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Li H, Chen C, Wang Y, Yi W, Guo P, Yao C, Liu J, Wei Y, Hu K, Shang X, Kang S. A meta-analysis on application and prospect of cell therapy in the treatment of diabetes mellitus. Stem Cell Res Ther 2025; 16:249. [PMID: 40390031 PMCID: PMC12090454 DOI: 10.1186/s13287-025-04377-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 05/02/2025] [Indexed: 05/21/2025] Open
Abstract
OBJECTIVE Diabetes mellitus (DM) is a grave autoimmune disorder because of no insulin self-generation. Currently, mainly clinical methods exist, serious adverse effects leading to stem cell therapy are considered. The mesenchymal stem cells (MSCs), require high differentiation capacity and are judged as crucial in DM treatment. The meta-analysis aimed to systemically analyze the particular types of MSCs which play a more important role in DM and which DM is treated more effectively. METHOD A systematic review was conducted on the published literature, clinical trials and observational studies, utilizing databases such as PubMed, Embase, Cochrane and clinicaltrial.gov. RevMan software was adopted to draw Forest Plot and Funnel Plot, and subgroup analysis were employed to evaluate heterogeneity between different groups. RESULTS We identified the meta-analyses of 34 unique random controlled trials and divided our own systematic reviews into 8 groups. The MSCs were associated with placebo (OR = 2.79, 95% CI [1.63, 4.75]), Standard Clinical Treatment (SCT) (OR = 4.12, 95% CI [2.76, 6.14]), and monocyte (OR = 6.52, 95% CI [3.56, 9.48]). The comparison between Autologous MSCs and Allogenic MSCs (OR = 4.64, 95% CI [3.42, 6.31]), Autologous BMMSCs and other MSCs (OR = 5.28, 95% CI [3.64, 7.66]), Allogenic ASCs and UCMSCs (OR = 3.54, 95% CI [1.83, 6.86]), Type I DM and Type II DM (OR = 3.10, 95% CI [1.79, 5.38]), intravenous injection and other injections (OR = 4.81, 95% CI [3.34, 6.94]), diabetic foot ulcers and diabetic neurological disease (OR = 3.88,,95% CI [2.53,5.95]). CONCLUSION Current evidence suggests that MSCs hold significant potential for treating DM, demonstrating considerably high safety and efficacy. MSCs exhibit higher therapeutic benefits compared to monocytes, with autologous MSCs offering better clinical outcomes than allogenic sources. MSCs (BMMSCs) proved more effective than other types of MSCs. However, no significant differences were observed between adipose-derived MSCs (ASCs) and umbilical cord-derived MSCs (UCMSCs) in the allogeneic setting. Moreover, MSCs show more pronounced therapeutic effects in Type II DM, and the difference among the injection methods is minimally observed. In conclusion, the research scope on DM is relatively limited in this study and further research is necessary to improve the reliability of the estimates.
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Affiliation(s)
- Hanluo Li
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Cheng Chen
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Yuansheng Wang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Wei Yi
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Peipei Guo
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Chenguang Yao
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Jinbiao Liu
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Yanhong Wei
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Kanghong Hu
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China
| | - Xiaoke Shang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China.
- Wuhan Vickor Medical Technology Co. Ltd., Building 3-3, 3-4, and 3-5, Zhaoshang·High-Tech Network Valley, No. 16, Luzling Third Road, East Lake High-Tech Development Zone, Wuhan (Wuhan Area of the Pilot Free Trade Zone), Wuhan, 430015, China.
| | - Sini Kang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei University of Technology, Wuhan, 430068, China.
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Ghassemifard L, Hasanlu M, Parsamanesh N, Atkin SL, Almahmeed W, Sahebkar A. Cell Therapies and Gene Therapy for Diabetes: Current Progress. Curr Diabetes Rev 2025; 21:e130524229899. [PMID: 38747221 DOI: 10.2174/0115733998292392240425122326] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 03/07/2024] [Accepted: 03/21/2024] [Indexed: 04/23/2025]
Abstract
The epidemic of diabetes continues to be an increasing problem, and there is a need for new therapeutic strategies. There are several promising drugs and molecules in synthetic medicinal chemistry that are developing for diabetes. In addition to this approach, extensive studies with gene and cell therapies are being conducted. Gene therapy is an existing approach in treating several diseases, such as cancer, autoimmune diseases, heart disease and diabetes. Several reports have also suggested that stem cells have the differentiation capability to functional pancreatic beta cell development in vitro and in vivo, with the utility to treat diabetes and prevent the progression of diabetes-related complications. In this current review, we have focused on the different types of cell therapies and vector-based gene therapy in treating or preventing diabetes.
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Affiliation(s)
- Leila Ghassemifard
- Department of Physiology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
- Department of Persian Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Masumeh Hasanlu
- Department of Internal Medicine, Vali-e-Asr Hospital, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Negin Parsamanesh
- Metabolic Diseases Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Stephen L Atkin
- Research Department, Royal College of Surgeons in Ireland Bahrain, Adliya, Bahrain
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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Karpf S, Glöckner Burmeister N, Dubreil L, Ghosh S, Hollandi R, Pichon J, Leroux I, Henkel A, Lutz V, Jurkevičius J, Latshaw A, Kilin V, Kutscher T, Wiggert M, Saavedra-Villanueva O, Vogel A, Huber RA, Horvath P, Rouger K, Bonacina L. Harmonic Imaging of Stem Cells in Whole Blood at GHz Pixel Rate. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2401472. [PMID: 38863131 DOI: 10.1002/smll.202401472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 05/21/2024] [Indexed: 06/13/2024]
Abstract
The pre-clinical validation of cell therapies requires monitoring the biodistribution of transplanted cells in tissues of host organisms. Real-time detection of these cells in the circulatory system and identification of their aggregation state is a crucial piece of information, but necessitates deep penetration and fast imaging with high selectivity, subcellular resolution, and high throughput. In this study, multiphoton-based in-flow detection of human stem cells in whole, unfiltered blood is demonstrated in a microfluidic channel. The approach relies on a multiphoton microscope with diffractive scanning in the direction perpendicular to the flow via a rapidly wavelength-swept laser. Stem cells are labeled with metal oxide harmonic nanoparticles. Thanks to their strong and quasi-instantaneous second harmonic generation (SHG), an imaging rate in excess of 10 000 frames per second is achieved with pixel dwell times of 1 ns, a duration shorter than typical fluorescence lifetimes yet compatible with SHG. Through automated cell identification and segmentation, morphological features of each individual detected event are extracted and cell aggregates are distinguished from isolated cells. This combination of high-speed multiphoton microscopy and high-sensitivity SHG nanoparticle labeling in turbid media promises the detection of rare cells in the bloodstream for assessing novel cell-based therapies.
