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Madkor HR, Abd El-Aziz MK, Abd El-Maksoud MS, Ibrahim IM, Ali FEM. Stem Cells Reprogramming in Diabetes Mellitus and Diabetic Complications: Recent Advances. Curr Diabetes Rev 2025; 21:21-37. [PMID: 38173073 DOI: 10.2174/0115733998275428231210055650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/09/2023] [Accepted: 11/21/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND The incidence of diabetes mellitus (DM) is dramatically increasing worldwide, and it is expected to affect 700 million cases by 2045. Diabetes influences health care economics, human quality of life, morbidity, and mortality, which were primarily seen extensively in developing countries. Uncontrolled DM, which results in consistent hyperglycemia, may lead to severe life-threatening complications such as nephropathy, retinopathy, neuropathy, and cardiovascular complications. METHODOLOGY In addition to traditional therapies with insulin and oral anti-diabetics, researchers have developed new approaches for treatment, including stem cell (SC) therapy, which exhibits promising outcomes. Besides its significant role in treating type one DM (T1DM) and type two DM (T2DM), it can also attenuate diabetic complications. Furthermore, the development of insulin- producing cells can be achieved by using the different types of SCs, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and multiple types of adult stem cells, such as pancreatic, hepatic, and mesenchymal stem cells (MSC). All these types have been extensively studied and proved their ability to develop insulin-producing cells, but every type has limitations. CONCLUSION This review aims to enlighten researchers about recent advances in stem cell research and their potential benefits in DM and diabetic complications.
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Affiliation(s)
- Hafez R Madkor
- Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt
| | | | | | - Islam M Ibrahim
- Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Fares E M Ali
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
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Grimus S, Sarangova V, Welzel PB, Ludwig B, Seissler J, Kemter E, Wolf E, Ali A. Immunoprotection Strategies in β-Cell Replacement Therapy: A Closer Look at Porcine Islet Xenotransplantation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2401385. [PMID: 38884159 PMCID: PMC11336975 DOI: 10.1002/advs.202401385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 05/28/2024] [Indexed: 06/18/2024]
Abstract
Type 1 diabetes mellitus (T1DM) is characterized by absolute insulin deficiency primarily due to autoimmune destruction of pancreatic β-cells. The prevailing treatment for T1DM involves daily subcutaneous insulin injections, but a substantial proportion of patients face challenges such as severe hypoglycemic episodes and poorly controlled hyperglycemia. For T1DM patients, a more effective therapeutic option involves the replacement of β-cells through allogeneic transplantation of either the entire pancreas or isolated pancreatic islets. Unfortunately, the scarcity of transplantable human organs has led to a growing list of patients waiting for an islet transplant. One potential alternative is xenotransplantation of porcine pancreatic islets. However, due to inter-species molecular incompatibilities, porcine tissues trigger a robust immune response in humans, leading to xenograft rejection. Several promising strategies aim to overcome this challenge and enhance the long-term survival and functionality of xenogeneic islet grafts. These strategies include the use of islets derived from genetically modified pigs, immunoisolation of islets by encapsulation in biocompatible materials, and the creation of an immunomodulatory microenvironment by co-transplanting islets with accessory cells or utilizing immunomodulatory biomaterials. This review concentrates on delineating the primary obstacles in islet xenotransplantation and elucidates the fundamental principles and recent breakthroughs aimed at addressing these challenges.
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Affiliation(s)
- Sarah Grimus
- Chair for Molecular Animal Breeding and BiotechnologyGene Center and Department of Veterinary SciencesLMU MunichD‐81377MunichGermany
- Center for Innovative Medical Models (CiMM)LMU MunichD‐85764OberschleißheimGermany
- Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICONLMU)LMU MunichD‐81377MunichGermany
| | - Victoria Sarangova
- Leibniz‐Institut für Polymerforschung Dresden e.V.Max Bergmann Center of Biomaterials DresdenD‐01069DresdenGermany
| | - Petra B. Welzel
- Leibniz‐Institut für Polymerforschung Dresden e.V.Max Bergmann Center of Biomaterials DresdenD‐01069DresdenGermany
| | - Barbara Ludwig
- Department of Medicine IIIUniversity Hospital Carl Gustav CarusTechnische Universität DresdenD‐01307DresdenGermany
- Paul Langerhans Institute Dresden of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the Technische Universität DresdenD‐01307DresdenGermany
- German Center for Diabetes Research (DZD e.V.)D‐85764NeuherbergGermany
- DFG‐Center for Regenerative Therapies DresdenTechnische Universität DresdenD‐01307DresdenGermany
| | - Jochen Seissler
- Medizinische Klinik und Poliklinik IVDiabetes Zentrum – Campus InnenstadtKlinikum der Ludwig‐Maximilians‐Universität MünchenD‐80336MunichGermany
| | - Elisabeth Kemter
- Chair for Molecular Animal Breeding and BiotechnologyGene Center and Department of Veterinary SciencesLMU MunichD‐81377MunichGermany
- Center for Innovative Medical Models (CiMM)LMU MunichD‐85764OberschleißheimGermany
- Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICONLMU)LMU MunichD‐81377MunichGermany
- German Center for Diabetes Research (DZD e.V.)D‐85764NeuherbergGermany
| | - Eckhard Wolf
- Chair for Molecular Animal Breeding and BiotechnologyGene Center and Department of Veterinary SciencesLMU MunichD‐81377MunichGermany
- Center for Innovative Medical Models (CiMM)LMU MunichD‐85764OberschleißheimGermany
- Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICONLMU)LMU MunichD‐81377MunichGermany
- German Center for Diabetes Research (DZD e.V.)D‐85764NeuherbergGermany
| | - Asghar Ali
- Chair for Molecular Animal Breeding and BiotechnologyGene Center and Department of Veterinary SciencesLMU MunichD‐81377MunichGermany
- Center for Innovative Medical Models (CiMM)LMU MunichD‐85764OberschleißheimGermany
- Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICONLMU)LMU MunichD‐81377MunichGermany
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Fu J, Zhang Q, Zhang N, Zhou S, Fang Y, Li Y, Yuan L, Chen L, Xiang C. Human Menstrual Blood-Derived Stem Cells Protect against Tacrolimus-Induced Islet Dysfunction via Cystathionine β-Synthase Mediated IL-6/STAT3 Inactivation. Biomolecules 2024; 14:671. [PMID: 38927074 PMCID: PMC11201965 DOI: 10.3390/biom14060671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 06/02/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024] Open
Abstract
Diabetes imposes a huge burden worldwide. Islet transplantation is an alternative therapy for diabetes. However, tacrolimus, a kind of immunosuppressant after organ transplantation, is closely related to post-transplant diabetes mellitus. Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate diabetes. In vivo experiments revealed that human menstrual blood-derived stem cells (MenSCs) treatment improved tacrolimus-induced blood glucose, body weight, and glucose tolerance disorders in mice. RNA sequencing was used to analyze the potential therapeutic targets of MenSCs. In this study, we illustrated that cystathionine β-synthase (CBS) contributed to tacrolimus -induced islet dysfunction. Using β-cell lines (MIN6, β-TC-6), we demonstrated that MenSCs ameliorated tacrolimus-induced islet dysfunction in vitro. Moreover, MenSC reduced the tacrolimus-induced elevation of CBS levels and significantly enhanced the viability, anti-apoptotic ability, glucose-stimulated insulin secretion (GSIS), and glycolytic flux of β-cells. We further revealed that MenSCs exerted their therapeutic effects by inhibiting CBS expression to activate the IL6/JAK2/STAT3 pathway. In conclusion, we showed that MenSCs may be a potential strategy to improve tacrolimus-induced islet dysfunction.
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Affiliation(s)
- Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Sining Zhou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Li Yuan
- Innovative Precision Medicine (IPM) Group, Hangzhou 311215, China;
| | - Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; (J.F.); (Q.Z.); (N.Z.); (S.Z.); (Y.F.); (Y.L.)
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou 310003, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China
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Kolahi Azar H, Imanpour A, Rezaee H, Ezzatifar F, Zarei-Behjani Z, Rostami M, Azami M, Behestizadeh N, Rezaei N. Mesenchymal stromal cells and CAR-T cells in regenerative medicine: The homing procedure and their effective parameters. Eur J Haematol 2024; 112:153-173. [PMID: 37254607 DOI: 10.1111/ejh.14014] [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: 03/19/2023] [Revised: 04/24/2023] [Accepted: 04/24/2023] [Indexed: 06/01/2023]
Abstract
Mesenchymal stromal cells (MSCs) and chimeric antigen receptor (CAR)-T cells are two core elements in cell therapy procedures. MSCs have significant immunomodulatory effects that alleviate inflammation in the tissue regeneration process, while administration of specific chemokines and adhesive molecules would primarily facilitate CAR-T cell trafficking into solid tumors. Multiple parameters affect cell homing, including the recipient's age, the number of cell passages, proper cell culture, and the delivery method. In addition, several chemokines are involved in the tumor microenvironment, affecting the homing procedure. This review discusses parameters that improve the efficiency of cell homing and significant cell therapy challenges. Emerging comprehensive mechanistic strategies such as non-systemic and systemic homing that revealed a significant role in cell therapy remodeling were also reviewed. Finally, the primary implications for the development of combination therapies that incorporate both MSCs and CAR-T cells for cancer treatment were discussed.
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Affiliation(s)
- Hanieh Kolahi Azar
- Department of Pathology, Tabriz University of Medical Sciences, Tabriz, Iran
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Aylar Imanpour
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hanieh Rezaee
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ezzatifar
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Molecular and Cell Biology Research Center, Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- Student Research Committee, Mazandaran University of Medical Sciences, Sari, Iran
| | - Zeinab Zarei-Behjani
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Tissue Engineering and Applied Cell Sciences, Advanced School of Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammadreza Rostami
- Division of Food Safety and Hygiene, Department of Environmental Health Engineering, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Food Science and Nutrition Group (FSAN), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahmoud Azami
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Behestizadeh
- Regenerative Medicine group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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Sionov RV, Ahdut-HaCohen R. A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome. Biomedicines 2023; 11:2558. [PMID: 37761001 PMCID: PMC10527322 DOI: 10.3390/biomedicines11092558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/06/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by a gradual destruction of insulin-producing β-cells in the endocrine pancreas due to innate and specific immune responses, leading to impaired glucose homeostasis. T1D patients usually require regular insulin injections after meals to maintain normal serum glucose levels. In severe cases, pancreas or Langerhans islet transplantation can assist in reaching a sufficient β-mass to normalize glucose homeostasis. The latter procedure is limited because of low donor availability, high islet loss, and immune rejection. There is still a need to develop new technologies to improve islet survival and implantation and to keep the islets functional. Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells with high plasticity that can support human pancreatic islet function both in vitro and in vivo and islet co-transplantation with MSCs is more effective than islet transplantation alone in attenuating diabetes progression. The beneficial effect of MSCs on islet function is due to a combined effect on angiogenesis, suppression of immune responses, and secretion of growth factors essential for islet survival and function. In this review, various aspects of MSCs related to islet function and diabetes are described.
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Affiliation(s)
- Ronit Vogt Sionov
- The Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Ahdut-HaCohen
- Department of Medical Neurobiology, Institute of Medical Research, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel;
- Department of Science, The David Yellin Academic College of Education, Jerusalem 9103501, Israel
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Lu K, Brauns T, Sluder AE, Poznansky MC, Dogan F. Combinatorial islet protective therapeutic approaches in β-cell transplantation: Rationally designed solutions using a target product profile. FASEB Bioadv 2023; 5:287-304. [PMID: 37415930 PMCID: PMC10320848 DOI: 10.1096/fba.2023-00029] [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: 03/19/2023] [Revised: 05/03/2023] [Accepted: 05/17/2023] [Indexed: 07/08/2023] Open
Abstract
While progress has been made in the development of islet cell transplantation (ICT) as a viable alternative to the use of exogenous insulin therapy in the treatment of type 1 diabetes, it has not yet achieved its full potential in clinical studies. Ideally, ICT would enable lifelong maintenance of euglycemia without the need for exogenous insulin, blood glucose monitoring or systemic immune suppression. To achieve such an optimal result, therapeutic approaches should simultaneously promote long-term islet viability, functionality, and localized immune protection. In practice, however, these factors are typically tackled individually. Furthermore, while the requirements of optimal ICT are implicitly acknowledged across numerous publications, the literature contains few comprehensive articulations of the target product profile (TPP) for an optimal ICT product, including key characteristics of safety and efficacy. This review aims to provide a novel TPP for ICT and presents promising tried and untried combinatorial approaches that could be used to achieve the target product profile. We also highlight regulatory barriers to the development and adoption of ICT, particularly in the United States, where ICT is only approved for use in academic clinical trials and is not reimbursed by insurance carriers. Overall, this review argues that the clear definition of a TPP in addition to the use of combinatorial approaches could help to overcome the clinical barriers to the widespread adoption of ICT for the treatment of type 1 diabetes.
