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Hoseinzadeh A, Esmaeili SA, Sahebi R, Melak AM, Mahmoudi M, Hasannia M, Baharlou R. Fate and long-lasting therapeutic effects of mesenchymal stromal/stem-like cells: mechanistic insights. Stem Cell Res Ther 2025; 16:33. [PMID: 39901306 PMCID: PMC11792531 DOI: 10.1186/s13287-025-04158-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 01/21/2025] [Indexed: 02/05/2025] Open
Abstract
A large body of evidence suggests that mesenchymal stromal cells (MSCs) are able to respond rapidly to the cytokine milieu following systemic infusion. This encounter has the potential to dictate their therapeutic efficacy (also referred to as licensing). MSCs are able to rapidly react to cellular damage by migrating to the inflamed tissue and ultimately modifying the inflammatory microenvironment. However, the limited use of MSCs in clinical practice can be attributed to a lack of understanding of the fate of MSCs in patients after administration and long term MSC-derived therapeutic activity. While the known physiological effectors of viable MSCs make a relative contribution, an innate property of MSCs as a therapeutic agent is their caspase-dependent cell death. These mechanisms may be involving the functional reprogramming of myeloid phagocytes via efferocytosis, the process by which apoptotic bodies (ABs) are identified for engulfment by both specialized and non-specialized phagocytic cells. Recent studies have provided evidence that the uptake of ABs with a distinct genetic component can induce changes in gene expression through the process of epigenetic remodeling. This phenomenon, known as 'trained immunity', has a significant impact on immunometabolism processes. It is hypothesized that the diversity of recipient cells within the inflammatory stroma adjacent to MSCs may potentially serve as a biomarker for predicting the clinical outcome of MSC treatment, while also contributing to the variable outcomes observed with MSC-based therapies. Therefore, the long-term reconstructive process of MSCs may potentially be mediated by MSC apoptosis and subsequent phagocyte-mediated efferocytosis.
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Affiliation(s)
- Akram Hoseinzadeh
- Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Seyed-Alireza Esmaeili
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Sahebi
- Department of Modern Sciences and Technologies, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Mahmoud Mahmoudi
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Maliheh Hasannia
- Cancer Research Center, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
| | - Rasoul Baharlou
- Department of Immunology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran.
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Dewhurst-Trigg R, Hopkinson J, Richardson S, Jones P, Rackham C. Mesenchymal stromal cells and their secretory products reduce the inflammatory crosstalk between islets and endothelial cells. Endocrine 2025; 87:94-105. [PMID: 39085567 PMCID: PMC11739262 DOI: 10.1007/s12020-024-03975-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 07/21/2024] [Indexed: 08/02/2024]
Abstract
PURPOSE Preculturing isolated islets with Mesenchymal Stromal Cells (MSCs) improves their functional survival in vitro and subsequent transplantation outcomes in vivo. The MSC secretory product Annexin A1 (ANXA1) is a key modulator of MSC-mediated improvements in islet function. The current study aims to determine the influence of MSCs and defined MSC secretory products, including ANXA1, on the inflammatory crosstalk between isolated islets and Endothelial Cells (ECs), using in vitro models of the clinically-preferred intraportal islet transplantation niche. METHODS Islets were cultured alone, with MSCs, or with MSC secretory products and exposed to pro-inflammatory cytokines. Islet gene expression of C-C Motif Chemokine Ligand 2 (CCL2), C-X-C Motif Chemokine Ligand (CXCL)-10 (CXCL10) and CXCL1 were assessed by RT-qPCR. EC activation was induced with 100 U/ml TNF for 24 h. Islet-EC co-cultures were used to determine the influence of MSCs, or MSC secretory products on the inflammatory crosstalk between isolated islets and ECs. VCAM-1 and ICAM-1 expression were assessed at the mRNA and protein level in ECs, using RT-qPCR and immunofluorescence. RESULTS MSCs reduce pro-inflammatory cytokine-induced islet CCL2, CXCL10, and CXCL1 gene expression, which is partially mimicked by ANXA1. MSCs and ANXA1 have a similar capacity to reduce TNF-induced EC activation. Isolated islets exacerbate TNF-induced EC activation. Preculturing islets with MSCs reduces islet-exacerbated EC activation. ANXA1 reduces islet-exacerbated EC activation, when present during the islet preculture and islet-EC co-culture period. CONCLUSION MSC-derived secretory factors, including ANXA1, may be used in islet transplantation protocols to target donor islet and host EC inflammation at the intraportal niche.
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Affiliation(s)
- Rebecca Dewhurst-Trigg
- Exeter Centre for Excellence in Diabetes, Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
| | - Jessica Hopkinson
- Exeter Centre for Excellence in Diabetes, Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
| | - Sarah Richardson
- Exeter Centre for Excellence in Diabetes, Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK
| | - Peter Jones
- Diabetes & Obesity, School of Cardiovascular and Metabolic Medicine & Sciences, London, UK
| | - Chloe Rackham
- Exeter Centre for Excellence in Diabetes, Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
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Zacharovová K, Berková Z, Girman P, Saudek F. Adipose tissue-derived mesenchymal stem cells promote the vascularization of pancreatic islets transplanted into decellularized pancreatic skeletons. Transpl Immunol 2024; 86:102106. [PMID: 39128811 DOI: 10.1016/j.trim.2024.102106] [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: 12/20/2023] [Revised: 08/08/2024] [Accepted: 08/08/2024] [Indexed: 08/13/2024]
Abstract
We have recently developed a model of pancreatic islet transplantation into a decellularized pancreatic tail in rats. As the pancreatic skeletons completely lack endothelial cells, we investigated the effect of co-transplantation of mesenchymal stem cells and endothelial cells to promote revascularization. Decellularized matrix of the pancreatic tail was prepared by perfusion with Triton X-100, sodium dodecyl sulfate and DNase solution. Isolated pancreatic islets were infused into the skeletons via the splenic vein either alone, together with adipose tissue-derived mesenchymal stem cells (adMSCs), or with a combination of adMSCs and rat endothelial cells (rat ECs). Repopulated skeletons were transplanted into the subcutaneous tissue and explanted 9 days later for histological examination. Possible immunomodulatory effects of rat adMSCs on the survival of highly immunogenic green protein-expressing human ECs were also tested after their transplantation beneath the renal capsule. The immunomodulatory effects of adMSCs were also tested in vitro using the Invitrogen Click-iT EdU system. In the presence of adMSCs, the proliferation of splenocytes as a response to phytohaemagglutinin A was reduced by 47% (the stimulation index decreased from 1.7 to 0.9, P = 0.008) and the reaction to human ECs was reduced by 58% (the stimulation index decreased from 1.6 to 0.7, P = 0.03). Histological examination of the explanted skeletons seeded only with the islets showed their partial disintegration and only a rare presence of CD31-positive cells. However, skeletons seeded with a combination of islets and adMSCs showed preserved islet morphology and rich vascularity. In contrast, the addition of syngeneic rat ECs resulted in islet-cell necrosis with only few endothelial cells present. Live green fluorescence-positive endothelial cells transplanted either alone or with adMSCs were not detected beneath the renal capsule. Though the adMSCs significantly reduced in vitro proliferation stimulated by either phytohaemagglutinin A or by xenogeneic human ECs, in vivo co-transplanted adMSCs did not suppress the post-transplant immune response to xenogeneic ECs. Even in the syngeneic model, ECs co-transplantation did not lead to sufficient vascularization in the transplant area. In contrast, islet co-transplantation together with adMSCs successfully promoted the revascularization of extracellular matrix in the subcutaneous tissue.
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Affiliation(s)
- Klára Zacharovová
- Laboratory of Pancreatic Islets, Experimental Medicine Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic.
| | - Zuzana Berková
- Laboratory of Pancreatic Islets, Experimental Medicine Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic.
| | - Peter Girman
- Laboratory of Pancreatic Islets, Experimental Medicine Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic; Diabetes Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic.
| | - František Saudek
- Laboratory of Pancreatic Islets, Experimental Medicine Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic; Diabetes Center, Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic.
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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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Shang KM, Kato H, Gonzalez N, Kandeel F, Tai YC, Komatsu H. A novel approach to determine the critical survival threshold of cellular oxygen within spheroids via integrating live/dead cell imaging with oxygen modeling. Am J Physiol Cell Physiol 2024; 326:C1262-C1271. [PMID: 38497111 PMCID: PMC11193515 DOI: 10.1152/ajpcell.00024.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 03/07/2024] [Accepted: 03/08/2024] [Indexed: 03/19/2024]
Abstract
Defining the oxygen level that induces cell death within 3-D tissues is vital for understanding tissue hypoxia; however, obtaining accurate measurements has been technically challenging. In this study, we introduce a noninvasive, high-throughput methodology to quantify critical survival partial oxygen pressure (pO2) with high spatial resolution within spheroids by using a combination of controlled hypoxic conditions, semiautomated live/dead cell imaging, and computational oxygen modeling. The oxygen-permeable, micropyramid patterned culture plates created a precisely controlled oxygen condition around the individual spheroid. Live/dead cell imaging provided the geometric information of the live/dead boundary within spheroids. Finally, computational oxygen modeling calculated the pO2 at the live/dead boundary within spheroids. As proof of concept, we determined the critical survival pO2 in two types of spheroids: isolated primary pancreatic islets and tumor-derived pseudoislets (2.43 ± 0.08 vs. 0.84 ± 0.04 mmHg), indicating higher hypoxia tolerance in pseudoislets due to their tumorigenic origin. We also applied this method for evaluating graft survival in cell transplantations for diabetes therapy, where hypoxia is a critical barrier to successful transplantation outcomes; thus, designing oxygenation strategies is required. Based on the elucidated critical survival pO2, 100% viability could be maintained in a typically sized primary islet under the tissue pO2 above 14.5 mmHg. This work presents a valuable tool that is potentially instrumental for fundamental hypoxia research. It offers insights into physiological responses to hypoxia among different cell types and may refine translational research in cell therapies.NEW & NOTEWORTHY Our study introduces an innovative combinatory approach for noninvasively determining the critical survival oxygen level of cells within small cell spheroids, which replicates a 3-D tissue environment, by seamlessly integrating three pivotal techniques: cell death induction under controlled oxygen conditions, semiautomated imaging that precisely identifies live/dead cells, and computational modeling of oxygen distribution. Notably, our method ensures high-throughput analysis applicable to various cell types, offering a versatile solution for researchers in diverse fields.
