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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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Goyal P, Malviya R. Stem Cell Therapy for the Management of Type 1 Diabetes: Advances and Perspectives. Endocr Metab Immune Disord Drug Targets 2024; 24:549-561. [PMID: 37861029 DOI: 10.2174/0118715303256582230919093535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 07/20/2023] [Accepted: 08/25/2023] [Indexed: 10/21/2023]
Abstract
Due to insulin resistance and excessive blood sugar levels, type 1 diabetes mellitus (T1DM) is characterized by pancreatic cell loss. This condition affects young people at a higher rate than any other chronic autoimmune disease. Regardless of the method, exogenous insulin cannot substitute for insulin produced by a healthy pancreas. An emerging area of medicine is pancreatic and islet transplantation for type 1 diabetics to restore normal blood sugar regulation. However, there are still obstacles standing in the way of the widespread use of these therapies, including very low availability of pancreatic and islets supplied from human organ donors, challenging transplantation conditions, high expenses, and a lack of easily accessible methods. Efforts to improve Type 1 Diabetes treatment have been conducted in response to the disease's increasing prevalence. Type 1 diabetes may one day be treated with stem cell treatment. Stem cell therapy has proven to be an effective treatment for type 1 diabetes. Recent progress in stem cell-based diabetes treatment is summarised, and the authors show how to isolate insulin-producing cells (IPCs) from a variety of progenitor cells.
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Affiliation(s)
- Priyanshi Goyal
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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3
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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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Jeon S, Lee YS, Oh SR, Jeong J, Lee DH, So KH, Hwang NS. Recent advances in endocrine organoids for therapeutic application. Adv Drug Deliv Rev 2023; 199:114959. [PMID: 37301512 DOI: 10.1016/j.addr.2023.114959] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/21/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
The endocrine system, consisting of the hypothalamus, pituitary, endocrine glands, and hormones, plays a critical role in hormone metabolic interactions. The complexity of the endocrine system is a significant obstacle to understanding and treating endocrine disorders. Notably, advances in endocrine organoid generation allow a deeper understanding of the endocrine system by providing better comprehension of molecular mechanisms of pathogenesis. Here, we highlight recent advances in endocrine organoids for a wide range of therapeutic applications, from cell transplantation therapy to drug toxicity screening, combined with development in stem cell differentiation and gene editing technologies. In particular, we provide insights into the transplantation of endocrine organoids to reverse endocrine dysfunctions and progress in developing strategies for better engraftments. We also discuss the gap between preclinical and clinical research. Finally, we provide future perspectives for research on endocrine organoids for the development of more effective treatments for endocrine disorders.
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Affiliation(s)
- Suwan Jeon
- Interdisciplinary Program for Biochemical Engineering and Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
| | - Young-Sun Lee
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea
| | - Seh Ri Oh
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea
| | - Jinseong Jeong
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea
| | - Dong-Hyun Lee
- Interdisciplinary Program for Biochemical Engineering and Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
| | - Kyoung-Ha So
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea; Bio-MAX/N-Bio Institute, Institute of Bio-Engineering, Seoul National University, Seoul 08826, Republic of Korea.
| | - Nathaniel S Hwang
- Interdisciplinary Program for Biochemical Engineering and Biotechnology, Seoul National University, Seoul 08826, Republic of Korea; School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea; Bio-MAX/N-Bio Institute, Institute of Bio-Engineering, Seoul National University, Seoul 08826, Republic of Korea; Institute of Engineering Research, Seoul National University, Seoul, 08826, Republic of Korea.
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5
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Marín-Llera JC, García-García D, Garay-Pacheco E, Adrian Cortes-Morales V, Montesinos-Montesinos JJ, Chimal-Monroy J. Commitment of human mesenchymal stromal cells to skeletal lineages is independent of their morphogenetic capacity. World J Stem Cells 2023; 15:701-712. [PMID: 37545756 PMCID: PMC10401422 DOI: 10.4252/wjsc.v15.i7.701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 05/18/2023] [Accepted: 06/25/2023] [Indexed: 07/25/2023] Open
Abstract
BACKGROUND Mesenchymal stromal cells (MSCs) are multipotent cell populations obtained from fetal and adult tissues. They share some characteristics with limb bud mesodermal cells such as differentiation potential into osteogenic, chondrogenic, and tenogenic lineages and an embryonic mesodermal origin. Although MSCs differentiate into skeletal-related lineages in vitro, they have not been shown to self-organize into complex skeletal structures or connective tissues, as in the limb. In this work, we demonstrate that the expression of molecular markers to commit MSCs to skeletal lineages is not sufficient to generate skeletal elements in vivo.
AIM To evaluate the potential of MSCs to differentiate into skeletal lineages and generate complex skeletal structures using the recombinant limb (RL) system.
METHODS We used the experimental system of RLs from dissociated-reaggregated human placenta (PL) and umbilical cord blood (UCB) MSCs. After being harvested and reaggregated in a pellet, cultured cells were introduced into an ectodermal cover obtained from an early chicken limb bud. Next, this filled ectoderm was grafted into the back of a donor chick embryo. Under these conditions, the cells received and responded to the ectoderm’s embryonic signals in a spatiotemporal manner to differentiate and pattern into skeletal elements. Their response to differentiation and morphogenetic signals was evaluated by quantitative polymerase chain reaction, histology, immunofluorescence, scanning electron microscopy, and in situ hybridization.
RESULTS We found that human PL-MSCs and UCB-MSCs constituting the RLs expressed chondrogenic, osteogenic, and tenogenic molecular markers while differentially committing into limb lineages but could not generate complex structures in vivo. MSCs-RL from PL or UCB were committed early to chondrogenic lineage. Nevertheless, the UCB-RL osteogenic commitment was favored, although preferentially to a tenogenic cell fate. These findings suggest that the commitment of MSCs to differentiate into skeletal lineages differs according to the source and is independent of their capacity to generate skeletal elements or connective tissue in vivo. Our results suggest that the failure to form skeletal structures may be due to the intrinsic characteristics of MSCs. Thus, it is necessary to thoroughly evaluate the biological aspects of MSCs and how they respond to morphogenetic signals in an in vivo context.
CONCLUSION PL-MSCs and UCB-MSCs express molecular markers of differentiation into skeletal lineages, but they are not sufficient to generate complex skeletal structures in vivo.
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Affiliation(s)
- Jessica Cristina Marín-Llera
- Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Coyoacan 04510, Mexico
| | - Damián García-García
- Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Coyoacan 04510, Mexico
| | - Estefania Garay-Pacheco
- Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Coyoacan 04510, Mexico
| | - Victor Adrian Cortes-Morales
- Laboratorio de Células Troncales Mesenquimales, Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
| | - Juan Jose Montesinos-Montesinos
- Laboratorio de Células Troncales Mesenquimales, Unidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico
| | - Jesus Chimal-Monroy
- Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Coyoacan 04510, Mexico
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Tokuda K, Ikemoto T, Yamashita S, Miyazaki K, Okikawa S, Yamada S, Saito Y, Morine Y, Shimada M. Syngeneically transplanted insulin producing cells differentiated from adipose derived stem cells undergo delayed damage by autoimmune responses in NOD mice. Sci Rep 2022; 12:5852. [PMID: 35393479 PMCID: PMC8991208 DOI: 10.1038/s41598-022-09838-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 03/21/2022] [Indexed: 11/09/2022] Open
Abstract
Insulin-producing cells (IPCs) generated by our established protocol have reached the non-clinical ‘proof of concept’ stage. Our strategy for their clinical application is the autotransplantation of IPCs into patients with type 1 diabetes mellitus (T1DM). In this context, the autoimmunity that characterized T1DM is important, rather than allorejection. We aimed to determine how these IPCs respond to T1DM autoimmunity. IPCs were generated from the subcutaneous fat tissue of non-obese diabetic (NOD) mice using our protocol. IPCs derived from NOD mice were transplanted under the kidney capsules of NOD mice at the onset of diabetes and the subsequent changes in blood glucose concentration were characterized. Blood glucose decreased within 30 days of transplantation, but increased again after 40–60 days in three of four recipient NOD mice. In tissue samples, the numbers of CD4+ and CD8+ T cells were significantly higher 60 days after transplantation than 30 days after transplantation. In conclusion, IPCs significantly ameliorate the diabetes of mice in the short term, but are damaged by autoimmunity in the longer term, as evidenced by local T cells accumulation. This study provides new insights into potential stem cell therapies for T1DM.
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Affiliation(s)
- Kazunori Tokuda
- Department of Digestive and Transplant Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Tetsuya Ikemoto
- Department of Digestive and Transplant Surgery, Tokushima University, Tokushima, 770-8503, Japan.
| | - Shoko Yamashita
- Department of Digestive and Transplant Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Katsuki Miyazaki
- Department of Digestive and Transplant Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Shohei Okikawa
- Department of Digestive and Transplant Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Shinichiro Yamada
- Department of Digestive and Transplant Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Yu Saito
- Department of Digestive and Transplant Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Yuji Morine
- Department of Digestive and Transplant Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Mitsuo Shimada
- Department of Digestive and Transplant Surgery, Tokushima University, Tokushima, 770-8503, Japan
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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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8
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Tur DA, Khotskin NV, Akulov AE. Sex difference feeding behaviour of NOD SCID mice in a pharmacological model of type 1 diabetes. J Anim Physiol Anim Nutr (Berl) 2021; 105:984-988. [PMID: 33655640 DOI: 10.1111/jpn.13517] [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: 03/02/2020] [Revised: 11/01/2020] [Accepted: 11/28/2020] [Indexed: 11/29/2022]
Abstract
This study aimed to assess the sex differences in the feeding behaviour of non-obese diabetic severe combined immunodeficient (NOD SCID) mice in a pharmacological model of type 1 diabetes mellitus (T1Dm). In our study, we chose NOD SCID mice of both sexes and assessed their feeding behaviour, body weight, body fat and water content under identical experimental conditions and diets. After 1 month of diabetes mellitus in mice in the experimental group, males and females did not show any increase in body weight, and they weighed significantly less than the control group. However, compared with the control group, in females with a background of T1Dm, there was a significant decrease in body fat. The amount of water consumed in the experimental groups was higher than that in the control groups. The amount of food consumed by males increased when they increased their water consumption, whereas food consumption in females decreased significantly with an increase in water consumption. Thus, we discovered sex differences in the feeding behaviour, body weight and body fat and water content in the pharmacological model of T1Dm after 1 month in NOD SCID mice.