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Affiliation(s)
- Katie Lu
- Vaccine and Immunotherapy CenterMassachusetts General HospitalBostonMassachusettsUSA
- Department of BiologyStanford UniversityStanfordCaliforniaUSA
| | - Timothy Brauns
- Vaccine and Immunotherapy CenterMassachusetts General HospitalBostonMassachusettsUSA
| | - Ann E. Sluder
- Vaccine and Immunotherapy CenterMassachusetts General HospitalBostonMassachusettsUSA
| | - Mark C. Poznansky
- Vaccine and Immunotherapy CenterMassachusetts General HospitalBostonMassachusettsUSA
| | - Fatma Dogan
- Vaccine and Immunotherapy CenterMassachusetts General HospitalBostonMassachusettsUSA
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Yang X, Li Q, Liu W, Zong C, Wei L, Shi Y, Han Z. Mesenchymal stromal cells in hepatic fibrosis/cirrhosis: from pathogenesis to treatment. Cell Mol Immunol 2023; 20:583-599. [PMID: 36823236 PMCID: PMC10229624 DOI: 10.1038/s41423-023-00983-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 01/29/2023] [Indexed: 02/25/2023] Open
Abstract
Hepatic fibrosis/cirrhosis is a significant health burden worldwide, resulting in liver failure or hepatocellular carcinoma (HCC) and accounting for many deaths each year. The pathogenesis of hepatic fibrosis/cirrhosis is very complex, which makes treatment challenging. Endogenous mesenchymal stromal cells (MSCs) have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis. Paradoxically, exogenous MSCs have also been used in clinical trials for liver cirrhosis, and their effectiveness has been observed in most completed clinical trials. There are still many issues to be resolved to promote the use of MSCs in the clinic in the future. In this review, we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis. We also investigated the clinical trials involving MSCs in liver cirrhosis, summarized the parameters that need to be standardized, and discussed how to promote the use of MSCs from a clinical perspective.
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Affiliation(s)
- Xue Yang
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy
| | - Qing Li
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Wenting Liu
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Chen Zong
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Lixin Wei
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Key Laboratory of Stem Cells and Medical Biomaterials of Jiangsu Province, Medical College of Soochow University, Soochow University, Suzhou, 215000, China.
- Department of Experimental Medicine, TOR, University of Rome Tor Vergata, 00133, Rome, Italy.
| | - Zhipeng Han
- Department of Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China.
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Naval Medical University, Shanghai, 200438, China.
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Zahmatkesh E, Khoshdel Rad N, Hossein-Khannazer N, Mohamadnejad M, Gramignoli R, Najimi M, Malekzadeh R, Hassan M, Vosough M. Cell and cell-derivative-based therapy for liver diseases: current approaches and future promises. Expert Rev Gastroenterol Hepatol 2023; 17:237-249. [PMID: 36692130 DOI: 10.1080/17474124.2023.2172398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
INTRODUCTION According to the recent updates from World Health Organization, liver diseases are the 12th most common cause of mortality. Currently, orthotopic liver transplantation (OLT) is the most effective and the only treatment for end-stage liver diseases. Owing to several shortcomings like finite numbers of healthy organ donors, lifelong immunosuppression, and complexity of the procedure, cell and cell-derivatives therapies have emerged as a potential therapeutic alternative for liver diseases. Various cell types and therapies have been proposed and their therapeutic effects evaluated in preclinical or clinical studies, including hepatocytes, hepatocyte-like cells (HLCs) derived from stem cells, human liver stem cells (HLSCs), combination therapies with various types of cells, organoids, and implantable cell-biomaterial constructs with synthetic and natural polymers or even decellularized extracellular matrix (ECM). AREAS COVERED In this review, we highlighted the current status of cell and cell-derivative-based therapies for liver diseases. Furthermore, we discussed future prospects of using HLCs, liver organoids, and their combination therapies. EXPERT OPINION Promising application of stem cell-based techniques including iPSC technology has been integrated into novel techniques such as gene editing, directed differentiation, and organoid technology. iPSCs offer promising prospects to represent novel therapeutic strategies and modeling liver diseases.
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Affiliation(s)
- Ensieh Zahmatkesh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Khoshdel Rad
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Nikoo Hossein-Khannazer
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Mohamadnejad
- Cell-Based Therapies Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Roberto Gramignoli
- Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium
| | - Reza Malekzadeh
- Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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9
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Miceli V, Bulati M, Gallo A, Iannolo G, Busà R, Conaldi PG, Zito G. Role of Mesenchymal Stem/Stromal Cells in Modulating Ischemia/Reperfusion Injury: Current State of the Art and Future Perspectives. Biomedicines 2023; 11:689. [PMID: 36979668 PMCID: PMC10045387 DOI: 10.3390/biomedicines11030689] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 02/15/2023] [Accepted: 02/21/2023] [Indexed: 02/26/2023] Open
Abstract
Ischemia/reperfusion injury (IRI) is a multistep damage that occurs in several tissues when a blood flow interruption is inevitable, such as during organ surgery or transplantation. It is responsible for cell death and tissue dysfunction, thus leading, in the case of transplantation, to organ rejection. IRI takes place during reperfusion, i.e., when blood flow is restored, by activating inflammation and reactive oxygen species (ROS) production, causing mitochondrial damage and apoptosis of parenchymal cells. Unfortunately, none of the therapies currently in use are definitive, prompting the need for new therapeutic approaches. Scientific evidence has proven that mesenchymal stem/stromal cells (MSCs) can reduce inflammation and ROS, prompting this cellular therapy to also be investigated for treatment of IRI. Moreover, it has been shown that MSC therapeutic effects were mediated in part by their secretome, which appears to be involved in immune regulation and tissue repair. For these reasons, mediated MSC paracrine function might be key for injury amelioration upon IRI damage. In this review, we highlight the scientific literature on the potential beneficial use of MSCs and their products for improving IRI outcomes in different tissues/organs, focusing in particular on the paracrine effects mediated by MSCs, and on the molecular mechanisms behind these effects.
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Affiliation(s)
- Vitale Miceli
- Research Department, IRCSS ISMETT (Istituto Mediterraneo per I Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
| | | | | | | | | | | | - Giovanni Zito
- Research Department, IRCSS ISMETT (Istituto Mediterraneo per I Trapianti e Terapie ad Alta Specializzazione), 90127 Palermo, Italy
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10
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Endothelial Dysfunction in Neurodegenerative Diseases. Int J Mol Sci 2023; 24:ijms24032909. [PMID: 36769234 PMCID: PMC9918222 DOI: 10.3390/ijms24032909] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 02/05/2023] Open
Abstract
The cerebral vascular system stringently regulates cerebral blood flow (CBF). The components of the blood-brain barrier (BBB) protect the brain from pathogenic infections and harmful substances, efflux waste, and exchange substances; however, diseases develop in cases of blood vessel injuries and BBB dysregulation. Vascular pathology is concurrent with the mechanisms underlying aging, Alzheimer's disease (AD), and vascular dementia (VaD), which suggests its involvement in these mechanisms. Therefore, in the present study, we reviewed the role of vascular dysfunction in aging and neurodegenerative diseases, particularly AD and VaD. During the development of the aforementioned diseases, changes occur in the cerebral blood vessel morphology and local cells, which, in turn, alter CBF, fluid dynamics, and vascular integrity. Chronic vascular inflammation and blood vessel dysregulation further exacerbate vascular dysfunction. Multitudinous pathogenic processes affect the cerebrovascular system, whose dysfunction causes cognitive impairment. Knowledge regarding the pathophysiology of vascular dysfunction in neurodegenerative diseases and the underlying molecular mechanisms may lead to the discovery of clinically relevant vascular biomarkers, which may facilitate vascular imaging for disease prevention and treatment.
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11
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Naqvi RA, Naqvi A. Co-transplantation with mesenchymal stem cells and endothelial cells improvise islet engraftment and survival in STZ treated hyperglycemic mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.01.24.525444. [PMID: 36747732 PMCID: PMC9900768 DOI: 10.1101/2023.01.24.525444] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Though intra-portal islet transplantation demonstrated as best suited strategy for the reversal of hyperglycemia without the threat of iatrogenic hyperglycemia in type 1 diabetes (T1D) in patients, the inferior quality of post-transplantation (tx) vascularization needs to be addressed for the maximization of post-tx islet survival. Therefore, in this study, we have first generated MSCs and endothelial progenitor cells (EPC) from mice bone marrow by in house optimized protocol and then 3-D co-cultured them with mice islets. Secretion of in the culture supernatant suggested the pro-angiogenic nature of 3D cultured mice islets. After 5 days post-tx of these pro-angiogenic islets in the omental pouch of syngeneic mice led to: 1) restoration of normoglycemia, 2) secretion of mouse C-peptide and 3) induction of angiogenic factors after 3 days of post-tx. The induction of angiogenic factors was done by RT-qPCR of omental biopsies. Importantly, pro-angiogenic islet recipient mice also demonstrated the clearance of glucose within 75 min, reflecting their efficient function and engraftment. Our results highlights needs of 3-D co-culture islets for superior quality post-tx islet vasculature and better engraftment â€" crux to improvise the challenges associated with post-tx islet vascularization and functions.
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12
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Wang Y, Zhang JW, Wang JW, Wang JL, Zhang SC, Ma RY, Zhang J, Li Y, Liu PJ, Xue WJ, Zheng J, Ding XM. BMSCs overexpressed ISL1 reduces the apoptosis of islet cells through ANLN carrying exosome, INHBA, and caffeine. Cell Mol Life Sci 2022; 79:538. [PMID: 36190571 PMCID: PMC11802980 DOI: 10.1007/s00018-022-04571-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 08/28/2022] [Accepted: 09/22/2022] [Indexed: 11/24/2022]
Abstract
Early apoptosis of grafted islets is one of the main factors affecting the efficacy of islet transplantation. The combined transplantation of islet cells and bone marrow mesenchymal stem cells (BMSCs) can significantly improve the survival rate of grafted islets. Transcription factor insulin gene enhancer binding protein 1 (ISL1) is shown to promote the angiogenesis of grafted islets and the paracrine function of mesenchymal stem cells during the co-transplantation, yet the regulatory mechanism remains unclear. By using ISL1-overexpressing BMSCs and the subtherapeutic doses of islets for co-transplantation, we managed to reduce the apoptosis and improve the survival rate of the grafts. Our metabolomics and proteomics data suggested that ISL1 upregulates aniline (ANLN) and Inhibin beta A chain (INHBA), and stimulated the release of caffeine in the BMSCs. We then demonstrated that the upregulation of ANLN and INHBA was achieved by the binding of ISL1 to the promoter regions of the two genes. In addition, ISL1 could also promote BMSCs to release exosomes with high expression of ANLN, secrete INHBA and caffeine, and reduce streptozocin (STZ)-induced islets apoptosis. Thus, our study provides mechanical insight into the islet/BMSCs co-transplantation and paves the foundation for using conditioned medium to mimic the ISL1-overexpressing BMSCs co-transplantation.
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Affiliation(s)
- Ying Wang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Jiang-Wei Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Jing-Wen Wang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Jia-Le Wang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Shu-Cong Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Rui-Yang Ma
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Jing Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Yang Li
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Pei-Jun Liu
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an, 710061, Shaanxi, China
| | - Wu-Jun Xue
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Jin Zheng
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China
| | - Xiao-Ming Ding
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an 710061, Shaanxi, China.
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13
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Cellular Therapies in Pediatric Liver Diseases. Cells 2022; 11:cells11162483. [PMID: 36010561 PMCID: PMC9406752 DOI: 10.3390/cells11162483] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 07/30/2022] [Accepted: 08/06/2022] [Indexed: 11/16/2022] Open
Abstract
Liver transplantation is the gold standard for the treatment of pediatric end-stage liver disease and liver based metabolic disorders. Although liver transplant is successful, its wider application is limited by shortage of donor organs, surgical complications, need for life long immunosuppressive medication and its associated complications. Cellular therapies such as hepatocytes and mesenchymal stromal cells (MSCs) are currently emerging as an attractive alternative to liver transplantation. The aim of this review is to present the existing world experience in hepatocyte and MSC transplantation and the potential for future effective applications of these modalities of treatment.