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Affiliation(s)
- Sebastian Karpf
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | | | | | - Shayantani Ghosh
- Department of Applied Physics, Université de Genève, Rue de l'Ecole-de-Médecine, 20, Geneva, 1205, Switzerland
| | - Reka Hollandi
- Synthetic and Systems Biology Unit, Biological Research Centre (BRC), Szeged, H-6726, Hungary
| | | | | | - Alessandra Henkel
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Valerie Lutz
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Jonas Jurkevičius
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Alexandra Latshaw
- Department of Applied Physics, Université de Genève, Rue de l'Ecole-de-Médecine, 20, Geneva, 1205, Switzerland
| | - Vasyl Kilin
- Department of Applied Physics, Université de Genève, Rue de l'Ecole-de-Médecine, 20, Geneva, 1205, Switzerland
| | - Tonio Kutscher
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Moritz Wiggert
- Department of Applied Physics, Université de Genève, Rue de l'Ecole-de-Médecine, 20, Geneva, 1205, Switzerland
| | | | - Alfred Vogel
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Robert A Huber
- Institute of Biomedical Optics (BMO), University Of Luebeck, 23562, Luebeck, Germany
| | - Peter Horvath
- Synthetic and Systems Biology Unit, Biological Research Centre (BRC), Szeged, H-6726, Hungary
| | - Karl Rouger
- Oniris, INRAE, PAnther, Nantes, F-44307, France
| | - Luigi Bonacina
- Department of Applied Physics, Université de Genève, Rue de l'Ecole-de-Médecine, 20, Geneva, 1205, Switzerland
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Annicchiarico A, Barile B, Buccoliero C, Nicchia GP, Brunetti G. Alternative therapeutic strategies in diabetes management. World J Diabetes 2024; 15:1142-1161. [PMID: 38983831 PMCID: PMC11229975 DOI: 10.4239/wjd.v15.i6.1142] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/17/2024] [Accepted: 04/12/2024] [Indexed: 06/11/2024] Open
Abstract
Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreatic β cells, insulin resistance in peripheral tissues, or both, and results in a non-sufficient production of insulin. To adjust blood glucose levels, diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity. With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities, different strategies have been investigated. The first approaches included enhancing endogenous β cell activity or transplanting new islets. The protocol for this kind of intervention has recently been optimized, leading to standardized procedures. It is indicated for diabetic patients with severe hypoglycemia, complicated by impaired hypoglycemia awareness or exacerbated glycemic lability. Transplantation has been associated with improvement in all comorbidities associated with diabetes, quality of life, and survival. However, different trials are ongoing to further improve the beneficial effects of transplantation. Furthermore, to overcome some limitations associated with the availability of islets/pancreas, alternative therapeutic strategies are under evaluation, such as the use of mesenchymal stem cells (MSCs) or induced pluripotent stem cells for transplantation. The cotransplantation of MSCs with islets has been successful, thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms, including exosome release. The use of induced pluripotent stem cells is recent and requires further investigation. The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities, such as wound healing. Despite the number of advantages of the direct injection of MSCs, new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results. In conclusion, this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.
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Affiliation(s)
- Alessia Annicchiarico
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Barbara Barile
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Cinzia Buccoliero
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Grazia Paola Nicchia
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
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Wang Q, Huang YX, Liu L, Zhao XH, Sun Y, Mao X, Li SW. Pancreatic islet transplantation: current advances and challenges. Front Immunol 2024; 15:1391504. [PMID: 38887292 PMCID: PMC11180903 DOI: 10.3389/fimmu.2024.1391504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 05/20/2024] [Indexed: 06/20/2024] Open
Abstract
Diabetes is a prevalent chronic disease that traditionally requires severe reliance on medication for treatment. Oral medication and exogenous insulin can only temporarily maintain blood glucose levels and do not cure the disease. Most patients need life-long injections of exogenous insulin. In recent years, advances in islet transplantation have significantly advanced the treatment of diabetes, allowing patients to discontinue exogenous insulin and avoid complications.Long-term follow-up results from recent reports on islet transplantation suggest that they provide significant therapeutic benefit although patients still require immunotherapy, suggesting the importance of future transplantation strategies. Although organ shortage remains the primary obstacle for the development of islet transplantation, new sources of islet cells, such as stem cells and porcine islet cells, have been proposed, and are gradually being incorporated into clinical research. Further research on new transplantation sites, such as the subcutaneous space and mesenteric fat, may eventually replace the traditional portal vein intra-islet cell infusion. Additionally, the immunological rejection reaction in islet transplantation will be resolved through the combined application of immunosuppressant agents, islet encapsulation technology, and the most promising mesenchymal stem cells/regulatory T cell and islet cell combined transplantation cell therapy. This review summarizes the progress achieved in islet transplantation, and discusses the research progress and potential solutions to the challenges faced.
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Affiliation(s)
- Qi Wang
- Department of Hepatobiliary and Pancreatic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Yu-xi Huang
- Department of Hepatobiliary and Pancreatic Surgery, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Long Liu
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xiao-hong Zhao
- Department of Pharmacy, Taizhou Hospital, Zhejiang University, Taizhou, Zhejiang, China
| | - Yi Sun
- MRL Global Medical Affairs, MSD China, Shanghai, China
| | - Xinli Mao
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
| | - Shao-wei Li
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
- Key Laboratory of Minimally Invasive Techniques and Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital Affiliated to Wenzhou Medical University, Linhai, Zhejiang, China
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Marquez-Curtis LA, Elliott JAW. Mesenchymal stromal cells derived from various tissues: Biological, clinical and cryopreservation aspects: Update from 2015 review. Cryobiology 2024; 115:104856. [PMID: 38340887 DOI: 10.1016/j.cryobiol.2024.104856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/26/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024]
Abstract
Mesenchymal stromal cells (MSCs) have become one of the most investigated and applied cells for cellular therapy and regenerative medicine. In this update of our review published in 2015, we show that studies continue to abound regarding the characterization of MSCs to distinguish them from other similar cell types, the discovery of new tissue sources of MSCs, and the confirmation of their properties and functions that render them suitable as a therapeutic. Because cryopreservation is widely recognized as the only technology that would enable the on-demand availability of MSCs, here we show that although the traditional method of cryopreserving cells by slow cooling in the presence of 10% dimethyl sulfoxide (Me2SO) continues to be used by many, several novel MSC cryopreservation approaches have emerged. As in our previous review, we conclude from these recent reports that viable and functional MSCs from diverse tissues can be recovered after cryopreservation using a variety of cryoprotectants, freezing protocols, storage temperatures, and periods of storage. We also show that for logistical reasons there are now more studies devoted to the cryopreservation of tissues from which MSCs are derived. A new topic included in this review covers the application in COVID-19 of MSCs arising from their immunomodulatory and antiviral properties. Due to the inherent heterogeneity in MSC populations from different sources there is still no standardized procedure for their isolation, identification, functional characterization, cryopreservation, and route of administration, and not likely to be a "one-size-fits-all" approach in their applications in cell-based therapy and regenerative medicine.
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Affiliation(s)
- Leah A Marquez-Curtis
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, Canada, T6G 1H9; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada, T6G 1C9
| | - Janet A W Elliott
- Department of Chemical and Materials Engineering, University of Alberta, Edmonton, AB, Canada, T6G 1H9; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada, T6G 1C9.