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Affiliation(s)
- Daria A Tur
- The Federal Research Center Institute of Cytology and Genetics, SB RAS, Novosibirsk, Russia
| | - Nikita V Khotskin
- The Federal Research Center Institute of Cytology and Genetics, SB RAS, Novosibirsk, Russia
| | - Andrey E Akulov
- The Federal Research Center Institute of Cytology and Genetics, SB RAS, Novosibirsk, Russia
- Novosibirsk State University, Novosibirsk, Russia
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Ghasemi A, Akbari E, Imani R. An Overview of Engineered Hydrogel-Based Biomaterials for Improved β-Cell Survival and Insulin Secretion. Front Bioeng Biotechnol 2021; 9:662084. [PMID: 34513805 PMCID: PMC8427138 DOI: 10.3389/fbioe.2021.662084] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 07/16/2021] [Indexed: 12/28/2022] Open
Abstract
Islet transplantation provides a promising strategy in treating type 1 diabetes as an autoimmune disease, in which damaged β-cells are replaced with new islets in a minimally invasive procedure. Although islet transplantation avoids the complications associated with whole pancreas transplantations, its clinical applications maintain significant drawbacks, including long-term immunosuppression, a lack of compatible donors, and blood-mediated inflammatory responses. Biomaterial-assisted islet transplantation is an emerging technology that embeds desired cells into biomaterials, which are then directly transplanted into the patient, overcoming the aforementioned challenges. Among various biomaterials, hydrogels are the preferred biomaterial of choice in these transplants due to their ECM-like structure and tunable properties. This review aims to present a comprehensive overview of hydrogel-based biomaterials that are engineered for encapsulation of insulin-secreting cells, focusing on new hydrogel design and modification strategies to improve β-cell viability, decrease inflammatory responses, and enhance insulin secretion. We will discuss the current status of clinical studies using therapeutic bioengineering hydrogels in insulin release and prospective approaches.
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Affiliation(s)
| | | | - Rana Imani
- Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran
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10
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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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11
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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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12
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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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13
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Gurlin RE, Giraldo JA, Latres E. 3D Bioprinting and Translation of Beta Cell Replacement Therapies for Type 1 Diabetes. TISSUE ENGINEERING PART B-REVIEWS 2020; 27:238-252. [PMID: 32907514 DOI: 10.1089/ten.teb.2020.0192] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Type 1 diabetes (T1D) is an autoimmune disorder in which the body's own immune system selectively attacks beta cells within pancreatic islets resulting in insufficient insulin production and loss of the ability to regulate blood glucose (BG) levels. Currently, the standard of care consists of BG level monitoring and insulin administration, which are essential to avoid the consequences of dysglycemia and long-term complications. Although recent advances in continuous glucose monitoring and automated insulin delivery systems have resulted in improved clinical outcomes for users, nearly 80% of people with T1D fail to achieve their target hemoglobin A1c (HbA1c) levels defined by the American Diabetes Association. Intraportal islet transplantation into immunosuppressed individuals with T1D suffering from impaired awareness of hypoglycemia has resulted in lower HbA1c, elimination of severe hypoglycemic events, and insulin independence, demonstrating the unique potential of beta cell replacement therapy (BCRT) in providing optimal glycemic control and a functional cure for T1D. BCRTs need to maximize cell engraftment, long-term survival, and function in the absence of immunosuppression to provide meaningful clinical outcomes to all people living with T1D. One innovative technology that could enable widespread translation of this approach into the clinic is three-dimensional (3D) bioprinting. Herein, we review how bioprinting could facilitate translation of BCRTs as well as the current and forthcoming techniques used for bioprinting of a BCRT product. We discuss the strengths and weaknesses of 3D bioprinting in this context in addition to the road ahead for the development of BCRTs. Impact statement Significant research developments in beta cell replacement therapies show its promise in providing a functional cure for type 1 diabetes (T1D); yet, their widespread clinical use has been difficult to achieve. This review provides a brief overview of the requirements for a beta cell replacement product followed by a discussion on both the promise and limitations of three-dimensional bioprinting in facilitating the fabrication of such products to enable translation into the clinic. Advancements in this area could be a key component to unlocking the safety and effectiveness of beta cell therapy for T1D.
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Affiliation(s)
- Rachel E Gurlin
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA
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14
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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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15
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Menger MM, Nalbach L, Roma LP, Körbel C, Wrublewsky S, Glanemann M, Laschke MW, Menger MD, Ampofo E. Erythropoietin accelerates the revascularization of transplanted pancreatic islets. Br J Pharmacol 2020; 177:1651-1665. [PMID: 31721150 DOI: 10.1111/bph.14925] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 10/30/2019] [Accepted: 11/03/2019] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND AND PURPOSE Pancreatic islet transplantation is a promising therapeutic approach for Type 1 diabetes. A major prerequisite for the survival of grafted islets is a rapid revascularization after transplantation. Erythropoietin (EPO), the primary regulator of erythropoiesis, has been shown to promote angiogenesis. Therefore, we investigated in this study whether EPO improves the revascularization of transplanted islets. EXPERIMENTAL APPROACH Islets from FVB/N mice were transplanted into dorsal skinfold chambers of recipient animals, which were daily treated with an intraperitoneal injection of EPO (500 IU·kg-1 ) or vehicle (control) throughout an observation period of 14 days. In a second set of experiments, animals were only pretreated with EPO over a 6-day period prior to islet transplantation. The revascularization of the grafts was assessed by repetitive intravital fluorescence microscopy and immunohistochemistry. In addition, a streptozotocin-induced diabetic mouse model was used to study the effect of EPO-pretreatment on the endocrine function of the grafts. KEY RESULTS EPO treatment slightly accelerated the revascularization of the islet grafts. This effect was markedly more pronounced in EPO-pretreated animals, resulting in significantly higher numbers of engrafted islets and an improved perfusion of endocrine tissue without affecting systemic haematocrit levels when compared with controls. Moreover, EPO-pretreatment significantly accelerated the recovery of normoglycaemia in diabetic mice after islet transplantation. CONCLUSION AND IMPLICATIONS These findings demonstrate that, particularly, short-term EPO-pretreatment represents a promising therapeutic approach to improve the outcome of islet transplantation, without an increased risk of thromboembolic events.
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Affiliation(s)
- Maximilian M Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Lisa Nalbach
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Leticia P Roma
- Biophysics Department, Center for Human and Molecular Biology, Saarland University, Homburg/Saar, Germany
| | - Christina Körbel
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Selina Wrublewsky
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Matthias Glanemann
- Department for General, Visceral, Vascular and Pediatric Surgery, Saarland University, Homburg/Saar, Germany
| | - Matthias W Laschke
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Michael D Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Emmanuel Ampofo
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
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16
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Abstract
Islet transplantation is a potential treatment for Type 1 diabetes; however, improvements need to be made before it could become clinically widely available. In preclinical studies, the mouse is often used to model islet transplantation, with most studies aiming to improve transplantation outcome by manipulating the islets prior to transplantation or by treating the recipient mouse. Here, we describe the process of islet transplantation in the mouse, including how one can make the mouse diabetic, isolate donor islets, and transplant the islets into two different sites. Finally, we discuss how to assess the outcome of the transplantation in order to determine whether the experimental intervention has been beneficial.
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Affiliation(s)
- Aileen J F King
- Diabetes Research Group, School of Life Course Sciences, King's College London, London, UK.
| | - Chloe L Rackham
- Diabetes Research Group, School of Life Course Sciences, King's College London, London, UK
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17
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Ishida N, Ishiyama K, Saeki Y, Tanaka Y, Ohdan H. Cotransplantation of preactivated mesenchymal stem cells improves intraportal engraftment of islets by inhibiting liver natural killer cells in mice. Am J Transplant 2019; 19:2732-2745. [PMID: 30859713 DOI: 10.1111/ajt.15347] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 02/10/2019] [Accepted: 03/03/2019] [Indexed: 01/25/2023]
Abstract
The activation of natural killer (NK) cells in the liver inhibits engraftment of intraportally transplanted islets. We attempted to modulate the activity of NK cells by cotransplanting mesenchymal stem cells (MSCs) with islets in mice. We first investigated the ability of MSCs to secrete prostaglandin E2 , a predominant inhibitor of NK cell function, in various combinations of inflammatory cytokines. Notably, we found that prostaglandin E2 production was partially delayed in MSCs activated by inflammatory cytokines in vitro, whereas liver NK cells were activated early after islet transplant in vivo. Accordingly, preactivated MSCs, but not naive MSCs, substantially suppressed the expression of activation markers in liver NK cells after cotransplant with islets. Similarly, cotransplant with preactivated MSCs, but not naive MSCs, markedly improved the survival of islet grafts. These results highlight MSC cotransplant as an effective and clinically feasible method for enhancing engraftment efficiency.
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Affiliation(s)
- Nobuki Ishida
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kohei Ishiyama
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.,Department of Surgery, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
| | - Yoshihiro Saeki
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuka Tanaka
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
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18
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Farooq T, Rehman K, Hameed A, Akash MSH. Stem Cell Therapy and Type 1 Diabetes Mellitus: Treatment Strategies and Future Perspectives. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1084:95-107. [PMID: 29896720 DOI: 10.1007/5584_2018_195] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is classified as an autoimmune disease which progressively results in the depletion of insulin-secreting β-cells. Consequently, the insulin secretion stops leading to hyperglycemic situations within the body. Under severe conditions, it also causes multi-organ diabetes-associated dysfunctionalities notably hypercoagulability, neuropathy, nephropathy, retinopathy, and sometimes organ failures. The prevalence of this disease has been noticed about 3% that has highlighted the serious concerns for healthcare professionals around the globe. For the treatment of this disease, the cell therapy is considered as an important therapeutic approach for the replacement of damaged β-cells. However, the development of autoantibodies unfortunately reduces their effectiveness with the passage of time and finally with the recurrence of diabetes mellitus. The development of new techniques for extraction and transplantation of islets failed to support this approach due to the issues related to major surgery and lifelong dependence on immunosuppression. For T1DM, such cells are supposed to produce, store, and supply insulin to maintain glucose homeostasis. The urgent need of much-anticipated substitute for insulin-secreting β-cells directed the researchers to focus on stem cells (SCs) to produce insulin-secreting β-cells. For being more specific and targeted therapeutic approaches, SC-based strategies opened up the new horizons to cure T1DM. This cell-based therapy aimed to produce functional insulin-secreting β-cells to cure diabetes on forever basis. The intrinsic regenerative potential along with immunomodulatory abilities of SCs highlights the therapeutic potential of SC-based strategies. In this article, we have comprehensively highlighted the role of SCs to treat diabetes mellitus.
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Affiliation(s)
- Tahir Farooq
- Department of Applied Chemistry, Government College University, Faisalabad, Pakistan
| | - Kanwal Rehman
- Institute of Pharmacy, Physiology and Pharmacology, University of Agriculture, Faisalabad, Pakistan.
| | - Arruje Hameed
- Department of Biochemistry, Government College University, Faisalabad, Pakistan
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19
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Human Fetal Bone Marrow-Derived Mesenchymal Stem Cells Promote the Proliferation and Differentiation of Pancreatic Progenitor Cells and the Engraftment Function of Islet-Like Cell Clusters. Int J Mol Sci 2019; 20:ijms20174083. [PMID: 31438545 PMCID: PMC6747176 DOI: 10.3390/ijms20174083] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/19/2019] [Accepted: 08/20/2019] [Indexed: 12/11/2022] Open
Abstract
Pancreatic progenitor cells (PPCs) are the primary source for all pancreatic cells, including beta-cells, and thus the proliferation and differentiation of PPCs into islet-like cell clusters (ICCs) opens an avenue to providing transplantable islets for diabetic patients. Meanwhile, mesenchymal stem cells (MSCs) can enhance the development and function of different cell types of interest, but their role on PPCs remains unknown. We aimed to explore the mechanism-of-action whereby MSCs induce the in vitro and in vivo PPC/ICC development by means of our established co-culture system of human PPCs with human fetal bone marrow-derived MSCs. We examined the effect of MSC-conditioned medium on PPC proliferation and survival. Meanwhile, we studied the effect of MSC co-culture enhanced PPC/ICC function in vitro and in vivo co-/transplantation. Furthermore, we identified IGF1 as a critical factor responsible for the MSC effects on PPC differentiation and proliferation via IGF1-PI3K/Akt and IGF1-MEK/ERK1/2, respectively. In conclusion, our data indicate that MSCs stimulated the differentiation and proliferation of human PPCs via IGF1 signaling, and more importantly, promoted the in vivo engraftment function of ICCs. Taken together, our protocol may provide a mechanism-driven basis for the proliferation and differentiation of PPCs into clinically transplantable islets.