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Affiliation(s)
- Kuang-Ming Shang
- Department of Medical Engineering, California Institute of Technology, Pasadena, California, United States
| | - Hiroyuki Kato
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute of City of Hope, Duarte, California, United States
| | - Nelson Gonzalez
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute of City of Hope, Duarte, California, United States
| | - Fouad Kandeel
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute of City of Hope, Duarte, California, United States
| | - Yu-Chong Tai
- Department of Medical Engineering, California Institute of Technology, Pasadena, California, United States
| | - Hirotake Komatsu
- Department of Translational Research & Cellular Therapeutics, Arthur Riggs Diabetes & Metabolism Research Institute of City of Hope, Duarte, California, United States
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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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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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Gooch AM, Chowdhury SS, Zhang PM, Hu ZM, Westenfelder C. Significant expansion of the donor pool achieved by utilizing islets of variable quality in the production of allogeneic "Neo-Islets", 3-D organoids of Mesenchymal Stromal and islet cells, a novel immune-isolating biotherapy for Type I Diabetes. PLoS One 2023; 18:e0290460. [PMID: 37616230 PMCID: PMC10449143 DOI: 10.1371/journal.pone.0290460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 08/09/2023] [Indexed: 08/26/2023] Open
Abstract
Novel biotherapies for Type 1 Diabetes that provide a significantly expanded donor pool and that deliver all islet hormones without requiring anti-rejection drugs are urgently needed. Scoring systems have improved islet allotransplantation outcomes, but their use may potentially result in the waste of valuable cells for novel therapies. To address these issues, we created "Neo-Islets" (NIs), islet-sized organoids, by co-culturing in ultralow adhesion flasks culture-expanded islet (ICs) and Mesenchymal Stromal Cells (MSCs) (x 24 hrs, 1:1 ratio). The MSCs exert powerful immune- and cyto-protective, anti-inflammatory, proangiogenic, and other beneficial actions in NIs. The robust in vitro expansion of all islet hormone-producing cells is coupled to their expected progressive de-differentiation mediated by serum-induced cell cycle entry and Epithelial-Mesenchymal Transition (EMT). Re-differentiation in vivo of the ICs and resumption of their physiological functions occurs by reversal of EMT and serum withdrawal-induced exit from the cell cycle. Accordingly, we reported that allogeneic, i.p.-administered NIs engraft in the omentum, increase Treg numbers and reestablish permanent normoglycemia in autoimmune diabetic NOD mice without immunosuppression. Our FDA-guided pilot study (INAD 012-0776) in insulin-dependent pet dogs showed similar responses, and both human- and canine-NIs established normoglycemia in STZ-diabetic NOD/SCID mice even though the utilized islets would be scored as unsuitable for transplantation. The present study further demonstrates that islet gene expression profiles (α, β, γ, δ) in human "non-clinical grade" islets obtained from diverse, non-diabetic human and canine donors (n = 6 each) closely correlate with population doublings, and the in vivo re-differentiation of endocrine islet cells clearly corresponds with the reestablishment of euglycemia in diabetic mice. Conclusion: human-NIs created from diverse, "non-clinical grade" donors have the potential to greatly expand patient access to this curative therapy of T1DM, facilitated by the efficient in vitro expansion of ICs that can produce ~ 270 therapeutic NI doses per donor for 70 kg recipients.
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Affiliation(s)
- Anna M. Gooch
- SymbioCellTech, LLC, Salt Lake City, Utah, United States of Ameirca
| | | | - Ping M. Zhang
- SymbioCellTech, LLC, Salt Lake City, Utah, United States of Ameirca
| | - Zhuma M. Hu
- SymbioCellTech, LLC, Salt Lake City, Utah, United States of Ameirca
| | - Christof Westenfelder
- SymbioCellTech, LLC, Salt Lake City, Utah, United States of Ameirca
- University of Utah, Health Sciences Center, Salt Lake City, Utah, United States of America
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Extracellular Vesicles Derived from Three-Dimensional-Cultured Human Umbilical Cord Blood Mesenchymal Stem Cells Prevent Inflammation and Dedifferentiation in Pancreatic Islets. Stem Cells Int 2023; 2023:5475212. [PMID: 36860546 PMCID: PMC9970714 DOI: 10.1155/2023/5475212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 12/16/2022] [Accepted: 02/08/2023] [Indexed: 02/22/2023] Open
Abstract
It is unclear whether extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) have a direct protective effect on pancreatic islets. In addition, whether culturing MSCs in three dimensions (3D) instead of a monolayer (2D) can induce changes in the cargo of EVs that facilitate the polarization of macrophages into an M2 phenotype has not been investigated. We sought to determine whether EVs from MSCs cultured in 3D can prevent inflammation and dedifferentiation in pancreatic islets and, if so, whether the protective effect is superior to that of EVs from 2D MSCs. Human umbilical cord blood- (hUCB-) MSCs cultured in 3D were optimized according to cell density, exposure to hypoxia, and cytokine treatment based on the ability of the hUCB-MSC-derived EVs to induce the M2 polarization of macrophages. Islets isolated from human islet amyloid polypeptide (hIAPP) heterozygote transgenic mice were cultured in serum-deprived conditions with hUCB-MSC-derived EVs. EVs derived from 3D hUCB-MSCs had more abundant microRNAs involved in M2 polarization of macrophages and had an enhanced M2 polarization ability on macrophages, which was optimized when the 3D culture condition was 2.5 × 104 cells per spheroid without preconditioning with hypoxia and cytokine exposure. When islets isolated from hIAPP heterozygote transgenic mice were cultured in serum-deprived conditions with hUCB-MSC-derived EVs, the EVs derived from 3D hUCB-MSCs suppressed the expression of proinflammatory cytokines and caspase-1 in pancreatic islets and increased the proportion of M2-polarized islet-resident macrophages. They improved glucose-stimulated insulin secretion, reduced the expression of Oct4 and NGN3, and induced the expression of Pdx1 and FoxO1. The greater suppression of IL-1β, NLRP3 inflammasome, caspase-1, and Oct4 and induction of Pdx1 and FoxO1 were found in islets cultured with the EVs derived from 3D hUCB-MSCs. In conclusion, EVs derived from 3D hUCB-MSCs optimized for M2 polarization attenuated nonspecific inflammation and preserved β-cell identity of pancreatic islets.
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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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11
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Gou W, Hua W, Swaby L, Cui W, Green E, Morgan KA, Strange C, Wang H. Stem Cell Therapy Improves Human Islet Graft Survival in Mice via Regulation of Macrophages. Diabetes 2022; 71:2642-2655. [PMID: 36084289 PMCID: PMC9750955 DOI: 10.2337/db22-0117] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 09/01/2022] [Indexed: 01/23/2023]
Abstract
Islet/β-cell transplantation offers great hope for patients with type 1 diabetes. We assessed the mechanisms of how intrahepatic coinfusion of human α-1 antitrypsin (hAAT)-engineered mesenchymal stromal cells (hAAT-MSCs) improves survival of human islet grafts posttransplantation (PT). Longitudinal in vivo bioluminescence imaging studies identified significantly more islets in the livers bearing islets cotransplanted with hAAT-MSCs compared with islets transplanted alone. In vitro mechanistic studies revealed that hAAT-MSCs inhibit macrophage migration and suppress IFN-γ-induced M1-like macrophages while promoting IL-4-induced M2-like macrophages. In vivo this translated to significantly reduced CD11c+ and F4/80+ cells and increased CD206+ cells around islets cotransplanted with hAAT-MSCs as identified by multiplex immunofluorescence staining. Recipient-derived F4/80+and CD11b+ macrophages were mainly present in the periphery of an islet, while CD11c+ and CD206+ cells appeared inside an islet. hAAT-MSCs inhibited macrophage migration and skewed the M1-like phenotype toward an M2 phenotype both in vitro and in vivo, which may have favored islet survival. These data provide evidence that hAAT-MSCs cotransplanted with islets remain in the liver and shift macrophages to a protective state that favors islet survival. This novel strategy may be used to enhance β-cell survival during islet/β-cell transplantation for the treatment of type 1 diabetes or other diseases.
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Affiliation(s)
- Wenyu Gou
- Department of Surgery, Medical University of South Carolina, Charleston, SC
- Center for Cellular Therapy, Medical University of South Carolina, Charleston, SC
| | - Wei Hua
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | - Lindsay Swaby
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | | | - Erica Green
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | | | - Charlie Strange
- Department of Medicine, Medical University of South Carolina, Charleston, SC
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC
- Center for Cellular Therapy, Medical University of South Carolina, Charleston, SC
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC
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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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Jang SB, Jin SM, Kim HS, Jeong YY, Lee SJ, Hahn S, Lee H, Lee HS, Kim JH, Lee DY. DAMP-modulating nanoparticle for successful pancreatic islet and stem cell transplantation. Biomaterials 2022; 287:121679. [PMID: 35849998 DOI: 10.1016/j.biomaterials.2022.121679] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 06/29/2022] [Accepted: 07/09/2022] [Indexed: 11/02/2022]
Abstract
Cell therapy is targeted at many organs, but locally or systemically delivered cells are shortly able to survive resulting from the immune/inflammation reactions and irregular cell targeting. Here we explore the multimodal nanoparticle having anti-inflammation and magnetic guidance for successful cell transplantation. We design magnetic resonance (MR)-active glycyrrhizin-chitosan coated superparamagnetic iron oxide nanoparticle (SPIO@Chitosan-GL) to inhibit release of inflammatory damage-associated molecular pattern (DAMP) protein and to offer noninvasive monitoring after intrahepatic transplantation of pancreatic islets and mesenchymal stem cell (MSC) spheroids. Intracellular delivered SPIO@Chitosan-GL is not cytotoxic to pancreatic islets and MSC spheroids and attenuate DAMP release from them. Also, therapeutic cells labeled with SPIO@Chitosan-GL are magnetically localized to the intended lobe of liver during transplantation procedure. If necessary, partial hepatectomy can be performed to remove the localized therapeutic cells for protection of the remaining liver lobes from systemic inflammation. Therapeutically, the cells selectively localized in the liver can treat blood glucose in diabetic mice to normal levels with DAMP modulation, and are visualized using in vivo MR imaging for over 4 weeks. Collectively, DAMP-modulating SPIO@Chitosan-GL can be used in multimodal nanomedince for attenuating the inflammation reaction by transplanted cells and for noninvasively long-term monitoring of transplanted cells.