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Hoang VT, Le DS, Hoang DM, Phan TTK, Ngo LAT, Nguyen TK, Bui VA, Nguyen Thanh L. Impact of tissue factor expression and administration routes on thrombosis development induced by mesenchymal stem/stromal cell infusions: re-evaluating the dogma. Stem Cell Res Ther 2024; 15:56. [PMID: 38414067 PMCID: PMC10900728 DOI: 10.1186/s13287-023-03582-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 11/22/2023] [Indexed: 02/29/2024] Open
Abstract
BACKGROUND Hyperactive coagulation might cause dangerous complications such as portal vein thrombosis and pulmonary embolism after mesenchymal stem/stromal cell (MSC) therapy. Tissue factor (TF), an initiator of the extrinsic coagulation pathway, has been suggested as a predictor of this process. METHODS The expression of TF and other pro- and anticoagulant genes was analyzed in xeno- and serum-free manufactured MSCs. Furthermore, culture factors affecting its expression in MSCs were investigated. Finally, coagulation tests of fibrinogen, D-dimer, aPPTs, PTs, and TTs were measured in patient serum after umbilical cord (UC)-MSC infusions to challenge a potential connection between TF expression and MSC-induced coagulant activity. RESULTS: Xeno- and serum-free cultured adipose tissue and UC-derived MSCs expressed the highest level of TF, followed by those from dental pulp, and the lowest expression was observed in MSCs of bone marrow origin. Environmental factors such as cell density, hypoxia, and inflammation impact TF expression, so in vitro analysis might fail to reflect their in vivo behaviors. MSCs also expressed heterogeneous levels of the coagulant factor COL1A1 and surface phosphatidylserine and anticoagulant factors TFPI and PTGIR. MSCs of diverse origins induced fibrin clots in healthy plasma that were partially suppressed by an anti-TF inhibitory monoclonal antibody. Furthermore, human umbilical vein endothelial cells exhibited coagulant activity in vitro despite their negative expression of TF and COL1A1. Patients receiving intravenous UC-MSC infusion exhibited a transient increase in D-dimer serum concentration, while this remained stable in the group with intrathecal infusion. There was no correlation between TF expression and D-dimer or other coagulation indicators. CONCLUSIONS The study suggests that TF cannot be used as a solid biomarker to predict MSC-induced hypercoagulation. Local administration, prophylactic intervention with anticoagulation drugs, and monitoring of coagulation indicators are useful to prevent thrombogenic events in patients receiving MSCs. Trial registration NCT05292625. Registered March 23, 2022, retrospectively registered, https://www. CLINICALTRIALS gov/ct2/show/NCT05292625?term=NCT05292625&draw=2&rank=1 . NCT04919135. Registered June 9, 2021, https://www. CLINICALTRIALS gov/ct2/show/NCT04919135?term=NCT04919135&draw=2&rank=1 .
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Affiliation(s)
- Van T Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam.
| | - Duc Son Le
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam
| | - Duc M Hoang
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam
| | - Trang Thi Kieu Phan
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam
| | - Lan Anh Thi Ngo
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam
- Center of Applied Science and Regenerative Medicine, Vinmec Health Care System, 458 Minh Khai, Hanoi, 10000, Vietnam
| | - Trung Kien Nguyen
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam
| | - Viet Anh Bui
- Center of Applied Science and Regenerative Medicine, Vinmec Health Care System, 458 Minh Khai, Hanoi, 10000, Vietnam
| | - Liem Nguyen Thanh
- Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Health Care System, 458 Minh Khai, Hai Ba Trung District, Hanoi, 100000, Vietnam.
- Vinmec International Hospital - Times City, Vinmec Health Care System, 458 Minh Khai, Hanoi, 11622, Vietnam.
- College of Health Science, VinUniversity, Vinhomes Ocean Park, Gia Lam District, Hanoi, 1310, Vietnam.
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Han C, Lv YW, Hu LH. Management of chronic pancreatitis: recent advances and future prospects. Therap Adv Gastroenterol 2024; 17:17562848241234480. [PMID: 38406795 PMCID: PMC10894541 DOI: 10.1177/17562848241234480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 01/30/2024] [Indexed: 02/27/2024] Open
Abstract
As a progressive fibroinflammatory disease, chronic pancreatitis (CP) often manifests as recurrent bouts of abdominal pain with or without complications, causing a heavy burden of health care. In recent years, some meaningful insights into the management of CP have been obtained from randomized controlled trials, systematic reviews, and meta-analyses, which were of great importance. Based on this research, it is shown that there are various treatments for CP. Therefore, it is of great importance to choose a suitable strategy for patients with CP individually. Relevant evidence on the management of CP was summarized in this review, including nutrition supplements, medication, endoscopy, surgery, exploration of novel therapies as well as evaluation and prediction of treatment response.
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Affiliation(s)
- Chao Han
- Department of Gastroenterology, The Hospital of 91876 Troops of Chinese People’s Liberation Army, Qinhuangdao, China
| | - Yan-Wei Lv
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
- Shanghai Institute of Pancreatic Diseases, Shanghai, China
| | - Liang-Hao Hu
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, 168 Changhai Road, Shanghai 200433, China
- National Key Laboratory of Immunity and Inflammation, Naval Medical University, Shanghai, China
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Ghoneim MA, Gabr MM, El-Halawani SM, Refaie AF. Current status of stem cell therapy for type 1 diabetes: a critique and a prospective consideration. Stem Cell Res Ther 2024; 15:23. [PMID: 38281991 PMCID: PMC10823744 DOI: 10.1186/s13287-024-03636-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 01/10/2024] [Indexed: 01/30/2024] Open
Abstract
Over the past decade, there had been progress in the development of cell therapy for insulin-dependent diabetes. Nevertheless, important hurdles that need to be overcome still remain. Protocols for the differentiation of pluripotent stem cells into pancreatic progenitors or fully differentiated β-cells have been developed. The resulting insulin-producing cells can control chemically induced diabetes in rodents and were the subject of several clinical trials. However, these cells are immunogenic and possibly teratogenic for their transplantation, and an immunoisolation device and/or immunosuppression is needed. A growing number of studies have utilized genetic manipulations to produce immune evasive cells. Evidence must be provided that in addition to the expected benefit, gene manipulations should not lead to any unforeseen complications. Mesenchymal stem/stromal cells (MSCs) can provide a viable alternative. MSCs are widely available from many tissues. They can form insulin-producing cells by directed differentiation. Experimentally, evidence has shown that the transplantation of allogenic insulin-producing cells derived from MSCs is associated with a muted allogeneic response that does not interfere with their functionality. This can be explained by the immunomodulatory functions of the MSC subpopulation that did not differentiate into insulin-producing cells. Recently, exosomes derived from naive MSCs have been used in the experimental domain to treat diabetes in rodents with varying degrees of success. Several mechanisms for their beneficial functions were proposed including a reduction in insulin resistance, the promotion of autophagy, and an increase in the T regulatory population. However, euglycemia was not achieved in any of these experiments. We suggest that exosomes derived from β-cells or insulin-producing cells (educated) can provide a better therapeutic effect than those derived from undifferentiated cells.
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Duan K, Liu J, Zhang J, Chu T, Liu H, Lou F, Liu Z, Gao B, Wei S, Wei F. Advancements in innate immune regulation strategies in islet transplantation. Front Immunol 2024; 14:1341314. [PMID: 38288129 PMCID: PMC10823010 DOI: 10.3389/fimmu.2023.1341314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 12/28/2023] [Indexed: 01/31/2024] Open
Abstract
As a newly emerging organ transplantation technique, islet transplantation has shown the advantages of minimal trauma and high safety since it was first carried out. The proposal of the Edmonton protocol, which has been widely applied, was a breakthrough in this method. However, direct contact between islets and portal vein blood will cause a robust innate immune response leading to massive apoptosis of the graft, and macrophages play an essential role in the innate immune response. Therefore, therapeutic strategies targeting macrophages in the innate immune response have become a popular research topic in recent years. This paper will summarize and analyze recent research on strategies for regulating innate immunity, primarily focusing on macrophages, in the field of islet transplantation, including drug therapy, optimization of islet preparation process, islet engineering and Mesenchymal stem cells cotransplantation. We also expounded the heterogeneity, plasticity and activation mechanism of macrophages in islet transplantation, providing a theoretical basis for further research.