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20
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Pancreatic ductal cells may have a negative effect on human islet transplantation. PLoS One 2019; 14:e0220064. [PMID: 31323061 PMCID: PMC6641198 DOI: 10.1371/journal.pone.0220064] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 07/07/2019] [Indexed: 02/07/2023] Open
Abstract
AIM To evaluate the effect of pancreatic ductal cells on experimental human islet transplantation. MATERIALS AND METHODS Isolated islets were additionally purified by handpicking. Ductal cells were purified by magnetic cell sorting and then clustered into ductal pancreatospheres (DPS). Islets, DPS, and islets + DPS (100 islets + 75 DPS, or 100 islets + 200 DPS) were cultured and glucose-stimulated insulin secretion, β-cell apoptosis, and gene expression was determined. Islets and islets + DPS preparations (800 islets + 600 DPS) were transplanted to streptozotocin-treated immunodeficient mice and glycemia, graft morphometry, and gene expression were determined. RESULTS Insulin stimulation index was higher in islets than in islets co-cultured with DPS (5.59 ± 0.93 vs 4.02 ± 0.46; p<0.05). IL1B and CXCL11 expression was higher in 100 islets + 200 DPS than in islets (p<0.01), and IL-1β was detected in supernatants collected from DPS and islets + DPS preparations, but not in islets. Hyperglycemia developed in 33% and 67% of mice transplanted with islets or with islets + DPS respectively. β-cell mass was 26% lower in islets + DPS than in islets grafts (p>0.05), and the ratio β-/endocrine non-β-cell mass was lower in islets + DPS grafts (islets: 2.05 ± 0.18, islets + DPS: 1.35 ± 0.15; p<0.01). IL1B and IL1RN expression was significantly higher in islets + DPS grafts. CONCLUSIONS Islet preparations enriched with ductal cells have a lower insulin stimulation index in vitro and achieved a worse metabolic outcome after transplantation. Inflammation may mediate the deleterious effects of ductal cells on islet cells.
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21
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Arzouni AA, Vargas-Seymour A, Dhadda PK, Rackham CL, Huang GC, Choudhary P, King AJF, Jones PM. Characterization of the Effects of Mesenchymal Stromal Cells on Mouse and Human Islet Function. Stem Cells Transl Med 2019; 8:935-944. [PMID: 31066521 PMCID: PMC6708063 DOI: 10.1002/sctm.19-0023] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 04/13/2019] [Indexed: 12/19/2022] Open
Abstract
Islet transplantation has the potential to cure type 1 diabetes, but current transplantation protocols are not optimal and there is extensive loss of islet β‐cell insulin secretory function during the immediate post‐transplantation period. Studies using experimental models of diabetes have shown that the coculture of islets with mesenchymal stromal cells (MSCs) prior to transplantation improves graft function, but several variables differed among research groups (e.g., type of MSCs used and the treatment conditions). We have therefore assessed the effects of MSCs on mouse and human islets by investigating the importance of tissue source for MSCs, the coculture protocol configuration and length, the effect of activated MSCs, and different β‐cell secretory stimuli. MSCs derived from adipose tissue (aMSCs) were the most effective at supporting β‐cell insulin secretion in both mouse and human islets, in a direct contact coculture configuration. Preculture with aMSCs enhanced both phases of glucose‐induced insulin secretion and further enhanced secretory responses to the non‐nutrients carbachol and arginine. These effects required a coculture period of 48–72 hours and were not dependent on activation of the MSCs. Thus, direct contact coculture with autologous, adipose‐derived MSCs for a minimum of 48 hours before implantation is likely to be an effective addition to human islet transplantation protocols. stem cells translational medicine2019;8:935&944
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Affiliation(s)
- Ahmed A Arzouni
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Andreia Vargas-Seymour
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Paramjeet K Dhadda
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Chloe L Rackham
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Guo-Cai Huang
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Pratik Choudhary
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Aileen J F King
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Peter M Jones
- Department of Diabetes, School of Life Course Sciences, King's College London, London, United Kingdom
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22
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Jiang K, Chaimov D, Patel SN, Liang JP, Wiggins SC, Samojlik MM, Rubiano A, Simmons CS, Stabler CL. 3-D physiomimetic extracellular matrix hydrogels provide a supportive microenvironment for rodent and human islet culture. Biomaterials 2019; 198:37-48. [PMID: 30224090 PMCID: PMC6397100 DOI: 10.1016/j.biomaterials.2018.08.057] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 07/31/2018] [Accepted: 08/27/2018] [Indexed: 01/19/2023]
Abstract
Organ-on-a-chip platforms serve as cost-efficient testbeds for screening pharmaceutical agents, mimicking natural physiology, and studying disease. In the field of diabetes, the development of an islet-on-a-chip platform would have broad implications in understanding disease pathology and discovering potential therapies. Islet microphysiological systems are limited, however, by their poor cell survival and function in culture. A key factor that has been implicated in this decline is the disruption of islet-matrix interactions following isolation. Herein, we sought to recapitulate the in vivo peri-islet niche using decellularized extracellular matrix (ECM) hydrogels. Sourcing from porcine bladder, lung, and pancreas tissues, 3-D ECM hydrogels were generated, characterized, and validated using both rodent and human pancreatic islets. Optimized decellularization protocols resulted in hydrogels with distinctive viscoelastic properties that correlated to their matrix composition. The in situ 3-D encapsulation of human or rat islets within ECM hydrogels resulted in improved functional stability over standard culture conditions. Islet composition and morphology were also altered, with enhanced retention of islet-resident endothelial cells and the formation of cord-like structures or sprouts emerging from the islet spheroid. These supportive 3-D physiomimetic ECM hydrogels can be leveraged within microfluidic platforms for the long-term culture of islets.
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Affiliation(s)
- K Jiang
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, United States
| | - D Chaimov
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, United States
| | - S N Patel
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, United States
| | - J-P Liang
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, United States
| | - S C Wiggins
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, United States
| | - M M Samojlik
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, United States
| | - A Rubiano
- Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL, United States
| | - C S Simmons
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, United States; Department of Mechanical and Aerospace Engineering, University of Florida, Gainesville, FL, United States
| | - C L Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, United States.
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Ren G, Rezaee M, Razavi M, Taysir A, Wang J, Thakor AS. Adipose tissue-derived mesenchymal stem cells rescue the function of islets transplanted in sub-therapeutic numbers via their angiogenic properties. Cell Tissue Res 2019; 376:353-364. [PMID: 30707291 DOI: 10.1007/s00441-019-02997-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 01/17/2019] [Indexed: 02/07/2023]
Abstract
A significant proportion of islets are lost following transplantation due to hypoxia and inflammation. We hypothesize that adipose tissue-derived mesenchymal stem cells (AD-MSCs) can rescue a sub-therapeutic number of transplanted islets by helping them establish a new blood supply and reducing inflammation. Diabetic mice received syngeneic transplantation with 75 (minimal), 150 (sub-therapeutic), or 225 (therapeutic) islets, with or without 1 × 106 mouse AD-MSCs. Fasting blood glucose (FBG) values were measured over 6 weeks with tissue samples collected for islet structure and morphology (H&E, insulin/glucagon staining). Histological and immunohistochemical analyses of islets were also performed at 2 weeks in animals transplanted with a sub-therapeutic number of islets, with and without AD-MSCs, to determine new blood vessel formation, the presence of pro-angiogenic factors facilitating revascularization, and the degree of inflammation. AD-MSCs had no beneficial effect on FBG values when co-transplanted with a minimal or therapeutic number of islets. However, AD-MSCs significantly reduced FBG values and restored glycemic control in diabetic animals transplanted with a sub-therapeutic number of islets. Islets co-transplanted with AD-MSCs preserved their native morphology and organization and exhibited less aggregation when compared to islets transplanted alone. In the sub-therapeutic group, AD-MSCs significantly increased islet revascularization and the expression of angiogenic factors including hepatocyte growth factor (HGF) and angiopoietin-1 (Ang-1) while also reducing inflammation. AD-MSCs can rescue the function of islets when transplanted in a sub-therapeutic number, for at least 6 weeks, via their ability to maintain islet architecture while concurrently facilitating islet revascularization and reducing inflammation.
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Affiliation(s)
- Gang Ren
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Melika Rezaee
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA.,Chicago Medical School, Rosalind Franklin University, North Chicago, IL, 60064, USA
| | - Mehdi Razavi
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Ahmed Taysir
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Jing Wang
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Stanford University, Department of Radiology, Palo Alto, CA, 94034, USA.
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Co-transplantation of mesenchymal stem cells improves spermatogonial stem cell transplantation efficiency in mice. Stem Cell Res Ther 2018; 9:317. [PMID: 30463610 PMCID: PMC6249754 DOI: 10.1186/s13287-018-1065-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 10/19/2018] [Accepted: 10/31/2018] [Indexed: 12/27/2022] Open
Abstract
Background Spermatogonial stem cell transplantation (SSCT) could become a fertility restoration tool for childhood cancer survivors. However, since in mice, the colonization efficiency of transplanted spermatogonial stem cells (SSCs) is only 12%, the efficiency of the procedure needs to be improved before clinical implementation is possible. Co-transplantation of mesenchymal stem cells (MSCs) might increase colonization efficiency of SSCs by restoring the SSC niche after gonadotoxic treatment. Methods A mouse model for long-term infertility was developed and used to transplant SSCs (SSCT, n = 10), MSCs (MSCT, n = 10), a combination of SSCs and MSCs (MS-SSCT, n = 10), or a combination of SSCs and TGFß1-treated MSCs (MSi-SSCT, n = 10). Results The best model for transplantation was obtained after intraperitoneal injection of busulfan (40 mg/kg body weight) at 4 weeks followed by CdCl2 (2 mg/kg body weight) at 8 weeks of age and transplantation at 11 weeks of age. Three months after transplantation, spermatogenesis resumed with a significantly better tubular fertility index (TFI) in all transplanted groups compared to non-transplanted controls (P < 0.001). TFI after MSi-SSCT (83.3 ± 19.5%) was significantly higher compared to MS-SSCT (71.5 ± 21.7%, P = 0.036) but did not differ statistically compared to SSCT (78.2 ± 12.5%). In contrast, TFI after MSCT (50.2 ± 22.5%) was significantly lower compared to SSCT (P < 0.001). Interestingly, donor-derived TFI was found to be significantly improved after MSi-SSCT (18.8 ± 8.0%) compared to SSCT (1.9 ± 1.1%; P < 0.001), MSCT (0.0 ± 0.0%; P < 0.001), and MS-SSCT (3.4 ± 1.9%; P < 0.001). While analyses showed that both native and TGFß1-treated MSCs maintained characteristics of MSCs, the latter showed less migratory characteristics and was not detected in other organs. Conclusion Co-transplanting SSCs and TGFß1-treated MSCs significantly improves the recovery of endogenous SSCs and increases the homing efficiency of transplanted SSCs. This procedure could become an efficient method to treat infertility in a clinical setup, once the safety of the technique has been proven. Electronic supplementary material The online version of this article (10.1186/s13287-018-1065-0) contains supplementary material, which is available to authorized users.
