, Heterotopic/methods
- Umbilical Cord/cytology
- Umbilical Cord/physiology
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Affiliation(s)
- Dan Wu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Shan Zou
- Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Haibin Chen
- Department of Histology and Embryology, Shantou University Medical College, Shantou, Guangdong 515000, China
| | - Xiaoyan Li
- Wuxi Maternal and Child Health Hospital, Jiangsu Province, China
| | - Yetao Xu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Qing Zuo
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Yi Pan
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
| | - Shi-Wen Jiang
- Department of Biomedical Science, Mercer University School of Medicine, Savannah, GA 31404, USA
| | - Huan Huang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
| | - Lizhou Sun
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.
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Zhang B, Zhang J, Shi H, Mao F, Wang J, Yan Y, Zhang X, Qian H, Xu W. A novel method to isolate mesenchymal stem cells from mouse umbilical cord. Mol Med Rep 2017; 17:861-869. [PMID: 29115623 PMCID: PMC5780165 DOI: 10.3892/mmr.2017.7950] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2016] [Accepted: 05/11/2017] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal stem cells (MSCs), derived from various tissues, are considered an ideal cell source for clinical use, among which MSCs from the umbilical cord exhibit advantages over those from adult tissues. In preclinical studies, mouse models and xenogeneic MSC treatment are most commonly used to imitate diseases and clinical practice, respectively. However, the efficiency of cross-species therapy remains controversial, making it difficult to elucidate the underlying mechanisms. Thus, allogeneic therapy may be more instructive and meaningful in clinical use. To confirm this hypothesis, the present study established a novel method for the isolation and expansion of MSCs from mouse umbilical cords (mUC-MSCs) to support in vivo experiments in mice. MSCs were isolated from mUCs and mouse bone marrow (mBM), and then identified by flow cytometry. The differences in mUC-MSCs and mBM-MSCs were analyzed using a growth curve and their differentiation ability. The results showed that the harvested cells exhibited general characteristics of MSCs and possessed the capacity for long-term culture. Despite having similar morphology and surface antigens to MSCs derived from mouse bone marrow, the mUC-MSCs showed differences in purification, proliferation, stem cell markers and differentiation. In addition to detailed characterization, the present study verified the presence of Toll-like receptor 3 (TLR3), an important component of immune responses, in mUC-MSCs. It was found that the activation of TLR3 upregulated the levels of stemness-related proteins, and enhanced the secretion and mRNA levels of inflammatory cytokines in the pre-treated mUC-MSCs. Collectively, the results of the present study provide further insight into the features of newly established mUC-MSCs, providing novel evidence for the selection of murine MSCs and their responses to TLR3 priming.
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Affiliation(s)
- Bin Zhang
- Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Jie Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Hospital of Traditional Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Hui Shi
- Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Fei Mao
- Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Juanjuan Wang
- Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Yongmin Yan
- Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Xu Zhang
- Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Hui Qian
- Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
| | - Wenrong Xu
- Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu 212013, P.R. China
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28
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Sun LL, Liu TJ, Li L, Tang W, Zou JJ, Chen XF, Zheng JY, Jiang BG, Shi YQ. Transplantation of betatrophin-expressing adipose-derived mesenchymal stem cells induces β-cell proliferation in diabetic mice. Int J Mol Med 2017; 39:936-948. [PMID: 28290605 PMCID: PMC5360423 DOI: 10.3892/ijmm.2017.2914] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 02/14/2017] [Indexed: 12/11/2022] Open
Abstract
Recent progress in regenerative medicine has suggested that mesenchymal stem cell (MSC)-based therapy is a novel potential cure for diabetes. Betatrophin is a newly identified hormone that can increase the production and expansion of insulin-secreting β-cells when administered to mice. In this study, we evaluated the effect of betatrophin overexpression by human adipose-derived MSCs (ADMSCs) by in vitro experiments, as well as following their transplantation into a mice with streptozotocin (STZ)-induced diabetes. The overexpression of betatrophin did not affect the ADMSCs in terms of proliferation, differentiation and morphology. However, the co-culture of human islets with ADMSCs overexpressing betatrophin (ADMSCs-BET) induced islet proliferation, β-cell specific transcription factor expression, and the islet production of insulin under the stimulation of glucose or KCl and Arg. In addition, ADMSCs-BET enhanced the anti-inflammatory and anti-apoptotic effects of the co-cultured islets compared with ADMSCs cultured alone. In mice with STZ-induced diabetes, the transplantation of ADMSCs-BET ameliorated the hyperglycemia and weight loss associated with STZ-induced diabetes; ADMSCs-BET also significantly enhanced the ratio of β-cells per islet compared to the transplantation of ADMSCs alone. Thus, our study demonstrates a novel strategy for inducing β-cell regeneration. ADMSCs-BET may replace insulin injections by increasing the number of endogenous insulin-producing cells in patients with diabetes. This combined strategy of ADMSC transplantation and gene therapy may prove to be a useful therapy for the treatment of diabetes.