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Affiliation(s)
- Soo Bin Jang
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Sang-Man Jin
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Hyung Shik Kim
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Yong Yeon Jeong
- Department of Radiology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, 58128, Republic of Korea
| | - Sang Jun Lee
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, 04763, Republic of Korea
| | - Soojung Hahn
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06355, Republic of Korea
| | - Hyemin Lee
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06355, Republic of Korea
| | - Han Sin Lee
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea
| | - Jae Hyeon Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea; Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06355, Republic of Korea.
| | - Dong Yun Lee
- Department of Bioengineering, College of Engineering, Hanyang University, Seoul, 04763, Republic of Korea; Institute of Nano Science & Technology (INST) & Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, 04763, Republic of Korea; Elixir Pharmatech Inc., Seoul, 04763, Republic of Korea.
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14
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Wang X, Wang K, Yu M, Velluto D, Hong X, Wang B, Chiu A, Melero-Martin JM, Tomei AA, Ma M. Engineered immunomodulatory accessory cells improve experimental allogeneic islet transplantation without immunosuppression. SCIENCE ADVANCES 2022; 8:eabn0071. [PMID: 35867788 PMCID: PMC9307254 DOI: 10.1126/sciadv.abn0071] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 06/08/2022] [Indexed: 05/05/2023]
Abstract
Islet transplantation has been established as a viable treatment modality for type 1 diabetes. However, the side effects of the systemic immunosuppression required for patients often outweigh its benefits. Here, we engineer programmed death ligand-1 and cytotoxic T lymphocyte antigen 4 immunoglobulin fusion protein-modified mesenchymal stromal cells (MSCs) as accessory cells for islet cotransplantation. The engineered MSCs (eMSCs) improved the outcome of both syngeneic and allogeneic islet transplantation in diabetic mice and resulted in allograft survival for up to 100 days without any systemic immunosuppression. Immunophenotyping revealed reduced infiltration of CD4+ or CD8+ T effector cells and increased infiltration of T regulatory cells within the allografts cotransplanted with eMSCs compared to controls. The results suggest that the eMSCs can induce local immunomodulation and may be applicable in clinical islet transplantation to reduce or minimize the need of systemic immunosuppression and ameliorate its negative impact.
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Affiliation(s)
- Xi Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Kai Wang
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Ming Yu
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Diana Velluto
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Xuechong Hong
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Bo Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Alan Chiu
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Juan M. Melero-Martin
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Alice A. Tomei
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
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15
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Du S, Li Y, Geng Z, Zhang Q, Buhler LH, Gonelle-Gispert C, Wang Y. Engineering Islets From Stem Cells: The Optimal Solution for the Treatment of Diabetes? Front Immunol 2022; 13:869514. [PMID: 35572568 PMCID: PMC9092457 DOI: 10.3389/fimmu.2022.869514] [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: 02/04/2022] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetes is a metabolic disease characterized by insulin deficiency. Bioengineering of stem cells with the aim to restore insulin production and glucose regulation has the potential to cure diabetic patients. In this review, we focus on the recent developments for bioengineering of induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), and pancreatic progenitor cells in view of generating insulin producing and glucose regulating cells for β-cell replacement therapies. Recent clinical trials using islet cells derived from stem cells have been initiated for the transplantation into diabetic patients, with crucial bottlenecks of tumorigenesis, post-transplant survival, genetic instability, and immunogenicity that should be further optimized. As a new approach given high expectations, bioengineered islets from stem cells occupies considerable potential for the future clinical application and addressing the treatment dilemma of diabetes.
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Affiliation(s)
- Suya Du
- Department of Clinical Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Yanjiao Li
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Zhen Geng
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China.,Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Qi Zhang
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Leo H Buhler
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China.,Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | | | - Yi Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Center of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China.,Institute of Organ Transplantation, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences, Sichuan Translational Medicine Research Hospital, Chengdu, China
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16
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Huang J, Bao H, Li X, Zhang Z. In vivo
CT imaging tracking of stem cells labeled with Au nanoparticles. VIEW 2022. [DOI: 10.1002/viw.20200119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Affiliation(s)
- Jie Huang
- CAS Key Laboratory of Nano‐Bio Interface, Division of Nanobiomedicine Suzhou Institute of Nano‐Tech and Nano‐bionics, Chinese Academy of Sciences Suzhou China
- School of Nano‐Tech and Nano‐Bionics University of Science and Technology of China Hefei China
| | - Hongying Bao
- CAS Key Laboratory of Nano‐Bio Interface, Division of Nanobiomedicine Suzhou Institute of Nano‐Tech and Nano‐bionics, Chinese Academy of Sciences Suzhou China
- School of Nano‐Tech and Nano‐Bionics University of Science and Technology of China Hefei China
| | - Xiaodi Li
- CAS Key Laboratory of Nano‐Bio Interface, Division of Nanobiomedicine Suzhou Institute of Nano‐Tech and Nano‐bionics, Chinese Academy of Sciences Suzhou China
- School of Nano‐Tech and Nano‐Bionics University of Science and Technology of China Hefei China
| | - Zhijun Zhang
- CAS Key Laboratory of Nano‐Bio Interface, Division of Nanobiomedicine Suzhou Institute of Nano‐Tech and Nano‐bionics, Chinese Academy of Sciences Suzhou China
- School of Nano‐Tech and Nano‐Bionics University of Science and Technology of China Hefei China
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17
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Critical Considerations in Bioluminescence Imaging of Transplanted Islets: Dynamic Signal Change in Early Posttransplant Phase and Signal Absorption by Tissues. Pancreas 2022; 51:234-242. [PMID: 35584380 DOI: 10.1097/mpa.0000000000002004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES In pancreatic islet transplantation studies, bioluminescence imaging enables quantitative and noninvasive tracking of graft survival. Amid the recent heightened interest in extrahepatic sites for islet and stem cell-derived beta-like cell transplantations, proper understanding the nature of bioluminescence imaging in these sites is important. METHODS Islets isolated from Firefly rats ubiquitously expressing luciferase reporter gene in Lewis rats were transplanted into subcutaneous or kidney capsule sites of wild-type Lewis rats or immunodeficient mice. Posttransplant changes of bioluminescence signal curves and absorption of bioluminescence signal in transplantation sites were examined. RESULTS The bioluminescence signal curve dynamically changed in the early posttransplantation phase; the signal was low within the first 5 days after transplantation. A substantial amount of bioluminescence signal was absorbed by tissues surrounding islet grafts, correlating to the depth of the transplanted site from the skin surface. Grafts in kidney capsules were harder to image than those in the subcutaneous site. Within the kidney capsule, locations that minimized depth from the skin surface improved the graft detectability. CONCLUSIONS Posttransplant phase and graft location/depth critically impact the bioluminescence images captured in islet transplantation studies. Understanding these parameters is critical for reducing experimental biases and proper interpretation of data.
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18
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Koehler N, Buhler L, Egger B, Gonelle-Gispert C. Multipotent Mesenchymal Stromal Cells Interact and Support Islet of Langerhans Viability and Function. Front Endocrinol (Lausanne) 2022; 13:822191. [PMID: 35222280 PMCID: PMC8864309 DOI: 10.3389/fendo.2022.822191] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/13/2022] [Indexed: 11/13/2022] Open
Abstract
Type 1 diabetes (T1D) is a widespread disease, affecting approximately 41.5 million people worldwide. It is generally treated with exogenous insulin, maintaining physiological blood glucose levels but also leading to long-term therapeutic complications. Pancreatic islet cell transplantation offers a potential alternative treatment to insulin injections. Shortage of human organ donors has raised the interest for porcine islet xenotransplantation. Neonatal porcine islets are highly available, can proliferate and mature in vitro as well as after transplantation in vivo. Despite promising preclinical results, delayed insulin secretion caused by immaturity and immunogenicity of the neonatal porcine islets remains a challenge for their clinical application. Multipotent mesenchymal stromal cells (MSCs) are known to have pro-angiogenic, anti-inflammatory and immunomodulatory effects. The current state of research emphasizes the great potential of co-culture and co-transplantation of islet cells with MSCs. Studies have shown enhanced islet proliferation and maturation, insulin secretion and graft survival, resulting in an improved graft outcome. This review summarizes the immunomodulatory and anti-inflammatory properties of MSC in the context of islet transplantation.
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Affiliation(s)
- Naomi Koehler
- Surgical Research Unit, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Leo Buhler
- Department of Surgery, Cantonal Hospital Fribourg, Fribourg, Switzerland
| | - Bernhard Egger
- Surgical Research Unit, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
- Department of Surgery, Cantonal Hospital Fribourg, Fribourg, Switzerland
| | - Carmen Gonelle-Gispert
- Surgical Research Unit, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
- *Correspondence: Carmen Gonelle-Gispert,
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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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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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Kenyon NS, Willman MA, Han D, Leeman RS, Rabassa A, Diaz WL, Geary JC, Poumian-Ruiz E, Griswold AJ, Van Booven DJ, Thompson R, Ordoukhanian P, Head SR, Kenyon NM, McHenry KG, Salomon DR, Bartholomew AM, Berman DM. Extended survival versus accelerated rejection of nonhuman primate islet allografts: Effect of mesenchymal stem cell source and timing. Am J Transplant 2021; 21:3524-3537. [PMID: 34008325 PMCID: PMC9034438 DOI: 10.1111/ajt.16693] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 04/23/2021] [Accepted: 05/06/2021] [Indexed: 01/25/2023]
Abstract
Mesenchymal stem cells (MSC) have been shown to be immunomodulatory, tissue regenerative, and graft promoting; however, several questions remain with regard to ideal MSC source and timing of administration. In this study, we utilized a rigorous preclinical model of allogeneic islet cell transplantation, incorporating reduced immune suppression and near to complete mismatch of major histocompatibility antigens between the diabetic cynomolgus monkey recipient and the islet donor, to evaluate both the graft promoting impact of MSC source, that is, derived from the islet recipient, the islet donor or an unrelated third party as well as the impact of timing. Co-transplant of MSC and islets on post-operative day 0, followed by additional IV MSC infusions in the first posttransplant month, resulted in prolongation of rejection free and overall islet survival and superior metabolic control for animals treated with recipient as compared to donor or third-party MSC. Immunological analyses demonstrated that infusion of MSC from either source did not prevent alloantibody formation to the islet or MSC donor; however, treatment with recipient MSC resulted in significant downregulation of memory T cells, decreased anti-donor T cell proliferation, and a trend toward increased Tregulatory:Tconventional ratios.