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Mesenchymal stem cells in combination with low-dose rapamycin significantly prolong islet allograft survival through induction of regulatory T cells. Biochem Biophys Res Commun 2018; 506:619-625. [DOI: 10.1016/j.bbrc.2018.10.070] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 10/11/2018] [Indexed: 12/13/2022]
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Rackham CL, Amisten S, Persaud SJ, King AJF, Jones PM. Mesenchymal stromal cell secretory factors induce sustained improvements in islet function pre- and post-transplantation. Cytotherapy 2018; 20:1427-1436. [PMID: 30377040 DOI: 10.1016/j.jcyt.2018.07.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 06/25/2018] [Accepted: 07/30/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) enhance islet function both in vitro and in vivo, at least in part by secreting ligands that activate islet G-protein coupled receptors (GPCRs). We assessed whether pre-treatment with a defined "cocktail" of MSC-secreted GPCR ligands enhances islet functional survival in vitro and improves the outcomes of islet transplantation in an experimental model of diabetes. METHODS Isolated islets were cultured for 48 h with ANXA1, SDF-1 or C3a, alone or in combination. Glucose-stimulated insulin secretion (GSIS) and cytokine-induced apoptosis were measured immediately after the 48 h culture period and at 24 h or 72 h following removal of the ligands from the culture media. Islets were syngeneically transplanted underneath the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice and blood glucose levels monitored for 28 days. RESULTS Pre-culturing islets with a cocktail of ANXA1/SDF-1/C3a potentiated GSIS and protected islet cells from cytokine-induced apoptosis in vitro. These effects were maintained for up to 72 h after the removal of the factors from the culture medium, suggesting a sustained protection of islet graft functional survival during the immediate post-transplantation period. Islets pre-treated with the cocktail of MSC secretory factors were more effective in reducing blood glucose in diabetic mice, consistent with their improved functional survival in vivo. DISCUSSION Pre-culturing islets with a cocktail of MSC secretory products offers a well-defined, cell-free approach to improve clinical islet transplantation outcomes while avoiding many of the safety, regulatory and logistical hurdles of incorporating MSCs into transplantation protocols.
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Affiliation(s)
- Chloe L Rackham
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
| | - Stefan Amisten
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Shanta J Persaud
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Aileen J F King
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Peter M Jones
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom.
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Navaei-Nigjeh M, Moloudizargari M, Baeeri M, Gholami M, Lotfibakhshaiesh N, Soleimani M, Vasheghani-Farahani E, Ai J, Abdollahi M. Reduction of marginal mass required for successful islet transplantation in a diabetic rat model using adipose tissue-derived mesenchymal stromal cells. Cytotherapy 2018; 20:1124-1142. [PMID: 30068495 DOI: 10.1016/j.jcyt.2018.06.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 05/10/2018] [Accepted: 06/06/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND AIMS Adipose tissue-derived mesenchymal stromal cells (AT-MSCs), widely known as multipotent progenitors, release several cytokines that support cell survival and repair. There are in vitro and in vivo studies reporting the regenerative role of AT-MSCs possibly mediated by their protective effects on functional islet cells as well as their capacity to differentiate into insulin-producing cells (IPCs). METHODS On such a basis, our goal in the present study was to use three different models including direct and indirect co-cultures and islet-derived conditioned medium (CM) to differentiate AT-MSCs into IPCs and to illuminate the molecular mechanisms of the beneficial impact of AT-MSCs on pancreatic islet functionality. Furthermore, we combined in vitro co-culture of islets and AT-MSCs with in vivo assessment of islet graft function to assess whether co-transplantation of islets with AT-MSCs can reduce marginal mass required for successful islet transplantation and prolong graft function in a diabetic rat model. RESULTS Our findings demonstrated that AT-MSCs are suitable for creating a microenvironment favorable for the repair and longevity of the pancreas β cells through the improvement of islet survival and maintenance of cell morphology and insulin secretion due to their potent properties in differentiation. Most importantly, hybrid transplantation of islets with AT-MSCs significantly promoted survival, engraftment and insulin-producing function of the graft and reduced the islet mass required for reversal of diabetes. CONCLUSIONS This strategy might be of therapeutic potential solving the problem of donor islet material loss that currently limits the application of allogeneic islet transplantation as a more widespread therapy for type 1 diabetes.
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Affiliation(s)
- Mona Navaei-Nigjeh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran; Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Science, Tehran, Iran
| | - Milad Moloudizargari
- Student Research Committee, Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Baeeri
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Science, Tehran, Iran
| | - Mahdi Gholami
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Science, Tehran, Iran
| | - Nasrin Lotfibakhshaiesh
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Masoud Soleimani
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | | | - Jafar Ai
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Science, Tehran, Iran; Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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Rackham CL, Jones PM. Potential of mesenchymal stromal cells for improving islet transplantation outcomes. Curr Opin Pharmacol 2018; 43:34-39. [PMID: 30103073 DOI: 10.1016/j.coph.2018.07.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 07/25/2018] [Accepted: 07/27/2018] [Indexed: 12/16/2022]
Abstract
Allogeneic islet transplantation as a therapy for Type 1 Diabetes (T1D) is restricted by the limited availability of donor islets, loss of functional islets during pre-transplantation culture in vitro and further extensive loss during the immediate post-transplantation period when islet function and survival is compromised by the hypoxic, inflammatory host environment. In the longer term pathogenic T cell responses drive autoimmunity and chronic allograft rejection. Experimental studies have demonstrated that mesenchymal stromal cells (MSCs) have significant potential to improve the outcomes of clinical islet transplantation. This review explores the potential for MSCs and their 'secretome' to influence donor islet cell function and survival, as well as the host niche. We discuss the possibility of harnessing the therapeutic benefits of MSCs in a cell-free strategy to offer a well-defined, cell-free approach to improve the outcomes of clinical islet transplantation.
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Affiliation(s)
- Chloe L Rackham
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London SE1 1UL, UK.
| | - Peter M Jones
- Department of Diabetes, School of Life Course Sciences, King's College London, Guy's Campus, London SE1 1UL, UK
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29
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Xiang C, Xie QP. Protection of mouse pancreatic islet function by co‑culture with hypoxia pre‑treated mesenchymal stromal cells. Mol Med Rep 2018; 18:2589-2598. [PMID: 30015882 DOI: 10.3892/mmr.2018.9235] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 04/19/2018] [Indexed: 11/05/2022] Open
Abstract
Ectogenic pancreatic islet transplantation has long been discussed as having the potential to reverse diabetes. The aim of the present study was to evaluate the therapeutic efficacy of co‑transplantation with hypoxia pretreated mesenchymal stem cells (MSCs) and islets in a diabetic mouse model. MSCs were isolated from femoral and tibial bone marrow aspirates from female BALB/c donor mice. MSC proliferation rates and the expression levels of vascular endothelial growth factor A (VEGFA), interleukin (IL)‑6, monocyte chemoattractant protein (MCP)‑1 and matrix metalloproteinase (MMP)‑9 were measured in hypoxic conditions. Subsequently, a streptozotocin‑induced diabetic model was established in BALB/c mice. Glucose tolerance and diabetes reversal rate following co‑transplantation of hypoxia pre‑cultured MSCs and islets were demonstrated at different conditions during transplantation. The present study results demonstrated that MSCs increased their proliferation rate and the secretion of growth‑related cytokines, including VEGFA, IL‑6, MCP‑1 and MMP‑9 in a hypoxic environment. In the diabetes animal model, fewer islets (~250) were required to reverse the impaired glucose tolerance condition in Islets + Hypoxia cultured MSCs transplant group compared with the Islets‑only group (~400 islets) and the Islets + Normal cultured MSCs group (~300 islets). Hypoxia‑cultured MSC co‑transplantation accelerated glycemic utilization following glucose intake. In subjects with hyperglycemia control for islet only transplantation group, MSCs pre‑cultured in hypoxic condition prior to co‑transplantation may potentially improve islet tissue regeneration.
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Affiliation(s)
- Cheng Xiang
- Department of Surgery, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
| | - Qiu-Ping Xie
- Department of Surgery, The Second Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China
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30
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Nie W, Ma X, Yang C, Chen Z, Rong P, Wu M, Jiang J, Tan M, Yi S, Wang W. Human mesenchymal-stem-cells-derived exosomes are important in enhancing porcine islet resistance to hypoxia. Xenotransplantation 2018; 25:e12405. [PMID: 29932262 DOI: 10.1111/xen.12405] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 03/25/2018] [Accepted: 04/16/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hypoxia-induced damage is one of the key factors associated with islet graft dysfunction. Mesenchymal stem cells (MSCs) could be used to enhance the therapeutic effect of islet transplantation due to their paracrine potential such as exosomes. In this study, we investigated whether exosomes from human umbilical cord-derived MSC-conditioned medium (hu-MSC-CM) could increase the survival and function of neonatal porcine islet cell clusters (NICCs) exposed to hypoxia. METHODS Neonatal porcine islet cell clusters were cultured with hu-MSC-CM, with or without exosomes, and native medium RPMI-1640 (Control) under hypoxic conditions (1% O2 ). The effects of exosomes on NICCs viability and function in vitro were examined by FACS, the Loops system, and the Extracellular Flux assay, respectively. RESULTS Compared with NICCs cultured in RPMI-1640 medium and hu-MSC-CM without exosomes, the survival ratio, viability, and function increased in NICCs cultured in hu-MSC-CM with exosomes. CONCLUSIONS This study found that hu-MSC-CM could protect NICCs from hypoxia-induced dysfunction, and exosomes played an important role in hypoxic resistance, suggesting a potential strategy to improve islet transplantation outcomes.