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14
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Nakafusa Y, Nitta N, Ishii K, Shirasu N, Iwamoto T, Nemoto T, Nakamura M, Goto M, Iwata H, Taniguchi M, Yasunami Y. Acceptance of Murine Islet Allografts Without Immunosuppression in Inguinal Subcutaneous White Adipose Tissue Pretreated With bFGF. Diabetes 2022; 71:1721-1734. [PMID: 35604856 DOI: 10.2337/db21-0684] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 04/24/2022] [Indexed: 11/13/2022]
Abstract
Prevention of immune rejection without immunosuppression is the ultimate goal of transplant immunobiology. One way to achieve this in cellular transplantation, such as with islet transplantation, is to create a favorable local environment at the transplant site. In the current study, we found that C57BL/6 mice with streptozotocin-induced diabetes remained normoglycemic for >1 year after transplantation of BALB/c islets without immunosuppression when the inguinal subcutaneous white adipose tissue (ISWAT) was the site of transplantation and when the site was pretreated with basic fibroblast growth factor. Mechanistically, mesenchymal stem cells (MSCs) expanded in the ISWAT after the treatment was found to produce transforming growth factor-β (TGF-β), and prevention of islet allograft rejection could be achieved by cotransplantation with syngeneic MSCs isolated from the ISWAT after the treatment, which was abolished by anti-TGF-β antibody treatment. Importantly, TGF-β-producing cells remained present at the site of cotransplantation up to the end of observation period at 240 days after transplantation. These findings indicate that prevention of islet allograft rejection without immunosuppression is feasible with the use of syngeneic TGF-β-producing MSCs expanded in the ISWAT after the treatment with bFGF, providing a novel strategy for prevention of islet allograft rejection without immunosuppression.
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Affiliation(s)
- Yuki Nakafusa
- Research Institute for Islet Biology, Fukuoka University Central Research Organization, Fukuoka, Japan
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoyoshi Nitta
- Research Institute for Islet Biology, Fukuoka University Central Research Organization, Fukuoka, Japan
| | - Kazunari Ishii
- Department of Microbiology and Immunology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Naoto Shirasu
- Department of Biochemistry, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Takahiro Iwamoto
- Research Institute for Islet Biology, Fukuoka University Central Research Organization, Fukuoka, Japan
- Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Takayuki Nemoto
- Department of Pharmacology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Goto
- Division of Transplantation and Regenerative Medicine, Tohoku University School of Medicine, Sendai, Japan
| | - Hiroo Iwata
- Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, Kobe, Japan
| | - Masaru Taniguchi
- RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan
| | - Yohichi Yasunami
- Research Institute for Islet Biology, Fukuoka University Central Research Organization, Fukuoka, Japan
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15
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Yuan M, Hu X, Yao L, Jiang Y, Li L. Mesenchymal stem cell homing to improve therapeutic efficacy in liver disease. Stem Cell Res Ther 2022; 13:179. [PMID: 35505419 PMCID: PMC9066724 DOI: 10.1186/s13287-022-02858-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 02/21/2022] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation, as an alternative strategy to orthotopic liver transplantation, has been evaluated for treating end-stage liver disease. Although the therapeutic mechanism of MSC transplantation remains unclear, accumulating evidence has demonstrated that MSCs can regenerate tissues and self-renew to repair the liver through differentiation into hepatocyte-like cells, immune regulation, and anti-fibrotic mechanisms. Multiple clinical trials have confirmed that MSC transplantation restores liver function and alleviates liver damage. A sufficient number of MSCs must be home to the target tissues after administration for successful application. However, inefficient homing of MSCs after systemic administration is a major limitation in MSC therapy. Here, we review the mechanisms and clinical application status of MSCs in the treatment of liver disease and comprehensively summarize the molecular mechanisms of MSC homing, and various strategies for promoting MSC homing to improve the treatment of liver disease.
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Affiliation(s)
- Mengqin Yuan
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xue Hu
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lichao Yao
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yingan Jiang
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China.
| | - Lanjuan Li
- Department of Infectious Diseases, Renmin Hospital of Wuhan University, Wuhan, China. .,State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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16
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Namdari H, Hosseini M, Yazdanifar M, Farajifard H, Parvizpour F, Karamigolbaghi M, Hamidieh AA, Rezaei F. Protective and pathological roles of regulatory immune cells in human cytomegalovirus infection following hematopoietic stem cell transplantation. Rev Med Virol 2021; 32:e2319. [PMID: 34914147 DOI: 10.1002/rmv.2319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/29/2021] [Accepted: 11/30/2021] [Indexed: 11/11/2022]
Abstract
Human cytomegalovirus (HCMV) is ubiquitously prevalent. Immune system in healthy individuals is capable of controlling HCMV infection; however, HCMV can be life-threatening for immunocompromised individuals, such as transplant recipients. Both innate and adaptive immune systems are critically involved in the HCMV infection. Recent studies have indicated that regulatory immune cells which play essential roles in maintaining a healthy immune environment are closely related to immune response in HCMV infection. However, the exact role of regulatory immune cells in immune regulation and homoeostasis during the battle between HCMV and host still requires further research. In this review, we highlight the protective and pathological roles of regulatory immune cells in HCMV infection following hematopoietic stem cell transplantation (HSCT).
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Affiliation(s)
- Haideh Namdari
- Iranian Tissue Bank and Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Hosseini
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahboubeh Yazdanifar
- Department of Pediatrics, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California, USA
| | - Hamid Farajifard
- Iranian Tissue Bank and Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzad Parvizpour
- Iranian Tissue Bank and Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Karamigolbaghi
- Iranian Tissue Bank and Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Ali Hamidieh
- Pediatric Cell and Gene Therapy Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Farhad Rezaei
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
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17
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Ghezelayagh Z, Zabihi M, Kazemi Ashtiani M, Ghezelayagh Z, Lynn FC, Tahamtani Y. Recapitulating pancreatic cell-cell interactions through bioengineering approaches: the momentous role of non-epithelial cells for diabetes cell therapy. Cell Mol Life Sci 2021; 78:7107-7132. [PMID: 34613423 PMCID: PMC11072828 DOI: 10.1007/s00018-021-03951-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 09/09/2021] [Accepted: 09/23/2021] [Indexed: 12/11/2022]
Abstract
Over the past few years, extensive efforts have been made to generate in-vitro pancreatic micro-tissue, for disease modeling or cell replacement approaches in pancreatic related diseases such as diabetes mellitus. To obtain these goals, a closer look at the diverse cells participating in pancreatic development is necessary. Five major non-epithelial pancreatic (pN-Epi) cell populations namely, pancreatic endothelium, mesothelium, neural crests, pericytes, and stellate cells exist in pancreas throughout its development, and they are hypothesized to be endogenous inducers of the development. In this review, we discuss different pN-Epi cells migrating to and existing within the pancreas and their diverse effects on pancreatic epithelium during organ development mediated via associated signaling pathways, soluble factors or mechanical cell-cell interactions. In-vivo and in-vitro experiments, with a focus on N-Epi cells' impact on pancreas endocrine development, have also been considered. Pluripotent stem cell technology and multicellular three-dimensional organoids as new approaches to generate pancreatic micro-tissues have also been discussed. Main challenges for reaching a detailed understanding of the role of pN-Epi cells in pancreas development in utilizing for in-vitro recapitulation have been summarized. Finally, various novel and innovative large-scale bioengineering approaches which may help to recapitulate cell-cell interactions and are crucial for generation of large-scale in-vitro multicellular pancreatic micro-tissues, are discussed.
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Affiliation(s)
- Zahra Ghezelayagh
- Department of Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Zabihi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Genetics, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
| | - Mohammad Kazemi Ashtiani
- Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Zeinab Ghezelayagh
- Department of Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Francis C Lynn
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Surgery and School of Biomedical Engineering , University of British Columbia, Vancouver, BC, Canada
| | - Yaser Tahamtani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
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18
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Wu MC, Meng QH. Current understanding of mesenchymal stem cells in liver diseases. World J Stem Cells 2021; 13:1349-1359. [PMID: 34630867 PMCID: PMC8474713 DOI: 10.4252/wjsc.v13.i9.1349] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 07/01/2021] [Accepted: 08/25/2021] [Indexed: 02/06/2023] Open
Abstract
Liver diseases caused by various factors have become a significant threat to public health worldwide. Liver transplantation has been considered as the only effective treatment for end-stage liver diseases; however, it is limited by the shortage of donor organs, postoperative complications, long-term immunosuppression, and high cost of treatment. Thus, it is not available for all patients. Recently, mesenchymal stem cells (MSCs) transplantation has been extensively explored for repairing hepatic injury in various liver diseases. MSCs are multipotent adult progenitor cells originated from the embryonic mesoderm, and can be found in mesenchymal tissues including the bone marrow, umbilical cord blood, adipose tissue, liver, lung, and others. Although the precise mechanisms of MSC transplantation remain mysterious, MSCs have been demonstrated to be able to prevent the progression of liver injury and improve liver function. MSCs can self-renew by dividing, migrating to injury sites and differentiating into multiple cell types including hepatocytes. Additionally, MSCs have immune-modulatory properties and release paracrine soluble factors. Indeed, the safety and effectiveness of MSC therapy for liver diseases have been demonstrated in animals. However, pre-clinical and clinical trials are largely required to confirm its safety and efficacy before large scale clinical application. In this review, we will explore the molecular mechanisms underlying therapeutic effects of MSCs on liver diseases. We also summarize clinical advances in MSC-based therapies.
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Affiliation(s)
- Mu-Chen Wu
- Department of Medical Oncology,You An Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-Hua Meng
- Department of Medical Oncology,You An Hospital, Capital Medical University, Beijing 100069, China.
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19
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Wang X, Brown NK, Wang B, Shariati K, Wang K, Fuchs S, Melero‐Martin JM, Ma M. Local Immunomodulatory Strategies to Prevent Allo-Rejection in Transplantation of Insulin-Producing Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2003708. [PMID: 34258870 PMCID: PMC8425879 DOI: 10.1002/advs.202003708] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 05/12/2021] [Indexed: 05/02/2023]
Abstract
Islet transplantation has shown promise as a curative therapy for type 1 diabetes (T1D). However, the side effects of systemic immunosuppression and limited long-term viability of engrafted islets, together with the scarcity of donor organs, highlight an urgent need for the development of new, improved, and safer cell-replacement strategies. Induction of local immunotolerance to prevent allo-rejection against islets and stem cell derived β cells has the potential to improve graft function and broaden the applicability of cellular therapy while minimizing adverse effects of systemic immunosuppression. In this mini review, recent developments in non-encapsulation, local immunomodulatory approaches for T1D cell replacement therapies, including islet/β cell modification, immunomodulatory biomaterial platforms, and co-transplantation of immunomodulatory cells are discussed. Key advantages and remaining challenges in translating such technologies to clinical settings are identified. Although many of the studies discussed are preliminary, the growing interest in the field has led to the exploration of new combinatorial strategies involving cellular engineering, immunotherapy, and novel biomaterials. Such interdisciplinary research will undoubtedly accelerate the development of therapies that can benefit the whole T1D population.
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Affiliation(s)
- Xi Wang
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Natalie K. Brown
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Bo Wang
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Kaavian Shariati
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Kai Wang
- Department of Cardiac SurgeryBoston Children's HospitalBostonMA02115USA
- Department of SurgeryHarvard Medical SchoolBostonMA02115USA
| | - Stephanie Fuchs
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
| | - Juan M. Melero‐Martin
- Department of Cardiac SurgeryBoston Children's HospitalBostonMA02115USA
- Department of SurgeryHarvard Medical SchoolBostonMA02115USA
- Harvard Stem Cell InstituteCambridgeMA02138USA
| | - Minglin Ma
- Department of Biological and Environmental EngineeringCornell UniversityIthacaNY14853USA
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20
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Shrestha M, Nguyen TT, Park J, Choi JU, Yook S, Jeong JH. Immunomodulation effect of mesenchymal stem cells in islet transplantation. Biomed Pharmacother 2021; 142:112042. [PMID: 34403963 DOI: 10.1016/j.biopha.2021.112042] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/06/2021] [Accepted: 08/09/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) therapy has brought a great enthusiasm to the treatment of various immune disorders, tissue regeneration and transplantation therapy. MSCs are being extensively investigated for their immunomodulatory actions. MSCs can deliver immunomodulatory signals to inhibit allogeneic T cell immune responses by downregulating pro-inflammatory cytokines and increasing regulatory cytokines and growth factors. Islet transplantation is a therapeutic alternative to the insulin therapy for the treatment of type 1 diabetes mellitus (T1DM). However, the acute loss of islets due to the lack of vasculature and hypoxic milieu in the immediate post-transplantation period may lead to treatment failure. Moreover, despite the use of potent immunosuppressive drugs, graft failure persists because of immunological rejection. Many in vitro and in vivo researches have demonstrated the multipotency of MSCs as a mediator of immunomodulation and a great approach for enhancement of islet engraftment. MSCs can interact with immune cells of the innate and adaptive immune systems via direct cell-cell contact or through secretomes containing numerous soluble growth and immunomodulatory factors or mitochondrial transfer. This review highlights the interactions between MSCs and different immune cells to mediate immunomodulatory functions along with the importance of MSCs therapy for the successful islet transplantation.