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Affiliation(s)
- Kehang Duan
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jiao Liu
- Department of Cardiology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jian Zhang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Tongjia Chu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Huan Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Fengxiang Lou
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Ziyu Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Bing Gao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Shixiong Wei
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Feng Wei
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
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11
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Wang H, Gou W, Nietert PJ, Hirsch J, Wang J, Allawi A, Mortadha AS, Cook K, Overstreet M, Wei H, Adams D, Lancaster WP, Morgan KA, Strange C. Alpha-1 Antitrypsin Augmentation Therapy in Chronic Pancreatitis Patients Undergoing Total Pancreatectomy and Islet Autotransplantation: A Randomized, Controlled Study. Cell Transplant 2024; 33:9636897241243014. [PMID: 38659255 PMCID: PMC11044796 DOI: 10.1177/09636897241243014] [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: 11/22/2023] [Revised: 02/28/2024] [Accepted: 03/04/2024] [Indexed: 04/26/2024] Open
Abstract
Stress-induced islet graft loss during the peri-transplantation period reduces the efficacy of islet transplantation. In this prospective, randomized, double-blind clinical trial, we evaluated the safety and efficacy of 60 mg/kg human alpha-1 antitrypsin (AAT) or placebo infusion weekly for four doses beginning before surgery in chronic pancreatitis (CP) patients undergoing total pancreatectomy and islet autotransplantation (TP-IAT). Subjects were followed for 12 months post-TP-IAT. The dose of AAT was safe, as there was no difference in the types and severity of adverse events in participants from both groups. There were some biochemical signals of treatment effect with a higher oxygen consumption rate in AAT islets before transplantation and a lower serum C-peptide (an indicator of islet death) in the AAT group at 15 min after islet infusion. Findings per the statistical analysis plan using a modified intention to treat analysis showed no difference in the C-peptide area under the curve (AUC) following a mixed meal tolerance test at 12 months post-TP-IAT. There was no difference in the secondary and exploratory outcomes. Although AAT therapy did not show improvement in C-peptide AUC in this study, AAT therapy is safe in CP patients and there are experiences gained on optimal clinical trial design in this challenging disease.
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Affiliation(s)
- Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA
| | - Wenyu Gou
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Paul J. Nietert
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, USA
| | - Jason Hirsch
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Jingjing Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Ahmed Allawi
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Abd S. Mortadha
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Kelsey Cook
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Morgan Overstreet
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Hua Wei
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - David Adams
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - William P. Lancaster
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Katherine A. Morgan
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Charlie Strange
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
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12
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Mei L, Yuwei Y, Weiping L, Zhiran X, Bingzheng F, Jibing C, Hongjun G. Strategy for Clinical Setting of Co-transplantation of Mesenchymal Stem Cells and Pancreatic Islets. Cell Transplant 2024; 33:9636897241259433. [PMID: 38877672 PMCID: PMC11179456 DOI: 10.1177/09636897241259433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/29/2024] [Accepted: 05/06/2024] [Indexed: 06/16/2024] Open
Abstract
Islet transplantation may be the most efficient therapeutic technique for patients with type 1 diabetes mellitus (T1DM). However, the clinical application of this method is faced with numerous limitations, including isolated islet apoptosis, recipient rejection, and graft vascular reconstruction. Mesenchymal stem cells (MSCs) possess anti-apoptotic, immunomodulatory, and angiogenic properties. Here, we review recent studies on co-culture and co-transplantation of islets with MSCs. We have summarized the methods of preparation of co-transplantation, especially the merits of co-culture, and the effects of co-transplantation. Accumulating experimental evidence shows that co-culture of islets with MSCs promotes islet survival, enhances islet secretory function, and prevascularizes islets through various pretransplant preparations. This review is expected to provide a reference for exploring the use of MSCs for clinical islet co-transplantation.
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Affiliation(s)
- Liang Mei
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Yang Yuwei
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Liang Weiping
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Xu Zhiran
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Feng Bingzheng
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Chen Jibing
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Clinical Research Center for Kidney Diseases of Integrated Traditional Chinese and Western Medicine, Nanning, China
| | - Gao Hongjun
- Ruikang Hospital affiliated to Guangxi University of Chinese Medicine, Nanning, China
- Guangxi Clinical Research Center for Kidney Diseases of Integrated Traditional Chinese and Western Medicine, Nanning, China
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13
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Morgan KA. Update on Total Pancreatectomy With Islet Autotransplantation. Am Surg 2023; 89:4241-4245. [PMID: 37840289 DOI: 10.1177/00031348231200669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2023]
Abstract
Total pancreatectomy with islet autotransplantation is a therapeutic option to effectively achieve pain relief and improvements in quality of life for selected patients with debilitating pain from chronic pancreatitis. The understanding of the best application and clinical execution of this procedure is in evolution, with outcomes studies and clinical trials in progress.
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Affiliation(s)
- Katherine A Morgan
- Division of Hepatopancreatobiliary Surgery, Medical University of South Carolina, Charleston, SC, USA
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14
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Chen ME, Desai CS. Current practices in islet cell autotransplantation. Expert Rev Endocrinol Metab 2023; 18:419-425. [PMID: 37680038 DOI: 10.1080/17446651.2023.2256407] [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: 07/24/2023] [Revised: 08/28/2023] [Accepted: 09/04/2023] [Indexed: 09/09/2023]
Abstract
INTRODUCTION Chronic pancreatitis and recurrent acute pancreatitis comprise a spectrum of disease that results in complications related to exocrine and endocrine insufficiency and chronic pain with narcotic dependence and poor quality of life. The mainstay of therapy has been medical and endoscopic therapy; surgery, especially total pancreatectomy, was historically reserved for few select patients as the obligate exocrine insufficiency and pancreatogenic diabetes (type 3C) are challenging to manage. The addition of islet cell autotransplantation after total pancreatectomy helps to mitigate brittle type 3c diabetes and prevents mortality related to severe hypoglycemic episodes and hypoglycemic unawareness. There have been more recent data demonstrating the safety of surgery and the beneficial long-term outcomes. AREAS COVERED The purpose of this review is to describe the current practices in the field of islet cell autotransplantation including the selection and evaluation of patients for surgery, their preoperative work up and management, surgical approach, post-operative management and outcomes. EXPERT OPINION Total pancreatectomy and islet cell autotransplantation has the ability to drastically improve quality of life and prevent brittle diabetes for patients suffering with chronic pancreatitis.
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Affiliation(s)
- Melissa E Chen
- Department of Surgery, University of North Carolina, Chapel Hill, NC, USA
| | - Chirag S Desai
- Department of Surgery, University of North Carolina, Chapel Hill, NC, USA
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15
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Kale A, Rogers NM. No Time to Die-How Islets Meet Their Demise in Transplantation. Cells 2023; 12:cells12050796. [PMID: 36899932 PMCID: PMC10000424 DOI: 10.3390/cells12050796] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/27/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Islet transplantation represents an effective treatment for patients with type 1 diabetes mellitus (T1DM) and severe hypoglycaemia unawareness, capable of circumventing impaired counterregulatory pathways that no longer provide protection against low blood glucose levels. The additional beneficial effect of normalizing metabolic glycaemic control is the minimisation of further complications related to T1DM and insulin administration. However, patients require allogeneic islets from up to three donors, and the long-term insulin independence is inferior to that achieved with solid organ (whole pancreas) transplantation. This is likely due to the fragility of islets caused by the isolation process, innate immune responses following portal infusion, auto- and allo-immune-mediated destruction and β-cell exhaustion following transplantation. This review covers the specific challenges related to islet vulnerability and dysfunction that affect long-term cell survival following transplantation.
