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Pinheiro-Machado E, de Haan BJ, Engelse MA, Smink AM. Secretome Analysis of Human and Rat Pancreatic Islets Co-Cultured with Adipose-Derived Stromal Cells Reveals a Signature with Enhanced Regenerative Capacities. Cells 2025; 14:302. [PMID: 39996773 PMCID: PMC11854805 DOI: 10.3390/cells14040302] [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: 12/02/2024] [Revised: 02/06/2025] [Accepted: 02/14/2025] [Indexed: 02/26/2025] Open
Abstract
Pancreatic islet transplantation (PIT) is a promising treatment for type 1 diabetes (T1D) but faces challenges pre- and post-transplantation. Co-transplantation with mesenchymal stromal cells (MSCs), known for their regenerative properties, has shown potential in improving PIT outcomes. This study examined the secretome of islets cultured alone compared to the secretomes of islets co-cultured with adipose-derived stromal cells (ASCs), a subtype of MSCs, under transplantation-relevant stressors: normoxia, cytokines, high glucose, hypoxia, and combined hypoxia and high glucose. Islet co-culture with ASCs significantly altered the proteome, affecting pathways related to energy metabolism, angiogenesis, extracellular matrix organization, and immune modulation. Key signaling molecules (e.g., VEGF, PDGF, bFGF, Collagen I alpha 1, IL-1α, and IL-10) were differentially regulated depending on culture conditions and ASC presence. Functional assays demonstrated that the co-culture secretome could enhance angiogenesis, collagen deposition, and immune modulation, depending on the stress conditions. These findings highlight possible mechanisms through which ASCs may support islet survival and function, offering insights into overcoming PIT challenges. Moreover, this work contributes to identifying biomarkers of the post-transplantation microenvironment, advancing therapeutic strategies for T1D and regenerative medicine.
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Affiliation(s)
- Erika Pinheiro-Machado
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Bart J. de Haan
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Marten A. Engelse
- Leiden Transplant Center, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Alexandra M. Smink
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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2
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Zhou JX, Jie-Zhou, Jin WR, Li JY, Zhang XC, Zhao CY, Lin YY, Wang XY, Yan LF, Kai-Yan, Liu QW. Human amniotic mesenchymal stem cell-islet organoids enhance the efficiency of islet engraftment in a mouse diabetes model. Life Sci 2024; 351:122812. [PMID: 38862063 DOI: 10.1016/j.lfs.2024.122812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 05/10/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024]
Abstract
AIMS Despite islet transplantation has proved a great potential to become the standard therapy for type 1 diabetes mellitus (T1DM), this approach remains limited by ischemia, hypoxia, and poor revascularization in early post-transplant period as well as inflammation and life-long host immune rejection. Here, we investigate the potential and mechanism of human amniotic mesenchymal stem cells (hAMSCs)-islet organoid to improve the efficiency of islet engraftment in immunocompetent T1DM mice. MAIN METHODS We generated the hAMSC-islet organoid structure through culturing the mixture of hAMSCs and islets on 3-dimensional-agarose microwells. Flow cytometry, whole-body fluorescent imaging, immunofluorescence, Calcein-AM/PI staining, ELISA, and qPCR were used to assess the potential and mechanism of shielding hAMSCs to improve the efficiency of islet transplantation. KEY FINDINGS Transplant of hAMSC-islet organoids results in remarkably better glycemic control, an enhanced glucose tolerance, and a higher β cell mass in vivo compared with control islets. Our results show that hAMSCs shielding provides an immune privileged microenvironment for islets and promotes graft revascularization in vivo. In addition, hAMSC-islet organoids show higher viability and reduced dysfunction after exposure to hypoxia and inflammatory cytokines in vitro. Finally, our results show that shielding with hAMSCs leads to the activation of PKA-CREB-IRS2-PI3K and PKA-PDX1 signaling pathways, up-regulation of SIL1 mRNA levels, and down-regulation of MT1 mRNA levels in β cells, which ultimately promotes the synthesis, folding and secretion of insulin, respectively. SIGNIFICANCE hAMSC-islet organoids can evidently increase the efficiency of islet engraftment and might develop into a promising alternative for the clinical treatment of T1DM.
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Affiliation(s)
- Jia-Xin Zhou
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China; Institute of Organoid Technology, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China
| | - Jie-Zhou
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China
| | - Wei-Ran Jin
- Huankui Academy, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China
| | - Jing-Yuan Li
- Normal College, East China University of Technology, Nanchang 330013, PR China
| | - Xiang-Cheng Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, PR China
| | - Chu-Yu Zhao
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China
| | - Ya-Yi Lin
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China; Institute of Organoid Technology, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China
| | - Xi-Yan Wang
- Institute of Organoid Technology, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China; School of Pharmacy, Jiangxi Medical College, Nanchang University, Nanchang 330006, PR China
| | - Ling-Fei Yan
- Department of Pathology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, PR China
| | - Kai-Yan
- Department of Pediatrics, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang 330006, PR China
| | - Quan-Wen Liu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China; Institute of Organoid Technology, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China; The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang 330031, PR China.