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Affiliation(s)
- Wei Nie
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Xiaoqian Ma
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Cejun Yang
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Zeyi Chen
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Pengfei Rong
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China
| | - Minghua Wu
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China
| | - Jianhui Jiang
- State Key Laboratory of Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha, China
| | - Mengqun Tan
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
| | - Shounan Yi
- Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China.,Center for Transplant and Renal Research, Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia
| | - Wei Wang
- Cell Transplantation and Gene Therapy Institute, The Third Xiang Ya Hospital, Central South University, Changsha, Hunan, China.,Engineering and Technology Research Center for Xenotransplantation of Hunan Province, Changsha, China
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Expansion of transplanted islets in mice by co-transplantation with adipose tissue-derived mesenchymal stem cells. Heliyon 2018; 4:e00632. [PMID: 29872765 PMCID: PMC5986537 DOI: 10.1016/j.heliyon.2018.e00632] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 03/14/2018] [Accepted: 05/15/2018] [Indexed: 01/09/2023] Open
Abstract
The shortage of donor islets is a significant obstacle for widespread clinical application of pancreatic islet transplantation. To investigate whether adipose tissue-derived mesenchymal stem cells (ADSCs) induce expansion of transplanted islets, we performed co-transplantation experiments in a mouse model. Streptozotosin (STZ)-induced diabetic mice transplanted with 50 syngeneic islets remained hyperglycemic. However, hyperglycemia was ameliorated gradually when 50 islets were co-transplanted with ADSCs but not separately grafted into the contralateral kidney. Insulin and proinsulin contents of 120-day grafts containing 50 islets co-transplanted with ADSCs were significantly increased compared with those of 50 isolated islets. The Ki67-positive ratios in islets of the naïve pancreas, at 30 and 120 days grafts were 0.23%, 2.12%, and 1.52%, respectively. Ki67-positive cells were predominantly Pdx1+ and insulin+ cells. These results demonstrate that co-transplantation with ADSCs induces proliferation of transplanted islets in mice, suggesting a potential solution for the low efficiency of islet transplantation.
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Arzouni AA, Vargas-Seymour A, Nardi N, J F King A, Jones PM. Using Mesenchymal Stromal Cells in Islet Transplantation. Stem Cells Transl Med 2018; 7:559-563. [PMID: 29749717 PMCID: PMC6090510 DOI: 10.1002/sctm.18-0033] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Accepted: 03/25/2018] [Indexed: 02/06/2023] Open
Abstract
Islet transplantation has the potential to cure type 1 diabetes, but current clinical transplantation protocols are inefficient because of the extensive loss of functional islets during the immediate post‐transplantation period. Studies in rodent models have demonstrated that co‐transplanting mesencyhmal stromal cells (MSCs) with islets improves graft functional survival and transplantation outcomes, and some of the beneficial effects of MSCs are attributable to bioactive molecules secreted by MSCs. Clinical islet transplantation is almost exclusively via the hepatic portal vein, which does not facilitate co‐engraftment of islets and MSCs, so attention is currently focused on using cell‐free cocktails of MSC‐derived products to treat islets prior to transplantation. This approach has the potential to overcome many of the technical and regulatory hurdles associated with using MSCs as an adjuvant therapy for human islet transplantation. Stem Cells Translational Medicine2018;7:559–563
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Affiliation(s)
- Ahmed A Arzouni
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Andreia Vargas-Seymour
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Nance Nardi
- Laboratory of Stem Cells and Tissue Engineering, Universidade Luterana do Brasil, Canoas, Rio Grande do Sul, Brazil
| | - Aileen J F King
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
| | - Peter M Jones
- Department of Diabetes, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
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Peng BY, Dubey NK, Mishra VK, Tsai FC, Dubey R, Deng WP, Wei HJ. Addressing Stem Cell Therapeutic Approaches in Pathobiology of Diabetes and Its Complications. J Diabetes Res 2018; 2018:7806435. [PMID: 30046616 PMCID: PMC6036791 DOI: 10.1155/2018/7806435] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 04/19/2018] [Accepted: 05/27/2018] [Indexed: 12/14/2022] Open
Abstract
High morbidity and mortality of diabetes mellitus (DM) throughout the human population is a serious threat which needs to be addressed cautiously. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are most prevalent forms. Disruption in insulin regulation and resistance leads to increased formation and accumulation of advanced end products (AGEs), which further enhance oxidative and nitrosative stress leading to microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular complications. These complications affect the normal function of organ and tissues and may cause life-threatening disorders, if hyperglycemia persists and improperly controlled. Current and traditional treatment procedures are only focused on to regulate the insulin level and do not cure the diabetic complications. Pancreatic transplantation seemed a viable alternative; however, it is limited due to lack of donors. Cell-based therapy such as stem cells is considered as a promising therapeutic agent against DM and diabetic complications owing to their multilineage differentiation and regeneration potential. Previous studies have demonstrated the various impacts of both pluripotent and multipotent stem cells on DM and its micro- and macrovascular complications. Therefore, this review summarizes the potential of stem cells to treat DM and its related complications.
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Affiliation(s)
- Bou-Yue Peng
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 110, Taiwan
- Department of Dentistry, Taipei Medical University Hospital, Taipei City 110, Taiwan
| | - Navneet Kumar Dubey
- Ceramics and Biomaterials Research Group, Advanced Institute of Materials Science, Ton Duc Thang University, Ho Chi Minh City, Vietnam
- Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
| | - Viraj Krishna Mishra
- Applied Biotech Engineering Centre (ABEC), Department of Biotechnology, Ambala College of Engineering and Applied Research, Ambala, India
| | - Feng-Chou Tsai
- Department of Stem Cell Research, Cosmetic Clinic Group, Taipei City 110, Taiwan
| | - Rajni Dubey
- Graduate Institute of Food Science and Technology, National Taiwan University, Taipei City 106, Taiwan
| | - Win-Ping Deng
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei City 110, Taiwan
- Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- Graduate Institute of Basic Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan
| | - Hong-Jian Wei
- Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei, Taiwan
- School of Dental Technology, College of Oral Medicine, Taipei Medical University, Taipei City 110, Taiwan
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Long G, Zhang G, Zhang F, Li M, Ye D, Yang D, Yang Y. Cotransplantation of Mesenchymal Stem Cells and Immature Dendritic Cells Potentiates the Blood Glucose Control of Islet Allografts. BIOMED RESEARCH INTERNATIONAL 2017; 2017:4107943. [PMID: 29410963 PMCID: PMC5749219 DOI: 10.1155/2017/4107943] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 10/23/2017] [Accepted: 11/21/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Transplantation of islets is a promising alternative to treat type 1 diabetes (T1D), but graft rejection is the major obstacle to its application in clinical practice. We evaluated the effects of mesenchymal stem cells (MSCs) and immature dendritic cells (imDCs) on islet transplantation in diabetic model. METHODS The streptozotocin T1D model was established in BABL/c mice. Rat islets were isolated and identified with dithizone (DTZ) staining. MSCs and imDCs were isolated from bone marrow of syngenic mice. Islets, alone or along with MSCs and/or imDCs, were transplanted to the left kidney capsule of diabetic mice. The blood glucose levels and glycosylated hemoglobin levels after transplantation were monitored. RESULTS Cotransplantation significantly decreased blood glucose and glycosylated hemoglobin levels in the diabetes mice. Transplantation of 200 islets + 2 × 105 MSCs + 2 × 105 imDCs could not only restore normal blood glucose levels, but also significantly prolong graft survival for 12.6 ± 3.48 days. CONCLUSIONS Cotransplantation of allogenic islets with imDCs and/or MSCs can significantly promote graft survival, reverse hyperglycemia, and effectively control the glycosylated hemoglobin levels.
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Affiliation(s)
- Guanghui Long
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Guangtao Zhang
- Department of Hepatobiliary Surgery, Peking University Shenzhen Hospital, Shenzhen, China
| | - Fangting Zhang
- Center Laboratory, Peking University Shenzhen Hospital, Shenzhen, China
| | - Minghua Li
- Center Laboratory, Peking University Shenzhen Hospital, Shenzhen, China
| | - Dongshuo Ye
- Shenzhen BioScien Pharmaceuticals Co. LTD, Shenzhen, China
| | - Dengke Yang
- Shenzhen BioScien Pharmaceuticals Co. LTD, Shenzhen, China
| | - Yinke Yang
- Shenzhen BioScien Pharmaceuticals Co. LTD, Shenzhen, China
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Shafiee A, Patel J, Lee JS, Hutmacher DW, Fisk NM, Khosrotehrani K. Mesenchymal stem/stromal cells enhance engraftment, vasculogenic and pro-angiogenic activities of endothelial colony forming cells in immunocompetent hosts. Sci Rep 2017; 7:13558. [PMID: 29051567 PMCID: PMC5648925 DOI: 10.1038/s41598-017-13971-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 10/04/2017] [Indexed: 02/08/2023] Open
Abstract
The clinical use of endothelial colony forming cells (ECFC) is hampered by their restricted engraftment. We aimed to assess engraftment, vasculogenic and pro-angiogenic activities of ECFC in immunocompetent (C57BL/6: WT) or immunodeficient (rag1 -/- C57BL/6: Rag1) mice. In addition, the impact of host immune system was investigated where ECFC were co-implanted with mesenchymal stem/stromal cells (MSC) from adult bone marrow (AdBM-MSC), fetal bone marrow (fBM-MSC), fetal placental (fPL-MSC), or maternal placental (MPL-MSC). Transplantation of ECFCs in Matrigel plugs resulted in less cell engraftment in WT mice compared to Rag1 mice. Co-implantation with different MSCs resulted in a significant increase in cell engraftment up to 9 fold in WT mice reaching levels of engraftment observed when using ECFCs alone in Rag1 mice but well below levels of engraftment with MSC-ECFC combination in Rag1 recipients. Furthermore, MSCs did not reduce murine splenic T cell proliferation in response to ECFCs in vitro. ECFCs enhanced the murine neo-vascularization through paracrine effect, but with no difference between Rag1 and WT mice. In conclusions, the host adaptive immune system affects the engraftment of ECFCs. MSC co-implantation improves ECFC engraftment and function even in immunocompetent hosts mostly through non-immune mechanisms.
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Affiliation(s)
- Abbas Shafiee
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, 4029, QLD, Australia
- Queensland University of Technology, Brisbane, 4000, QLD, Australia
| | - Jatin Patel
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, 4029, QLD, Australia
- The University of Queensland, UQ Diamantina Institute, Brisbane, 4102, QLD, Australia
| | - James S Lee
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, 4029, QLD, Australia
- The University of Queensland, UQ Diamantina Institute, Brisbane, 4102, QLD, Australia
| | | | - Nicholas M Fisk
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, 4029, QLD, Australia
- Centre for Advanced Prenatal Care, Royal Brisbane & Women's Hospital, Brisbane, 4029, QLD, Australia
| | - Kiarash Khosrotehrani
- The University of Queensland, UQ Centre for Clinical Research, Brisbane, 4029, QLD, Australia.
- The University of Queensland, UQ Diamantina Institute, Brisbane, 4102, QLD, Australia.