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Affiliation(s)
- Norma S. Kenyon
- Diabetes Research Institute, University of Miami, Miami, Florida, USA,Department of Surgery, University of Miami, Miami, Florida, USA,Department of Microbiology and Immunology, University of Miami, Miami, Florida, USA,Department of Biomedical Engineering, University of Miami, Miami, Florida, USA
| | | | - Dongmei Han
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - Rachel S. Leeman
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - Alex Rabassa
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - Waldo L. Diaz
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - James C. Geary
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - Ena Poumian-Ruiz
- Diabetes Research Institute, University of Miami, Miami, Florida, USA
| | - Anthony J. Griswold
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA,The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA
| | - Derek J. Van Booven
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA
| | - Ryan Thompson
- The Scripps Research Institute, La Jolla, California, USA
| | - Philip Ordoukhanian
- The Scripps Research Institute, La Jolla, California, USA,The Scripps Research Institute Genomics Core Facility, La Jolla, California, USA
| | - Steven R. Head
- The Scripps Research Institute, La Jolla, California, USA,The Scripps Research Institute Genomics Core Facility, La Jolla, California, USA
| | - Norman M. Kenyon
- Diabetes Research Institute, University of Miami, Miami, Florida, USA,Department of Surgery, University of Miami, Miami, Florida, USA
| | - Kenton G. McHenry
- National Center for Supercomputing Applications, University of Illinois, Urbana-Champaign, Chicago, Illinois, USA
| | | | | | - Dora M. Berman
- Diabetes Research Institute, University of Miami, Miami, Florida, USA,Department of Surgery, University of Miami, Miami, Florida, USA
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22
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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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23
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Abdul-Al M, Kyeremeh GK, Saeinasab M, Heidari Keshel S, Sefat F. Stem Cell Niche Microenvironment: Review. Bioengineering (Basel) 2021; 8:bioengineering8080108. [PMID: 34436111 PMCID: PMC8389324 DOI: 10.3390/bioengineering8080108] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 12/13/2022] Open
Abstract
The cornea comprises a pool of self-regenerating epithelial cells that are crucial to preserving clarity and visibility. Limbal epithelial stem cells (LESCs), which live in a specialized stem cell niche (SCN), are crucial for the survival of the human corneal epithelium. They live at the bottom of the limbal crypts, in a physically enclosed microenvironment with a number of neighboring niche cells. Scientists also simplified features of these diverse microenvironments for more analysis in situ by designing and recreating features of different SCNs. Recent methods for regenerating the corneal epithelium after serious trauma, including burns and allergic assaults, focus mainly on regenerating the LESCs. Mesenchymal stem cells, which can transform into self-renewing and skeletal tissues, hold immense interest for tissue engineering and innovative medicinal exploration. This review summarizes all types of LESCs, identity and location of the human epithelial stem cells (HESCs), reconstruction of LSCN and artificial stem cells for self-renewal.
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Affiliation(s)
- Mohamed Abdul-Al
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD71DP, UK; (M.A.-A.); (G.K.K.)
| | - George Kumi Kyeremeh
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD71DP, UK; (M.A.-A.); (G.K.K.)
| | - Morvarid Saeinasab
- Department of Biology, Faculty of Science, Ferdowsi University of Mashhad, Mashhad 91779 48974, Iran;
| | - Saeed Heidari Keshel
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839 69411, Iran;
| | - Farshid Sefat
- Department of Biomedical and Electronics Engineering, School of Engineering, University of Bradford, Bradford BD71DP, UK; (M.A.-A.); (G.K.K.)
- Interdisciplinary Research Centre in Polymer Science & Technology (Polymer IRC), University of Bradford, Bradford BD71DP, UK
- Correspondence:
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24
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Lopez-Mendez TB, Santos-Vizcaino E, Pedraz JL, Orive G, Hernandez RM. Cell microencapsulation technologies for sustained drug delivery: Latest advances in efficacy and biosafety. J Control Release 2021; 335:619-636. [PMID: 34116135 DOI: 10.1016/j.jconrel.2021.06.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 06/04/2021] [Accepted: 06/06/2021] [Indexed: 10/21/2022]
Abstract
The development of cell microencapsulation systems began several decades ago. However, today few systems have been tested in clinical trials. For this reason, in the last years, researchers have directed efforts towards trying to solve some of the key aspects that still limit efficacy and biosafety, the two major criteria that must be satisfied to reach the clinical practice. Regarding the efficacy, which is closely related to biocompatibility, substantial improvements have been made, such as the purification or chemical modification of the alginates that normally form the microspheres. Each of the components that make up the microcapsules has been carefully selected to avoid toxicities that can damage the encapsulated cells or generate an immune response leading to pericapsular fibrosis. As for the biosafety, researchers have developed biological circuits capable of actively responding to the needs of the patients to precisely and accurately release the demanded drug dose. Furthermore, the structure of the devices has been subject of study to adequately protect the encapsulated cells and prevent their spread in the body. The objective of this review is to describe the latest advances made by scientist to improve the efficacy and biosafety of cell microencapsulation systems for sustained drug delivery, also highlighting those points that still need to be optimized.
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Affiliation(s)
- Tania B Lopez-Mendez
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029 Madrid, Spain
| | - Edorta Santos-Vizcaino
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029 Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Jose Luis Pedraz
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029 Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain
| | - Gorka Orive
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029 Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain; University Institute for Regenerative Medicine and Oral Implantology - UIRMI (UPV/EHU-Fundación Eduardo Anitua), BTI Biotechnology Institute, Vitoria-Gasteiz, Spain; Singapore Eye Research Institute, The Academia, 20 College Road, Discovery Tower, Singapore.
| | - Rosa Maria Hernandez
- NanoBioCel Research Group, School of Pharmacy, University of the Basque Country (UPV/EHU), Paseo de la Universidad, 7, 01006 Vitoria-Gasteiz, Spain; Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, C/Monforte de Lemos 3-5, 28029 Madrid, Spain; Bioaraba, NanoBioCel Research Group, Vitoria-Gasteiz, Spain.
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25
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Montanari E, Szabó L, Balaphas A, Meyer J, Perriraz-Mayer N, Pimenta J, Giraud MN, Egger B, Gerber-Lemaire S, Bühler L, Gonelle-Gispert C. Multipotent mesenchymal stromal cells derived from porcine exocrine pancreas improve insulin secretion from juvenile porcine islet cell clusters. Xenotransplantation 2021; 28:e12666. [PMID: 33538027 DOI: 10.1111/xen.12666] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 10/30/2020] [Accepted: 11/26/2020] [Indexed: 01/03/2023]
Abstract
Neonatal and juvenile porcine islet cell clusters (ICC) present an unlimited source for islet xenotransplantation to treat type 1 diabetes patients. We isolated ICC from pancreata of 14 days old juvenile piglets and characterized their maturation by immunofluorescence and insulin secretion assays. Multipotent mesenchymal stromal cells derived from exocrine tissue of same pancreata (pMSC) were characterized for their differentiation potential and ability to sustain ICC insulin secretion in vitro and in vivo. Isolation of ICC resulted in 142 ± 50 × 103 IEQ per pancreas. Immunofluorescence staining revealed increasing presence of insulin-positive beta cells between day 9 and 21 in culture and insulin content per 500IEC of ICC increased progressively over time from 1178.4 ± 450 µg/L to 4479.7 ± 1954.2 µg/L from day 7 to 14, P < .001. Highest glucose-induced insulin secretion by ICC was obtained at day 7 of culture and reached a fold increase of 2.9 ± 0.4 compared to basal. Expansion of adherent cells from the pig exocrine tissue resulted in a homogenous CD90+ , CD34- , and CD45- fibroblast-like cell population and differentiation into adipocytes and chondrocytes demonstrated their multipotency. Insulin release from ICC was increased in the presence of pMSC and dependent on cell-cell contact (glucose-induced fold increase: ICC alone: 1.6 ± 0.2; ICC + pMSC + contact: 3.2 ± 0.5, P = .0057; ICC + pMSC no-contact: 1.9 ± 0.3; theophylline stimulation: alone: 5.4 ± 0.7; pMSC + contact: 8.4 ± 0.9, P = .013; pMSC no-contact: 5.2 ± 0.7). After transplantation of encapsulated ICC using Ca2+ -alginate (alg) microcapsules into streptozotocin-induced diabetic and immunocompetent mice, transient normalization of glycemia was obtained up to day 7 post-transplant, whereas ICC co-encapsulated with pMSC did not improve glycemia and showed increased pericapsular fibrosis. We conclude that pMSC derived from juvenile porcine exocrine pancreas improves insulin secretion of ICC by direct cell-cell contact. For transplantation purposes, the use of pMSC to support beta-cell function will depend on the development of new anti-fibrotic polymers and/or on genetically modified pigs with lower immunogenicity.
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Affiliation(s)
- Elisa Montanari
- Surgical Research Unit, CMU-1, University Hospitals of Geneva, Geneva, Switzerland
| | - Luca Szabó
- Group for Functionalized Biomaterials, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL SB ISIC SCI-SB-SG, Lausanne, Switzerland
| | - Alexandre Balaphas
- Surgical Research Unit, CMU-1, University Hospitals of Geneva, Geneva, Switzerland
| | - Jeremy Meyer
- Surgical Research Unit, CMU-1, University Hospitals of Geneva, Geneva, Switzerland
| | - Nadja Perriraz-Mayer
- Surgical Research Unit, CMU-1, University Hospitals of Geneva, Geneva, Switzerland
| | - Joel Pimenta
- Surgical Research Unit, CMU-1, University Hospitals of Geneva, Geneva, Switzerland
| | - Marie-Noelle Giraud
- Cardiology, Dpt EMC, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Bernhard Egger
- Surgical Research Unit, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Sandrine Gerber-Lemaire
- Group for Functionalized Biomaterials, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, EPFL SB ISIC SCI-SB-SG, Lausanne, Switzerland
| | - Leo Bühler
- Surgical Research Unit, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Carmen Gonelle-Gispert
- Surgical Research Unit, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
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26
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Bertera S, Knoll MF, Knoll C, Hara H, Kimbrel EA, Kouris NA, Lanza R, Philips BE, Garciafigueroa Y, Giannoukakis N, Cooper DKC, Trucco M, Bottino R. Human Hemangioblast-Derived Mesenchymal Stem Cells Promote Islet Engraftment in a Minimal Islet Mass Transplantation Model in Mice. Front Med (Lausanne) 2021; 8:660877. [PMID: 33937296 PMCID: PMC8081894 DOI: 10.3389/fmed.2021.660877] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/15/2021] [Indexed: 12/04/2022] Open
Abstract
Islet transplantation can restore glycemic control in patients with type 1 diabetes. Using this procedure, the early stages of engraftment are often crucial to long-term islet function, and outcomes are not always successful. Numerous studies have shown that mesenchymal stem cells (MSCs) facilitate islet graft function. However, experimental data can be inconsistent due to variables associated with MSC generation (including donor characteristics and tissue source), thus, demonstrating the need for a well-characterized and uniform cell product before translation to the clinic. Unlike bone marrow- or adipose tissue-derived MSCs, human embryonic stem cell-derived-MSCs (hESC-MSCs) offer an unlimited source of stable and highly-characterized cells that are easily scalable. Here, we studied the effects of human hemangioblast-derived mesenchymal cells (HMCs), (i.e., MSCs differentiated from hESCs using a hemangioblast intermediate), on islet cell transplantation using a minimal islet mass model. The co-transplantation of the HMCs allowed a mass of islets that was insufficient to correct diabetes on its own to restore glycemic control in all recipients. Our in vitro studies help to elucidate the mechanisms including reduction of cytokine stress by which the HMCs support islet graft protection in vivo. Derivation, stability, and scalability of the HMC source may offer unique advantages for clinical applications, including fewer islets needed for successful islet transplantation.