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Annicchiarico A, Barile B, Buccoliero C, Nicchia GP, Brunetti G. Alternative therapeutic strategies in diabetes management. World J Diabetes 2024; 15:1142-1161. [PMID: 38983831 PMCID: PMC11229975 DOI: 10.4239/wjd.v15.i6.1142] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/17/2024] [Accepted: 04/12/2024] [Indexed: 06/11/2024] Open
Abstract
Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreatic β cells, insulin resistance in peripheral tissues, or both, and results in a non-sufficient production of insulin. To adjust blood glucose levels, diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity. With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities, different strategies have been investigated. The first approaches included enhancing endogenous β cell activity or transplanting new islets. The protocol for this kind of intervention has recently been optimized, leading to standardized procedures. It is indicated for diabetic patients with severe hypoglycemia, complicated by impaired hypoglycemia awareness or exacerbated glycemic lability. Transplantation has been associated with improvement in all comorbidities associated with diabetes, quality of life, and survival. However, different trials are ongoing to further improve the beneficial effects of transplantation. Furthermore, to overcome some limitations associated with the availability of islets/pancreas, alternative therapeutic strategies are under evaluation, such as the use of mesenchymal stem cells (MSCs) or induced pluripotent stem cells for transplantation. The cotransplantation of MSCs with islets has been successful, thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms, including exosome release. The use of induced pluripotent stem cells is recent and requires further investigation. The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities, such as wound healing. Despite the number of advantages of the direct injection of MSCs, new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results. In conclusion, this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.
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Affiliation(s)
- Alessia Annicchiarico
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Barbara Barile
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Cinzia Buccoliero
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Grazia Paola Nicchia
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
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Wang Q, Huang YX, Liu L, Zhao XH, Sun Y, Mao X, Li SW. Pancreatic islet transplantation: current advances and challenges. Front Immunol 2024; 15:1391504. [PMID: 38887292 PMCID: PMC11180903 DOI: 10.3389/fimmu.2024.1391504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 05/20/2024] [Indexed: 06/20/2024] Open
Abstract
Diabetes is a prevalent chronic disease that traditionally requires severe reliance on medication for treatment. Oral medication and exogenous insulin can only temporarily maintain blood glucose levels and do not cure the disease. Most patients need life-long injections of exogenous insulin. In recent years, advances in islet transplantation have significantly advanced the treatment of diabetes, allowing patients to discontinue exogenous insulin and avoid complications.Long-term follow-up results from recent reports on islet transplantation suggest that they provide significant therapeutic benefit although patients still require immunotherapy, suggesting the importance of future transplantation strategies. Although organ shortage remains the primary obstacle for the development of islet transplantation, new sources of islet cells, such as stem cells and porcine islet cells, have been proposed, and are gradually being incorporated into clinical research. Further research on new transplantation sites, such as the subcutaneous space and mesenteric fat, may eventually replace the traditional portal vein intra-islet cell infusion. Additionally, the immunological rejection reaction in islet transplantation will be resolved through the combined application of immunosuppressant agents, islet encapsulation technology, and the most promising mesenchymal stem cells/regulatory T cell and islet cell combined transplantation cell therapy. This review summarizes the progress achieved in islet transplantation, and discusses the research progress and potential solutions to the challenges faced.
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Affiliation(s)
- Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yu-xi Huang
- Department of Hepatobiliary and Pancreatic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Long Liu
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao-hong Zhao
- Department of Pharmacy, Taizhou Hospital, Zhejiang University, Taizhou, Zhejiang, China
| | - Yi Sun
- MRL Global Medical Affairs, MSD China, Shanghai, China
| | - Xinli Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shao-wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
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5
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Hong T, Caxaria S, Daniels Gatward LF, Hussain S, Zhao M, King AJF, Rackham CL, Jones PM. Mesenchymal stromal cell secretory molecules improve the functional survival of human islets. Diabet Med 2023; 40:e15227. [PMID: 37728506 PMCID: PMC10915897 DOI: 10.1111/dme.15227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 09/04/2023] [Accepted: 09/05/2023] [Indexed: 09/21/2023]
Abstract
AIMS Human islet transplantation as a therapy for type 1 diabetes is compromised by the loss of functional beta cells in the immediate post-transplantation period. Mesenchymal stromal cells (MSCs) and MSC-derived secretory peptides improve the outcomes of islet transplantation in rodent models of diabetes. Here, we utilized a mouse model for human islet transplantation and assessed the effects of a cocktail of MSC-secreted peptides (screened by MSC-secretome for human islet GPCRs) on the functional survival of human islets. METHODS Human islets from nine donors (Age: 36-57; BMI: 20-35) were treated with a cocktail of human recombinant annexin A1 (ANXA1), stromal cell-derived factor-1 (SDF-1/CXCL12) and complement component C3 (C3a). Glucose-stimulated insulin secretion (GSIS) was assessed in static incubation, and cytokine-induced apoptosis was assessed by measuring caspase 3/7 activity. mRNA expression levels were determined by qPCR. Human islet function in vivo was assessed using a novel model for human islet transplantation into a T1D mouse model. Human islet function in vivo was assessed using islet transplantation under the kidney capsule of immunodeficient mice prior to STZ destruction of endogenous mouse beta cells to model T1DM. RESULTS Pretreatment with a cocktail of MSC-secreted peptides increased GSIS in vitro and protected against cytokine-induced apoptosis in human islets isolated from nine donors. Animals transplanted with either treated or untreated human islets remained normoglycaemic for up to 28 days after STZ-administration to ablate the endogenous mouse beta cells, whereas non-transplanted animals showed significantly increased blood glucose immediately after STZ administration. Removal of the human islet graft by nephrectomy resulted in rapid increases in blood glucose to similar levels as the non-transplanted controls. Pretreating human islets with the MSC-derived cocktail significantly improved glucose tolerance in graft recipients, consistent with enhanced functional survival of the treated islets in vivo. CONCLUSION Pretreating human islets before transplantation with a defined cocktail of MSC-derived molecules could be employed to improve the quality of human islets for transplantation therapy for type 1 diabetes.