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Affiliation(s)
- Atharva Kale
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
| | - Natasha M. Rogers
- Centre for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2006, Australia
- Renal and Transplant Unit, Westmead Hospital, Westmead, NSW 2145, Australia
- Correspondence:
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16
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Extracellular Vesicles Derived from Three-Dimensional-Cultured Human Umbilical Cord Blood Mesenchymal Stem Cells Prevent Inflammation and Dedifferentiation in Pancreatic Islets. Stem Cells Int 2023; 2023:5475212. [PMID: 36860546 PMCID: PMC9970714 DOI: 10.1155/2023/5475212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 12/16/2022] [Accepted: 02/08/2023] [Indexed: 02/22/2023] Open
Abstract
It is unclear whether extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) have a direct protective effect on pancreatic islets. In addition, whether culturing MSCs in three dimensions (3D) instead of a monolayer (2D) can induce changes in the cargo of EVs that facilitate the polarization of macrophages into an M2 phenotype has not been investigated. We sought to determine whether EVs from MSCs cultured in 3D can prevent inflammation and dedifferentiation in pancreatic islets and, if so, whether the protective effect is superior to that of EVs from 2D MSCs. Human umbilical cord blood- (hUCB-) MSCs cultured in 3D were optimized according to cell density, exposure to hypoxia, and cytokine treatment based on the ability of the hUCB-MSC-derived EVs to induce the M2 polarization of macrophages. Islets isolated from human islet amyloid polypeptide (hIAPP) heterozygote transgenic mice were cultured in serum-deprived conditions with hUCB-MSC-derived EVs. EVs derived from 3D hUCB-MSCs had more abundant microRNAs involved in M2 polarization of macrophages and had an enhanced M2 polarization ability on macrophages, which was optimized when the 3D culture condition was 2.5 × 104 cells per spheroid without preconditioning with hypoxia and cytokine exposure. When islets isolated from hIAPP heterozygote transgenic mice were cultured in serum-deprived conditions with hUCB-MSC-derived EVs, the EVs derived from 3D hUCB-MSCs suppressed the expression of proinflammatory cytokines and caspase-1 in pancreatic islets and increased the proportion of M2-polarized islet-resident macrophages. They improved glucose-stimulated insulin secretion, reduced the expression of Oct4 and NGN3, and induced the expression of Pdx1 and FoxO1. The greater suppression of IL-1β, NLRP3 inflammasome, caspase-1, and Oct4 and induction of Pdx1 and FoxO1 were found in islets cultured with the EVs derived from 3D hUCB-MSCs. In conclusion, EVs derived from 3D hUCB-MSCs optimized for M2 polarization attenuated nonspecific inflammation and preserved β-cell identity of pancreatic islets.
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17
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Ross EA, Turner LA, Donnelly H, Saeed A, Tsimbouri MP, Burgess KV, Blackburn G, Jayawarna V, Xiao Y, Oliva MAG, Willis J, Bansal J, Reynolds P, Wells JA, Mountford J, Vassalli M, Gadegaard N, Oreffo ROC, Salmeron-Sanchez M, Dalby MJ. Nanotopography reveals metabolites that maintain the immunomodulatory phenotype of mesenchymal stromal cells. Nat Commun 2023; 14:753. [PMID: 36765065 PMCID: PMC9918539 DOI: 10.1038/s41467-023-36293-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 01/25/2023] [Indexed: 02/12/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent progenitor cells that are of considerable clinical potential in transplantation and anti-inflammatory therapies due to their capacity for tissue repair and immunomodulation. However, MSCs rapidly differentiate once in culture, making their large-scale expansion for use in immunomodulatory therapies challenging. Although the differentiation mechanisms of MSCs have been extensively investigated using materials, little is known about how materials can influence paracrine activities of MSCs. Here, we show that nanotopography can control the immunomodulatory capacity of MSCs through decreased intracellular tension and increasing oxidative glycolysis. We use nanotopography to identify bioactive metabolites that modulate intracellular tension, growth and immunomodulatory phenotype of MSCs in standard culture and during larger scale cell manufacture. Our findings demonstrate an effective route to support large-scale expansion of functional MSCs for therapeutic purposes.
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Affiliation(s)
- Ewan A Ross
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK
| | - Lesley-Anne Turner
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Hannah Donnelly
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Anwer Saeed
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Monica P Tsimbouri
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Karl V Burgess
- Glasgow Polyomics, Wolfson Wohl Cancer Research Centre, Garscube Campus, Bearsden, Glasgow, G61 1QH, UK
| | - Gavin Blackburn
- Glasgow Polyomics, Wolfson Wohl Cancer Research Centre, Garscube Campus, Bearsden, Glasgow, G61 1QH, UK
| | - Vineetha Jayawarna
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, James Watt School of Engineering, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Yinbo Xiao
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Mariana A G Oliva
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, James Watt School of Engineering, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Jennifer Willis
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK
| | - Jaspreet Bansal
- School of Biosciences, College of Health and Life Sciences, Aston University, Birmingham, B4 7ET, UK
| | - Paul Reynolds
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Julia A Wells
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK
| | - Joanne Mountford
- Scottish National Blood Transfusion Service, Advanced Therapeutics, Jack Copland Centre, 52 Research Avenue North, Heriot Watt Research Park, Edinburgh, EH14 4BE, UK
| | - Massimo Vassalli
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, James Watt School of Engineering, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Nikolaj Gadegaard
- Division of Biomedical Engineering, James Watt School of Engineering, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Richard O C Oreffo
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, SO16 6YD, UK
| | - Manuel Salmeron-Sanchez
- Centre for the Cellular Microenvironment, Division of Biomedical Engineering, James Watt School of Engineering, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK
| | - Matthew J Dalby
- Centre for the Cellular Microenvironment, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, Mazumdar-Shaw Advanced Research Centre, University of Glasgow, Glasgow, G11 6EW, UK.
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18
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Pathogenic Role of Adipose Tissue-Derived Mesenchymal Stem Cells in Obesity and Obesity-Related Inflammatory Diseases. Cells 2023; 12:cells12030348. [PMID: 36766689 PMCID: PMC9913687 DOI: 10.3390/cells12030348] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/12/2023] [Accepted: 01/14/2023] [Indexed: 01/19/2023] Open
Abstract
Adipose tissue-derived mesenchymal stem cells (ASCs) are adult stem cells, endowed with self-renewal, multipotent capacities, and immunomodulatory properties, as mesenchymal stem cells (MSCs) from other origins. However, in a pathological context, ASCs like MSCs can exhibit pro-inflammatory properties and attract inflammatory immune cells at their neighborhood. Subsequently, this creates an inflammatory microenvironment leading to ASCs' or MSCs' dysfunctions. One such example is given by obesity where adipogenesis is impaired and insulin resistance is initiated. These opposite properties have led to the classification of MSCs into two categories defined as pro-inflammatory ASC1 or anti-inflammatory ASC2, in which plasticity depends on the micro-environmental stimuli. The aim of this review is to (i) highlight the pathogenic role of ASCs during obesity and obesity-related inflammatory diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, and cancer; and (ii) describe some of the mechanisms leading to ASCs dysfunctions. Thus, the role of soluble factors, adhesion molecules; TLRs, Th17, and Th22 cells; γδ T cells; and immune checkpoint overexpression will be addressed.