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Affiliation(s)
- Liang-Liang Sun
- Department of Endocrinology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Tian-Jin Liu
- Institute of Biochemistry and Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, P.R. China
| | - Limei Li
- Clinical and Translational Research Center Shanghai East Hospital, Key Laboratory of Arrhythmias of Ministry of Education, Shanghai 200120, P.R. China
| | - Wei Tang
- Department of Endocrinology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Jun-Jie Zou
- Department of Endocrinology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Xiang-Fang Chen
- Department of Endocrinology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Jiao-Yang Zheng
- Department of Endocrinology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Bei-Ge Jiang
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, P.R. China
| | - Yong-Quan Shi
- Department of Endocrinology, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
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29
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Li XL, Zhang J, Luo HN, Zhao XY, Zhang AL, Wang ZH. Characterization of Sox9-overexpressing human umbilical cord blood-derived mesenchymal stem cells-based engineered cartilage bothin vitroandin vivo. J Biomed Mater Res A 2017; 105:1150-1155. [PMID: 28028895 DOI: 10.1002/jbm.a.35989] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 12/09/2016] [Accepted: 12/21/2016] [Indexed: 12/22/2022]
Affiliation(s)
- Xiao-Li Li
- Department of Dermatology; The Second Affiliated Hospital, Xi'an Jiaotong University; Xi'an 710004 China
| | - Jun Zhang
- Department of Otolaryngology; The Affiliated Hospital of Yan'an University; Yan'an China
| | - Hua-Nan Luo
- Department of Otolaryngology-Head and Neck Surgery; The Second Affiliated Hospital, Xi'an Jiaotong University; Xi'an 710004 China
| | - Xiao-Yan Zhao
- Department of Otolaryngology-Head and Neck Surgery; The Second Affiliated Hospital, Xi'an Jiaotong University; Xi'an 710004 China
| | - A-Ling Zhang
- Department of Otolaryngology-Head and Neck Surgery; The Second Affiliated Hospital, Xi'an Jiaotong University; Xi'an 710004 China
| | - Zheng-Hui Wang
- Department of Otolaryngology-Head and Neck Surgery; The Second Affiliated Hospital, Xi'an Jiaotong University; Xi'an 710004 China
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30
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Barrachina L, Remacha AR, Romero A, Vázquez FJ, Albareda J, Prades M, Gosálvez J, Roy R, Zaragoza P, Martín-Burriel I, Rodellar C. Priming Equine Bone Marrow-Derived Mesenchymal Stem Cells with Proinflammatory Cytokines: Implications in Immunomodulation–Immunogenicity Balance, Cell Viability, and Differentiation Potential. Stem Cells Dev 2017; 26:15-24. [DOI: 10.1089/scd.2016.0209] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Laura Barrachina
- Laboratorio de Genetica Bioquimica LAGENBIO (Universidad de Zaragoza), Instituto Agroalimentario de Aragon– IA2 – (Universidad de Zaragoza-CITA), Instituto de Investigacion Sanitaria de Aragon (IIS), Zaragoza, Spain
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, Zaragoza, Spain
| | - Ana Rosa Remacha
- Laboratorio de Genetica Bioquimica LAGENBIO (Universidad de Zaragoza), Instituto Agroalimentario de Aragon– IA2 – (Universidad de Zaragoza-CITA), Instituto de Investigacion Sanitaria de Aragon (IIS), Zaragoza, Spain
| | - Antonio Romero
- Laboratorio de Genetica Bioquimica LAGENBIO (Universidad de Zaragoza), Instituto Agroalimentario de Aragon– IA2 – (Universidad de Zaragoza-CITA), Instituto de Investigacion Sanitaria de Aragon (IIS), Zaragoza, Spain
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, Zaragoza, Spain
| | - Francisco José Vázquez
- Laboratorio de Genetica Bioquimica LAGENBIO (Universidad de Zaragoza), Instituto Agroalimentario de Aragon– IA2 – (Universidad de Zaragoza-CITA), Instituto de Investigacion Sanitaria de Aragon (IIS), Zaragoza, Spain