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Affiliation(s)
- Tzu‐Wen Hong
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine and SciencesKing's College LondonLondonUK
| | - Sara Caxaria
- William Harvey Research Institute, Barts and the London School of MedicineQueen Mary University of LondonLondonUK
| | - Lydia F. Daniels Gatward
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine and SciencesKing's College LondonLondonUK
| | - Sufyan Hussain
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine and SciencesKing's College LondonLondonUK
- Department of Diabetes and Endocrinology, Guy's and St Thomas' NHS Foundation TrustLondonUK
| | - Min Zhao
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine and SciencesKing's College LondonLondonUK
| | - Aileen J. F. King
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine and SciencesKing's College LondonLondonUK
| | - Chloe L. Rackham
- Exeter Centre for Excellence in Diabetes, Institute of Biomedical and Clinical ScienceUniversity of ExeterExeterUK
| | - Peter M. Jones
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine and SciencesKing's College LondonLondonUK
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6
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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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7
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Doherty DT, Khambalia HA, van Dellen D, Jennings RE, Piper Hanley K. Unlocking the post-transplant microenvironment for successful islet function and survival. Front Endocrinol (Lausanne) 2023; 14:1250126. [PMID: 37711891 PMCID: PMC10497759 DOI: 10.3389/fendo.2023.1250126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 08/07/2023] [Indexed: 09/16/2023] Open
Abstract
Islet transplantation (IT) offers the potential to restore euglycemia for patients with type 1 diabetes mellitus (T1DM). Despite improvements in islet isolation techniques and immunosuppressive regimes, outcomes remain suboptimal with UK five-year graft survivals (5YGS) of 55% and most patients still requiring exogenous insulin after multiple islet infusions. Native islets have a significant non-endocrine component with dense extra-cellular matrix (ECM), important for islet development, cell survival and function. Collagenase isolation necessarily disrupts this complex islet microenvironment, leaving islets devoid of a supporting framework and increasing vulnerability of transplanted islets. Following portal venous transplantation, a liver injury response is potentially induced, which typically results in inflammation and ECM deposition from liver specific myofibroblasts. The impact of this response may have important impact on islet survival and function. A fibroblast response and ECM deposition at the kidney capsule and eye chamber alongside other implantation sites have been shown to be beneficial for survival and function. Investigating the implantation site microenvironment and the interactions of transplanted islets with ECM proteins may reveal therapeutic interventions to improve IT and stem-cell derived beta-cell therapy.
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Affiliation(s)
- Daniel T. Doherty
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Hussein A. Khambalia
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - David van Dellen
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Renal & Pancreatic Transplantation, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Rachel E. Jennings
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
- Department of Endocrinology, Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Karen Piper Hanley
- Faculty of Biology, Medicine & Health, University of Manchester, Manchester, United Kingdom
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Converti A, Bianchi MS, Martinez MD, Montaner AD, Lux‐Lantos V, Bonaventura MM. IMT504 protects beta cells against apoptosis and maintains beta cell identity, without modifying proliferation. Physiol Rep 2023; 11:e15790. [PMID: 37568265 PMCID: PMC10421975 DOI: 10.14814/phy2.15790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 07/26/2023] [Accepted: 07/28/2023] [Indexed: 08/13/2023] Open
Abstract
We have demonstrated that oligodeoxynucleotide IMT504 promotes significant improvement in the diabetic condition in diverse animal models. Based on these results, here we evaluated whether these effects observed in vivo could be due to direct effects on β-cells. We demonstrate by immunofluorescence that IMT504 enters the cell and locates in cytoplasm where it induces GSK-3β phosphorylation that inactivates this kinase. As GSK-3β tags Pdx1 for proteasomal degradation, by inactivating GSK-3β, IMT504 induces an increase in Pdx1 protein levels, demonstrated by Western blotting. Concomitantly, an increase in Ins2 and Pdx1 gene transcription was observed, with no significant increase in insulin content or secretion. Enhanced Pdx1 is promising since it is a key transcription factor for insulin synthesis and is also described as an essential factor for the maintenance β-cell phenotype and function. Dose-dependent inhibition of H2 O2 -induced apoptosis determined by ELISA as well as decreased expression of Bax was also observed. These results were confirmed in another β-cell line, beta-TC-6 cells, in which a cytokine mix induced apoptosis that was reversed by IMT504. In addition, an inhibitor of IMT504 entrance into cells abrogated the effect IMT504. Based on these results we conclude that the β-cell recovery observed in vivo may include direct effects of IMT504 on β-cells, by maintaining their identity/phenotype and protecting them from oxidative stress and cytokine-induced apoptosis. Thus, this work positions IMT504 as a promising option in the framework of the search of new therapies for type I diabetes treatment.