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Affiliation(s)
- Manju Shrestha
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Tiep Tien Nguyen
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Jooho Park
- Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Republic of Korea
| | - Jeong Uk Choi
- College of Pharmacy, Chonnam University, Gwangju 61186, Republic of Korea
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
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21
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Sousa AR, Mano JF, Oliveira MB. Engineering Strategies for Allogeneic Solid Tissue Acceptance. Trends Mol Med 2021; 27:572-587. [PMID: 33865718 DOI: 10.1016/j.molmed.2021.03.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 03/05/2021] [Accepted: 03/12/2021] [Indexed: 10/21/2022]
Abstract
Advances in allogeneic transplantation of solid organs and tissues depend on our understanding of mechanisms that mediate the prevention of graft rejection. For the past decades, clinical practice has established guidelines to prevent allograft rejection, which mostly rely on the intake of nontargeted immunosuppressants as the gold standard. However, such lifelong regimens have been reported to trigger severe morbidities and commonly fail in preventing late allograft loss. In this review, the biology of allogeneic rejection and self-tolerance is analyzed, as well as the mechanisms of cellular-based therapeutics driving suppression and/or tolerance. Bioinspired engineering strategies that take advantage of cells, biomaterials, or combinations thereof to prevent allograft rejection are addressed, as well as biological mechanisms that drive their efficacy.
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Affiliation(s)
- Ana Rita Sousa
- Department of Chemistry, CICECO - Aveiro Institute of Materials, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal
| | - João F Mano
- Department of Chemistry, CICECO - Aveiro Institute of Materials, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
| | - Mariana B Oliveira
- Department of Chemistry, CICECO - Aveiro Institute of Materials, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
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22
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Kuwabara R, Hu S, Smink AM, Orive G, Lakey JRT, de Vos P. Applying Immunomodulation to Promote Longevity of Immunoisolated Pancreatic Islet Grafts. TISSUE ENGINEERING PART B-REVIEWS 2021; 28:129-140. [PMID: 33397201 DOI: 10.1089/ten.teb.2020.0326] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Islet transplantation is a promising therapy for insulin-dependent diabetes, but large-scale application is hampered by the lack of a consistent source of insulin-producing cells and need for lifelong administration of immunosuppressive drugs, which are associated with severe side effects. To avoid chronic immunosuppression, islet grafts can be enveloped in immunoisolating polymeric membranes. These immunoisolating polymeric membranes protect islet grafts from cell-mediated rejection while allowing diffusion of oxygen, nutrients, and insulin. Although clinical trials have shown the safety and feasibility of encapsulated islets to control glucose homeostasis, the strategy does up till now not support long-term graft survival. This partly can be explained by a significant loss of insulin-producing cells in the immediate period after implantation. The loss can be prevented by combining immunoisolation with immunomodulation, such as combined administration of immunomodulating cytokines or coencapsulation of immunomodulating cell types such as regulatory T cells, mesenchymal stem cells, or Sertoli cells. Also, administration of specific antibodies or apoptotic donor leucocytes is considered to create a tolerant microenvironment around immunoisolated grafts. In this review, we describe the outcomes and limitations of these approaches, as well as the recent progress in immunoisolating devices. Impact statement Immunoisolation by enveloping islets in semipermeable membranes allows for successful transplantation of islet grafts in the absence of chronic immunosuppression, but the duration of graft survival is still not permanent. The reasons for long-term final graft failure is not fully understood, but combining immunoisolation with immunomodulation of tissues or host immune system has been proposed to enhance the longevity of grafts. This article reviews the recent progress and challenges of immunoisolation, as well as the benefits and feasibility of combining encapsulation approaches with immunomodulation to promote longevity of encapsulated grafts.
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Affiliation(s)
- Rei Kuwabara
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.,Department of Biomaterials, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shuxian Hu
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Alexandra M Smink
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gorka Orive
- NanoBioCel Group, Laboratory of Pharmaceutics, School of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain
| | - Jonathan R T Lakey
- Department of Surgery and Biomedical Engineering, University of California Irvine, Irvine, California, USA
| | - Paul de Vos
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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23
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Qu Z, Lou Q, Cooper DKC, Pu Z, Lu Y, Chen J, Ni Y, Zhan Y, Chen J, Li Z, Zhan N, Zeng Y, Tu Z, Cao H, Dai Y, Cai Z, Mou L. Potential roles of mesenchymal stromal cells in islet allo- and xenotransplantation for type 1 diabetes mellitus. Xenotransplantation 2021; 28:e12678. [PMID: 33569837 DOI: 10.1111/xen.12678] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 01/05/2021] [Accepted: 01/23/2021] [Indexed: 12/14/2022]
Abstract
Islet transplantation is poised to play an important role in the treatment of type 1 diabetes mellitus (T1DM). However, there are several challenges limiting its widespread use, including the instant blood-mediated inflammatory reaction, hypoxic/ischemic injury, and the immune response. Mesenchymal stem/stromal cells (MSCs) are known to exert regenerative, immunoregulatory, angiogenic, and metabolic properties. Here, we review recent reports on the application of MSCs in islet allo- and xenotransplantation. We also document the clinical trials that have been undertaken or are currently underway, relating to the co-transplantation of islets and MSCs. Increasing evidence indicates that co-transplantation of MSCs prolongs islet graft survival by locally secreted protective factors that reduce immune reactivity and promote vascularization, cell survival, and regeneration. MSC therapy may be a promising option for islet transplantation in patients with T1DM.
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Affiliation(s)
- Zepeng Qu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Qi Lou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China.,Shenzhen Lansi Institute of Artificial Intelligence in Medicine, Shenzhen, China
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, The University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zuhui Pu
- Department of Radiology, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Ying Lu
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Jiao Chen
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yong Ni
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yongqiang Zhan
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Jun Chen
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Zhenjie Li
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Naiyang Zhan
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yi Zeng
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Ziwei Tu
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Huayi Cao
- Department of Hepatopancreatobiliary Surgery, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Yifan Dai
- Jiangsu Key Laboratory of Xenotransplantation, Nanjing Medical University, Nanjing, China
| | - Zhiming Cai
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
| | - Lisha Mou
- Shenzhen Xenotransplantation Medical Engineering Research and Development Center, Institute of Translational Medicine, Shenzhen University Health Science Center, Shenzhen University School of Medicine, First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, China
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24
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Hubber EL, Rackham CL, Jones PM. Protecting islet functional viability using mesenchymal stromal cells. Stem Cells Transl Med 2021; 10:674-680. [PMID: 33544449 PMCID: PMC8046085 DOI: 10.1002/sctm.20-0466] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/20/2020] [Accepted: 12/06/2020] [Indexed: 12/11/2022] Open
Abstract
Islet transplantation is an emerging treatment for type 1 diabetes which offers the prospect of physiological control of blood glucose and reductions in acute hypoglycaemic episodes. However, current protocols are limited by a rapid decline in islet functional viability during the isolation process, culture period, and post-transplantation. Much of this can be attributed to the deleterious effects of hypoxic and cytokine stressors on β cells. One experimental strategy to improve the functional viability of islets is coculture or cotransplantation with mesenchymal stromal cells (MSCs). Numerous studies have shown that MSCs have the capacity to improve islet survival and insulin secretory function, and the mechanisms of these effects are becoming increasingly well understood. In this review, we will focus on recent studies demonstrating the capacity for MSCs to protect islets from hypoxia- and cytokine-induced stress. Islets exposed to acute hypoxia (1%-2% O2 ) or to inflammatory cytokines (including IFN-γ, TNF-α, and IL-B) in vitro undergo apoptosis and a rapid decline in glucose-stimulated insulin secretion. Coculture of islets with MSCs, or with MSC-conditioned medium, protects from these deleterious effects, primarily with secreted factors. These protective effects are distinct from the immunomodulatory and structural support MSCs provide when cotransplanted with islets. Recent studies suggest that MSCs may support secretory function by the physical transfer of functional mitochondria, particularly to metabolically compromised β cells. Understanding how MSCs respond to stressed islets will facilitate the development of MSC secretome based, cell-free approaches to supporting islet graft function during transplantation by protecting or repairing β cells.
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Affiliation(s)
- Ella L Hubber
- Department of Diabetes, School of Life Course Sciences, King's College London, London, UK
| | - Chloe L Rackham
- Exeter Centre for Excellence in Diabetes (EXCEED), Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Peter M Jones
- Department of Diabetes, School of Life Course Sciences, King's College London, London, UK
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25
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Forbes S, Bond AR, Thirlwell KL, Burgoyne P, Samuel K, Noble J, Borthwick G, Colligan D, McGowan NWA, Lewis PS, Fraser AR, Mountford JC, Carter RN, Morton NM, Turner ML, Graham GJ, Campbell JDM. Human umbilical cord perivascular cells improve human pancreatic islet transplant function by increasing vascularization. Sci Transl Med 2021; 12:12/526/eaan5907. [PMID: 31941825 DOI: 10.1126/scitranslmed.aan5907] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 06/24/2019] [Accepted: 12/03/2019] [Indexed: 12/12/2022]
Abstract
Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation. Transplanting an islet equivalent (IEQ):HUCPVC ratio of 1:30 under the kidney capsule in diabetic NSG mice demonstrated the fastest return to normoglycemia by 3 days after transplant: Superior glycemic control was seen at both early (2.7 weeks) and later stages (7, 12, and 16 weeks) versus ratios of 1:0, 1:10, and 1:50, respectively. Syngeneic islet transplantation in immunocompetent mice using the clinically relevant hepatic portal route with a marginal islet mass showed that mice transplanted with an IEQ:HUCPVC ratio of 1:150 had superior glycemic control versus ratios of 1:0, 1:90, and 1:210 up to 6 weeks after transplant. Immunodeficient mice transplanted with human islets (IEQ:HUCPVC ratio of 1:150) exhibited better glycemic control for 7 weeks after transplant versus islet transplant alone, and islets transplanted via the hepatic portal vein in an allogeneic mouse model using a curative islet mass demonstrated delayed rejection of islets when cotransplanted with HUCPVCs (IEQ:HUCPVC ratio of 1:150). The immunosuppressive and proregenerative properties of HUCPVCs demonstrated long-term positive effects on graft function in vivo, indicating that they may improve long-term human islet allotransplantation outcomes.