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, Zaragoza, Spain
| | - Jorge Albareda
- Laboratorio de Genetica Bioquimica LAGENBIO (Universidad de Zaragoza), Instituto Agroalimentario de Aragon– IA2 – (Universidad de Zaragoza-CITA), Instituto de Investigacion Sanitaria de Aragon (IIS), Zaragoza, Spain
- Servicio de Cirugía Ortopédica y Traumatología, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Zaragoza, Spain
| | - Marta Prades
- Laboratorio de Genetica Bioquimica LAGENBIO (Universidad de Zaragoza), Instituto Agroalimentario de Aragon– IA2 – (Universidad de Zaragoza-CITA), Instituto de Investigacion Sanitaria de Aragon (IIS), Zaragoza, Spain
- Departament de Medicina i Cirugia Animal, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Jaime Gosálvez
- Departamento de Biología, Universidad Autónoma de Madrid, Ciudad Universitaria de Cantoblanco, Madrid, Spain
| | - Rosa Roy
- Departamento de Biología, Universidad Autónoma de Madrid, Ciudad Universitaria de Cantoblanco, Madrid, Spain
| | - Pilar Zaragoza
- Laboratorio de Genetica Bioquimica LAGENBIO (Universidad de Zaragoza), Instituto Agroalimentario de Aragon– IA2 – (Universidad de Zaragoza-CITA), Instituto de Investigacion Sanitaria de Aragon (IIS), Zaragoza, Spain
| | - Inmaculada Martín-Burriel
- Laboratorio de Genetica Bioquimica LAGENBIO (Universidad de Zaragoza), Instituto Agroalimentario de Aragon– IA2 – (Universidad de Zaragoza-CITA), Instituto de Investigacion Sanitaria de Aragon (IIS), Zaragoza, Spain
| | - Clementina Rodellar
- Laboratorio de Genetica Bioquimica LAGENBIO (Universidad de Zaragoza), Instituto Agroalimentario de Aragon– IA2 – (Universidad de Zaragoza-CITA), Instituto de Investigacion Sanitaria de Aragon (IIS), Zaragoza, Spain
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Elham H, Fardin F, Mahmod H. The roles of the co-culture of mEScs with pancreatic islets and liver stromal cells in the differentiation of definitive endoderm cells. Biologicals 2017; 45:9-14. [DOI: 10.1016/j.biologicals.2016.11.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Revised: 11/02/2016] [Accepted: 11/03/2016] [Indexed: 12/09/2022] Open
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Mesenchymal stem cells moderate immune response of type 1 diabetes. Cell Tissue Res 2016; 368:239-248. [DOI: 10.1007/s00441-016-2499-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2015] [Accepted: 08/17/2016] [Indexed: 12/11/2022]
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Liu H, Tan Y, Xie L, Yang L, Zhao J, Bai J, Huang P, Zhan W, Wan Q, Zou C, Han Y, Wang Z. Self-assembled dual-modality contrast agents for non-invasive stem cell tracking via near-infrared fluorescence and magnetic resonance imaging. J Colloid Interface Sci 2016; 478:217-26. [PMID: 27299677 DOI: 10.1016/j.jcis.2016.05.063] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 05/26/2016] [Accepted: 05/27/2016] [Indexed: 01/15/2023]
Abstract
Stem cells hold great promise for treating various diseases. However, one of the main drawbacks of stem cell therapy is the lack of non-invasive image-tracking technologies. Although magnetic resonance imaging (MRI) and near-infrared fluorescence (NIRF) imaging have been employed to analyse cellular and subcellular events via the assistance of contrast agents, the sensitivity and temporal resolution of MRI and the spatial resolution of NIRF are still shortcomings. In this study, superparamagnetic iron oxide nanocrystals and IR-780 dyes were co-encapsulated in stearic acid-modified polyethylenimine to form a dual-modality contrast agent with nano-size and positive charge. These resulting agents efficiently labelled stem cells and did not influence the cellular viability and differentiation. Moreover, the labelled cells showed the advantages of dual-modality imaging in vivo.