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Affiliation(s)
- Suzanne Bertera
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Michael F. Knoll
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Carmela Knoll
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Hidetaka Hara
- Department of Surgery, Xenotransplantation Program, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Erin A. Kimbrel
- Astellas Institute for Regenerative Medicine, Westborough, MA, United States
| | - Nickolas A. Kouris
- Astellas Institute for Regenerative Medicine, Westborough, MA, United States
| | - Robert Lanza
- Astellas Institute for Regenerative Medicine, Westborough, MA, United States
| | - Brett E. Philips
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Yesica Garciafigueroa
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
| | - Nick Giannoukakis
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
| | - David K. C. Cooper
- Department of Surgery, Xenotransplantation Program, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Massimo Trucco
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
| | - Rita Bottino
- Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, United States
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Wang Y, Wang JW, Li Y, Tian XH, Feng XS, Zhang SC, Liu PJ, Xue WJ, Zheng J, Ding XM. Bone marrow-derived mesenchymal stem cells improve rat islet graft revascularization by upregulating ISL1. STEM CELLS (DAYTON, OHIO) 2021; 39:1033-1048. [PMID: 33754392 DOI: 10.1002/stem.3378] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 03/01/2021] [Indexed: 11/12/2022]
Abstract
Revascularization of the islet transplant is a crucial step that defines the success rate of patient recovery. Bone marrow-derived mesenchymal stem cells (BMSCs) have been reported to promote revascularization; however, the underlying cellular mechanism remains unclear. Moreover, our liquid chromatography-tandem mass spectrometry results showed that BMSCs could promote the expression of insulin gene enhancer binding protein-1 (ISL1) in islets. ISL1 is involved in islets proliferation and plays a potential regulatory role in the revascularization of islets. This study identifies the ISL1 protein as a potential modulator in BMSCs-mediated revascularization of islet grafts. We demonstrated that the survival rate and insulin secretion of islets were increased in the presence of BMSCs, indicating that BMSCs promote islet revascularization in a coculture system and rat diabetes model. Interestingly, we also observed that the presence of BMSCs led to an increase in ISL1 and vascular endothelial growth factor A (VEGFA) expression in both islets and the INS-1 rat insulinoma cell line. In silico protein structure modeling indicated that ISL1 is a transcription factor that has four binding sites with VEGFA mRNA. Further results showed that overexpression of ISL1 increased both the abundance of VEGFA transcripts and protein accumulation, while inhibition of ISL1 decreased the abundance of VEGFA. Using a ChIP-qPCR assay, we demonstrated that direct molecular interactions between ISL1 and VEGFA occur in INS-1 cells. Together, these findings reveal that BMSCs promote the expression of ISL1 in islets and lead to an increase in VEGFA in islet grafts. Hence, ISL1 is a potential target to induce early revascularization in 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, Xi'an, Shaanxi Province, People's Republic of China
| | - Jing-Wen Wang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Yang Li
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xiao-Hui Tian
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xin-Shun Feng
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Shu-Cong Zhang
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Pei-Jun Liu
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Wu-Jun Xue
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 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, Xi'an, Shaanxi Province, People's Republic of China
| | - Xiao-Ming Ding
- Department of Renal Transplantation, Hospital of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
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28
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Komatsu H, Gonzalez N, Ortiz J, Rawson J, Omori K, Kandeel F, Mullen Y. Early-Phase Luciferase Signals of Islet Grafts Predicts Successful Subcutaneous Site Transplantation in Rats. Mol Imaging Biol 2021; 23:173-179. [PMID: 33140260 PMCID: PMC9870595 DOI: 10.1007/s11307-020-01560-2] [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] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 10/16/2020] [Accepted: 10/22/2020] [Indexed: 01/25/2023]
Abstract
PURPOSE The transplantation of pancreatic islets is a promising cell replacement therapy for type 1 diabetes. Subcutaneous islet transplantation is currently under investigation as a means to circumvent problems associated with standard intra-hepatic islet transplantation. As modifications are being developed to improve the efficacy of subcutaneous islet transplantation, it is important to have robust methods to assess engraftment. Experimentally, ATP-dependent bioluminescence imaging using luciferase reporter genes has been effective for non-invasively tracking engraftment. However, it was heretofore unknown if the bioluminescence of subcutaneously transplanted luciferase-expressing islet grafts correlates with diabetes reversal, a primary outcome of transplantation. PROCEDURES A retrospective analysis was conducted using data obtained from subcutaneous islet transplantations in Lewis rats. The analysis included transplantations from our laboratory in which islet donors were transgenic rats ubiquitously expressing luciferase and recipients were wild type, streptozotocin-induced diabetic rats. Data from 79 bioluminescence scans were obtained from 27 islet transplantations during the post-transplant observation period (up to 6 weeks). The bioluminescence intensity of the subcutaneously transplanted grafts, captured after the intravenous administration of luciferin, was correlated with diabetes reversal. RESULTS After subcutaneous transplantation, islet bioluminescence decreased over time, dropping > 50 % from 1 to 3 weeks post-transplant. Bioluminescence intensity in the early post-transplant phase (1-2 weeks) correlated with the subsequent reversal of diabetes; based on optimized bioluminescence cutoff values, the bioluminescence intensity of islets at 1 and 2 weeks predicted successful transplantations. However, intensity in the late post-transplant phase (≥ 4 weeks) did not reflect transplantation outcomes. CONCLUSIONS Early-phase bioluminescence imaging of luciferase-expressing islets could serve as a useful tool to predict the success of subcutaneous islet transplantations by preceding changes in glucose homeostasis.
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Affiliation(s)
- Hirotake Komatsu
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA.
| | - Nelson Gonzalez
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA
| | - Jose Ortiz
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA
| | - Jeffrey Rawson
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA
| | - Keiko Omori
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA
| | - Fouad Kandeel
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA
| | - Yoko Mullen
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA, 91010, USA
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29
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Docherty FM, Sussel L. Islet Regeneration: Endogenous and Exogenous Approaches. Int J Mol Sci 2021; 22:ijms22073306. [PMID: 33804882 PMCID: PMC8037662 DOI: 10.3390/ijms22073306] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/17/2021] [Accepted: 03/17/2021] [Indexed: 02/07/2023] Open
Abstract
Both type 1 and type 2 diabetes are characterized by a progressive loss of beta cell mass that contributes to impaired glucose homeostasis. Although an optimal treatment option would be to simply replace the lost cells, it is now well established that unlike many other organs, the adult pancreas has limited regenerative potential. For this reason, significant research efforts are focusing on methods to induce beta cell proliferation (replication of existing beta cells), promote beta cell formation from alternative endogenous cell sources (neogenesis), and/or generate beta cells from pluripotent stem cells. In this article, we will review (i) endogenous mechanisms of beta cell regeneration during steady state, stress and disease; (ii) efforts to stimulate endogenous regeneration and transdifferentiation; and (iii) exogenous methods of beta cell generation and transplantation.
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Abstract
Abstract
Purpose of Review
β cell replacement via whole pancreas or islet transplantation has greatly evolved for the cure of type 1 diabetes. Both these strategies are however still affected by several limitations. Pancreas bioengineering holds the potential to overcome these hurdles aiming to repair and regenerate β cell compartment. In this review, we detail the state-of-the-art and recent progress in the bioengineering field applied to diabetes research.
Recent Findings
The primary target of pancreatic bioengineering is to manufacture a construct supporting insulin activity in vivo. Scaffold-base technique, 3D bioprinting, macro-devices, insulin-secreting organoids, and pancreas-on-chip represent the most promising technologies for pancreatic bioengineering.
Summary
There are several factors affecting the clinical application of these technologies, and studies reported so far are encouraging but need to be optimized. Nevertheless pancreas bioengineering is evolving very quickly and its combination with stem cell research developments can only accelerate this trend.
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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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32
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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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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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Gavazzo P, Viti F, Donnelly H, Oliva MAG, Salmeron-Sanchez M, Dalby MJ, Vassalli M. Biophysical phenotyping of mesenchymal stem cells along the osteogenic differentiation pathway. Cell Biol Toxicol 2021; 37:915-933. [PMID: 33420657 DOI: 10.1007/s10565-020-09569-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 10/30/2020] [Indexed: 12/22/2022]
Abstract
Mesenchymal stem cells represent an important resource, for bone regenerative medicine and therapeutic applications. This review focuses on new advancements and biophysical tools which exploit different physical and chemical markers of mesenchymal stem cell populations, to finely characterize phenotype changes along their osteogenic differentiation process. Special attention is paid to recently developed label-free methods, which allow monitoring cell populations with minimal invasiveness. Among them, quantitative phase imaging, suitable for single-cell morphometric analysis, and nanoindentation, functional to cellular biomechanics investigation. Moreover, the pool of ion channels expressed in cells during differentiation is discussed, with particular interest for calcium homoeostasis.Altogether, a biophysical perspective of osteogenesis is proposed, offering a valuable tool for the assessment of the cell stage, but also suggesting potential physiological links between apparently independent phenomena.