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Affiliation(s)
- Shareen Forbes
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. .,Clinical Islet Transplantation Programme, Royal Infirmary of Edinburgh, Edinburgh EH16 4SU, UK
| | - Andrew R Bond
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Kayleigh L Thirlwell
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK.,Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
| | - Paul Burgoyne
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK.,Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK.,Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
| | - Kay Samuel
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - June Noble
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Gary Borthwick
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - David Colligan
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Neil W A McGowan
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Philip Starkey Lewis
- Medical Research Council (MRC) Centre for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Alasdair R Fraser
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Joanne C Mountford
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Roderick N Carter
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Nicholas M Morton
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK
| | - Marc L Turner
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK
| | - Gerard J Graham
- Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
| | - John D M Campbell
- Advanced Therapeutics, Scottish National Blood Transfusion Service, Edinburgh EH14 4BE, UK. .,Chemokine Research Group, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK
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26
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Chen J, Wang Y, Hu H, Xiong Y, Wang S, Yang J. Adipose-derived cellular therapies prolong graft survival in an allogenic hind limb transplantation model. Stem Cell Res Ther 2021; 12:94. [PMID: 33514430 PMCID: PMC7847016 DOI: 10.1186/s13287-021-02162-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 01/12/2021] [Indexed: 12/05/2022] Open
Abstract
Background The long-term survival after vascularized composite allotransplantation (VCA) is often limited by systemic rejection as well as the adverse effects of immunosuppressants. The stromal vascular fraction (SVF) can be expanded to produce adipose-derived stem cells (ADSC) which represents a combination of endothelial cells, preadipocytes, immune cells, and ADSC. It has been demonstrated that ADSC possess consistently reliable clinical results. However, literature is scarce regarding SVF in VCA. This study seeks to determine the impact of ex vivo allograft pretreatment in combination with SVF cells in the ability to promote composite tissue allotransplantation immunotolerance. Methods A rat hind limb allotransplant model was used to investigate the influence of ex vivo pretreatment of SVF and ADSC on VCA survival. Intravascular cell-free saline, ADSC, or SVF was infused into the models with immunosuppressants. The histopathological examination and duration that the allografts went without displaying symptoms of rejection was documented. Peripheral T lymphocytes and Tregs were quantified with flow cytometry while allotissue expressions of CD31 were quantified with immunohistochemical staining (IHC). ELISA was used to detect vascular endothelial growth factor (VEGF)-A as well as anti- and pro-inflammatory cytokines. Results We demonstrated that ex vivo treatment of allografts with SVF or ADSC prolonged allograft survival in contrast to medium control cohorts. There were also enhanced levels of immunomodulatory cytokines and increased VEGF-A and CD31 expression as well as reduced infiltration and proliferation of T lymphocytes along with raised Treg expressions. Conclusion These studies demonstrated that adipose-derived cellular therapies prolong graft survival in an allogenic hind limb transplantation model and have the potential to establish immunotolerance. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02162-7.
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Affiliation(s)
- Jingting Chen
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yinmin Wang
- Department of Plastic and Reconstructive Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haoyue Hu
- Basic Medical School , Jining Medical University , Jining, 272000, China
| | - Yao Xiong
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Shoubao Wang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jun Yang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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27
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Akolpoglu MB, Inceoglu Y, Bozuyuk U, Sousa AR, Oliveira MB, Mano JF, Kizilel S. Recent advances in the design of implantable insulin secreting heterocellular islet organoids. Biomaterials 2020; 269:120627. [PMID: 33401104 DOI: 10.1016/j.biomaterials.2020.120627] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 12/14/2020] [Accepted: 12/18/2020] [Indexed: 12/11/2022]
Abstract
Islet transplantation has proved one of the most remarkable transmissions from an experimental curiosity into a routine clinical application for the treatment of type I diabetes (T1D). Current efforts for taking this technology one-step further are now focusing on overcoming islet donor shortage, engraftment, prolonged islet availability, post-transplant vascularization, and coming up with new strategies to eliminate lifelong immunosuppression. To this end, insulin secreting 3D cell clusters composed of different types of cells, also referred as heterocellular islet organoids, spheroids, or pseudoislets, have been engineered to overcome the challenges encountered by the current islet transplantation protocols. β-cells or native islets are accompanied by helper cells, also referred to as accessory cells, to generate a cell cluster that is not only able to accurately secrete insulin in response to glucose, but also superior in terms of other key features (e.g. maintaining a vasculature, longer durability in vivo and not necessitating immunosuppression after transplantation). Over the past decade, numerous 3D cell culture techniques have been integrated to create an engineered heterocellular islet organoid that addresses current obstacles. Here, we first discuss the different cell types used to prepare heterocellular organoids for islet transplantation and their contribution to the organoids design. We then introduce various cell culture techniques that are incorporated to prepare a fully functional and insulin secreting organoids with select features. Finally, we discuss the challenges and present a future outlook for improving clinical outcomes of islet transplantation.
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Affiliation(s)
- M Birgul Akolpoglu
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey
| | - Yasemin Inceoglu
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey
| | - Ugur Bozuyuk
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey
| | - Ana Rita Sousa
- Department of Chemistry, CICECO - Aveiro Institute of Materials. University of Aveiro. Campus Universitário de Santiago. 3810-193 Aveiro. Portugal
| | - Mariana B Oliveira
- Department of Chemistry, CICECO - Aveiro Institute of Materials. University of Aveiro. Campus Universitário de Santiago. 3810-193 Aveiro. Portugal.
| | - João F Mano
- Department of Chemistry, CICECO - Aveiro Institute of Materials. University of Aveiro. Campus Universitário de Santiago. 3810-193 Aveiro. Portugal
| | - Seda Kizilel
- Chemical and Biological Engineering, Koc University, Sariyer, 34450, Istanbul, Turkey.
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28
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Ryu JS, Jeong EJ, Kim JY, Park SJ, Ju WS, Kim CH, Kim JS, Choo YK. Application of Mesenchymal Stem Cells in Inflammatory and Fibrotic Diseases. Int J Mol Sci 2020; 21:ijms21218366. [PMID: 33171878 PMCID: PMC7664655 DOI: 10.3390/ijms21218366] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 10/29/2020] [Accepted: 11/05/2020] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stem cells that can be isolated from various tissues in the adult body. MSCs should be characterized by three criteria for regenerative medicine. MSCs must (1) adhere to plastic surfaces, (2) express specific surface antigens, and (3) differentiate into mesodermal lineages, including chondrocytes, osteoblasts, and adipocytes, in vitro. Interestingly, MSCs have immunomodulatory features and secrete trophic factors and immune receptors that regulate the microenvironment in host tissue. These specific and unique therapeutic properties make MSCs ideal as therapeutic agents in vivo. Specifically, pre-clinical and clinical investigators generated inflammatory and fibrotic diseases models, and then transplantation of MSCs into diseases models for therapeutic effects investigation. In this review, we characterize MSCs from various tissues and describe their applications for treating various inflammation and fibrotic diseases.
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Affiliation(s)
- Jae-Sung Ryu
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Konyang University, Daejeon 35365, Korea; (J.-S.R.); (J.-Y.K.)
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Eun-Jeong Jeong
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea;
| | - Jong-Yeup Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Konyang University, Daejeon 35365, Korea; (J.-S.R.); (J.-Y.K.)
- Department of Biomedical Informatics, College of Medicine, Konyang University, Daejeon 35365, Korea
| | - Soon Ju Park
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
| | - Won Seok Ju
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
| | - Chang-Hyun Kim
- College of Medicine, Dongguk University, Goyang 10326, Korea;
| | - Jang-Seong Kim
- Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea;
- Department of Functional Genomics, University of Science and Technology (UST), Daejeon 34141, Korea
| | - Young-Kug Choo
- Department of Biological Science, College of Natural Sciences, Wonkwang University, Iksan 54538, Korea; (E.-J.J.); (S.J.P.); (W.S.J.)
- Institute for Glycoscience, Wonkwang University, Iksan 54538, Korea
- Correspondence:
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29
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Yang X, Meng Y, Han Z, Ye F, Wei L, Zong C. Mesenchymal stem cell therapy for liver disease: full of chances and challenges. Cell Biosci 2020; 10:123. [PMID: 33117520 PMCID: PMC7590738 DOI: 10.1186/s13578-020-00480-6] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 10/06/2020] [Indexed: 12/13/2022] Open
Abstract
Liver disease is a major health problem that endangers human health worldwide. Currently, whole organ allograft transplantation is the gold standard for the treatment of end-stage liver disease. A shortage of suitable organs, high costs and surgical complications limit the application of liver transplantation. Mesenchymal stem cell therapy has been considered as a promising alternative approach for end-stage liver disease. Some clinical trials have confirmed the effectiveness of MSC therapy for liver disease, but its application has not been promoted and approved. There are still many issues that should be solved prior to using MSC therapy in clinical applications. The types of liver disease that are most suitable for MSC application should be determined, and the preparation and engraftment of MSCs should be standardized. These may be bottlenecks that limit the use of MSCs. We investigated 22 completed and several ongoing clinical trials to discuss these questions from a clinical perspective. We also discussed the important mechanisms by which MSCs play a therapeutic role in liver disease. Finally, we also proposed novel prospective approaches that can improve the therapeutic effect of MSCs.
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Affiliation(s)
- Xue Yang
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Fei Ye
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
| | - Chen Zong
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, 225 Changhai Road, Shanghai, 200438 China
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30
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Marinaro F, Casado JG, Blázquez R, Brun MV, Marcos R, Santos M, Duque FJ, López E, Álvarez V, Usón A, Sánchez-Margallo FM. Laparoscopy for the Treatment of Congenital Hernia: Use of Surgical Meshes and Mesenchymal Stem Cells in a Clinically Relevant Animal Model. Front Pharmacol 2020; 11:01332. [PMID: 33101010 PMCID: PMC7546355 DOI: 10.3389/fphar.2020.01332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/11/2020] [Indexed: 12/20/2022] Open
Abstract
More than a century has passed since the first surgical mesh for hernia repair was developed, and, to date, this is still the most widely used method despite the great number of complications it poses. The purpose of this study was to combine stem cell therapy and laparoscopy for the treatment of congenital hernia in a swine animal model. Porcine bone marrow-derived mesenchymal stem cells (MSCs) were seeded on polypropylene surgical meshes using a fibrin sealant solution as a vehicle. Meshes with (cell group) or without (control group) MSCs were implanted through laparoscopy in Large White pigs with congenital abdominal hernia after the approximation of hernia borders (implantation day). A successive laparoscopic biopsy of the mesh and its surrounding tissues was performed a week after implantation, and surgical meshes were excised a month after implantation. Ultrasonography was used to measure hernia sizes. Flow cytometry, histological, and gene expression analyses of the biopsy and necropsy samples were performed. The fibrin sealant solution was easy to prepare and preserved the viability of MSCs in the surgical meshes. Ultrasonography demonstrated a significant reduction in hernia size 1 week after implantation in the cell group relative to that on the day of implantation (p < 0.05). Flow cytometry of the mesh-infiltrated cells showed a non-significant increase of M2 macrophages when the cell group was compared with the control group 1 week after implantation. A significant decrease in the gene expression of VEGF and a significant increase in TNF expression were determined in the cell group 1 month after implantation compared with gene expressions in the control group (p < 0.05). Here, we propose an easy and feasible method to combine stem cell therapy and minimally invasive surgical techniques for hernia repair. In this study, stem cell therapy did not show a great immunomodulatory or regenerative effect in overcoming hernia-related complications. However, our clinically relevant animal model with congenital hernia closely resembles the clinical human condition. Further studies should be focused on this valuable animal model to evaluate stem cell therapies in hernia surgery.
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Affiliation(s)
- Federica Marinaro
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain
| | - Javier G Casado
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain.,CIBER de Enfermedades Cardiovasculares, Madrid, Spain
| | - Rebeca Blázquez
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain.,CIBER de Enfermedades Cardiovasculares, Madrid, Spain
| | - Mauricio Veloso Brun
- Department of Small Animal Clinics, Center of Rural Science, Federal University of Santa Maria (UFSM), Santa Maria, Brazil
| | - Ricardo Marcos
- Laboratory of Histology and Embryology, Department of Microscopy, Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal
| | - Marta Santos
- Laboratory of Histology and Embryology, Department of Microscopy, Abel Salazar Institute of Biomedical Sciences, University of Porto, Porto, Portugal
| | - Francisco Javier Duque
- Animal Medicine Department, Faculty of Veterinary Medicine, University of Extremadura, Cáceres, Spain
| | - Esther López
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain
| | - Verónica Álvarez
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain
| | - Alejandra Usón
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain
| | - Francisco Miguel Sánchez-Margallo
- CIBER de Enfermedades Cardiovasculares, Madrid, Spain.,Scientific Direction, Jesús Usón Minimally Invasive Surgery Centre, Cáceres, Spain
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31
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Gardin C, Ferroni L, Chachques JC, Zavan B. Could Mesenchymal Stem Cell-Derived Exosomes Be a Therapeutic Option for Critically Ill COVID-19 Patients? J Clin Med 2020; 9:E2762. [PMID: 32858940 PMCID: PMC7565764 DOI: 10.3390/jcm9092762] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 08/25/2020] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a pandemic viral disease originated in Wuhan, China, in December 2019, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severe form of the disease is often associated with acute respiratory distress syndrome (ARDS), and most critically ill patients require mechanical ventilation and support in intensive care units. A significant portion of COVID-19 patients also develop complications of the cardiovascular system, primarily acute myocardial injury, arrhythmia, or heart failure. To date, no specific antiviral therapy is available for patients with SARS-CoV-2 infection. Exosomes derived from mesenchymal stem cells (MSCs) are being explored for the management of a number of diseases that currently have limited or no therapeutic options, thanks to their anti-inflammatory, immunomodulatory, and pro-angiogenic properties. Here, we briefly introduce the pathogenesis of SARS-CoV-2 and its implications in the heart and lungs. Next, we describe some of the most significant clinical evidence of the successful use of MSC-derived exosomes in animal models of lung and heart injuries, which might strengthen our hypothesis in terms of their utility for also treating critically ill COVID-19 patients.