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Affiliation(s)
- Hong Liu
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Key Laboratory for MRI, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China; School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, Guangdong 510006, PR China
| | - Yan Tan
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Key Laboratory for MRI, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China
| | - Lisi Xie
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, Fujian 361005, PR China
| | - Lei Yang
- Laboratory for Gene and Cell Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China
| | - Jing Zhao
- Laboratory for Gene and Cell Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China
| | - Jingxuan Bai
- Laboratory for Gene and Cell Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China
| | - Ping Huang
- Laboratory for Gene and Cell Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China
| | - Wugen Zhan
- Laboratory for Gene and Cell Engineering, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China
| | - Qian Wan
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Key Laboratory for MRI, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China
| | - Chao Zou
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Key Laboratory for MRI, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China
| | - Yali Han
- School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou, Guangdong 510006, PR China.
| | - Zhiyong Wang
- Paul C. Lauterbur Research Center for Biomedical Imaging, Shenzhen Key Laboratory for MRI, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China.
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Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Kao WWY. Extrinsic and Intrinsic Mechanisms by Which Mesenchymal Stem Cells Suppress the Immune System. Ocul Surf 2016; 14:121-34. [PMID: 26804815 DOI: 10.1016/j.jtos.2015.11.004] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 11/12/2015] [Accepted: 11/23/2015] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) are a group of fibroblast-like multipotent mesenchymal stromal cells that have the ability to differentiate into osteoblasts, adipocytes, and chondrocytes. Recent studies have demonstrated that MSCs possess a unique ability to exert suppressive and regulatory effects on both adaptive and innate immunity in an autologous and allogeneic manner. A vital step in stem cell transplantation is overcoming the potential graft-versus-host disease, which is a limiting factor to transplantation success. Given that MSCs attain powerful differentiation capabilities and also present immunosuppressive properties, which enable them to survive host immune rejection, MSCs are of great interest. Due to their ability to differentiate into different cell types and to suppress and modulate the immune system, MSCs are being developed for treating a plethora of diseases, including immune disorders. Moreover, in recent years, MSCs have been genetically engineered to treat and sometimes even cure some diseases, and the use of MSCs for cell therapy presents new perspectives for overcoming tissue rejection. In this review, we discuss the potential extrinsic and intrinsic mechanisms that underlie MSCs' unique ability to modulate inflammation, and both innate and adaptive immunity.
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Affiliation(s)
- Vivien J Coulson-Thomas
- Department of Ophthalmology, University of Cincinnati, Ohio, USA; John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.
| | | | | | - Winston W-Y Kao
- Department of Ophthalmology, University of Cincinnati, Ohio, USA.