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Affiliation(s)
- Ayelén Converti
- Instituto de Biología y Medicina Experimental (IBYME‐CONICET)Buenos AiresArgentina
| | - María Silvia Bianchi
- Instituto de Biología y Medicina Experimental (IBYME‐CONICET)Buenos AiresArgentina
| | - Mario D. Martinez
- CONICET‐Universidad de Buenos Aires, UMYMFORBuenos AiresArgentina
- Departamento de Química Orgánica, Facultad de Ciencias Exactas y NaturalesUniversidad de Buenos AiresBuenos AiresArgentina
| | | | - Victoria Lux‐Lantos
- Instituto de Biología y Medicina Experimental (IBYME‐CONICET)Buenos AiresArgentina
| | - María Marta Bonaventura
- Instituto de Biología y Medicina Experimental (IBYME‐CONICET)Buenos AiresArgentina
- Universidad Nacional de San Martin (UNSAM), ECyTBuenos AiresArgentina
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9
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Kabakchieva P, Assyov Y, Gerasoudis S, Vasilev G, Peshevska-Sekulovska M, Sekulovski M, Lazova S, Miteva DG, Gulinac M, Tomov L, Velikova T. Islet transplantation-immunological challenges and current perspectives. World J Transplant 2023; 13:107-121. [PMID: 37388389 PMCID: PMC10303418 DOI: 10.5500/wjt.v13.i4.107] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 05/16/2023] [Accepted: 06/06/2023] [Indexed: 06/16/2023] Open
Abstract
Pancreatic islet transplantation is a minimally invasive procedure aiming to reverse the effects of insulin deficiency in patients with type 1 diabetes (T1D) by transplanting pancreatic beta cells. Overall, pancreatic islet transplantation has improved to a great extent, and cellular replacement will likely become the mainstay treatment. We review pancreatic islet transplantation as a treatment for T1D and the immunological challenges faced. Published data demonstrated that the time for islet cell transfusion varied between 2 and 10 h. Approximately 54% of the patients gained insulin independence at the end of the first year, while only 20% remained insulin-free at the end of the second year. Eventually, most transplanted patients return to using some form of exogenous insulin within a few years after the transplantation, which imposed the need to improve immunological factors before transplantation. We also discuss the immunosuppressive regimens, apoptotic donor lymphocytes, anti-TIM-1 antibodies, mixed chimerism-based tolerance induction, induction of antigen-specific tolerance utilizing ethylene carbodiimide-fixed splenocytes, pretransplant infusions of donor apoptotic cells, B cell depletion, preconditioning of isolated islets, inducing local immunotolerance, cell encapsulation and immunoisolation, using of biomaterials, immunomodulatory cells, etc.
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Affiliation(s)
- Plamena Kabakchieva
- Clinic of Internal Diseases, Naval Hospital-Varna, Military Medical Academy, Varna 9010, Bulgaria
| | - Yavor Assyov
- Clinic of Endocrinology, Department of Internal Diseases, University Hospital "Alexandrovska", Medical University-Sofia, Sofia 1434, Bulgaria
| | | | - Georgi Vasilev
- Department of Neurology, Faculty of Medicine, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
| | - Monika Peshevska-Sekulovska
- Department of Gastroenterology, University Hospital Lozenetz, Sofia 1407, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
| | - Metodija Sekulovski
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
- Department of Anesthesiology and Intensive Care, University hospital Lozenetz, Sofia 1407, Bulgaria
| | - Snezhina Lazova
- Department of Pediatric, University Hospital "N. I. Pirogov", Sofia 1606, Bulgaria
- Department of Healthcare, Faculty of Public Health "Prof. Tsekomir Vodenicharov, MD, DSc", Medical University of Sofia, Sofia 1527, Bulgaria
| | | | - Milena Gulinac
- Department of General and Clinical Pathology, Medical University of Plovdiv, Plovdiv 4000, Bulgaria
| | - Latchezar Tomov
- Department of Informatics, New Bulgarian University, Sofia 1618, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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10
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Zhang J, Zheng Y, Huang L, He J. Research Progress on Mesenchymal Stem Cells for the Treatment of Diabetes and Its Complications. Int J Endocrinol 2023; 2023:9324270. [PMID: 37143697 PMCID: PMC10151724 DOI: 10.1155/2023/9324270] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 01/22/2023] [Accepted: 04/18/2023] [Indexed: 05/06/2023] Open
Abstract
Diabetes mellitus (DM) is a chronic disease that threatens human health. Although many drugs are available to treat DM, various complications caused by DM are unavoidable. As an emerging treatment for DM, mesenchymal stem cells (MSCs) have shown many advantages and are gradually gaining public attention. This review summarizes the clinical studies on the use of MSCs to treat DM and the potential mechanisms of complications such as pancreatic dysfunction, cardiovascular lesions, renal lesions, neurological lesions, and trauma repair. This review focuses on the research progress on MSC-mediated secretion of cytokines, improvements in the microenvironment, repair of tissue morphology, and related signaling pathways. At present, the sample sizes in clinical studies of MSCs in treating DM are small, and there is a lack of standardized quality control systems in the preparation, transportation, and infusion methods, so we need to conduct more in-depth studies. In conclusion, MSCs have shown superior potential for use in the treatment of DM and its complications and will hopefully become a novel therapeutic approach in the future.