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Montanari E, Meier RPH, Mahou R, Seebach JD, Wandrey C, Gerber-Lemaire S, Buhler LH, Gonelle-Gispert C. Multipotent mesenchymal stromal cells enhance insulin secretion from human islets via N-cadherin interaction and prolong function of transplanted encapsulated islets in mice. Stem Cell Res Ther 2017; 8:199. [PMID: 28962589 PMCID: PMC5622460 DOI: 10.1186/s13287-017-0646-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 06/13/2017] [Accepted: 08/14/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Multipotent mesenchymal stromal cells (MSC) enhance viability and function of islets of Langerhans. We aimed to examine the interactions between human MSC and human islets of Langerhans that influence the function of islets. METHODS Human MSC and human islets (or pseudoislets, obtained after digestion and reaggregation of islet cells) were cocultured with or without cellular contact and glucose-stimulated insulin secretion assays were performed to assess cell function. The expression of several adhesion molecules, notably ICAM-1 and N-cadherin on islets and MSC, was investigated by qPCR. The role of N-cadherin was analyzed by adding an anti-N-cadherin antibody in islets cultured with or without MSC for 24 h followed by insulin measurements in static incubation assays. Islets and MSC were coencapsulated in new hydrogel microspheres composed of calcium alginate and covalently crosslinked polyethylene glycol. Encapsulated cells were transplanted intraperitoneally in streptozotocin-induced diabetic mice and glycemia was monitored. Islet function was evaluated by the intraperitoneal glucose tolerance test. RESULTS In vitro, free islets and pseudoislets cocultured in contact with MSC showed a significantly increased insulin secretion when compared to islets or pseudoislets cultured alone or cocultured without cell-to-cell contact with MSC (p < 0.05). The expression of ICAM-1 and N-cadherin was present on islets and MSC. Blocking N-cadherin prevented the enhanced insulin secretion by islets cultured in contact with MSC whereas it did not affect insulin secretion by islets cultured alone. Upon transplantation in diabetic mice, islets microencapsulated together with MSC showed significantly prolonged normoglycemia when compared with islets alone (median 69 and 39 days, respectively, p < 0.01). The intraperitoneal glucose tolerance test revealed an improved glycemic response in mice treated with islets microencapsulated together with MSC compared to mice transplanted with islets alone (p < 0.001). CONCLUSIONS MSC improve survival and function of islets of Langerhans by cell-to-cell contact mediated by the adhesion molecule N-cadherin.
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Affiliation(s)
- Elisa Montanari
- Department of Surgery, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland
| | - Raphael P H Meier
- Department of Surgery, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland
| | - Redouan Mahou
- Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada.,Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland
| | - Jörg D Seebach
- Division of Immunology and Allergy, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland
| | - Christine Wandrey
- Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland
| | - Sandrine Gerber-Lemaire
- Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne, 1015, Lausanne, Switzerland
| | - Leo H Buhler
- Department of Surgery, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland
| | - Carmen Gonelle-Gispert
- Department of Surgery, Geneva University Hospitals and Medical Faculty, 1211, Geneva, Switzerland.
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Abstract
PURPOSE OF REVIEW Mesenchymal stromal cells (MSCs) are adult stromal cells with therapeutic potential in allogeneic islet transplantation for type 1 diabetes patients. The process of islet isolation alone has been shown to negatively impact islet survival and function in vivo. In addition, insults mediated by the instant blood-mediated inflammatory reaction, hypoxia, ischemia and immune response significantly impact the islet allograft post transplantation. MSCs are known to exert cytoprotective and immune modulatory properties and thus are an attractive therapeutic in this context. Herein, the recent progress in the field of MSC therapy in islet transplantation is discussed. RECENT FINDINGS MSC can promote islet survival and function in vivo. Importantly, studies have shown that human MSC donors have differential abilities in promoting islet regeneration/survival. Recently, several biomarkers associated with MSC islet regenerative capacity have been identified. Expressions of Annexin A1, Elastin microfibril interface 1 and integrin-linked protein kinase are upregulated in MSC displaying protective effects on islet survival and function in vivo. SUMMARY The discovery of biomarkers associated with MSC therapeutic efficacy represents an important step forward for the utilization of MSC therapy in islet transplantation; however, much remains to be elucidated about the mechanisms utilized by MSC in protection against transplanted islet loss, autoimmune-mediated and alloimmune-mediated rejection.
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Perteghella S, Vigani B, Mastracci L, Grillo F, Antonioli B, Galuzzi M, Tosca MC, Crivelli B, Preda S, Tripodo G, Marazzi M, Chlapanidas T, Torre ML. Stromal Vascular Fraction Loaded Silk Fibroin Mats Effectively Support the Survival of Diabetic Mice after Pancreatic Islet Transplantation. Macromol Biosci 2017; 17. [PMID: 28691373 DOI: 10.1002/mabi.201700131] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 05/31/2017] [Indexed: 09/19/2023]
Abstract
The aim of this study is to assess whether stromal vascular fraction (SVF)-soaked silk fibroin nonwoven mats (silk-SVF) can preserve the functionality of encapsulated pancreatic endocrine cells (alginate-PECs) after transplantation in the subcutaneous tissue of diabetic mice. Silk scaffolds are selected to create an effective 3D microenvironment for SVF delivery in the subcutaneous tissue before diabetes induction: silk-SVF is subcutaneously implanted in the dorsal area of five healthy animals; after 15 d, mice are treated with streptozotocin to induce diabetes and then alginate-PECs are implanted on the silk-SVF. All animals appear in good health, increasing weight during time, and among them, one presents euglycemia until the end of experiments. On the contrary, when PECs are simultaneously implanted with SVF after diabetes induction, mice are euthanized due to suffering. This work clearly demonstrates that silk-SVF creates a functional niche in subcutaneous tissue and preserves endocrine cell survival and engraftment.
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Affiliation(s)
- Sara Perteghella
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy
| | - Barbara Vigani
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy
| | - Luca Mastracci
- Section of Histopathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), IRCCS San Martino IST Hospital, University of Genoa, Largo R. Benzi 8, 16121, Genoa, Italy
| | - Federica Grillo
- Section of Histopathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), IRCCS San Martino IST Hospital, University of Genoa, Largo R. Benzi 8, 16121, Genoa, Italy
| | - Barbara Antonioli
- Struttura Semplice Tissue Therapy, ASST Grande Ospedale Metropolitano, Piazza Ospedale Maggiore 3, 20162, Milan, Italy
| | - Marta Galuzzi
- Struttura Semplice Tissue Therapy, ASST Grande Ospedale Metropolitano, Piazza Ospedale Maggiore 3, 20162, Milan, Italy
| | - Marta Cecilia Tosca
- Struttura Semplice Tissue Therapy, ASST Grande Ospedale Metropolitano, Piazza Ospedale Maggiore 3, 20162, Milan, Italy
| | - Barbara Crivelli
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy
| | - Stefania Preda
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy
| | - Giuseppe Tripodo
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy
| | - Mario Marazzi
- Struttura Semplice Tissue Therapy, ASST Grande Ospedale Metropolitano, Piazza Ospedale Maggiore 3, 20162, Milan, Italy
| | - Theodora Chlapanidas
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy
| | - Maria Luisa Torre
- Department of Drug Sciences, University of Pavia, Viale Taramelli 12, 27100, Pavia, Italy
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Song L, Sun Z, Kim DS, Gou W, Strange C, Dong H, Cui W, Gilkeson G, Morgan KA, Adams DB, Wang H. Adipose stem cells from chronic pancreatitis patients improve mouse and human islet survival and function. Stem Cell Res Ther 2017; 8:192. [PMID: 28854965 PMCID: PMC5577777 DOI: 10.1186/s13287-017-0627-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 05/09/2017] [Accepted: 07/03/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Chronic pancreatitis has surgical options including total pancreatectomy to control pain. To avoid surgical diabetes, the explanted pancreas can have islets harvested and transplanted. Immediately following total pancreatectomy with islet autotransplantation (TP-IAT), many islet cells die due to isolation and transplantation stresses. The percentage of patients remaining insulin free after TP-IAT is therefore low. We determined whether cotransplantation of adipose-derived mesenchymal stem cells (ASCs) from chronic pancreatitis patients (CP-ASCs) would protect islets after transplantation. METHODS In a marginal mass islet transplantation model, islets from C57BL/6 mice were cotransplanted with CP-ASCs into syngeneic streptozotocin-treated diabetic mice. Treatment response was defined by the percentage of recipients reaching normoglycemia, and by the area under the curve for glucose and c-peptide in a glucose tolerance test. Macrophage infiltration, β-cell apoptosis, and islet graft vasculature were measured in transplanted islet grafts by immunohistochemistry. mRNA expression profiling of 84 apoptosis-related genes in islet grafts transplanted alone or with CP-ASCs was measured by the RT2 Profiler™ Apoptosis PCR Array. The impact of insulin-like growth factor-1 (IGF-1) on islet apoptosis was determined in islets stimulated with cytokines (IL-1β and IFN-γ) in the presence and absence of CP-ASC conditioned medium. RESULTS CP-ASC-treated mice were more often normoglycemic compared to mice receiving islets alone. ASC cotransplantation reduced macrophage infiltration, β-cell death, suppressed expression of TNF-α and Bcl-2 modifying factor (BMF), and upregulated expressions of IGF-1 and TNF Receptor Superfamily Member 11b (TNFRSF11B) in islet grafts. Islets cultured in conditioned medium from CP-ASCs showed reduced cell death. This protective effect was diminished when IGF-1 was blocked in the conditioned medium by the anti-IGF-1 antibody. CONCLUSION Cotransplantation of islets with ASCs from the adipose of chronic pancreatitis patients improved islet survival and islet function after transplantation. The effects are in part mediated by paracrine secretion of IGF-1, suppression of inflammation, and promotion of angiogenesis. ASCs from chronic pancreatitis patients have the potential to be used as a synergistic therapy to enhance the efficacy of islet transplantation following pancreatectomy.
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Affiliation(s)
- Lili Song
- Department of Surgery, Medical University of South Carolina, BSB 641, 173 Ashley Avenue, Charleston, SC, 29425, USA
| | - Zhen Sun
- Department of Surgery, Medical University of South Carolina, BSB 641, 173 Ashley Avenue, Charleston, SC, 29425, USA
| | - Do-Sung Kim
- Department of Surgery, Medical University of South Carolina, BSB 641, 173 Ashley Avenue, Charleston, SC, 29425, USA
| | - Wenyu Gou
- Department of Surgery, Medical University of South Carolina, BSB 641, 173 Ashley Avenue, Charleston, SC, 29425, USA
| | - Charlie Strange
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Huansheng Dong
- Department of Surgery, Medical University of South Carolina, BSB 641, 173 Ashley Avenue, Charleston, SC, 29425, USA
| | - Wanxing Cui
- Medstar Georgetown University Hospital, Washington, DC, USA
| | - Gary Gilkeson
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Katherine A Morgan
- Department of Surgery, Medical University of South Carolina, BSB 641, 173 Ashley Avenue, Charleston, SC, 29425, USA
| | - David B Adams
- Department of Surgery, Medical University of South Carolina, BSB 641, 173 Ashley Avenue, Charleston, SC, 29425, USA
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, BSB 641, 173 Ashley Avenue, Charleston, SC, 29425, USA. .,Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.