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Zhou Y, Hu Q, Chen F, Zhang J, Guo J, Wang H, Gu J, Ma L, Ho G. Human umbilical cord matrix-derived stem cells exert trophic effects on β-cell survival in diabetic rats and isolated islets. Dis Model Mech 2015; 8:1625-33. [PMID: 26398949 PMCID: PMC4728317 DOI: 10.1242/dmm.021857] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 09/11/2015] [Indexed: 02/05/2023] Open
Abstract
Human umbilical cord matrix-derived stem cells (uMSCs), owing to their cellular and procurement advantages compared with mesenchymal stem cells derived from other tissue sources, are in clinical trials to treat type 1 (T1D) and type 2 diabetes (T2D). However, the therapeutic basis remains to be fully understood. The immunomodulatory property of uMSCs could explain the use in treating T1D; however, the mere immune modulation might not be sufficient to support the use in T2D. We thus tested whether uMSCs could exert direct trophic effects on β-cells. Infusion of uMSCs into chemically induced diabetic rats prevented hyperglycemic progression with a parallel preservation of islet size and cellularity, demonstrating the protective effect of uMSCs on β-cells. Mechanistic analyses revealed that uMSCs engrafted long-term in the injured pancreas and the engraftment markedly activated the pancreatic PI3K pathway and its downstream anti-apoptotic machinery. The pro-survival pathway activation was associated with the expression and secretion of β-cell growth factors by uMSCs, among which insulin-like growth factor 1 (IGF1) was highly abundant. To establish the causal relationship between the uMSC-secreted factors and β-cell survival, isolated rat islets were co-cultured with uMSCs in the transwell system. Co-culturing improved the islet viability and insulin secretion. Furthermore, reduction of uMSC-secreted IGF1 via siRNA knockdown diminished the protective effects on islets in the co-culture. Thus, our data support a model whereby uMSCs exert trophic effects on islets by secreting β-cell growth factors such as IGF1. The study reveals a novel therapeutic role of uMSCs and suggests that multiple mechanisms are employed by uMSCs to treat diabetes.
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Affiliation(s)
- Yunting Zhou
- Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Qi Hu
- Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Fuyi Chen
- Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Juan Zhang
- Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Jincheng Guo
- Department of Molecular Pathology, Shantou University Medical College, Shantou 515041, China
| | - Hongwu Wang
- Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
| | - Jiang Gu
- Department of Molecular Pathology, Shantou University Medical College, Shantou 515041, China
| | - Lian Ma
- Department of Pediatrics, The Women and Children's Hospital of Shenzhen University, Shenzhen 518122, China
| | - Guyu Ho
- Department of Pediatrics, The Second Affiliated Hospital of Shantou University Medical College, Shantou 515041, China
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36
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LI SHENGYING, WANG YUXIA, GUAN LIPING, JI MINGLI. Characteristics of human umbilical cord mesenchymal stem cells during ex vivo expansion. Mol Med Rep 2015; 12:4320-4325. [DOI: 10.3892/mmr.2015.3999] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 01/30/2015] [Indexed: 02/07/2023] Open
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Zhu SF, Hu HB, Xu HY, Fu XF, Peng DX, Su WY, He YL. Human umbilical cord mesenchymal stem cell transplantation restores damaged ovaries. J Cell Mol Med 2015; 19:2108-17. [PMID: 25922900 PMCID: PMC4568915 DOI: 10.1111/jcmm.12571] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 01/29/2015] [Indexed: 12/20/2022] Open
Abstract
Ovarian injury because of chemotherapy can decrease the levels of sexual hormones and potentia generandi of patients, thereby greatly reducing quality of life. The goal of this study was to investigate which transplantation method for human umbilical cord mesenchymal stem cells (HUMSCs) can recover ovarian function that has been damaged by chemotherapy. A rat model of ovarian injury was established using an intraperitoneal injection of cyclophosphamide. Membrane-labelled HUMSCs were subsequently injected directly into ovary tissue or tail vein. The distribution of fluorescently labelled HUMSCs, estrous cycle, sexual hormone levels, and potentia generandi of treated and control rats were then examined. HUMSCs injected into the ovary only distributed to the ovary and uterus, while HUMSCs injected via tail vein were detected in the ovary, uterus, kidney, liver and lung. The estrous cycle, levels of sex hormones and potentia generandi of the treated rats were also recovered to a certain degree. Moreover, in some transplanted rats, fertility was restored and their offspring developed normally. While ovary injection could recover ovarian function faster, both methods produced similar results in the later stages of observation. Therefore, our results suggest that transplantation of HUMSCs by tail vein injection represents a minimally invasive and effective treatment method for ovarian injury.