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Affiliation(s)
- Jiarui Zhang
- Medical School, Kunming University of Science and Technology, No. 727 Jingming South Road, Kunming 650000, Yunnan, China
| | - Yongqin Zheng
- Department of Endocrinology and Metabolism, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jingbi Road, Kunming 650000, Yunnan, China
| | - Lichenlu Huang
- Medical School, Kunming University of Science and Technology, No. 727 Jingming South Road, Kunming 650000, Yunnan, China
| | - Jundong He
- Medical School, Kunming University of Science and Technology, No. 727 Jingming South Road, Kunming 650000, Yunnan, China
- Department of Endocrinology and Metabolism, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jingbi Road, Kunming 650000, Yunnan, China
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11
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Navarro Chica CE, Qin T, Pinheiro-Machado E, de Haan BJ, Faas M, Smink AM, Sierra L, López BL, de Vos P. Species-dependent impact of immunosuppressive squalene-gusperimus nanoparticles and adipose-derived stem cells on isolated human and rat pancreatic islets. Islets 2022; 14:164-183. [PMID: 35838041 PMCID: PMC9291694 DOI: 10.1080/19382014.2022.2100191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Transplantation of pancreatic islets is a promising approach to controlling glucose levels in type 1 diabetes mellitus (T1DM), but islet survival is still limited. To overcome this, islet co-culture with mesenchymal stromal cells (MSCs) together with safe immunosuppressive agents like squalene-gusperimus nanoparticles (Sq-GusNPs) may be applied. This could support islet survival and engraftment. Here, we studied how Sq-GusNPs and adipose-derived stem cells (ASCs) influence islets response under pro-inflammatory conditions. Through qRT-PCR, we studied the expression of specific genes at 24 hours in human and rat islets and ASCs in co-culture under indirect contact with or without treatment with Sq-GusNPs. We characterized how the response of islets and ASCs starts at molecular level before impaired viability or function is observed and how this response differs between species. Human islets and ASCs responses showed to be principally influenced by NF-κB activation, whereas rat islet and ASCs responses showed to be principally mediated by nitrosative stress. Rat islets showed tolerance to inflammatory conditions due to IL-1Ra secretion which was also observed in rat ASCs. Human islets induced the expression of cytokines and chemokines with pro-angiogenic, tissue repair, and anti-apoptotic properties in human ASCs under basal conditions. This expression was not inhibited by Sq-GusNPs. Our results showed a clear difference in the response elicited by human and rat islets and ASCs in front of an inflammatory stimulus and Sq-GusNPs. Our data support the use of ASCs and Sq-GusNP to facilitate engraftment of islets for T1DM treatment.
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Affiliation(s)
- Carlos E. Navarro Chica
- Department of Pathology and Medical Biology, Section of Immunoendocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
- Grupo de Investigación Ciencia de los Materiales, Instituto de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, Colombia
- CONTACT Carlos E. Navarro Chica Pathology and Medical Biology, Section of Immunoendocrinology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, EA11, 9713 GZGroningen, the Netherlands
| | - Tian Qin
- Department of Pathology and Medical Biology, Section of Immunoendocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Erika Pinheiro-Machado
- Department of Pathology and Medical Biology, Section of Immunoendocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Bart J. de Haan
- Department of Pathology and Medical Biology, Section of Immunoendocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - M.M. Faas
- Department of Pathology and Medical Biology, Section of Immunoendocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Alexandra M. Smink
- Department of Pathology and Medical Biology, Section of Immunoendocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Ligia Sierra
- Grupo de Investigación Ciencia de los Materiales, Instituto de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, Colombia
| | - Betty L. López
- Grupo de Investigación Ciencia de los Materiales, Instituto de Química, Facultad de Ciencias Exactas y Naturales, Universidad de Antioquia, Medellín, Colombia
| | - Paul de Vos
- Department of Pathology and Medical Biology, Section of Immunoendocrinology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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12
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Wang J, Wang J, Wang Y, Ma R, Zhang S, Zheng J, Xue W, Ding X. Bone Marrow Mesenchymal Stem Cells-Derived miR-21-5p Protects Grafted Islets Against Apoptosis by Targeting PDCD4. Stem Cells 2022; 41:169-183. [PMID: 36512434 PMCID: PMC9982070 DOI: 10.1093/stmcls/sxac085] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 12/01/2022] [Indexed: 12/15/2022]
Abstract
The apoptosis of grafted islets is an urgent problem due to the high rate of islet loss soon after transplantation. MicroRNA-21-5p (miR-21-5p) is an essential mediator of bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exo) during anti-apoptosis, but its effect and the underlying molecular mechanism in islet transplantation remain partially understood. Here, we found that miR-21-5p could be delivered to islet cells via BMSCs-Exo. Subsequently, we demonstrated that miR-21-5p overexpression reduced apoptosis in islets and INS-1 cells, whereas miR-21-5p inhibition enhanced apoptosis. A mechanistic analysis involving RNA sequencing and bioinformatic analysis was performed to determine the interaction between miR-21-5p and its target gene programmed cell death 4 (PDCD4), which was further verified by a dual luciferase assay. In vivo, the grafted islets overexpressing miR-21-5p showed a higher survival rate, better insulin secretion function, and a lower apoptosis rate. In conclusion, these results demonstrated that miR‑21‑5p from BMSCs-Exo protects against the apoptosis of grafted islets by inhibiting PDCD4 expression. Hence, miR-21-5p can be used as a cell-free therapeutic agent to minimize β-cell apoptosis at the early stage of islet 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 Province, People’s Republic of China
| | - Ruiyang 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 Province, People’s Republic of China
| | - Shucong 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 Province, People’s Republic of 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 Province, People’s Republic of China
| | - Wujun 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 Province, People’s Republic of China
| | - Xiaoming Ding
- Corresponding author: Xiaoming 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 Province, People’s Republic of China. Tel: +8613991238632; E-mail:
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13
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Bolla AM, Montefusco L, Pastore I, Lunati ME, Ben Nasr M, Fiorina P. Benefits and Hurdles of Pancreatic β-Cell Replacement. Stem Cells Transl Med 2022; 11:1029-1039. [PMID: 36073717 PMCID: PMC9585952 DOI: 10.1093/stcltm/szac058] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/02/2022] [Indexed: 11/13/2022] Open
Abstract
Insulin represents a life-saving treatment in patients with type 1 diabetes, and technological advancements have improved glucose control in an increasing number of patients. Despite this, adequate control is often still difficult to achieve and insulin remains a therapy and not a cure for the disease. β-cell replacement strategies can potentially restore pancreas endocrine function and aim to maintain normoglycemia; both pancreas and islet transplantation have greatly progressed over the last decades and, in subjects with extreme glycemic variability and diabetes complications, represent a concrete and effective treatment option. Some issues still limit the adoption of this approach on a larger scale. One is represented by the strict selection criteria for the recipient who can benefit from a transplant and maintain the lifelong immunosuppression necessary to avoid organ rejection. Second, with regard to islet transplantation, up to 40% of islets can be lost during hepatic engraftment. Recent studies showed very preliminarily but promising results to overcome these hurdles: the ability to induce β-cell maturation from stem cells may represent a solution to the organ shortage, and the creation of semi-permeable membranes that envelope or package cells in either micro- or macro- encapsulation strategies, together with engineering cells to be hypo-immunogenic, pave the way for developing strategies without immunosuppression. The aim of this review is to describe the state of the art in β-cell replacement with a focus on its efficacy and clinical benefits, on the actual limitations and still unmet needs, and on the latest findings and future directions.
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Affiliation(s)
| | - Laura Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy.,International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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14
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Azizi Z, Abbaszadeh R, Sahebnasagh R, Norouzy A, Motevaseli E, Maedler K. Bone marrow mesenchymal stromal cells for diabetes therapy: touch, fuse, and fix? Stem Cell Res Ther 2022; 13:348. [PMID: 35883121 PMCID: PMC9327419 DOI: 10.1186/s13287-022-03028-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/04/2022] [Indexed: 12/26/2022] Open
Abstract
Bone marrow mesenchymal stromal cells (BM-MSCs) have anti-inflammatory and pro-survival properties. Naturally, they do not express human leukocyte antigen class II surface antigens and have immunosuppressive capabilities. Together with their relatively easy accessibility and expansion, they are an attractive tool for organ support in transplantation and regenerative therapy. Autologous BM-MSC transplantation alone or together with transplanted islets improves β-cell function, graft survival, and glycemic control in diabetes. Albeit MSCs’ capacity to transdifferentiate into β-cell is limited, their protective effects are mediated mainly by paracrine mechanisms through BM-MSCs circulating through the body. Direct cell–cell contact and spontaneous fusion of BM-MSCs with injured cells, although at a very low rate, are further mechanisms of their supportive effect and for tissue regeneration. Diabetes is a disease of long-term chronic inflammation and cell therapy requires stable, highly functional cells. Several tools and protocols have been developed by mimicking natural fusion events to induce and accelerate fusion in vitro to promote β-cell-specific gene expression in fused cells. BM-MSC-islet fusion before transplantation may be a strategy for long-term islet survival and improved function. This review discusses the cell-protective and anti-inflammatory characteristics of BM-MSCs to boost highly functional insulin-producing cells in vitro and in vivo, and the efficacy of their fusion with β-cells as a path to promote β-cell regeneration.
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Affiliation(s)
- Zahra Azizi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, No. 88, Italia St, Keshavarz Blvd., Tehran, Iran.
| | - Roya Abbaszadeh
- Department of Biology, Philipps-University Marburg, Marburg, Germany
| | - Roxana Sahebnasagh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, No. 88, Italia St, Keshavarz Blvd., Tehran, Iran
| | - Amir Norouzy
- Department of Energy & Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Elahe Motevaseli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, No. 88, Italia St, Keshavarz Blvd., Tehran, Iran
| | - Kathrin Maedler
- Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen, University of Bremen,, Leobener Straße 5, NW2, 28359, Bremen, Germany.
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15
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Shi Y, Zhao YZ, Jiang Z, Wang Z, Wang Q, Kou L, Yao Q. Immune-Protective Formulations and Process Strategies for Improved Survival and Function of Transplanted Islets. Front Immunol 2022; 13:923241. [PMID: 35903090 PMCID: PMC9315421 DOI: 10.3389/fimmu.2022.923241] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/13/2022] [Indexed: 11/25/2022] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by the immune system attacking and destroying insulin-producing β cells in the pancreas. Islet transplantation is becoming one of the most promising therapies for T1D patients. However, its clinical use is limited by substantial cell loss after islet infusion, closely related to immune reactions, including instant blood-mediated inflammatory responses, oxidative stress, and direct autoimmune attack. Especially the grafted islets are not only exposed to allogeneic immune rejection after transplantation but are also subjected to an autoimmune process that caused the original disease. Due to the development and convergence of expertise in biomaterials, nanotechnology, and immunology, protective strategies are being investigated to address this issue, including exploring novel immune protective agents, encapsulating islets with biomaterials, and searching for alternative implantation sites, or co-transplantation with functional cells. These methods have significantly increased the survival rate and function of the transplanted islets. However, most studies are still limited to animal experiments and need further studies. In this review, we introduced the immunological challenges for islet graft and summarized the recent developments in immune-protective strategies to improve the outcomes of islet transplantation.