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19
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Wang J, Wang J, Wang Y, Ma R, Zhang S, Zheng J, Xue W, Ding X. Bone Marrow Mesenchymal Stem Cells-Derived miR-21-5p Protects Grafted Islets Against Apoptosis by Targeting PDCD4. Stem Cells 2022; 41:169-183. [PMID: 36512434 PMCID: PMC9982070 DOI: 10.1093/stmcls/sxac085] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 12/01/2022] [Indexed: 12/15/2022]
Abstract
The apoptosis of grafted islets is an urgent problem due to the high rate of islet loss soon after transplantation. MicroRNA-21-5p (miR-21-5p) is an essential mediator of bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exo) during anti-apoptosis, but its effect and the underlying molecular mechanism in islet transplantation remain partially understood. Here, we found that miR-21-5p could be delivered to islet cells via BMSCs-Exo. Subsequently, we demonstrated that miR-21-5p overexpression reduced apoptosis in islets and INS-1 cells, whereas miR-21-5p inhibition enhanced apoptosis. A mechanistic analysis involving RNA sequencing and bioinformatic analysis was performed to determine the interaction between miR-21-5p and its target gene programmed cell death 4 (PDCD4), which was further verified by a dual luciferase assay. In vivo, the grafted islets overexpressing miR-21-5p showed a higher survival rate, better insulin secretion function, and a lower apoptosis rate. In conclusion, these results demonstrated that miR‑21‑5p from BMSCs-Exo protects against the apoptosis of grafted islets by inhibiting PDCD4 expression. Hence, miR-21-5p can be used as a cell-free therapeutic agent to minimize β-cell apoptosis at the early stage of islet transplantation.
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Affiliation(s)
| | | | - Ying Wang
- Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China
| | - Ruiyang Ma
- Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China
| | - Shucong Zhang
- Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China
| | - Jin Zheng
- Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China
| | - Wujun Xue
- Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China
| | - Xiaoming Ding
- Corresponding author: Xiaoming Ding, Department of Renal Transplantation, Hospital of Nephrology, the First Affiliated Hospital of Xi’an Jiaotong University, 277 Yanta Western Rd, Xi’an 710061, Shaanxi Province, People’s Republic of China. Tel: +8613991238632; E-mail:
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20
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Gou W, Hua W, Swaby L, Cui W, Green E, Morgan KA, Strange C, Wang H. Stem Cell Therapy Improves Human Islet Graft Survival in Mice via Regulation of Macrophages. Diabetes 2022; 71:2642-2655. [PMID: 36084289 PMCID: PMC9750955 DOI: 10.2337/db22-0117] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 09/01/2022] [Indexed: 01/23/2023]
Abstract
Islet/β-cell transplantation offers great hope for patients with type 1 diabetes. We assessed the mechanisms of how intrahepatic coinfusion of human α-1 antitrypsin (hAAT)-engineered mesenchymal stromal cells (hAAT-MSCs) improves survival of human islet grafts posttransplantation (PT). Longitudinal in vivo bioluminescence imaging studies identified significantly more islets in the livers bearing islets cotransplanted with hAAT-MSCs compared with islets transplanted alone. In vitro mechanistic studies revealed that hAAT-MSCs inhibit macrophage migration and suppress IFN-γ-induced M1-like macrophages while promoting IL-4-induced M2-like macrophages. In vivo this translated to significantly reduced CD11c+ and F4/80+ cells and increased CD206+ cells around islets cotransplanted with hAAT-MSCs as identified by multiplex immunofluorescence staining. Recipient-derived F4/80+and CD11b+ macrophages were mainly present in the periphery of an islet, while CD11c+ and CD206+ cells appeared inside an islet. hAAT-MSCs inhibited macrophage migration and skewed the M1-like phenotype toward an M2 phenotype both in vitro and in vivo, which may have favored islet survival. These data provide evidence that hAAT-MSCs cotransplanted with islets remain in the liver and shift macrophages to a protective state that favors islet survival. This novel strategy may be used to enhance β-cell survival during islet/β-cell transplantation for the treatment of type 1 diabetes or other diseases.
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Affiliation(s)
- Wenyu Gou
- Department of Surgery, Medical University of South Carolina, Charleston, SC
- Center for Cellular Therapy, Medical University of South Carolina, Charleston, SC
| | - Wei Hua
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | - Lindsay Swaby
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | | | - Erica Green
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | | | - Charlie Strange
- Department of Medicine, Medical University of South Carolina, Charleston, SC
| | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC
- Center for Cellular Therapy, Medical University of South Carolina, Charleston, SC
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC
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21
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Co-transplantation of pancreatic islets and microvascular fragments effectively restores normoglycemia in diabetic mice. NPJ Regen Med 2022; 7:67. [PMCID: PMC9636251 DOI: 10.1038/s41536-022-00262-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 10/12/2022] [Indexed: 11/06/2022] Open
Abstract
AbstractInsufficient revascularization of pancreatic islets is one of the major obstacles impairing the success of islet transplantation. To overcome this problem, we introduce in the present study a straightforward strategy to accelerate the engraftment of isolated islets. For this purpose, we co-transplanted 250 islets and 20,000 adipose tissue-derived microvascular fragments (MVF) from donor mice under the kidney capsule as well as 500 or 1000 islets with 40,000 MVF into the subcutaneous space of diabetic mice. We found that the co-transplantation of islets and MVF markedly accelerates the restoration of normoglycemia in diabetic recipients compared with the transplantation of islets alone. In fact, the transplantation of 250 islets with 20,000 MVF under the kidney capsule reversed diabetes in 88% of mice and the subcutaneous transplantation of 500 or 1000 islets with 40,000 MVF restored normoglycemia in 100% of mice. Moreover, diabetic mice receiving islets and MVF exhibited plasma insulin levels similar to nondiabetic control animals. Additional immunohistochemical analyses of the grafts revealed a significantly higher number of islet cells and microvessels in the co-transplantation groups. These findings demonstrate that the co-transplantation of islets and MVF is a promising strategy to improve the success rates of islet transplantation, which could be easily implemented into future clinical practice.
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22
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Jeyagaran A, Lu CE, Zbinden A, Birkenfeld AL, Brucker SY, Layland SL. Type 1 diabetes and engineering enhanced islet transplantation. Adv Drug Deliv Rev 2022; 189:114481. [PMID: 36002043 PMCID: PMC9531713 DOI: 10.1016/j.addr.2022.114481] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 01/24/2023]
Abstract
The development of new therapeutic approaches to treat type 1 diabetes mellitus (T1D) relies on the precise understanding and deciphering of insulin-secreting β-cell biology, as well as the mechanisms responsible for their autoimmune destruction. β-cell or islet transplantation is viewed as a potential long-term therapy for the millions of patients with diabetes. To advance the field of insulin-secreting cell transplantation, two main research areas are currently investigated by the scientific community: (1) the identification of the developmental pathways that drive the differentiation of stem cells into insulin-producing cells, providing an inexhaustible source of cells; and (2) transplantation strategies and engineered transplants to provide protection and enhance the functionality of transplanted cells. In this review, we discuss the biology of pancreatic β-cells, pathology of T1D and current state of β-cell differentiation. We give a comprehensive view and discuss the different possibilities to engineer enhanced insulin-secreting cell/islet transplantation from a translational perspective.
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Affiliation(s)
- Abiramy Jeyagaran
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; NMI Natural and Medical Sciences Institute at the University Tübingen, 72770 Reutlingen, Germany
| | - Chuan-En Lu
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Aline Zbinden
- Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Andreas L Birkenfeld
- Department of Internal Medicine IV, University Hospital Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, German Center for Diabetes Research (DZD e.V.), Munich, Germany
| | - Sara Y Brucker
- Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany
| | - Shannon L Layland
- Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Department of Women's Health, Eberhard Karls University, 72076 Tübingen, Germany.