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Affiliation(s)
- Paola Gavazzo
- Institute of Biophysics, National Research Council, Genoa, Italy
| | - Federica Viti
- Institute of Biophysics, National Research Council, Genoa, Italy.
| | - Hannah Donnelly
- Centre for the Cellular Microenvironment, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Mariana Azevedo Gonzalez Oliva
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow, UK
| | - Manuel Salmeron-Sanchez
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow, UK
| | - Matthew J Dalby
- Centre for the Cellular Microenvironment, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Massimo Vassalli
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, School of Engineering, University of Glasgow, Glasgow, UK
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35
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Kh S, Haider KH. Stem Cells: A Renewable Source of Pancreatic β-Cells and Future for Diabetes Treatment. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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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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Lebreton F, Wassmer CH, Belofatto K, Berney T, Berishvili E. [Insulin-secreting organoids: a first step towards the bioartificial pancreas]. Med Sci (Paris) 2020; 36:879-885. [PMID: 33026330 DOI: 10.1051/medsci/2020129] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Pancreatic islet transplantation is a valid cure for selected type-1 diabetic patients. It offers a minimally invasive β-cell replacement approach and has proven its capacity to significantly enhance patients quality of life. However, these insulin-secreting mini-organs suffer from the loss of intrinsic vascularization and extra-cellular matrix occurring during isolation, resulting in hypoxic stress and necrosis. In addition, they have to face inflammatory and immune destruction once transplanted in the liver. Organoid generation represents a strategy to overcome these obstacles by allowing size and shape control as well as composition. It does offer the possibility to add supporting cells such as endothelial cells, in order to facilitate revascularization or cells releasing anti-inflammatory and/or immunomodulatory factors. This review describes the limitations of pancreatic islet transplantation and details the benefits offered by organoids as a cornerstone toward the generation of a bioartificial pancreas.
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Affiliation(s)
- Fanny Lebreton
- Laboratoire de transplantation cellulaire, Département de Chirurgie, Centre médical universitaire, Hôpitaux de l'université de Genève et université de Genève, Genève, Suisse - Centre facultaire du diabète, Centre médical de l'université de Genève, Genève, Suisse
| | - Charles-Henri Wassmer
- Laboratoire de transplantation cellulaire, Département de Chirurgie, Centre médical universitaire, Hôpitaux de l'université de Genève et université de Genève, Genève, Suisse - Centre facultaire du diabète, Centre médical de l'université de Genève, Genève, Suisse
| | - Kevin Belofatto
- Laboratoire de transplantation cellulaire, Département de Chirurgie, Centre médical universitaire, Hôpitaux de l'université de Genève et université de Genève, Genève, Suisse - Centre facultaire du diabète, Centre médical de l'université de Genève, Genève, Suisse
| | - Thierry Berney
- Laboratoire de transplantation cellulaire, Département de Chirurgie, Centre médical universitaire, Hôpitaux de l'université de Genève et université de Genève, Genève, Suisse - Centre facultaire du diabète, Centre médical de l'université de Genève, Genève, Suisse
| | - Ekaterine Berishvili
- Laboratoire de transplantation cellulaire, Département de Chirurgie, Centre médical universitaire, Hôpitaux de l'université de Genève et université de Genève, Genève, Suisse - Centre facultaire du diabète, Centre médical de l'université de Genève, Genève, Suisse - Institute of Medical Research, Ilia State University, Tbilissi, Géorgie
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Wassmer CH, Lebreton F, Bellofatto K, Bosco D, Berney T, Berishvili E. Generation of insulin-secreting organoids: a step toward engineering and transplanting the bioartificial pancreas. Transpl Int 2020; 33:1577-1588. [PMID: 32852858 PMCID: PMC7756715 DOI: 10.1111/tri.13721] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 07/06/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023]
Abstract
Diabetes is a major health issue of increasing prevalence. ß‐cell replacement, by pancreas or islet transplantation, is the only long‐term curative option for patients with insulin‐dependent diabetes. Despite good functional results, pancreas transplantation remains a major surgery with potentially severe complications. Islet transplantation is a minimally invasive alternative that can widen the indications in view of its lower morbidity. However, the islet isolation procedure disrupts their vasculature and connection to the surrounding extracellular matrix, exposing them to ischemia and anoikis. Implanted islets are also the target of innate and adaptive immune attacks, thus preventing robust engraftment and prolonged full function. Generation of organoids, defined as functional 3D structures assembled with cell types from different sources, is a strategy increasingly used in regenerative medicine for tissue replacement or repair, in a variety of inflammatory or degenerative disorders. Applied to ß‐cell replacement, it offers the possibility to control the size and composition of islet‐like structures (pseudo‐islets), and to include cells with anti‐inflammatory or immunomodulatory properties. In this review, we will present approaches to generate islet cell organoids and discuss how these strategies can be applied to the generation of a bioartificial pancreas for the treatment of type 1 diabetes.
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Affiliation(s)
- Charles-Henri Wassmer
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.,Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland.,Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Fanny Lebreton
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.,Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
| | - Kevin Bellofatto
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.,Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
| | - Domenico Bosco
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.,Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
| | - Thierry Berney
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.,Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland.,Division of Transplantation, Department of Surgery, University of Geneva Hospitals, Geneva, Switzerland
| | - Ekaterine Berishvili
- Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.,Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland.,Institute of Medical and Public Health Research, Ilia State University, Tbilisi, Georgia
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Childs PG, Reid S, Salmeron-Sanchez M, Dalby MJ. Hurdles to uptake of mesenchymal stem cells and their progenitors in therapeutic products. Biochem J 2020; 477:3349-3366. [PMID: 32941644 PMCID: PMC7505558 DOI: 10.1042/bcj20190382] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 08/15/2020] [Accepted: 08/24/2020] [Indexed: 12/11/2022]
Abstract
Twenty-five years have passed since the first clinical trial utilising mesenchymal stomal/stem cells (MSCs) in 1995. In this time academic research has grown our understanding of MSC biochemistry and our ability to manipulate these cells in vitro using chemical, biomaterial, and mechanical methods. Research has been emboldened by the promise that MSCs can treat illness and repair damaged tissues through their capacity for immunomodulation and differentiation. Since 1995, 31 therapeutic products containing MSCs and/or progenitors have reached the market with the level of in vitro manipulation varying significantly. In this review, we summarise existing therapeutic products containing MSCs or mesenchymal progenitor cells and examine the challenges faced when developing new therapeutic products. Successful progression to clinical trial, and ultimately market, requires a thorough understanding of these hurdles at the earliest stages of in vitro pre-clinical development. It is beneficial to understand the health economic benefit for a new product and the reimbursement potential within various healthcare systems. Pre-clinical studies should be selected to demonstrate efficacy and safety for the specific clinical indication in humans, to avoid duplication of effort and minimise animal usage. Early consideration should also be given to manufacturing: how cell manipulation methods will integrate into highly controlled workflows and how they will be scaled up to produce clinically relevant quantities of cells. Finally, we summarise the main regulatory pathways for these clinical products, which can help shape early therapeutic design and testing.
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Affiliation(s)
- Peter G. Childs
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, School of Engineering, College of Science and Engineering, University of Glasgow, Glasgow G12 8QQ, U.K
- Centre for the Cellular Microenvironment, SUPA Department of Biomedical Engineering, University of Strathclyde, Glasgow G1 1QE, U.K
| | - Stuart Reid
- Centre for the Cellular Microenvironment, SUPA Department of Biomedical Engineering, University of Strathclyde, Glasgow G1 1QE, U.K
| | - Manuel Salmeron-Sanchez
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, School of Engineering, College of Science and Engineering, University of Glasgow, Glasgow G12 8QQ, U.K
| | - Matthew J. Dalby
- Centre for the Cellular Microenvironment, Institute for Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, U.K
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Razavi M, Ren T, Zheng F, Telichko A, Wang J, Dahl JJ, Demirci U, Thakor AS. Facilitating islet transplantation using a three-step approach with mesenchymal stem cells, encapsulation, and pulsed focused ultrasound. Stem Cell Res Ther 2020; 11:405. [PMID: 32948247 PMCID: PMC7501701 DOI: 10.1186/s13287-020-01897-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/06/2020] [Accepted: 08/24/2020] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND The aim of this study was to examine the effect of a three-step approach that utilizes the application of adipose tissue-derived mesenchymal stem cells (AD-MSCs), encapsulation, and pulsed focused ultrasound (pFUS) to help the engraftment and function of transplanted islets. METHODS In step 1, islets were co-cultured with AD-MSCs to form a coating of AD-MSCs on islets: here, AD-MSCs had a cytoprotective effect on islets; in step 2, islets coated with AD-MSCs were conformally encapsulated in a thin layer of alginate using a co-axial air-flow method: here, the capsule enabled AD-MSCs to be in close proximity to islets; in step 3, encapsulated islets coated with AD-MSCs were treated with pFUS: here, pFUS enhanced the secretion of insulin from islets as well as stimulated the cytoprotective effect of AD-MSCs. RESULTS Our approach was shown to prevent islet death and preserve islet functionality in vitro. When 175 syngeneic encapsulated islets coated with AD-MSCs were transplanted beneath the kidney capsule of diabetic mice, and then followed every 3 days with pFUS treatment until day 12 post-transplantation, we saw a significant improvement in islet function with diabetic animals re-establishing glycemic control over the course of our study (i.e., 30 days). In addition, our approach was able to enhance islet engraftment by facilitating their revascularization and reducing inflammation. CONCLUSIONS This study demonstrates that our clinically translatable three-step approach is able to improve the function and viability of transplanted islets.
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Affiliation(s)
- Mehdi Razavi
- Department of Radiology, Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94304, USA
- Biionix™ (Bionic Materials, Implants & Interfaces) Cluster, Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
- Department of Materials Science and Engineering, University of Central Florida, Orlando, FL, 32816, USA
| | - Tanchen Ren
- Department of Radiology, Bio-Acoustic MEMS in Medicine Laboratory (BAMM), Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Fengyang Zheng
- Department of Radiology, Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94304, USA
| | - Arsenii Telichko
- Department of Radiology, Dahl Ultrasound Laboratory, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Jing Wang
- Department of Radiology, Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94304, USA
| | - Jeremy J Dahl
- Department of Radiology, Dahl Ultrasound Laboratory, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Utkan Demirci
- Department of Radiology, Bio-Acoustic MEMS in Medicine Laboratory (BAMM), Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Avnesh S Thakor
- Department of Radiology, Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94304, USA.