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40
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Wang L, Qing L, Liu H, Liu N, Qiao J, Cui C, He T, Zhao R, Liu F, Yan F, Wang C, Liang K, Guo X, Shen YH, Hou X, Chen L. Mesenchymal stromal cells ameliorate oxidative stress-induced islet endothelium apoptosis and functional impairment via Wnt4-β-catenin signaling. Stem Cell Res Ther 2017; 8:188. [PMID: 28807051 PMCID: PMC5557510 DOI: 10.1186/s13287-017-0640-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 07/09/2017] [Accepted: 07/24/2017] [Indexed: 12/26/2022] Open
Abstract
Background Islet dysfunction and destruction are the common cause for both type 1 and type 2 diabetes mellitus (T2DM). The islets of Langerhans are highly vascularized miniorgans, and preserving the structural integrity and full function of the microvascular endothelium is vital for protecting the islets from the infiltration of immune cells and secondary inflammatory attack. Mesenchymal stromal cell (MSC)-based therapies have been proven to promote angiogenesis of the islets; however, the underlying mechanism for the protective role of MSCs in the islet endothelium is still vague. Methods In this study, we used MS-1, a murine islet microvascular endothelium cell line, and an MSC-MS1 transwell culturing system to investigate the protective mechanism of rat bone marrow-derived MSCs under oxidative stress in vitro. Cell apoptosis was detected by TUNEL staining, annexin V/PI flow cytometry analysis, and cleaved caspase 3 western blotting analysis. Endothelial cell activation was determined by expression of intercellular cell adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as well as eNOS phosphorylation/activation. The changes of VCAM-1, eNOS, and the β-catenin expression were also tested in the isolated islets of T2DM rats infused with MSCs. Results We observed that treating MS-1 cells with H2O2 triggered significant apoptosis, induction of VCAM expression, and reduction of eNOS phosphorylation. Importantly, coculturing MS-1 cells with MSCs prevented oxidative stress-induced apoptosis, eNOS inhibition, and VCAM elevation in MS-1 cells. Similar changes in VCAM-1 and eNOS phosphorylation could also be observed in the islets isolated from T2DM rats infused with MSCs. Moreover, MSCs cocultured with MS-1 in vitro or their administration in vivo could both result in an increase of β-catenin, which suggested activation of the β-catenin-dependent Wnt signaling pathway. In MS-1 cells, activation of the β-catenin-dependent Wnt signaling pathway partially mediated the protective effects of MSCs against H2O2-induced apoptosis and eNOS inhibition. Furthermore, MSCs produced a significant amount of Wnt4 and Wnt5a. Although both Wnt4 and Wnt5a participated in the interaction between MSCs and MS-1 cells, Wnt4 exhibited a protective role while Wnt5a seemed to show a destructive role in MS-1 cells. Conclusions Our observations provide evidence that the orchestration of the MSC-secreted Wnts could promote the survival and improve the endothelial function of the injured islet endothelium via activating the β-catenin-dependent Wnt signaling in target endothelial cells. This finding might inspire further in-vivo studies.
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Affiliation(s)
- Lingshu Wang
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Li Qing
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - He Liu
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Na Liu
- College of Public Health, Shandong University, Jinan, Shandong, 250012, China
| | - Jingting Qiao
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Chen Cui
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Tianyi He
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Ruxing Zhao
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Fuqiang Liu
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Fei Yan
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Chuan Wang
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Kai Liang
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Xinghong Guo
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Ying H Shen
- Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.,Texas Heart Institute, Houston, TX, USA
| | - Xinguo Hou
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China.
| | - Li Chen
- Department of Endocrinology, Institute of Endocrinology and Metabolism, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China.
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Westenfelder C, Gooch A, Hu Z, Ahlstrom J, Zhang P. Durable Control of Autoimmune Diabetes in Mice Achieved by Intraperitoneal Transplantation of "Neo-Islets," Three-Dimensional Aggregates of Allogeneic Islet and "Mesenchymal Stem Cells". Stem Cells Transl Med 2017; 6:1631-1643. [PMID: 28467694 PMCID: PMC5689775 DOI: 10.1002/sctm.17-0005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 03/01/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
Novel interventions that reestablish endogenous insulin secretion and thereby halt progressive end-organ damage and prolong survival of patients with autoimmune Type 1 diabetes mellitus (T1DM) are urgently needed. While this is currently accomplished with allogeneic pancreas or islet transplants, their utility is significantly limited by both the scarcity of organ donors and life-long need for often-toxic antirejection drugs. Coadministering islets with bone marrow-derived mesenchymal stem cells (MSCs) that exert robust immune-modulating, anti-inflammatory, anti-apoptotic, and angiogenic actions, improves intrahepatic islet survival and function. Encapsulation of insulin-producing cells to prevent immune destruction has shown both promise and failures. Recently, stem cell-derived insulin secreting β-like cells induced euglycemia in diabetic animals, although their clinical use would still require encapsulation or anti-rejection drugs. Instead of focusing on further improvements in islet transplantation, we demonstrate here that the intraperitoneal administration of islet-sized "Neo-Islets" (NIs), generated by in vitro coaggregation of allogeneic, culture-expanded islet cells with high numbers of immuno-protective and cyto-protective MSCs, resulted in their omental engraftment in immune-competent, spontaneously diabetic nonobese diabetic (NOD) mice. This achieved long-term glycemic control without immunosuppression and without hypoglycemia. In preparation for an Food and Drug Administration-approved clinical trial in dogs with T1DM, we show that treatment of streptozotocin-diabetic NOD/severe combined immunodeficiency mice with identically formed canine NIs produced durable euglycemia, exclusively mediated by dog-specific insulin. We conclude that this novel technology has significant translational relevance for canine and potentially clinical T1DM as it effectively addresses both the organ donor scarcity (>80 therapeutic NI doses/donor pancreas can be generated) and completely eliminates the need for immunosuppression. Stem Cells Translational Medicine 2017;6:1631-1643.
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Affiliation(s)
- Christof Westenfelder
- Department of Medicine, Division of Nephrology, University of Utah and VA Medical Centers, Salt Lake City, Utah, USA
| | - Anna Gooch
- SymbioCellTech, LLC, Salt Lake City, Utah, USA
| | - Zhuma Hu
- SymbioCellTech, LLC, Salt Lake City, Utah, USA
| | | | - Ping Zhang
- SymbioCellTech, LLC, Salt Lake City, Utah, USA
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Hayward JA, Ellis CE, Seeberger K, Lee T, Salama B, Mulet-Sierra A, Kuppan P, Adesida A, Korbutt GS. Cotransplantation of Mesenchymal Stem Cells With Neonatal Porcine Islets Improve Graft Function in Diabetic Mice. Diabetes 2017; 66:1312-1321. [PMID: 28246290 DOI: 10.2337/db16-1068] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 02/19/2017] [Indexed: 11/13/2022]
Abstract
Mesenchymal stem cells (MSCs) possess immunoregulatory, anti-inflammatory, and proangiogenic properties and, therefore, have the potential to improve islet engraftment and survival. We assessed the effect human bone marrow-derived MSCs have on neonatal porcine islets (NPIs) in vitro and determined islet engraftment and metabolic outcomes when cotransplanted in a mouse model. NPIs cocultured with MSCs had greater cellular insulin content and increased glucose-stimulated insulin secretion. NPIs were cotransplanted with or without MSCs in diabetic B6.129S7-Rag1tm1Mom/J mice. Blood glucose and weight were monitored until reversal of diabetes; mice were then given an oral glucose tolerance test. Islet grafts were assessed for the degree of vascularization and total cellular insulin content. Cotransplantation of NPIs and MSCs resulted in significantly earlier normoglycemia and vascularization, improved glucose tolerance, and increased insulin content. One experiment conducted with MSCs from a donor with an autoimmune disorder had no positive effects on transplant outcomes. Cotransplantation of human MSCs with NPIs demonstrated a beneficial metabolic effect likely as a result of earlier islet vascularization and improved islet engraftment. In addition, donor pathology of MSCs can influence the functional capacity of MSCs.
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Affiliation(s)
- Julie A Hayward
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Cara E Ellis
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Karen Seeberger
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Timothy Lee
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Bassem Salama
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | | | - Purushothaman Kuppan
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Adetola Adesida
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
| | - Gregory S Korbutt
- Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
- Department of Surgery, University of Alberta, Edmonton, Alberta, Canada
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Cunha JPMCM, Leuckx G, Sterkendries P, Korf H, Bomfim-Ferreira G, Overbergh L, Vaes B, Heimberg H, Gysemans C, Mathieu C. Human multipotent adult progenitor cells enhance islet function and revascularisation when co-transplanted as a composite pellet in a mouse model of diabetes. Diabetologia 2017; 60:134-142. [PMID: 27704164 PMCID: PMC6518081 DOI: 10.1007/s00125-016-4120-3] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Accepted: 09/06/2016] [Indexed: 12/28/2022]
Abstract
AIMS/HYPOTHESIS Hypoxia in the initial days after islet transplantation leads to considerable loss of islet mass and contributes to disappointing outcomes in the clinical setting. The aim of the present study was to investigate whether co-transplantation of human non-endothelial bone marrow-derived multipotent adult progenitor cells (MAPCs), which are non-immunogenic and can secrete angiogenic growth factors during the initial days after implantation, could improve islet engraftment and survival. METHODS Islets (150) were co-transplanted, with or without human MAPCs (2.5 × 105) as separate or composite pellets, under the kidney capsule of syngeneic alloxan-induced diabetic C57BL/6 mice. Blood glucose levels were frequently monitored and IPGTTs were carried out. Grafts and serum were harvested at 2 and 5 weeks after transplantation to assess outcome. RESULTS Human MAPCs produced high amounts of angiogenic growth factors, including vascular endothelial growth factor, in vitro and in vivo, as demonstrated by the induction of neo-angiogenesis in the chorioallantoic membrane assay. Islet-human MAPC co-transplantation as a composite pellet significantly improved the outcome of islet transplantation as measured by the initial glycaemic control, diabetes reversal rate, glucose tolerance and serum C-peptide concentration compared with the outcome following transplantation of islets alone. Histologically, a higher blood vessel area and density in addition to a higher vessel/islet ratio were detected in recipients of islet-human MAPC composites. CONCLUSIONS/INTERPRETATION The present data suggest that co-transplantation of mouse pancreatic islets with human MAPCs, which secrete high amounts of angiogenic growth factors, enhance islet graft revascularisation and subsequently improve islet graft function.
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Affiliation(s)
- João Paulo M C M Cunha
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium
| | - Gunter Leuckx
- Beta cell neogenesis laboratory, Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | | | - Hannelie Korf
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium
| | - Gabriela Bomfim-Ferreira
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium
| | - Lutgart Overbergh
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium
| | | | - Harry Heimberg
- Beta cell neogenesis laboratory, Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
| | - Conny Gysemans
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium.
| | - Chantal Mathieu
- Laboratory of Clinical and Experimental Endocrinology, Katholieke Universiteit Leuven (KULEUVEN), Campus Gasthuisberg O&N1, Herestraat 49 bus 902, 3000, Leuven, Belgium
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Wang D, Ding X, Xue W, Zheng J, Tian X, Li Y, Wang X, Song H, Liu H, Luo X. A new scaffold containing small intestinal submucosa and mesenchymal stem cells improves pancreatic islet function and survival in vitro and in vivo. Int J Mol Med 2016; 39:167-173. [PMID: 27909715 PMCID: PMC5179187 DOI: 10.3892/ijmm.2016.2814] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 11/25/2016] [Indexed: 12/23/2022] Open
Abstract
It is unknown whether a scaffold containing both small intestinal submucosa (SIS) and mesenchymal stem cells (MSCs) for transplantation may improve pancreatic islet function and survival. In this study, we examined the effects of a SIS-MSC scaffold on islet function and survival in vitro and in vivo. MSCs and pancreatic islets were isolated from Sprague-Dawley rats, and SIS was isolated from Bamei pigs. The islets were apportioned among 3 experimental groups as follows: SIS-islets, SIS-MSC-islets and control-islets. In vitro, islet function was measured by a glucose-stimulated insulin secretion test; cytokines in cultured supernatants were assessed by enzyme-linked immunosorbent assay; and gene expression was analyzed by reverse transcription-quantitative PCR. In vivo, islet transplantation was performed in rats, and graft function and survival were monitored by measuring the blood glucose levels. In vitro, the SIS-MSC scaffold was associated with improved islet viability and enhanced insulin secretion compared with the controls, as well as with the increased the expression of insulin 1 (Ins1), pancreatic and duodenal homeobox 1 (Pdx1), platelet endothelial cell adhesion molecule 1 [Pecam1; also known as cluster of differentiation 31 (CD31)] and vascular endothelial growth factor A (Vegfa) in the islets, increased growth factor secretion, and decreased tumor necrosis factor (TNF) secretion. In vivo, the SIS-MSC scaffold was associated with improved islet function and graft survival compared with the SIS and control groups. On the whole, our findings demonstrate that the SIS-MSC scaffold significantly improved pancreatic islet function and survival in vitro and in vivo. This improvement may be associated with the upregulation of insulin expression, the improvement of islet microcirculation and the secretion of cytokines.