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23
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Bolla AM, Montefusco L, Pastore I, Lunati ME, Ben Nasr M, Fiorina P. Benefits and Hurdles of Pancreatic β-Cell Replacement. Stem Cells Transl Med 2022; 11:1029-1039. [PMID: 36073717 PMCID: PMC9585952 DOI: 10.1093/stcltm/szac058] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/02/2022] [Indexed: 11/13/2022] Open
Abstract
Insulin represents a life-saving treatment in patients with type 1 diabetes, and technological advancements have improved glucose control in an increasing number of patients. Despite this, adequate control is often still difficult to achieve and insulin remains a therapy and not a cure for the disease. β-cell replacement strategies can potentially restore pancreas endocrine function and aim to maintain normoglycemia; both pancreas and islet transplantation have greatly progressed over the last decades and, in subjects with extreme glycemic variability and diabetes complications, represent a concrete and effective treatment option. Some issues still limit the adoption of this approach on a larger scale. One is represented by the strict selection criteria for the recipient who can benefit from a transplant and maintain the lifelong immunosuppression necessary to avoid organ rejection. Second, with regard to islet transplantation, up to 40% of islets can be lost during hepatic engraftment. Recent studies showed very preliminarily but promising results to overcome these hurdles: the ability to induce β-cell maturation from stem cells may represent a solution to the organ shortage, and the creation of semi-permeable membranes that envelope or package cells in either micro- or macro- encapsulation strategies, together with engineering cells to be hypo-immunogenic, pave the way for developing strategies without immunosuppression. The aim of this review is to describe the state of the art in β-cell replacement with a focus on its efficacy and clinical benefits, on the actual limitations and still unmet needs, and on the latest findings and future directions.
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Affiliation(s)
| | - Laura Montefusco
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Ida Pastore
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | | | - Moufida Ben Nasr
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paolo Fiorina
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy.,International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy.,Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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24
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Azizi Z, Abbaszadeh R, Sahebnasagh R, Norouzy A, Motevaseli E, Maedler K. Bone marrow mesenchymal stromal cells for diabetes therapy: touch, fuse, and fix? Stem Cell Res Ther 2022; 13:348. [PMID: 35883121 PMCID: PMC9327419 DOI: 10.1186/s13287-022-03028-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 07/04/2022] [Indexed: 12/26/2022] Open
Abstract
Bone marrow mesenchymal stromal cells (BM-MSCs) have anti-inflammatory and pro-survival properties. Naturally, they do not express human leukocyte antigen class II surface antigens and have immunosuppressive capabilities. Together with their relatively easy accessibility and expansion, they are an attractive tool for organ support in transplantation and regenerative therapy. Autologous BM-MSC transplantation alone or together with transplanted islets improves β-cell function, graft survival, and glycemic control in diabetes. Albeit MSCs’ capacity to transdifferentiate into β-cell is limited, their protective effects are mediated mainly by paracrine mechanisms through BM-MSCs circulating through the body. Direct cell–cell contact and spontaneous fusion of BM-MSCs with injured cells, although at a very low rate, are further mechanisms of their supportive effect and for tissue regeneration. Diabetes is a disease of long-term chronic inflammation and cell therapy requires stable, highly functional cells. Several tools and protocols have been developed by mimicking natural fusion events to induce and accelerate fusion in vitro to promote β-cell-specific gene expression in fused cells. BM-MSC-islet fusion before transplantation may be a strategy for long-term islet survival and improved function. This review discusses the cell-protective and anti-inflammatory characteristics of BM-MSCs to boost highly functional insulin-producing cells in vitro and in vivo, and the efficacy of their fusion with β-cells as a path to promote β-cell regeneration.
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Affiliation(s)
- Zahra Azizi
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, No. 88, Italia St, Keshavarz Blvd., Tehran, Iran.
| | - Roya Abbaszadeh
- Department of Biology, Philipps-University Marburg, Marburg, Germany
| | - Roxana Sahebnasagh
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, No. 88, Italia St, Keshavarz Blvd., Tehran, Iran
| | - Amir Norouzy
- Department of Energy & Environmental Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Elahe Motevaseli
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, No. 88, Italia St, Keshavarz Blvd., Tehran, Iran
| | - Kathrin Maedler
- Islet Biology Laboratory, Centre for Biomolecular Interactions Bremen, University of Bremen,, Leobener Straße 5, NW2, 28359, Bremen, Germany.
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25
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Wang X, Wang K, Yu M, Velluto D, Hong X, Wang B, Chiu A, Melero-Martin JM, Tomei AA, Ma M. Engineered immunomodulatory accessory cells improve experimental allogeneic islet transplantation without immunosuppression. SCIENCE ADVANCES 2022; 8:eabn0071. [PMID: 35867788 PMCID: PMC9307254 DOI: 10.1126/sciadv.abn0071] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 06/08/2022] [Indexed: 05/05/2023]
Abstract
Islet transplantation has been established as a viable treatment modality for type 1 diabetes. However, the side effects of the systemic immunosuppression required for patients often outweigh its benefits. Here, we engineer programmed death ligand-1 and cytotoxic T lymphocyte antigen 4 immunoglobulin fusion protein-modified mesenchymal stromal cells (MSCs) as accessory cells for islet cotransplantation. The engineered MSCs (eMSCs) improved the outcome of both syngeneic and allogeneic islet transplantation in diabetic mice and resulted in allograft survival for up to 100 days without any systemic immunosuppression. Immunophenotyping revealed reduced infiltration of CD4+ or CD8+ T effector cells and increased infiltration of T regulatory cells within the allografts cotransplanted with eMSCs compared to controls. The results suggest that the eMSCs can induce local immunomodulation and may be applicable in clinical islet transplantation to reduce or minimize the need of systemic immunosuppression and ameliorate its negative impact.
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Affiliation(s)
- Xi Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Kai Wang
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Ming Yu
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Diana Velluto
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Xuechong Hong
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
| | - Bo Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Alan Chiu
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
| | - Juan M. Melero-Martin
- Department of Cardiac Surgery, Boston Children’s Hospital, Boston, MA 02115, USA
- Department of Surgery, Harvard Medical School, Boston, MA 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA 02138, USA
| | - Alice A. Tomei
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Department of Biomedical Engineering, University of Miami, Miami, FL 33146, USA
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Minglin Ma
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA
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26
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Campa-Carranza JN, Paez-Mayorga J, Chua CYX, Nichols JE, Grattoni A. Emerging local immunomodulatory strategies to circumvent systemic immunosuppression in cell transplantation. Expert Opin Drug Deliv 2022; 19:595-610. [PMID: 35588058 DOI: 10.1080/17425247.2022.2076834] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Cell transplantation is a promising curative therapeutic strategy whereby impaired organ functions can be restored without the need for whole organ transplantation. A key challenge in allotransplantation is the requirement for life-long systemic immunosuppression to prevent rejection, which is associated with serious adverse effects such as increased risk of opportunistic infections and the development of neoplasms. This challenge underscores the urgent need for novel strategies to prevent graft rejection while abrogating toxicity-associated adverse events. AREAS COVERED We review recent advances in immunoengineering strategies for localized immunomodulation that aim to support allograft function and provide immune tolerance in a safe and effective manner. EXPERT OPINION Immunoengineering strategies are tailored approaches for achieving immunomodulation of the transplant microenvironment. Biomaterials can be adapted for localized and controlled release of immunomodulatory agents, decreasing the effective dose threshold and frequency of administration. The future of transplant rejection management lies in the shift from systemic to local immunomodulation with suppression of effector and activation of regulatory T cells, to promote immune tolerance.