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Affiliation(s)
- Chiara Gardin
- Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola (RA), Italy; (C.G.); (L.F.)
- Department of Morphology, Experimental Medicine and Surgery, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Letizia Ferroni
- Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola (RA), Italy; (C.G.); (L.F.)
- Department of Morphology, Experimental Medicine and Surgery, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
| | - Juan Carlos Chachques
- Department of Cardiac Surgery Pompidou Hospital, Laboratory of Biosurgical Research, Carpentier Foundation, University Paris Descartes, 75015 Paris, France;
| | - Barbara Zavan
- Maria Cecilia Hospital, GVM Care & Research, 48033 Cotignola (RA), Italy; (C.G.); (L.F.)
- Department of Morphology, Experimental Medicine and Surgery, University of Ferrara, via Fossato di Mortara 70, 44121 Ferrara, Italy
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Effect of Timing and Complement Receptor Antagonism on Intragraft Recruitment and Protolerogenic Effects of Mesenchymal Stromal Cells in Murine Kidney Transplantation. Transplantation 2020; 103:1121-1130. [PMID: 30801518 DOI: 10.1097/tp.0000000000002611] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) have protolerogenic effects in renal transplantation, but they induce long-term regulatory T cells (Treg)-dependent graft acceptance only when infused before transplantation. When given posttransplant, MSCs home to the graft where they promote engraftment syndrome and do not induce Treg. Unfortunately, pretransplant MSC administration is unfeasible in deceased-donor kidney transplantation. METHODS To make MSCs a therapeutic option also for deceased organ recipients, we tested whether MSC infusion at the time of transplant (day 0) or posttransplant (day 2) together with inhibition of complement receptors prevents engraftment syndrome and allows their homing to secondary lymphoid organs for promoting tolerance. We analyzed intragraft and splenic MSC localization, graft survival, and alloimmune response in mice recipients of kidney allografts and syngeneic MSCs given on day 0 or on posttransplant day 2. C3a receptor (C3aR) or C5a receptor (C5aR) antagonists were administered to mice in combination with the cells or were used together to treat MSCs before infusion. RESULTS Syngeneic MSCs given at day 0 homed to the spleen increased Treg numbers and induced long-term graft acceptance. Posttransplant MSC infusion, combined with a short course of C3aR or C5aR antagonist or administration of MSCs pretreated with C3aR and C5aR antagonists, prevented intragraft recruitment of MSCs and graft inflammation, inhibited antidonor T-cell reactivity, but failed to induce Treg, resulting in mild prolongation of graft survival. CONCLUSIONS These data support testing the safety/efficacy profile of administering MSCs on the day of transplant in deceased-donor transplant recipients and indicate that complement is crucial for MSC recruitment into the kidney allograft.
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Identifying the Therapeutic Significance of Mesenchymal Stem Cells. Cells 2020; 9:cells9051145. [PMID: 32384763 PMCID: PMC7291143 DOI: 10.3390/cells9051145] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/04/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022] Open
Abstract
The pleiotropic behavior of mesenchymal stem cells (MSCs) has gained global attention due to their immense potential for immunosuppression and their therapeutic role in immune disorders. MSCs migrate towards inflamed microenvironments, produce anti-inflammatory cytokines and conceal themselves from the innate immune system. These signatures are the reason for the uprising in the sciences of cellular therapy in the last decades. Irrespective of their therapeutic role in immune disorders, some factors limit beneficial effects such as inconsistency of cell characteristics, erratic protocols, deviating dosages, and diverse transfusion patterns. Conclusive protocols for cell culture, differentiation, expansion, and cryopreservation of MSCs are of the utmost importance for a better understanding of MSCs in therapeutic applications. In this review, we address the immunomodulatory properties and immunosuppressive actions of MSCs. Also, we sum up the results of the enhancement, utilization, and therapeutic responses of MSCs in treating inflammatory diseases, metabolic disorders and diabetes.
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Lanzoni G, Linetsky E, Correa D, Alvarez RA, Marttos A, Hirani K, Cayetano SM, Castro JG, Paidas MJ, Efantis Potter J, Xu X, Glassberg M, Tan J, Patel AN, Goldstein B, Kenyon NS, Baidal D, Alejandro R, Vianna R, Ruiz P, Caplan AI, Ricordi C. Umbilical Cord-derived Mesenchymal Stem Cells for COVID-19 Patients with Acute Respiratory Distress Syndrome (ARDS). CELLR4-- REPAIR, REPLACEMENT, REGENERATION, & REPROGRAMMING 2020; 8. [PMID: 34164564 DOI: 10.32113/cellr4_20204_2839] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer's Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (l00 × 106 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH).
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Affiliation(s)
- G Lanzoni
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - E Linetsky
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - D Correa
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Orthopedics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - R A Alvarez
- University of Miami Health System and Jackson Health System, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - A Marttos
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA
| | - K Hirani
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - S Messinger Cayetano
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - J G Castro
- University of Miami Health System and Jackson Health System, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - M J Paidas
- University of Miami Health System and Jackson Health System, Miami, FL, USA.,Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - J Efantis Potter
- Department of Obstetrics, Gynecology and Reproductive Sciences, University of Miami Miller School of Medicine, Miami, FL, USA
| | - X Xu
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - M Glassberg
- Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA
| | - J Tan
- Organ Transplant Institute, Fuzhou General Hospital, Xiamen University, Fuzhou, China
| | - A N Patel
- Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, USA.,HCA Research Institute, Nashville, TN, USA
| | - B Goldstein
- Department of Head and Neck Surgery and Communication Sciences, Duke University, Durham, NC, USA
| | - N S Kenyon
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - D Baidal
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - R Alejandro
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - R Vianna
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA.,Miami Transplant Institute, Jackson Health System, Miami, FL, USA
| | - P Ruiz
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA.,Miami Transplant Institute, Jackson Health System, Miami, FL, USA
| | - A I Caplan
- Department of Medicine, University of Arizona College of Medicine, Phoenix, AZ, USA
| | - C Ricordi
- Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA.,University of Miami Health System and Jackson Health System, Miami, FL, USA
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Villard O, Armanet M, Couderc G, Bony C, Moreaux J, Noël D, De Vos J, Klein B, Veyrune JL, Wojtusciszyn A. Characterization of immortalized human islet stromal cells reveals a MSC-like profile with pancreatic features. Stem Cell Res Ther 2020; 11:158. [PMID: 32303252 PMCID: PMC7165390 DOI: 10.1186/s13287-020-01649-z] [Citation(s) in RCA: 5] [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: 10/23/2019] [Revised: 02/12/2020] [Accepted: 03/10/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) represent an interesting tool to improve pancreatic islet transplantation. They have immunomodulatory properties and secrete supportive proteins. However, the functional properties of MSCs vary according to many factors such as donor characteristics, tissue origin, or isolation methods. To counteract this heterogeneity, we aimed to immortalize and characterize adherent cells derived from human pancreatic islets (hISCs), using phenotypic, transcriptomic, and functional analysis. METHODS Adherent cells derived from human islets in culture were infected with a hTERT retrovirus vector and then characterized by microarray hybridization, flow cytometry analysis, and immunofluorescence assays. Osteogenic, adipogenic, and chondrogenic differentiation as well as PBMC proliferation suppression assays were used to compare the functional abilities of hISCs and MSCs. Extracellular matrix (ECM) gene expression profile analysis was performed using the SAM (Significance Analysis of Microarrays) software, and protein expression was confirmed by western blotting. RESULTS hISCs kept an unlimited proliferative potential. They exhibited several properties of MSCs such as CD73, CD90, and CD105 expression and differentiation capacity. From a functional point of view, hISCs inhibited the proliferation of activated peripheral blood mononuclear cells. The transcriptomic profile of hISCs highly clusterized with bone marrow (BM)-MSCs and revealed a differential enrichment of genes involved in the organization of the ECM. Indeed, the expression and secretion profiles of ECM proteins including collagens I, IV, and VI, fibronectin, and laminins, known to be expressed in abundance around and within the islets, were different between hISCs and BM-MSCs. CONCLUSION We generated a new human cell line from pancreatic islets, with MSCs properties and retaining some pancreatic specificities related to the production of ECM proteins. hISCs appear as a very promising tool in islet transplantation by their availability (as a source of inexhaustible source of cells) and ability to secrete a supportive "pancreatic" microenvironment.
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Affiliation(s)
- Orianne Villard
- Laboratory of Cell Therapy for Diabetes, Institute of Regenerative Medicine and Biotherapy, Univ. Montpellier, CHU Montpellier, Montpellier, France
- Department of Endocrinology, Diabetes, and Nutrition, Univ. Montpellier, CHU Montpellier, Montpellier, France
| | - Mathieu Armanet
- Laboratory of Cell Therapy for Diabetes, Institute of Regenerative Medicine and Biotherapy, Univ. Montpellier, CHU Montpellier, Montpellier, France
- Cell Therapy Unit, Hospital Saint- Louis, AP-HP, Paris, France
- Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, 8 avenue de la Sallaz - 1011, Lausanne, Switzerland
| | - Guilhem Couderc
- Department of Biological Haematology, Univ. Montpellier, CHU Montpellier, Montpellier, France
- Department of Cell and Tissue Engineering, Univ. Montpellier, CHU Montpellier, Montpellier, France
| | - Claire Bony
- IRMB, INSERM U 1183, Univ Montpellier, INSERM, Montpellier, France
| | - Jerome Moreaux
- Department of Biological Haematology, Univ. Montpellier, CHU Montpellier, Montpellier, France
- IGH, Univ Montpellier, CNRS, Montpellier, France
| | - Daniele Noël
- IRMB, INSERM U 1183, Univ Montpellier, INSERM, Montpellier, France
| | - John De Vos
- Department of Biological Haematology, Univ. Montpellier, CHU Montpellier, Montpellier, France
- Department of Cell and Tissue Engineering, Univ. Montpellier, CHU Montpellier, Montpellier, France
- IRMB, INSERM U 1183, Univ Montpellier, INSERM, Montpellier, France
| | - Bernard Klein
- Department of Cell and Tissue Engineering, Univ. Montpellier, CHU Montpellier, Montpellier, France
| | - Jean-Luc Veyrune
- Department of Biological Haematology, Univ. Montpellier, CHU Montpellier, Montpellier, France
- Department of Cell and Tissue Engineering, Univ. Montpellier, CHU Montpellier, Montpellier, France
| | - Anne Wojtusciszyn
- Laboratory of Cell Therapy for Diabetes, Institute of Regenerative Medicine and Biotherapy, Univ. Montpellier, CHU Montpellier, Montpellier, France.
- Department of Endocrinology, Diabetes, and Nutrition, Univ. Montpellier, CHU Montpellier, Montpellier, France.
- Department of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, 8 avenue de la Sallaz - 1011, Lausanne, Switzerland.
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Park HS, Ashour D, Elsharoud A, Chugh RM, Ismail N, El Andaloussi A, Al-Hendy A. Towards Cell free Therapy of Premature Ovarian Insufficiency: Human Bone Marrow Mesenchymal Stem Cells Secretome Enhances Angiogenesis in Human Ovarian Microvascular Endothelial Cells. ACTA ACUST UNITED AC 2019; 5. [PMID: 32494757 PMCID: PMC7269190 DOI: 10.24966/srdt-2060/100019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Primary Ovarian Insufficiency (POI) refers to an ovarian loss of function in women under the age of 40. Unfortunately, currently, there is no effective treatment available for POI-related infertility. Alternatives such as the use of egg donations are culturally and ethically unacceptable to many couples. Human Bone marrow-derived Mesenchymal Stem Cells (MSCs) are known for their ability to differentiate into other cell types, once primed by the organ microenvironment. Importantly MSCs produce a vast array of bioactive factors many of them have been shown to enhance neovascularization in various tissues. Recently, preliminary data from our ongoing clinical trial revealed encouraging preliminary data after autologous MSC engraftment into the ovaries of 2 POI patients with durable elevation in serum estrogen levels and increase in size of treated ovaries sustained up to one-year post cell therapy. In this study, we investigated the action of the mechanisms of MSCs treatment on a POI ovary. We designed an in vitro study using MSC secretome and Human Ovarian Endothelial Cells (HOVECs) to understand the molecular mechanisms by which MSC mediates their angiogenic properties and regenerative effects. Human primary HOVECs were treatment with MSC secretome and examined by FACS for the expression of angiogenesis markers such as Endoglin, Tie-2, and VEGF. The formation of vessels was evaluated by using a 3D Matrigel tubulogenesis assay. We observed that the expression of proliferation marker Ki67 was significantly increased under treatment with MSC secretome in HOVEC cells (P4). MSCs secretome treatment also induced significantly higher expression of several angiogenic markers such as VEGFR2, Tie2/Tek, VE-Cadherin, Endoglin, and VEGF compared to matched control (P4). Furthermore, MSC secretome significantly increased the number of branching points in tubulogenesis assay (P4). Our study suggests that MSC secretome likely contains bioactive factors that can enhance ovarian angiogenesis. Further characterization of these factors can lead to novel therapeutic options for women with premature ovarian insufficiency and other related causes of female infertility.