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Komatsu H, Gonzalez N, Kandeel F, Mullen Y. Intermittent normobaric oxygen inhalation enhances subcutaneous prevascularization for cell transplantation. Microvasc Res 2020; 132:104070. [PMID: 32890600 DOI: 10.1016/j.mvr.2020.104070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 01/16/2023]
Abstract
PURPOSE Subcutaneous tissue is a promising site for cell transplantation; advantages include minimally invasive procedures and easy post-transplant monitoring. However, limited vascularity is the major known challenge. To address this challenge, a prevascularized graft bed is prepared in recipients. We aimed to establish an improved, clinically applicable approach to promote prevascularization of the subcutaneous graft bed prior to cell transplantation. METHODS We applied a conventional prevascularization approach by subcutaneously implanting nylon discs into the backs of Lewis rats. After disc implantation, we treated rats with or without intermittent normobaric 100% oxygen inhalation (1 h, twice a day, for consecutive 7 days). We used histology to compare vascular density between the oxygen-treated or control groups. To assess the functional effects of prevascularization, we transplanted three hundred islets isolated from luciferase-transgenic Lewis rats into the oxygen-treated or control wild type Lewis recipients, then used bioluminescence imaging to track engraftment for 4 weeks. RESULTS Oxygen treatment significantly augmented prevascularization in the subcutaneous site compared to controls. Islet transplantation into prevascularized graft beds demonstrated significant improvement in engraftment efficiency in oxygen-treated recipients compared to controls at 2-4 weeks post-transplantation. CONCLUSION Combining intermittent normobaric 100% oxygen inhalation with a conventional vascularization approach promotes a functional vasculature within a week. A simple approach using normobaric oxygen has the potential for translation into clinical application in subcutaneous site cell transplantations.
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Affiliation(s)
- Hirotake Komatsu
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA.
| | - Nelson Gonzalez
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Fouad Kandeel
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Yoko Mullen
- Department of Translational Research & Cellular Therapeutics, Beckman Research Institute of City of Hope, Duarte, CA, USA
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Menger MM, Nalbach L, Wrublewsky S, Glanemann M, Gu Y, Laschke MW, Menger MD, Ampofo E. Darbepoetin-α increases the blood volume flow in transplanted pancreatic islets in mice. Acta Diabetol 2020; 57:1009-1018. [PMID: 32221724 PMCID: PMC8318962 DOI: 10.1007/s00592-020-01512-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 03/04/2020] [Indexed: 11/30/2022]
Abstract
AIMS The minimal-invasive transplantation of pancreatic islets is a promising approach to treat diabetes mellitus type 1. However, islet transplantation is still hampered by the insufficient process of graft revascularization, leading to a poor clinical outcome. Accordingly, the identification of novel compounds, which accelerate and improve the revascularization of transplanted islets, is of great clinical interest. Previous studies have shown that darbepoetin (DPO)-α, a long lasting analogue of erythropoietin, is capable of promoting angiogenesis. Hence, we investigated in this study whether DPO improves the revascularization of transplanted islets. METHODS Islets were isolated from green fluorescent protein-positive FVB/N donor mice and transplanted into dorsal skinfold chambers of FVB/N wild-type animals, which were treated with DPO low dose (2.5 µg/kg), DPO high dose (10 µg/kg) or vehicle (control). The revascularization was assessed by repetitive intravital fluorescence microscopy over an observation period of 14 days. Subsequently, the cellular composition of the grafts was analyzed by immunohistochemistry. RESULTS The present study shows that neither low- nor high-dose DPO treatment accelerates the revascularization of free pancreatic islet grafts. However, high-dose DPO treatment increased the blood volume flow of the transplanted islet. CONCLUSIONS These findings demonstrated that DPO treatment does not affect the revascularization of transplanted islets. However, the glycoprotein increases the blood volume flow of the grafts, which results in an improved microvascular function and may facilitate successful transplantation.
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Affiliation(s)
- Maximilian M Menger
- Institute for Clinical and Experimental Surgery, Saarland University, 66421, Homburg, Saar, Germany
| | - Lisa Nalbach
- Institute for Clinical and Experimental Surgery, Saarland University, 66421, Homburg, Saar, Germany
| | - Selina Wrublewsky
- Institute for Clinical and Experimental Surgery, Saarland University, 66421, Homburg, Saar, Germany
| | - Matthias Glanemann
- Department for General, Visceral, Vascular and Pediatric Surgery, Saarland University, 66421, Homburg, Saar, Germany
| | - Yuan Gu
- Institute for Clinical and Experimental Surgery, Saarland University, 66421, Homburg, Saar, Germany
| | - Matthias W Laschke
- Institute for Clinical and Experimental Surgery, Saarland University, 66421, Homburg, Saar, Germany
| | - Michael D Menger
- Institute for Clinical and Experimental Surgery, Saarland University, 66421, Homburg, Saar, Germany
| | - Emmanuel Ampofo
- Institute for Clinical and Experimental Surgery, Saarland University, 66421, Homburg, Saar, Germany.
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Lebreton F, Bellofatto K, Wassmer CH, Perez L, Lavallard V, Parnaud G, Cottet-Dumoulin D, Kerr-Conte J, Pattou F, Bosco D, Othenin-Girard V, Martinez de Tejada B, Berishvili E. Shielding islets with human amniotic epithelial cells enhances islet engraftment and revascularization in a murine diabetes model. Am J Transplant 2020; 20:1551-1561. [PMID: 32031745 DOI: 10.1111/ajt.15812] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 01/12/2020] [Accepted: 01/28/2020] [Indexed: 01/25/2023]
Abstract
Hypoxia is a major cause of considerable islet loss during the early posttransplant period. Here, we investigate whether shielding islets with human amniotic epithelial cells (hAECs), which possess anti-inflammatory and regenerative properties, improves islet engraftment and survival. Shielded islets were generated on agarose microwells by mixing rat islets (RIs) or human islets (HI) and hAECs (100 hAECs/IEQ). Islet secretory function and viability were assessed after culture in hypoxia (1% O2 ) or normoxia (21% O2 ) in vitro. In vivo function was evaluated after transplant under the kidney capsule of diabetic immunodeficient mice. Graft morphology and vascularization were evaluated by immunohistochemistry. Both shielded RIs and HIs show higher viability and increased glucose-stimulated insulin secretion after exposure to hypoxia in vitro compared with control islets. Transplant of shielded islets results in considerably earlier normoglycemia and vascularization, an enhanced glucose tolerance, and a higher β cell mass. Our results show that hAECs have a clear cytoprotective effect against hypoxic damages in vitro. This strategy improves β cell mass engraftment and islet revascularization, leading to an improved capacity of islets to reverse hyperglycemia, and could be rapidly applicable in the clinical situation seeing that the modification to HIs are minor.
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Affiliation(s)
- Fanny Lebreton
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Kevin Bellofatto
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Charles H Wassmer
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Lisa Perez
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Vanessa Lavallard
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Géraldine Parnaud
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - David Cottet-Dumoulin
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Julie Kerr-Conte
- INSERM U1190, Translational Research for Diabetes, University of Lille, France
| | - François Pattou
- INSERM U1190, Translational Research for Diabetes, University of Lille, France
| | - Domenico Bosco
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Véronique Othenin-Girard
- Department of Pediatrics, Gynecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland
| | - Begoña Martinez de Tejada
- Department of Pediatrics, Gynecology and Obstetrics, Geneva University Hospitals, Geneva, Switzerland.,Faculty of Medicine, University of Geneva, Switzerland
| | - Ekaterine Berishvili
- Cell Isolation and Transplantation Center, Department of Surgery, Faculty Diabetes Center, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.,Institute of Medical Research, Ilia State University, Tbilisi, Georgia
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Rambøl MH, Han E, Niklason LE. Microvessel Network Formation and Interactions with Pancreatic Islets in Three-Dimensional Chip Cultures. Tissue Eng Part A 2020; 26:556-568. [PMID: 31724494 PMCID: PMC7249478 DOI: 10.1089/ten.tea.2019.0186] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 11/01/2019] [Indexed: 12/13/2022] Open
Abstract
The pancreatic islet is a highly vascularized micro-organ, and rapid revascularization postislet transplantation is important for islet survival and function. However, the various mechanisms involved in islet revascularization are not fully understood, and we currently lack good in vitro platforms to explore this. Our aim for this study was to generate perfusable microvascular networks in a microfluidic chip device, in which islets could be easily integrated, to establish an in vitro platform for investigations on islet-microvasculature interactions. We compared the ability of mesenchymal stem cells (MSCs) and fibroblasts to support microvascular network formation by human umbilical vein endothelial cells (HUVECs) and human induced pluripotent stem cell-derived endothelial colony-forming cell in two-dimensional and three-dimensional models of angiogenesis, and tested the effect of different culture media on microvessel formation. HUVECs that were supported by MSCs formed patent and perfusable networks in a fibrin gel, whereas networks supported by fibroblasts rapidly regressed. Network morphology could be controlled by adjusting relative cell numbers and densities. Incorporation of isolated rat islets demonstrated that islets recruit local microvasculature in vitro, but that the microvessels did not invade islets, at least during the course of these studies. This in vitro microvascularization platform can provide a useful tool to study how various parameters affect islet integration with microvascular networks and could also be utilized for studies of vascularization of other organ systems. Impact statement To improve pancreatic islet graft survival and function posttransplantation, rapid and adequate revascularization is critical. Efforts to improve islet revascularization are demanding due to an insufficient understanding of the mechanisms involved in the process. We have applied a microfluidics platform to generate microvascular networks, and by incorporating pancreatic islets, we were able to study microvasculature-islet interactions in real time. This platform can provide a useful tool to study islet integration with microvascular networks, and could be utilized for studies of vascularization of other organ systems. Moreover, this work may be adapted toward developing a prevascularized islet construct for transplantation.
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Affiliation(s)
- Mia H. Rambøl
- Department of Molecular Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Edward Han
- Department of Biomedical Engineering and Yale University, New Haven, Connecticut, USA
- Department of Anesthesiology, Yale University, New Haven, Connecticut, USA
| | - Laura E. Niklason
- Department of Biomedical Engineering and Yale University, New Haven, Connecticut, USA
- Department of Anesthesiology, Yale University, New Haven, Connecticut, USA
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Huang J, Huang JH, Bao H, Ning X, Yu C, Chen Z, Chao J, Zhang Z. CT/MR Dual-Modality Imaging Tracking of Mesenchymal Stem Cells Labeled with a Au/GdNC@SiO 2 Nanotracer in Pulmonary Fibrosis. ACS APPLIED BIO MATERIALS 2020; 3:2489-2498. [PMID: 35025299 DOI: 10.1021/acsabm.0c00195] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem cells (MSCs) have shown potential as an innovative treatment for pulmonary fibrosis (PF), due to their capability to ameliorate the inflammation and moderate the deterioration of PF. The fate of the stem cells transplanted into the lung, including survival, migration, homing, and functions, however, has not been fully understood yet. In this paper, we report the development of a computed tomography/magnetic resonance (CT/MR) dual-modal nanotracer, gold/gadolinium nanoclusters overcoated with a silica shell (Au/GdNC@SiO2), for noninvasive labeling and tracking of the transplanted human MSCs (hMSCs) in a PF model. The Au/GdNC@SiO2 nanotracer exhibits good colloidal and chemical stability, high biocompatibility, enhanced longitudinal MR relaxivity, and superior X-ray attenuation property. The hMSCs can be effectively labeled with Au/GdNC@SiO2, resulting in a significantly increased cellular CT/MR imaging contrast, without any obvious adverse effect on the function, including proliferation and differentiation of the labeled stem cells. Moreover, by using the Au/GdNC@SiO2 nanotracer, the hMSCs transplanted in the lung can be tracked for 7 d via in vivo CT/MR dual-modality imaging. This work may provide an insight into the role the transplanted hMSCs play in PF therapy, thus promoting the stem cell-based regenerative medicine.