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Affiliation(s)
- Dan Wang
- Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaoming Ding
- Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Wujun Xue
- Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jin Zheng
- Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaohui Tian
- Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yang Li
- Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaohong Wang
- Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Huanjin Song
- Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Hua Liu
- Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Xiaohui Luo
- Department of Renal Transplantation, Center of Nephropathy, The First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Marfy‐Smith SJ, Clarkin CE. Are Mesenchymal Stem Cells So Bloody Great After All? Stem Cells Transl Med 2016; 6:3-6. [PMID: 28170195 PMCID: PMC5442748 DOI: 10.5966/sctm.2016-0026] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 07/15/2016] [Indexed: 12/26/2022] Open
Abstract
This Perspective discusses some activities of mesenchymal stem cells (MSCs) in the context of angiogenesis, focusing on contrasting effects that could call into question the extent to which MSCs can be used clinically in the future. We report on the antiangiogenic/antiproliferative effects of specific MSC populations (including bone marrow MSCs), their paracrine activity, tissue heterogeneity, and endothelial cell interactions. Also discussed are what could lead to contrasting effects of the influence of MSCs in regulating angiogenesis, pointing to some negative effects of these cells. In conclusion, this article highlights important aspects of MSC behavior within the perspective of translational medicine applications. Stem Cells Translational Medicine2017;6:3–6
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Affiliation(s)
| | - Claire E. Clarkin
- Biological Sciences, University of Southampton, Southampton, United Kingdom
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Vanikar AV, Trivedi HL, Thakkar UG. Stem cell therapy emerging as the key player in treating type 1 diabetes mellitus. Cytotherapy 2016; 18:1077-86. [PMID: 27424148 DOI: 10.1016/j.jcyt.2016.06.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 05/24/2016] [Accepted: 06/07/2016] [Indexed: 02/06/2023]
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease causing progressive destruction of pancreatic β cells, ultimately resulting in loss of insulin secretion producing hyperglycemia usually affecting children. Replacement of damaged β cells by cell therapy can treat it. Currently available strategies are insulin replacement and islet/pancreas transplantation. Unfortunately these offer rescue for variable duration due to development of autoantibodies. For pancreas/islet transplantation a deceased donor is required and various shortfalls of treatment include quantum, cumbersome technique, immune rejection and limited availability of donors. Stem cell therapy with assistance of cellular reprogramming and β-cell regeneration can open up new therapeutic modalities. The present review describes the history and current knowledge of T1DM, evolution of cell therapies and different cellular therapies to cure this condition.
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Affiliation(s)
- Aruna V Vanikar
- Department of Regenerative Medicine and Stem Cell Therapy, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases & Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Gujarat, India; Department of Pathology, Laboratory Medicine, Transfusion Services and Immunohematology, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases & Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Gujarat, India.
| | - Hargovind L Trivedi
- Department of Regenerative Medicine and Stem Cell Therapy, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases & Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Gujarat, India; Department of Nephrology and Transplantation Medicine, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases & Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Gujarat, India
| | - Umang G Thakkar
- Department of Regenerative Medicine and Stem Cell Therapy, G.R. Doshi and K.M. Mehta Institute of Kidney Diseases & Research Centre, Dr. H.L. Trivedi Institute of Transplantation Sciences, Gujarat, India
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Publisher's note. Regen Ther 2016. [DOI: 10.1016/j.reth.2016.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Lima MJ, Muir KR, Docherty HM, McGowan NWA, Forbes S, Heremans Y, Heimberg H, Casey J, Docherty K. Generation of Functional Beta-Like Cells from Human Exocrine Pancreas. PLoS One 2016; 11:e0156204. [PMID: 27243814 PMCID: PMC4887015 DOI: 10.1371/journal.pone.0156204] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 05/10/2016] [Indexed: 12/24/2022] Open
Abstract
Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply of islets for transplantation in the treatment of diabetes. Exocrine tissue can be efficiently reprogrammed to islet-like cells using a cocktail of transcription factors: Pdx1, Ngn3, MafA and Pax4 in combination with growth factors. We show here that overexpression of exogenous Pax4 in combination with suppression of the endogenous transcription factor ARX considerably enhances the production of functional insulin-secreting β-like cells with concomitant suppression of α-cells. The efficiency was further increased by culture on laminin-coated plates in media containing low glucose concentrations. Immunocytochemistry revealed that reprogrammed cultures were composed of ~45% islet-like clusters comprising >80% monohormonal insulin+ cells. The resultant β-like cells expressed insulin protein levels at ~15–30% of that in adult human islets, efficiently processed proinsulin and packaged insulin into secretory granules, exhibited glucose responsive insulin secretion, and had an immediate and prolonged effect in normalising blood glucose levels upon transplantation into diabetic mice. We estimate that approximately 3 billion of these cells would have an immediate therapeutic effect following engraftment in type 1 diabetes patients and that one pancreas would provide sufficient tissue for numerous transplants.
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Affiliation(s)
- Maria J. Lima
- School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
- * E-mail:
| | - Kenneth R. Muir
- School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
| | - Hilary M. Docherty
- School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
| | - Neil W. A. McGowan
- Department of Surgery, University of Edinburgh, Edinburgh Royal Infirmary, Edinburgh, EH16 4SU, United Kingdom
| | - Shareen Forbes
- Endocrinology Unit, University/BHF Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, United Kingdom
| | - Yves Heremans
- Diabetes Research Centre, Vrije Universiteit Brussel, B1090 Brussels, Belgium
| | - Harry Heimberg
- Diabetes Research Centre, Vrije Universiteit Brussel, B1090 Brussels, Belgium
| | - John Casey
- Department of Surgery, University of Edinburgh, Edinburgh Royal Infirmary, Edinburgh, EH16 4SU, United Kingdom
| | - Kevin Docherty
- School of Medical Sciences, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom
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King AJF, Griffiths LA, Persaud SJ, Jones PM, Howell SL, Welsh N. Imatinib prevents beta cell death in vitro but does not improve islet transplantation outcome. Ups J Med Sci 2016; 121:140-5. [PMID: 26953716 PMCID: PMC4900069 DOI: 10.3109/03009734.2016.1151090] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Introduction Improving islet transplantation outcome could not only bring benefits to individual patients but also widen the patient pool to which this life-changing treatment is available. Imatinib has previously been shown to protect beta cells from apoptosis in a variety of in vitro and in vivo models. The aim of this study was to investigate whether imatinib could be used to improve islet transplantation outcome. Methods Islets were isolated from C57Bl/6 mice and pre-cultured with imatinib prior to exposure to streptozotocin and cytokines in vitro. Cell viability and glucose-induced insulin secretion were measured. For transplantation experiments, islets were pre-cultured with imatinib for either 72 h or 24 h prior to transplantation into streptozotocin-diabetic C57Bl/6 mice. In one experimental series mice were also administered imatinib after islet transplantation. Results Imatinib partially protected islets from beta cell death in vitro. However, pre-culturing islets in imatinib or administering the drug to the mice in the days following islet transplantation did not improve blood glucose concentrations more than control-cultured islets. Conclusion Although imatinib protected against beta cell death from cytokines and streptozotocin in vitro, it did not significantly improve syngeneic islet transplantation outcome.
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Affiliation(s)
- Aileen J. F. King
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King’s College London, London, United Kingdom
- CONTACT Aileen King Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King’s College London, Guy’s Campus, London SE1 1UL, United Kingdom
| | - Lisa A. Griffiths
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King’s College London, London, United Kingdom
| | - Shanta J. Persaud
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King’s College London, London, United Kingdom
| | - Peter M. Jones
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King’s College London, London, United Kingdom
| | - Simon L. Howell
- Diabetes Research Group, Division of Diabetes and Nutritional Sciences, King’s College London, London, United Kingdom
| | - Nils Welsh
- Department of Medical Cell Biology, Uppsala University, Biomedicum, Uppsala, Sweden
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Xiao X, Fischbach S, Song Z, Gaffar I, Zimmerman R, Wiersch J, Prasadan K, Shiota C, Guo P, Ramachandran S, Witkowski P, Gittes GK. Transient Suppression of TGFβ Receptor Signaling Facilitates Human Islet Transplantation. Endocrinology 2016; 157:1348-1356. [PMID: 26872091 PMCID: PMC4816736 DOI: 10.1210/en.2015-1986] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 02/09/2016] [Indexed: 11/19/2022]
Abstract
Although islet transplantation is an effective treatment for severe diabetes, its broad application is greatly limited due to a shortage of donor islets. Suppression of TGFβ receptor signaling in β-cells has been shown to increase β-cell proliferation in mice, but has not been rigorously examined in humans. Here, treatment of human islets with a TGFβ receptor I inhibitor, SB-431542 (SB), significantly improved C-peptide secretion by β-cells, and significantly increased β-cell number by increasing β-cell proliferation. In addition, SB increased cell-cycle activators and decreased cell-cycle suppressors in human β-cells. Transplantation of SB-treated human islets into diabetic immune-deficient mice resulted in significant improvement in blood glucose control, significantly higher serum and graft insulin content, and significantly greater increases in β-cell proliferation in the graft, compared with controls. Thus, our data suggest that transient suppression of TGFβ receptor signaling may improve the outcome of human islet transplantation, seemingly through increasing β-cell number and function.
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Affiliation(s)
| | | | | | | | - Ray Zimmerman
- Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637
| | - John Wiersch
- Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637
| | - Krishna Prasadan
- Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637
| | - Chiyo Shiota
- Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637
| | - Ping Guo
- Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637
| | - Sabarinathan Ramachandran
- Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637
| | - Piotr Witkowski
- Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637
| | - George K. Gittes
- Division of Pediatric Surgery (X.X., S.F., Z.S., I.G., R.Z., J.W., K.P., C.S., P.G., G.K.G.), Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224; Department of General Surgery (Z.S.), The Third Xiangya Hospital of Central S University, Changsha 410013, China; and Department of Surgery (S.R., P.W.), University of Chicago, Chicago, Illinois 60637
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