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Affiliation(s)
- Yannan Shi
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Ying-Zheng Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Zhikai Jiang
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zeqing Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Qian Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Longfa Kou
- The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- *Correspondence: Qing Yao, ; Longfa Kou,
| | - Qing Yao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
- *Correspondence: Qing Yao, ; Longfa Kou,
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16
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Yan S, Ye P, Aleem MT, Chen X, Xie N, Zhang Y. Mesenchymal Stem Cells Overexpressing ACE2 Favorably Ameliorate LPS-Induced Inflammatory Injury in Mammary Epithelial Cells. Front Immunol 2022; 12:796744. [PMID: 35095873 PMCID: PMC8795506 DOI: 10.3389/fimmu.2021.796744] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 12/22/2021] [Indexed: 01/15/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are capable of homing injury sites to exert anti-inflammatory as well as anti-damage effects and can be used as a vehicle for gene therapy. Angiotensin-converting enzyme 2 (ACE2) plays an important role in numerous inflammatory diseases, but fewer studies have been reported in animal mastitis. We hypothesized that MSCs overexpressing ACE2 is more effective in ameliorating lipopolysaccharide (LPS)-induced inflammatory injury in mammary epithelial cells compared to MSCs alone. The results showed that MSC-ACE2 inhibited the LPS induction by upregulation of TNF-α, IL-Iβ, IL-6, and iNOS mRNA expression levels in EpH4-Ev cells compared with MSCs. Furthermore, results showed that both MSC and MSC-ACE2 were significantly activated IL-10/STAT3/SOCS3 signaling pathway as well as inhibited TLR4/NF-κB and MAPK signaling pathways, but MSC-ACE2 had more significant effects. Meanwhile, MSC-ACE2 promoted the expression of proliferation-associated proteins and inhibited the expression of the apoptosis-associated proteins in EpH4-Ev cells. In addition, MSC and MSC-ACE2 reversed the LPS-induced downregulation expression levels of the tight junction proteins in mammary epithelial cells, indicating that both MSC as well as MSC-ACE2 could promote blood-milk barrier repair, and MSC-ACE2 was more effective. These results suggested that MSCs overexpressing ACE2 were more anti-inflammatory as well as anti-injurious action into LPS-induced inflammatory injury in the EpH4-Ev cells. Thus, MSCs overexpressing ACE2 is expected to serve as a potential strategy for mastitis treatment.
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Affiliation(s)
- Shuping Yan
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Pingsheng Ye
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Muhammad Tahir Aleem
- Ministry of Education (MOE) Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Xi Chen
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Nana Xie
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
| | - Yuanshu Zhang
- Key Laboratory of Animal Physiology and Biochemistry, Ministry of Agriculture, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China
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17
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Walker S, Appari M, Forbes S. Considerations and challenges of islet transplantation and future therapies on the horizon. Am J Physiol Endocrinol Metab 2022; 322:E109-E117. [PMID: 34927459 DOI: 10.1152/ajpendo.00310.2021] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Islet transplantation is a treatment for selected adults with type 1 diabetes and severe hypoglycemia. Islets from two or more donor pancreases, a scarce resource, are usually required to impact glycemic control, but the treatment falls short of a cure. Islets are avascular when transplanted into the hypoxic liver environment and subjected to inflammatory insults, immune attack, and toxicity from systemic immunosuppression. The Collaborative Islet Transplant Registry, with outcome data on over 1,000 islet transplant recipients, has demonstrated that larger islet numbers transplanted and older age of recipients are associated with better outcomes. Induction with T-cell depleting agents and the TNF-α inhibitor etanercept and maintenance systemic immunosuppression with mTOR inhibitors in combination with calcineurin inhibitors also appear advantageous, but concerns remain over immunosuppressive toxicity. We discuss strategies and therapeutics that address specific challenges of islet transplantation, many of which are at the preclinical stage of development. On the horizon are adjuvant cell therapies with mesenchymal stromal cells and regulatory T cells that have been used in preclinical models and in humans in other contexts; such a strategy may enable reductions in immunosuppression in the early peri-transplant period when the islets are vulnerable to apoptosis. Human embryonic stem cell-derived islets are in early-phase clinical trials and hold the promise of an inexhaustible supply of insulin-producing cells; effective encapsulation of such cells or, silencing of the human leukocyte antigen (HLA) complex would eliminate the need for immunosuppression, enabling this therapy to be used in all those with type 1 diabetes.
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Affiliation(s)
- Sophie Walker
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Mahesh Appari
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Shareen Forbes
- BHF Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
- Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom
- Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada
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18
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Papoz A, Clément F, Laporte C, Tubbs E, Gidrol X, Pitaval A. [Generating pancreatic islets organoids: Langerhanoids]. Med Sci (Paris) 2022; 38:52-58. [PMID: 35060887 DOI: 10.1051/medsci/2021244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The extension of islet transplantation to a wider number of Type 1 diabetic patients is compromised by the scarcity of donors, the reduced ex vivo survival of pancreatic islets and the use of immunosuppressive treatments. Islets of Langerhans isolated from brain-dead donors are currently the only cell source for transplantation. Thus, it is crucial to find an alternative and an abundant source of functional insulin secreting cells not only for clinical use but also for the development of research dedicated to the screening of drugs and to the development of new therapeutic targets. Several groups around the world, including ours, develop 3D culture models as Langerhanoids that closely mimick human pancreatic islets physiology. In this review, we describe recent advances to mimic the pancreatic niche (extracellular matrix, vascularization, microfluidics) allowing better functionality of Langerhanoids.