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Affiliation(s)
- Jie Huang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| | - Jie Holly Huang
- Department of Physiology, School of Medicine, Southeast University, Nanjing 210009 Jiangsu, China
| | - Hongying Bao
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| | - Xinyu Ning
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| | - Chenggong Yu
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| | - Zhongjin Chen
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
| | - Jie Chao
- Department of Physiology, School of Medicine, Southeast University, Nanjing 210009 Jiangsu, China
| | - Zhijun Zhang
- CAS Key Laboratory of Nano-Bio Interface, Division of Nanobiomedicine, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123 Jiangsu, China
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Primavera R, Kevadiya BD, Swaminathan G, Wilson RJ, De Pascale A, Decuzzi P, Thakor AS. Emerging Nano- and Micro-Technologies Used in the Treatment of Type-1 Diabetes. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E789. [PMID: 32325974 PMCID: PMC7221526 DOI: 10.3390/nano10040789] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/07/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
Type-1 diabetes is characterized by high blood glucose levels due to a failure of insulin secretion from beta cells within pancreatic islets. Current treatment strategies consist of multiple, daily injections of insulin or transplantation of either the whole pancreas or isolated pancreatic islets. While there are different forms of insulin with tunable pharmacokinetics (fast, intermediate, and long-acting), improper dosing continues to be a major limitation often leading to complications resulting from hyper- or hypo-glycemia. Glucose-responsive insulin delivery systems, consisting of a glucose sensor connected to an insulin infusion pump, have improved dosing but they still suffer from inaccurate feedback, biofouling and poor patient compliance. Islet transplantation is a promising strategy but requires multiple donors per patient and post-transplantation islet survival is impaired by inflammation and suboptimal revascularization. This review discusses how nano- and micro-technologies, as well as tissue engineering approaches, can overcome many of these challenges and help contribute to an artificial pancreas-like system.
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Affiliation(s)
- Rosita Primavera
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, USA; (R.P.); (B.D.K.); (G.S.); (R.J.W.)
- Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, 16163 Genoa, Italy
| | - Bhavesh D Kevadiya
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, USA; (R.P.); (B.D.K.); (G.S.); (R.J.W.)
| | - Ganesh Swaminathan
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, USA; (R.P.); (B.D.K.); (G.S.); (R.J.W.)
| | - Rudilyn Joyce Wilson
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, USA; (R.P.); (B.D.K.); (G.S.); (R.J.W.)
| | - Angelo De Pascale
- Unit of Endocrinology, Department of Internal Medicine & Medical Specialist (DIMI), University of Genoa, 16163 Genoa, Italy;
| | - Paolo Decuzzi
- Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, 16163 Genoa, Italy
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, USA; (R.P.); (B.D.K.); (G.S.); (R.J.W.)
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Komatsu H, Gonzalez N, Salgado M, Cook CA, Li J, Rawson J, Omori K, Tai Y, Kandeel F, Mullen Y. A subcutaneous pancreatic islet transplantation platform using a clinically applicable, biodegradable Vicryl mesh scaffold ‐ an experimental study. Transpl Int 2020; 33:806-818. [DOI: 10.1111/tri.13607] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 12/27/2019] [Accepted: 03/17/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Hirotake Komatsu
- Department of Translational Research & Cellular Therapeutics Beckman Research Institute of City of Hope Duarte CA USA
| | - Nelson Gonzalez
- Department of Translational Research & Cellular Therapeutics Beckman Research Institute of City of Hope Duarte CA USA
| | - Mayra Salgado
- Department of Translational Research & Cellular Therapeutics Beckman Research Institute of City of Hope Duarte CA USA
| | - Colin A. Cook
- Department of Electrical Engineering California Institute of Technology Pasadena CA USA
| | - Junfeng Li
- Department of Translational Research & Cellular Therapeutics Beckman Research Institute of City of Hope Duarte CA USA
| | - Jeffrey Rawson
- Department of Translational Research & Cellular Therapeutics Beckman Research Institute of City of Hope Duarte CA USA
| | - Keiko Omori
- Department of Translational Research & Cellular Therapeutics Beckman Research Institute of City of Hope Duarte CA USA
| | - Yu‐Chong Tai
- Department of Electrical Engineering California Institute of Technology Pasadena CA USA
| | - Fouad Kandeel
- Department of Translational Research & Cellular Therapeutics Beckman Research Institute of City of Hope Duarte CA USA
| | - Yoko Mullen
- Department of Translational Research & Cellular Therapeutics Beckman Research Institute of City of Hope Duarte CA USA
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Kuppan P, Seeberger K, Kelly S, Rosko M, Adesida A, Pepper AR, Korbutt GS. Co‐transplantation of human adipose‐derived mesenchymal stem cells with neonatal porcine islets within a prevascularized subcutaneous space augments the xenograft function. Xenotransplantation 2020; 27:e12581. [DOI: 10.1111/xen.12581] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/19/2019] [Accepted: 12/27/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Purushothaman Kuppan
- Alberta Diabetes Institute University of Alberta Edmonton AB Canada
- Department of Surgery University of Alberta Edmonton AB Canada
| | - Karen Seeberger
- Alberta Diabetes Institute University of Alberta Edmonton AB Canada
- Department of Surgery University of Alberta Edmonton AB Canada
| | - Sandra Kelly
- Alberta Diabetes Institute University of Alberta Edmonton AB Canada
- Department of Surgery University of Alberta Edmonton AB Canada
| | - Mandy Rosko
- Alberta Diabetes Institute University of Alberta Edmonton AB Canada
- Department of Surgery University of Alberta Edmonton AB Canada
| | - Adetola Adesida
- Department of Surgery 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 AB Canada
| | - Gregory S. Korbutt
- Alberta Diabetes Institute University of Alberta Edmonton AB Canada
- Department of Surgery University of Alberta Edmonton AB Canada
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Characterization and therapeutic applications of mesenchymal stem cells for regenerative medicine. Tissue Cell 2020; 64:101330. [PMID: 32473704 DOI: 10.1016/j.tice.2020.101330] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/04/2020] [Accepted: 01/05/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) are multipotent, genomic stable, self-renewable, and culturally expandable adult stem cells. MSCs facilitate tissue development, maintenance and repair, and produce secretory factors that support engraftment and trophic functions, marking them an attractive option in cell therapy, regenerative medicine and tissue engineering. METHOD In this review, we summarize the recent researches regarding the isolation and characterization of MSCs, therapeutic applications and advanced engineering techniques. We also discuss the advantages and limitations that remain to be overcome for MSCs based therapy. RESULTS It has been demonstrated that MSCs are able to modulate endogenous tissue and immune cells. Preclinical studies and early phase clinical trials have shown their great potential for tissue engineering of bone, cartilage, marrow stroma, muscle, fat, and other connective tissues. CONCLUSIONS MSC-based therapy show considerable promise to rebuild damaged or diseased tissues, which could be a promising therapeutic method for regeneration medicine.
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Chen P, He F, Liu T, Ma S, Shi B. Construction of calcitonin gene-related peptide-modified mesenchymal stem cells and analysis of their effects on the migration and proliferation of vascular smooth muscle cells. In Vitro Cell Dev Biol Anim 2020; 56:181-191. [PMID: 31912458 DOI: 10.1007/s11626-019-00429-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 12/09/2019] [Indexed: 10/25/2022]
Abstract
Lentiviral expression vectors for calcitonin gene-related peptide (CGRP) were used to transfect rat bone marrow mesenchymal stem cells (MSCs). After assessing the biological characteristics of proliferation and aging in MSCs transfected with CGRP, we observed the effects of the CGRP-modified rat MSCs on the migration and proliferation of rat vascular smooth muscle cells (VSMCs) in vitro. Rat MSCs were isolated, cultured in vitro, and identified by flow cytometry. A CGRP recombinant lentivirus was transfected into MSCs. The transfection efficiency was determined by fluorescence microscopy and flow cytometry, and CGRP in MSCs was detected by real-time quantitative PCR, ELISA, and immunofluorescence. The proliferation and senescence of CGRP-modified MSCs were evaluated by MTT assay and beta-galactosidase staining. VSMCs were isolated, cultured in vitro, and identified by immunofluorescence. CGRP-modified MSCs and VSMCs were cocultured in a Transwell system. The proliferation and migration of VSMCs were evaluated by scratch testing and the MTT method. Rat bone marrow MSCs showed a spindle-shaped morphology, adherent growth in vitro, positive CD29 and CD90 expression, and negative CD45 expression. CGRP was stably expressed in MSCs after 48 h of recombinant lentivirus transfection. CGRP mRNA and protein secretion in CGRP recombinant lentivirus-transfected MSCs were higher than that in control MSCs. Immunofluorescence showed that CGRP protein could be expressed in CGRP-modified MSCs. The proliferation ability and senescence rates did not differ between lentivirus-transfected MSCs and untransfected MSCs. Rat VSMCs expressed α-SMA protein and exhibited a spindle-shaped morphology and adherent growth in vitro. In Transwell coculture experiments, scratch testing of VSMCs showed that CGRP-modified MSCs could reduce VSMC proliferation and migration. The CGRP gene can be stably expressed in MSCs after CGRP recombinant lentivirus transfection. CGRP recombinant lentivirus transfection has little effect on the proliferation or senescence of MSCs, and CGRP-modified MSCs can inhibit the proliferation and migration of VSMCs. These results lay a foundation for research on the use of CGRP gene-engineered MSCs in restenosis therapy.
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Affiliation(s)
- Panke Chen
- Department of Cardiology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Fang He
- Key Laboratory of Cell Engineering in Guizhou Province, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Tao Liu
- Department of Neurology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Shuai Ma
- Department of Cardiology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China
| | - Bei Shi
- Department of Cardiology, The Affiliated Hospital of Zunyi Medical University, Zunyi, 563003, Guizhou, China.
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