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Affiliation(s)
- Hang-Soo Park
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Dalia Ashour
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA.,Department of Pathology, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Amro Elsharoud
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Rishi Man Chugh
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
| | - Nahed Ismail
- Department of Pathology, University at Illinois at Chicago, Medical College, Chicago, USA
| | | | - Ayman Al-Hendy
- Department of Surgery, University at Illinois at Chicago, Medical College, Chicago, USA
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Khan MA, Alanazi F, Ahmed HA, Shamma T, Kelly K, Hammad MA, Alawad AO, Assiri AM, Broering DC. iPSC-derived MSC therapy induces immune tolerance and supports long-term graft survival in mouse orthotopic tracheal transplants. Stem Cell Res Ther 2019; 10:290. [PMID: 31547869 PMCID: PMC6757436 DOI: 10.1186/s13287-019-1397-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 07/16/2019] [Accepted: 08/26/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Lung transplantation is a life-saving surgical replacement of diseased lungs in patients with end-stage respiratory malfunctions. Despite remarkable short-term recovery, long-term lung survival continues to face several major challenges, including chronic rejection and severe toxic side effects due to global immunosuppression. Stem cell-based immunotherapy has been recognized as a crucial immunoregulatory regimen in various preclinical and clinical studies. Despite initial therapeutic outcomes, conventional stem cells face key limitations. The novel Cymerus™ manufacturing facilitates production of a virtually limitless supply of consistent human induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells, which could play a key role in selective immunosuppression and graft repair during rejection. METHODS Here, we demonstrated the impact of iPSC-derived human MSCs on the development of immune tolerance and long-term graft survival in mouse orthotopic airway allografts. BALB/c → C57BL/6 allografts were reconstituted with iPSC-derived MSCs (2 million/transplant/at d0), and allografts were examined for regulatory T cells (Tregs), oxygenation, microvascular blood flow, airway epithelium, and collagen deposition during rejection. RESULTS We demonstrated that iPSC-derived MSC treatment leads to significant increases in hTSG-6 protein, followed by an upregulation of mouse Tregs and IL-5, IL-10, and IL-15 cytokines, which augments graft microvascular blood flow and oxygenation, and thereby maintained a healthy airway epithelium and prevented the subepithelial deposition of collagen at d90 post transplantation. CONCLUSIONS Collectively, these data confirmed that iPSC-derived MSC-mediated immunosuppression has potential to establish immune tolerance and rescue allograft from sustained hypoxic/ischemic phase, and subsequently limits long-term airway epithelial injury and collagen progression, which therapeutically warrant a study of Cymerus iPSC-derived MSCs as a potential management option for immunosuppression in transplant recipients.
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Affiliation(s)
- Mohammad Afzal Khan
- Organ Transplant Research Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
| | - Fatimah Alanazi
- Organ Transplant Research Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
| | - Hala Abdalrahman Ahmed
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
| | - Talal Shamma
- Organ Transplant Research Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
| | - Kilian Kelly
- Cynata Therapeutics Limited, Melbourne, Australia
| | - Mohamed A. Hammad
- National Center for Stem Cell Technology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Abdullah O. Alawad
- National Center for Stem Cell Technology, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia
| | - Abdullah Mohammed Assiri
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Dieter Clemens Broering
- Organ Transplant Research Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia
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Bowers DT, Song W, Wang LH, Ma M. Engineering the vasculature for islet transplantation. Acta Biomater 2019; 95:131-151. [PMID: 31128322 PMCID: PMC6824722 DOI: 10.1016/j.actbio.2019.05.051] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 04/13/2019] [Accepted: 05/20/2019] [Indexed: 12/17/2022]
Abstract
The microvasculature in the pancreatic islet is highly specialized for glucose sensing and insulin secretion. Although pancreatic islet transplantation is a potentially life-changing treatment for patients with insulin-dependent diabetes, a lack of blood perfusion reduces viability and function of newly transplanted tissues. Functional vasculature around an implant is not only necessary for the supply of oxygen and nutrients but also required for rapid insulin release kinetics and removal of metabolic waste. Inadequate vascularization is particularly a challenge in islet encapsulation. Selectively permeable membranes increase the barrier to diffusion and often elicit a foreign body reaction including a fibrotic capsule that is not well vascularized. Therefore, approaches that aid in the rapid formation of a mature and robust vasculature in close proximity to the transplanted cells are crucial for successful islet transplantation or other cellular therapies. In this paper, we review various strategies to engineer vasculature for islet transplantation. We consider properties of materials (both synthetic and naturally derived), prevascularization, local release of proangiogenic factors, and co-transplantation of vascular cells that have all been harnessed to increase vasculature. We then discuss the various other challenges in engineering mature, long-term functional and clinically viable vasculature as well as some emerging technologies developed to address them. The benefits of physiological glucose control for patients and the healthcare system demand vigorous pursuit of solutions to cell transplant challenges. STATEMENT OF SIGNIFICANCE: Insulin-dependent diabetes affects more than 1.25 million people in the United States alone. Pancreatic islets secrete insulin and other endocrine hormones that control glucose to normal levels. During preparation for transplantation, the specialized islet blood vessel supply is lost. Furthermore, in the case of cell encapsulation, cells are protected within a device, further limiting delivery of nutrients and absorption of hormones. To overcome these issues, this review considers methods to rapidly vascularize sites and implants through material properties, pre-vascularization, delivery of growth factors, or co-transplantation of vessel supporting cells. Other challenges and emerging technologies are also discussed. Proper vascular growth is a significant component of successful islet transplantation, a treatment that can provide life-changing benefits to patients.
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Affiliation(s)
- Daniel T Bowers
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Wei Song
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Long-Hai Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA.
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Khan RS, Newsome PN. A Comparison of Phenotypic and Functional Properties of Mesenchymal Stromal Cells and Multipotent Adult Progenitor Cells. Front Immunol 2019; 10:1952. [PMID: 31555259 PMCID: PMC6724467 DOI: 10.3389/fimmu.2019.01952] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 08/02/2019] [Indexed: 12/15/2022] Open
Abstract
Both Multipotent Adult Progenitor Cells and Mesenchymal Stromal Cells are bone-marrow derived, non-haematopoietic adherent cells, that are well-known for having immunomodulatory and pro-angiogenic properties, whilst being relatively non-immunogenic. However, they are phenotypically and functionally distinct cell types, which has implications for their efficacy in different settings. In this review we compare the phenotypic and functional properties of these two cell types, to help in determining which would be the superior cell type for different applications.
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Affiliation(s)
- Reenam S Khan
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | - Philip N Newsome
- National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, Birmingham, United Kingdom.,Centre for Liver Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.,Liver Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
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40
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Arzouni AA, Vargas-Seymour A, Dhadda PK, Rackham CL, Huang GC, Choudhary P, King AJF, Jones PM. Characterization of the Effects of Mesenchymal Stromal Cells on Mouse and Human Islet Function. Stem Cells Transl Med 2019; 8:935-944. [PMID: 31066521 PMCID: PMC6708063 DOI: 10.1002/sctm.19-0023] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 04/13/2019] [Indexed: 12/19/2022] Open
Abstract
Islet transplantation has the potential to cure type 1 diabetes, but current transplantation protocols are not optimal and there is extensive loss of islet β‐cell insulin secretory function during the immediate post‐transplantation period. Studies using experimental models of diabetes have shown that the coculture of islets with mesenchymal stromal cells (MSCs) prior to transplantation improves graft function, but several variables differed among research groups (e.g., type of MSCs used and the treatment conditions). We have therefore assessed the effects of MSCs on mouse and human islets by investigating the importance of tissue source for MSCs, the coculture protocol configuration and length, the effect of activated MSCs, and different β‐cell secretory stimuli. MSCs derived from adipose tissue (aMSCs) were the most effective at supporting β‐cell insulin secretion in both mouse and human islets, in a direct contact coculture configuration. Preculture with aMSCs enhanced both phases of glucose‐induced insulin secretion and further enhanced secretory responses to the non‐nutrients carbachol and arginine. These effects required a coculture period of 48–72 hours and were not dependent on activation of the MSCs. Thus, direct contact coculture with autologous, adipose‐derived MSCs for a minimum of 48 hours before implantation is likely to be an effective addition to human islet transplantation protocols. stem cells translational medicine2019;8:935&944
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Affiliation(s)
- Ahmed A Arzouni
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Andreia Vargas-Seymour
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Paramjeet K Dhadda
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Chloe L Rackham
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Guo-Cai Huang
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Pratik Choudhary
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Aileen J F King
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Peter M Jones
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
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Wang J, Zhang Y, Cloud C, Duke T, Owczarski S, Mehrotra S, Adams DB, Morgan K, Gilkeson G, Wang H. Mesenchymal Stem Cells from Chronic Pancreatitis Patients Show Comparable Potency Compared to Cells from Healthy Donors. Stem Cells Transl Med 2019; 8:418-429. [PMID: 30680957 PMCID: PMC6477001 DOI: 10.1002/sctm.18-0093] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 11/07/2018] [Indexed: 12/27/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are proven to be beneficial in islet transplantation, suggesting a potential therapeutic role of them in total pancreatectomy with islet autotransplantation (TP-IAT) for chronic pancreatitis (CP) patients. We investigated whether MSCs derived from CP patients are suitable for use in autologous cell therapy. MSCs from healthy donors (H-MSCs) and CP patients (CP-MSCs) were studied for phenotype, colony formation potential, multilineage differentiation ability, proliferation, senescence, secretory characters, and immunosuppressive functions. The potential protective effect of CP-MSCs was evaluated on hypoxia-induced islet cell death. Cell surface markers were similar between H-MSCs and CP-MSCs, as well as the ability of colony formation, multilineage differentiation, secretion of vascular endothelial growth factor and transforming growth factor (TGF-β), senescence, and inhibition of T cells proliferation in vitro. We found that growth differentiation factor 6 and hepatocyte growth factor (HGF) were significantly downregulated, whereas TGFβ and matrix metalloproteinase-2 were significantly upregulated in CP-MSCs compared with H-MSCs, among 84 MSC-related genes investigated in this study. MSCs from CP patients secreted less HGF, compared with the H-MSCs. A higher interferon-γ-induced indoleamine 2,3-dioxygenase expression was observed in CP-MSCs compared to H-MSCs. Moreover, CP-MSCs prevented hypoxia-induced β cell deaths to a similar extent as H-MSCs. Regardless of moderate difference in gene expression, CP-MSCs possess similar immunomodulatory and prosurvival functions to H-MSCs, and may be suitable for autologous cell therapy in CP patients undergoing TP-IAT. Stem Cells Translational Medicine 2019;8:418-429.
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Affiliation(s)
- Jingjing Wang
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Yong Zhang
- College of Life ScienceQingdao Agricultural UniversityQingdaoPeople's Republic of China
| | - Colleen Cloud
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Tara Duke
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Stefanie Owczarski
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Shikhar Mehrotra
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - David B. Adams
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Katherine Morgan
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Gary Gilkeson
- Department of MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Hongjun Wang
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
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Iansante V, Chandrashekran A, Dhawan A. Cell-based liver therapies: past, present and future. Philos Trans R Soc Lond B Biol Sci 2019; 373:rstb.2017.0229. [PMID: 29786563 DOI: 10.1098/rstb.2017.0229] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/23/2017] [Indexed: 12/16/2022] Open
Abstract
Liver transplantation represents the standard treatment for people with an end-stage liver disease and some liver-based metabolic disorders; however, shortage of liver donor tissues limits its availability. Furthermore, whole liver replacement eliminates the possibility of using native liver as a possible target for future gene therapy in case of liver-based metabolic defects. Cell therapy has emerged as a potential alternative, as cells can provide the hepatic functions and engraft in the liver parenchyma. Various options have been proposed, including human or other species hepatocytes, hepatocyte-like cells derived from stem cells or more futuristic alternatives, such as combination therapies with different cell types, organoids and cell-biomaterial combinations. In this review, we aim to give an overview of the cell therapies developed so far, highlighting preclinical and/or clinical achievements as well as the limitations that need to be overcome to make them fully effective and safe for clinical applications.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'.