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Affiliation(s)
- Anastasia Papoz
- Univ. Grenoble Alpes, CEA, Inserm, IRIG, Biomics, F-38000, Grenoble, France
| | - Flora Clément
- Univ. Grenoble Alpes, CEA, Inserm, IRIG, Biomics, F-38000, Grenoble, France
| | - Camille Laporte
- Univ. Grenoble Alpes, CEA, Leti, Division for biology and healthcare technologies, Microfluidic systems and bioengineering Lab, F-38000, Grenoble, France
| | - Emily Tubbs
- Univ. Grenoble Alpes, CEA, Inserm, IRIG, Biomics, F-38000, Grenoble, France - Univ. Grenoble Alpes, LBFA et BEeSy, Inserm U1055, F-38000, Grenoble, France
| | - Xavier Gidrol
- Univ. Grenoble Alpes, CEA, Inserm, IRIG, Biomics, F-38000, Grenoble, France
| | - Amandine Pitaval
- Univ. Grenoble Alpes, CEA, Inserm, IRIG, Biomics, F-38000, Grenoble, France
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19
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Torres-Castro K, Azimi MS, Varhue WB, Honrado C, Peirce SM, Swami NS. Biophysical quantification of reorganization dynamics of human pancreatic islets during co-culture with adipose-derived stem cells. Analyst 2022; 147:2731-2738. [DOI: 10.1039/d2an00222a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Reorganization dynamics of human islets during co-culture with adipose stem cells depends on islet size and the heterogeneity can be assessed based on biomechanical opacity of individual islets.
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Affiliation(s)
- Karina Torres-Castro
- Department of Electrical & Computer Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
| | - Mohammad S. Azimi
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
| | - Walter B. Varhue
- Department of Electrical & Computer Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
| | - Carlos Honrado
- Department of Electrical & Computer Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
| | - Shayn M. Peirce
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
| | - Nathan S. Swami
- Department of Electrical & Computer Engineering, University of Virginia, Charlottesville, Virginia-22904, USA
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20
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Krentz NAJ, Shea LD, Huising MO, Shaw JAM. Restoring normal islet mass and function in type 1 diabetes through regenerative medicine and tissue engineering. Lancet Diabetes Endocrinol 2021; 9:708-724. [PMID: 34480875 PMCID: PMC10881068 DOI: 10.1016/s2213-8587(21)00170-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/17/2021] [Accepted: 06/08/2021] [Indexed: 02/09/2023]
Abstract
Type 1 diabetes is characterised by autoimmune-mediated destruction of pancreatic β-cell mass. With the advent of insulin therapy a century ago, type 1 diabetes changed from a progressive, fatal disease to one that requires lifelong complex self-management. Replacing the lost β-cell mass through transplantation has proven successful, but limited donor supply and need for lifelong immunosuppression restricts widespread use. In this Review, we highlight incremental advances over the past 20 years and remaining challenges in regenerative medicine approaches to restoring β-cell mass and function in type 1 diabetes. We begin by summarising the role of endocrine islets in glucose homoeostasis and how this is altered in disease. We then discuss the potential regenerative capacity of the remaining islet cells and the utility of stem cell-derived β-like cells to restore β-cell function. We conclude with tissue engineering approaches that might improve the engraftment, function, and survival of β-cell replacement therapies.
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Affiliation(s)
- Nicole A J Krentz
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
| | - Lonnie D Shea
- Departments of Biomedical Engineering, Chemical Engineering, and Surgery, College of Engineering and School of Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mark O Huising
- Department of Neurobiology, Physiology and Behavior, College of Biological Sciences, University of California, Davis, Davis, CA, USA; Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, CA, USA
| | - James A M Shaw
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; Institute of Transplantation, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
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21
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Swentek L, Chung D, Ichii H. Antioxidant Therapy in Pancreatitis. Antioxidants (Basel) 2021; 10:657. [PMID: 33922756 PMCID: PMC8144986 DOI: 10.3390/antiox10050657] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatitis is pathologic inflammation of the pancreas characterized by acinar cell destruction and oxidative stress. Repeated pancreatic insults can result in the development of chronic pancreatitis, characterized by irreversible fibrosis of the pancreas and many secondary sequelae, ultimately leading to the loss of this important organ. We review acute pancreatitis, chronic pancreatitis, and pancreatitis-related complications. We take a close look at the pathophysiology with a focus on oxidative stress and how it contributes to the complications of the disease. We also take a deep dive into the evolution and current status of advanced therapies for management including dietary modification, antioxidant supplementation, and nuclear factor erythroid-2-related factor 2-Kelch-like ECH-associated protein 1(Nrf2-keap1) pathway activation. In addition, we discuss the surgeries aimed at managing pain and preventing further endocrine dysfunction, such as total pancreatectomy with islet auto-transplantation.
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Affiliation(s)
| | | | - Hirohito Ichii
- Department of Surgery, University of California, Irvine, CA 92868, USA; (L.S.); (D.C.)
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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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