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Affiliation(s)
- Shao-Fang Zhu
- Medical College of Shaoguan University, Shaoguan, GuangDong, China.,Department of Obstetrics and Gynaecology, Zhujiang Hospital, Southern Medical University, Guangzhou, GuangDong, China
| | - Hong-Bo Hu
- Department of Obstetrics and Gynaecology, The Yuebei People's Hospital of Shaoguan, Shaoguan, GuangDong, China
| | - Hong-Yan Xu
- Department of Obstetrics and Gynaecology, The Yuebei People's Hospital of Shaoguan, Shaoguan, GuangDong, China
| | - Xia-Fei Fu
- Department of Obstetrics and Gynaecology, Zhujiang Hospital, Southern Medical University, Guangzhou, GuangDong, China
| | - Dong-Xian Peng
- Department of Obstetrics and Gynaecology, Zhujiang Hospital, Southern Medical University, Guangzhou, GuangDong, China
| | - Wei-Yan Su
- Medical College of Shaoguan University, Shaoguan, GuangDong, China
| | - Yuan-Li He
- Department of Obstetrics and Gynaecology, Zhujiang Hospital, Southern Medical University, Guangzhou, GuangDong, China
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Ali H, Al-Yatama MK, Abu-Farha M, Behbehani K, Al Madhoun A. Multi-lineage differentiation of human umbilical cord Wharton's Jelly Mesenchymal Stromal Cells mediates changes in the expression profile of stemness markers. PLoS One 2015; 10:e0122465. [PMID: 25848763 PMCID: PMC4388513 DOI: 10.1371/journal.pone.0122465] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 02/11/2015] [Indexed: 12/22/2022] Open
Abstract
Wharton's Jelly- derived Mesenchymal stem cells (WJ-MSCs) have gained interest as an alternative source of stem cells for regenerative medicine because of their potential for self-renewal, differentiation and unique immunomodulatory properties. Although many studies have characterized various WJ-MSCs biologically, the expression profiles of the commonly used stemness markers have not yet been addressed. In this study, WJ-MSCs were isolated and characterized for stemness and surface markers expression. Flow cytometry, immunofluorescence and qRT-PCR analysis revealed predominant expression of CD29, CD44, CD73, CD90, CD105 and CD166 in WJ-MSCs, while the hematopoietic and endothelial markers were absent. Differential expression of CD 29, CD90, CD105 and CD166 following adipogenic, osteogenic and chondrogenic induction was observed. Furthermore, our results demonstrated a reduction in CD44 and CD73 expressions in response to the tri-lineage differentiation induction, suggesting that they can be used as reliable stemness markers, since their expression was associated with undifferentiated WJ-MSCs only.