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Affiliation(s)
- Valeria Iansante
- Dhawan Lab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London at King's College Hospital, London SE5 9PJ, UK
| | - Anil Chandrashekran
- Dhawan Lab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London at King's College Hospital, London SE5 9PJ, UK
| | - Anil Dhawan
- Dhawan Lab, Paediatric Liver GI and Nutrition Center and MowatLabs, Institute of Liver Studies, King's College London at King's College Hospital, London SE5 9PJ, UK
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43
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Farina M, Alexander JF, Thekkedath U, Ferrari M, Grattoni A. Cell encapsulation: Overcoming barriers in cell transplantation in diabetes and beyond. Adv Drug Deliv Rev 2019; 139:92-115. [PMID: 29719210 DOI: 10.1016/j.addr.2018.04.018] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 03/19/2018] [Accepted: 04/25/2018] [Indexed: 02/07/2023]
Abstract
Cell-based therapy is emerging as a promising strategy for treating a wide range of human diseases, such as diabetes, blood disorders, acute liver failure, spinal cord injury, and several types of cancer. Pancreatic islets, blood cells, hepatocytes, and stem cells are among the many cell types currently used for this strategy. The encapsulation of these "therapeutic" cells is under intense investigation to not only prevent immune rejection but also provide a controlled and supportive environment so they can function effectively. Some of the advanced encapsulation systems provide active agents to the cells and enable a complete retrieval of the graft in the case of an adverse body reaction. Here, we review various encapsulation strategies developed in academic and industrial settings, including the state-of-the-art technologies in advanced preclinical phases as well as those undergoing clinical trials, and assess their advantages and challenges. We also emphasize the importance of stimulus-responsive encapsulated cell systems that provide a "smart and live" therapeutic delivery to overcome barriers in cell transplantation as well as their use in patients.
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44
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Päth G, Perakakis N, Mantzoros CS, Seufert J. Stem cells in the treatment of diabetes mellitus - Focus on mesenchymal stem cells. Metabolism 2019; 90:1-15. [PMID: 30342065 DOI: 10.1016/j.metabol.2018.10.005] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 09/25/2018] [Accepted: 10/14/2018] [Indexed: 12/14/2022]
Abstract
Diabetes mellitus type 1 and type 2 have become a global epidemic with dramatically increasing incidences. Poorly controlled diabetes is associated with severe life-threatening complications. Beside traditional treatment with insulin and oral anti-diabetic drugs, clinicians try to improve patient's care by cell therapies using embryonic stem cells (ESC), induced pluripotent stem cells (iPSC) and adult mesenchymal stem cells (MSC). ESC display a virtually unlimited plasticity, including the differentiation into insulin producing β-cells, but they raise ethical concerns and bear, like iPSC, the risk of tumours. IPSC may further inherit somatic mutations and remaining somatic transcriptional memory upon incomplete re-programming, but allow the generation of patient/disease-specific cell lines. MSC avoid such issues but have not been successfully differentiated into β-cells. Instead, MSC and their pericyte phenotypes outside the bone marrow have been recognized to secrete numerous immunomodulatory and tissue regenerative factors. On this account, the term 'medicinal signaling cells' has been proposed to define the new conception of a 'drug store' for injured tissues and to stay with the MSC nomenclature. This review presents the biological background and the resulting clinical potential and limitations of ESC, iPSC and MSC, and summarizes the current status quo of cell therapeutic concepts and trials.
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Affiliation(s)
- Günter Päth
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.
| | - Nikolaos Perakakis
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Jochen Seufert
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany
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45
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Abstract
In this chapter, we describe the history of transplantation, the multiple cell types, and mechanisms that are involved in rejection and tolerance of a transplanted organ, as well as summarize the common and promising new therapeutics used in transplant patients.
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Affiliation(s)
- Jessica Stolp
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Masaaki Zaitsu
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK
| | - Kathryn J Wood
- Transplantation Research Immunology Group, Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford, Oxford, UK.
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46
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Mehler VJ, Burns C, Moore ML. Concise Review: Exploring Immunomodulatory Features of Mesenchymal Stromal Cells in Humanized Mouse Models. Stem Cells 2018; 37:298-305. [PMID: 30395373 PMCID: PMC6446739 DOI: 10.1002/stem.2948] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 09/26/2018] [Accepted: 10/25/2018] [Indexed: 12/15/2022]
Abstract
With their immunosuppressive features, human mesenchymal stromal cells (MSCs), sometimes also termed as mesenchymal stem cells, hold great potential as a cell-based therapy for various immune-mediated diseases. Indeed, MSCs have already been approved as a treatment for graft versus host disease. However, contradictory data from clinical trials and lack of conclusive proof of efficacy hinder the progress toward wider clinical use of MSCs and highlight the need for more relevant disease models. Humanized mice are increasingly used as models to study immune-mediated disease, as they simulate human immunobiology more closely than conventional murine models. With further advances in their resemblance to human immunobiology, it is very likely that humanized mice will be used more commonly as models to investigate MSCs with regard to their therapeutic safety and their immunomodulatory effect and its underlying mechanisms. Recent studies that explore the immunosuppressive features of MSCs in humanized mouse models will be discussed in this review. Stem Cells 2019;37:298-305.
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Affiliation(s)
- Vera J Mehler
- Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, United Kingdom.,Division of Infection and Immunity, University College London, London, United Kingdom
| | - Chris Burns
- Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, United Kingdom
| | - Melanie L Moore
- Endocrinology Section, Biotherapeutics, National Institute for Biological Standards and Control, South Mimms, United Kingdom
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Gamble A, Pawlick R, Pepper AR, Bruni A, Adesida A, Senior PA, Korbutt GS, Shapiro AMJ. Improved islet recovery and efficacy through co-culture and co-transplantation of islets with human adipose-derived mesenchymal stem cells. PLoS One 2018; 13:e0206449. [PMID: 30419033 PMCID: PMC6231609 DOI: 10.1371/journal.pone.0206449] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 10/13/2018] [Indexed: 02/07/2023] Open
Abstract
Islet transplantation is an established clinical procedure for select patients with type 1 diabetes and severe hypoglycemia to stabilize glycemic control. Post-transplant, substantial beta cell mass is lost, necessitating multiple donors to maintain euglycemia. A potential strategy to augment islet engraftment is the co-transplantation of islets with multipotent mesenchymal stem cells to capitalize upon their pro-angiogenic and anti-inflammatory properties. Herein, we examine the in vitro and in vivo effect of co-culturing murine islets with human adipose-derived mesenchymal stem cells (Ad-MSCs). Islets co-cultured with Ad-MSCs for 48 hours had decreased cell death, superior viability as measured by membrane integrity, improved glucose stimulated insulin secretion and reduced apoptosis compared to control islets. These observations were recapitulated with human islets, albeit tested in a limited capacity. Recipients of marginal mouse islet mass grafts, co-transplanted with Ad-MSCs without a co-culture period, did not reverse to normoglycemia as efficiently as islets alone. However, utilizing a 48-hour co-culture period, marginal mouse islets grafts with Ad-MSCs achieved a superior percent euglycemia rate when compared to islets cultured and transplanted alone. A co-culture period of human islets with human Ad-MSCs may have a clinical benefit improving engraftment outcomes.
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Affiliation(s)
- Anissa Gamble
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, AB, Canada
| | - Rena Pawlick
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Andrew R. Pepper
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Antonio Bruni
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
| | - Adetola Adesida
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Peter A. Senior
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
| | - Gregory S. Korbutt
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - A. M. James Shapiro
- Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
- Members of the Canadian National Transplant Research Project (CNTRP), Edmonton, AB, Canada
- Clinical Islet Transplant Program, University of Alberta, Edmonton, AB, Canada
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
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Groot Nibbelink M, Skrzypek K, Karbaat L, Both S, Plass J, Klomphaar B, van Lente J, Henke S, Karperien M, Stamatialis D, van Apeldoorn A. An important step towards a prevascularized islet microencapsulation device: in vivo prevascularization by combination of mesenchymal stem cells on micropatterned membranes. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2018; 29:174. [PMID: 30413974 PMCID: PMC6244873 DOI: 10.1007/s10856-018-6178-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 10/17/2018] [Indexed: 06/08/2023]
Abstract
Extrahepatic transplantation of islets of Langerhans could aid in better survival of islets after transplantation. When islets are transfused into the liver 60-70% of them are lost immediately after transplantation. An important factor for a successful extrahepatic transplantation is a well-vascularized tissue surrounding the implant. There are many strategies known for enhancing vessel formation such as adding cells with endothelial potential, the combination with angiogenic factors and / or applying surface topography at the exposed surface of the device. Previously we developed porous, micropatterned membranes which can be applied as a lid for an islet encapsulation device and we showed that the surface topography induces human umbilical vein endothelial cell (HUVEC) alignment and interconnection. This was achieved without the addition of hydrogels, often used in angiogenesis assays. In this work, we went one step further towards clinical implementation of the device by combining this micropatterned lid with Mesenchymal Stem Cells (MSCs) to facilitate prevascularization in vivo. As for HUVECs, the micropatterned membranes induced MSC alignment and organization in vitro, an important contributor to vessel formation, whereas in vivo (subcutaneous rat model) they contributed to improved implant prevascularization. In fact, the combination of MSCs seeded on the micropatterned membrane induced the highest vessel formation score in 80% of the sections.
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Affiliation(s)
- Milou Groot Nibbelink
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands.
| | - Katarzyna Skrzypek
- (Bio)artificial organs. Department of Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine University of Twente, Maastricht, The Netherlands
| | - Lisanne Karbaat
- (Bio)artificial organs. Department of Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine University of Twente, Maastricht, The Netherlands
| | - Sanne Both
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Jacqueline Plass
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Bettie Klomphaar
- Biomedical Signals and Systems, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Jéré van Lente
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Sieger Henke
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Marcel Karperien
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
| | - Dimitrios Stamatialis
- (Bio)artificial organs. Department of Biomaterials Science and Technology, MIRA Institute of Biomedical Technology and Technical Medicine University of Twente, Maastricht, The Netherlands
| | - Aart van Apeldoorn
- Developmental BioEngineering, MIRA Institute of Biomedical Technology and Technical Medicine, University of Twente, Maastricht, The Netherlands
- Complex Tissue Regeneration, MERLN Institute for Technology Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
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49
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Mesenchymal stem cells in combination with low-dose rapamycin significantly prolong islet allograft survival through induction of regulatory T cells. Biochem Biophys Res Commun 2018; 506:619-625. [DOI: 10.1016/j.bbrc.2018.10.070] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 10/11/2018] [Indexed: 12/13/2022]
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50
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Perez-Basterrechea M, Esteban MM, Vega JA, Obaya AJ. Tissue-engineering approaches in pancreatic islet transplantation. Biotechnol Bioeng 2018; 115:3009-3029. [PMID: 30144310 DOI: 10.1002/bit.26821] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 08/08/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Pancreatic islet transplantation is a promising alternative to whole-pancreas transplantation as a treatment of type 1 diabetes mellitus. This technique has been extensively developed during the past few years, with the main purpose of minimizing the complications arising from the standard protocols used in organ transplantation. By using a variety of strategies used in tissue engineering and regenerative medicine, pancreatic islets have been successfully introduced in host patients with different outcomes in terms of islet survival and functionality, as well as the desired normoglycemic control. Here, we describe and discuss those strategies to transplant islets together with different scaffolds, in combination with various cell types and diffusible factors, and always with the aim of reducing host immune response and achieving islet survival, regardless of the site of transplantation.
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Affiliation(s)
- Marcos Perez-Basterrechea
- Unidad de Terapia Celular y Medicina Regenerativa, Servicio de Hematología y Hemoterapia, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.,Plataforma de Terapias Avanzadas, Instituto de Investigación Biosanitaria del Principado de Asturias (ISPA), Oviedo, Spain
| | - Manuel M Esteban
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
| | - Jose A Vega
- Departamento de Morfología y Biología Celular, Universidad de Oviedo, Oviedo, Spain.,Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile
| | - Alvaro J Obaya
- Departamento de Biología Funcional, Universidad de Oviedo, Oviedo, Spain
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