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Affiliation(s)
- Hamad Ali
- Department of Basic Science Research, Dasman Diabetes Institute, 1180 Dasman, Kuwait
- Department of Medical Laboratory Sciences (MLS), Faculty of Allied Health Sciences, Health Sciences Center, Kuwait University, Kuwait City, Kuwait
| | | | - Mohamed Abu-Farha
- Biochemistry and Molecular Biology Unit, Dasman Diabetes Institute, 1180 Dasman, Kuwait
| | - Kazem Behbehani
- Department of Basic Science Research, Dasman Diabetes Institute, 1180 Dasman, Kuwait
| | - Ashraf Al Madhoun
- Department of Basic Science Research, Dasman Diabetes Institute, 1180 Dasman, Kuwait
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Watson N, Divers R, Kedar R, Mehindru A, Mehindru A, Borlongan MC, Borlongan CV. Discarded Wharton jelly of the human umbilical cord: a viable source for mesenchymal stromal cells. Cytotherapy 2014; 17:18-24. [PMID: 25442786 DOI: 10.1016/j.jcyt.2014.08.009] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 08/15/2014] [Accepted: 08/18/2014] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are multi-potent cells that have the capability of differentiating into adipogenic, osteogenic, chondrogenic and neural cells. With these multiple capabilities, MSCs have been highly regarded as an effective transplantable cell source for regenerative medicine. A large bank of these cells can be found in several regions of the human umbilical cord, including the umbilical cord lining, the subendothelial layer, the perivascular zone and, most important, in Wharton jelly (WJ). These cells, all umbilical cord-derived MSCs, are durable, have large loading capacities and are considered ethical to harvest because the umbilical cord is often considered waste. These logistical advantages make WJ as appealing source of stem cells for transplant therapy. In particular, WJ is a predominantly good source of cells because MSCs in WJ are maintained in an early embryologic phase and therefore have retained some of the primitive stemness properties. WJ-MSCs can easily differentiate into a plethora of cell types leading to a variety of applications. In addition, WJ-MSCs are slightly easier to harvest compared with other MSCs (such as bone marrow-derived MSCs). The fascinating stemness properties and therapeutic potential of WJ-MSCs provide great promise in many aspects of regenerative medicine and should be considered for further investigations as safe and effective donor cells for transplantation therapy in many debilitating disorders, which are discussed here. We previously reviewed the therapeutic potential of WJ-MSCs and now provide an update on their recent preclinical and clinical applications.
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Affiliation(s)
- Nate Watson
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Ryan Divers
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Roshan Kedar
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Ankur Mehindru
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Anuj Mehindru
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Mia C Borlongan
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida
| | - Cesar V Borlongan
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, Florida.
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40
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Li X, Chang H, Luo H, Wang Z, Zheng G, Lu X, He X, Chen F, Wang T, Liang J, Xu M. Poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) scaffolds coated with PhaP-RGD fusion protein promotes the proliferation and chondrogenic differentiation of human umbilical cord mesenchymal stem cells in vitro. J Biomed Mater Res A 2014; 103:1169-75. [PMID: 25044338 DOI: 10.1002/jbm.a.35265] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 06/09/2014] [Accepted: 06/13/2014] [Indexed: 01/09/2023]
Abstract
Human umbilical cord blood-derived mesenchymal stem cells (hUC-MSCs) have been widely used in tissue engineering. The aim of this study is to evaluate the ability of poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) scaffolds coated with polyhydroxyalkanoate binding protein fused with arginyl-glycyl-aspartic acid (PhaP-RGD) to promote the proliferation and chondrogenic differentiation of hUC-MSCs seeded on them. The PhaP-RGD fusion protein was expressed by Escherichia coli. PHBHHx films were coated with PhaP-RGD fusion protein and the physiochemical properties were examined. hUC-MSCs were seeded on PHBHHx films with or without PhaP-RGD precoating and tested for changes in morphology, viability, and chondrogenic differentiation. We found that PhaP-RGD-coated PHBHHx films had similar surface morphology to uncoated PHBHHx. The water contact angle of the coated PHBHHx surface was lower than that of the uncoated surface (10.63° vs. 98.69°). At 7 and 14 days after seeding, the PhaP-RGD-coated PHBHHx group showed greater numbers of viable cells compared to the uncoated PHBHHx group. The expression levels of aggrecan and collagen II were enhanced in the PhaP-RGD-coated PHBHHx group relative to the uncoated PHBHHx group. Histological analysis using toluidine blue staining showed elevated formation of proteoglycan producing chondrocytes in the PhaP-RGD-coated PHBHHx group. Additionally, the synthesis of proteoglycan and collagen was significantly enhanced within the PhaP-RGD constructs. Taken together, PhaP-RGD coating promotes the proliferation and chondrogenic differentiation of hUC-MSCs seeded on PHBHHx films. PhaP-RGD-coated PHBHHx may be a useful scaffold for cartilage tissue engineering.
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Affiliation(s)
- Xiaoli Li
- Department of Dermatology, The Second Hospital, Xi'an Jiaotong University, Xi'an, China
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