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Affiliation(s)
- Jocelyn Nikita Campa-Carranza
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.,School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, NL, Mexico
| | - Jesus Paez-Mayorga
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.,School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey, NL, Mexico
| | - Corrine Ying Xuan Chua
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA
| | - Joan E Nichols
- Center for Tissue Engineering, Houston Methodist Research Institute, Houston, TX, USA.,Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - Alessandro Grattoni
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030, USA.,Department of Surgery, Houston Methodist Hospital, Houston, TX, USA.,Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX, USA
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27
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Yang Y, Lei T, Bi W, Xiao Z, Zhang X, Du H. The combined therapy of mesenchymal stem cell transplantation and resveratrol for diabetes: Future applications and challenges. Life Sci 2022; 301:120563. [PMID: 35460708 DOI: 10.1016/j.lfs.2022.120563] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/07/2022] [Accepted: 04/14/2022] [Indexed: 12/22/2022]
Abstract
Diabetes mellitus (DM) is a worldwide chronic epidemic disease of impaired glucose metabolism. Transplantation of mesenchymal stem cells (MSCs) is considered a promising emerging treatment strategy for diabetes. However, the harsh internal environment of DM patients can inhibit the treatment effects of transplanted MSCs. Fortunately, this adverse effect can be reversed by resveratrol (Res). Therefore, we investigated and summarized relevant studies on the combined treatment of diabetes with MSCs and resveratrol. This review presents the therapeutic effects of this combination therapy strategy on DM in glycemic control, anti-inflammatory, anti-oxidative stress and anti-fibrotic. Moreover, this review explained the mechanisms of MSCs and resveratrol in diabetes treatment from 3 aspects, including promoting cell survival and inhibiting apoptosis, inhibiting histiocyte fibrosis, and improving glucose metabolism. These findings help to understand in-depth mechanisms of the treatment of DM and help to propose a potential treatment strategy for DM and its complications.
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Affiliation(s)
- Yanjie Yang
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Tong Lei
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Wangyu Bi
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Zhuangzhuang Xiao
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Xiaoshuang Zhang
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Hongwu Du
- Daxing Research Institute, University of Science and Technology Beijing, Beijing 100083, China; School of Chemistry and Biological Engineering, University of Science and Technology Beijing, Beijing 100083, China.
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28
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Zhou Z, Zhu X, Huang H, Xu Z, Jiang J, Chen B, Zhu H. Recent Progress of Research Regarding the Applications of Stem Cells for Treating Diabetes Mellitus. Stem Cells Dev 2022; 31:102-110. [PMID: 35072537 DOI: 10.1089/scd.2021.0083] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
At present, the number of diabetes patients has exceeded 537 million worldwide and this number continues to increase. Stem cell therapy represents a new direction for the treatment of diabetes; the use of stem cells overcomes some shortcomings associated with traditional therapies. Functional β-cells play an important role in the pathogenesis of diabetes. As therapeutic targets, functional β-cells are restored by a variety of stem cells, including pluripotent stem cells, mesenchymal cells, and urine-derived stem cells. Although all types of stem cells have their own characteristics, they mainly promote the repair and regeneration of β-cells through directional differentiation, immunomodulation, and paracrine signaling after homing to the injured site. However, stem cell therapy still faces many obstacles, such as low long-term cell survival rate after transplantation, low maintenance time of blood glucose homeostasis, immune rejection, and tumorigenesis. Recently, genetically edited pluripotent stem cells and the co-transplantation of mesenchymal stem cells and islet cells have made significant progress in improving the efficacy of stem cell transplantation processes, also providing powerful tools for the study of the mechanisms underlying diabetes and disease modeling. In this review, we first focused on: (1) stem cells as a pool for the differentiation of insulin-producing cells; (2) stem cells as a source for regenerative repair of damaged islets and as a potential co-transplanted population with islets; (3) the potential of combining gene editing with stem cell therapy; and (4) selection of the stem cell transplantation approach. Based on these topics, we discuss the challenges within the field of adapting stem cell-supported and stem cell-derived transplantations, and the promising routes for overcoming these problems.
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Affiliation(s)
- Zijun Zhou
- The First Affiliated Hospital of Wenzhou Medical University, 89657, Endocrinology, Wenzhou, Zhejiang, China, 325000;
| | - Xiandong Zhu
- Wenzhou Medical University First Affiliated Hospital, 89657, Wenzhou, China, 325000;
| | - Hongjian Huang
- Wenzhou Medical College First Affiliated Hospital, 89657, Wenzhou, China, 325000;
| | - Zeru Xu
- The First Affiliated Hospital of Wenzhou Medical University, 89657, Wenzhou, China, 325000;
| | - Jiahong Jiang
- The First Affiliated Hospital of Wenzhou Medical University, 89657, endocrinology, Wenzhou, Zhejiang, China, 325000;
| | - Bicheng Chen
- Wenzhou Medical University First Affiliated Hospital, 89657, Wenzhou, China, 325000;
| | - Hong Zhu
- The First Affiliated Hospital of Wenzhou Medical University, 89657, Endocrinology, Wenzhou, Zhejiang, China, 325000;
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29
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Li J, Thomson AW, Rogers NM. Myeloid and Mesenchymal Stem Cell Therapies for Solid Organ Transplant Tolerance. Transplantation 2021; 105:e303-e321. [PMID: 33756544 PMCID: PMC8455706 DOI: 10.1097/tp.0000000000003765] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Transplantation is now performed globally as a routine procedure. However, the increased demand for donor organs and consequent expansion of donor criteria has created an imperative to maximize the quality of these gains. The goal is to balance preservation of allograft function against patient quality-of-life, despite exposure to long-term immunosuppression. Elimination of immunosuppressive therapy to avoid drug toxicity, with concurrent acceptance of the allograft-so-called operational tolerance-has proven elusive. The lack of recent advances in immunomodulatory drug development, together with advances in immunotherapy in oncology, has prompted interest in cell-based therapies to control the alloimmune response. Extensive experimental work in animals has characterized regulatory immune cell populations that can induce and maintain tolerance, demonstrating that their adoptive transfer can promote donor-specific tolerance. An extension of this large body of work has resulted in protocols for manufacture, as well as early-phase safety and feasibility trials for many regulatory cell types. Despite the excitement generated by early clinical trials in autoimmune diseases and organ transplantation, there is as yet no clinically validated, approved regulatory cell therapy for transplantation. In this review, we summarize recent advances in this field, with a focus on myeloid and mesenchymal cell therapies, including current understanding of the mechanisms of action of regulatory immune cells, and clinical trials in organ transplantation using these cells as therapeutics.
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Affiliation(s)
- Jennifer Li
- Center of Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, Australia
- Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney, Australia
| | - Angus W Thomson
- Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Natasha M Rogers
- Center of Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, Australia
- Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Sydney, Australia
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30
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Riedl J, Popp C, Eide C, Ebens C, Tolar J. Mesenchymal stromal cells in wound healing applications: role of the secretome, targeted delivery and impact on recessive dystrophic epidermolysis bullosa treatment. Cytotherapy 2021; 23:961-973. [PMID: 34376336 PMCID: PMC8569889 DOI: 10.1016/j.jcyt.2021.06.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/25/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022]
Abstract
Mesenchymal stromal cells (MSCs) are multi-potent stromal-derived cells capable of self-renewal that possess several advantageous properties for wound healing, making them of interest to the field of dermatology. Research has focused on characterizing the unique properties of MSCs, which broadly revolve around their regenerative and more recently discovered immunomodulatory capacities. Because of ease of harvesting and expansion, differentiation potential and low immunogenicity, MSCs have been leading candidates for tissue engineering and regenerative medicine applications for wound healing, yet results from clinical studies have been variable, and promising pre-clinical work has been difficult to reproduce. Therefore, the specific mechanisms of how MSCs influence the local microenvironment in distinct wound etiologies warrant further research. Of specific interest in MSC-mediated healing is harnessing the secretome, which is composed of components known to positively influence wound healing. Molecules released by the MSC secretome can promote re-epithelialization and angiogenesis while inhibiting fibrosis and microbial invasion. This review focuses on the therapeutic interest in MSCs with regard to wound healing applications, including burns and diabetic ulcers, with specific attention to the genetic skin disease recessive dystrophic epidermolysis bullosa. This review also compares various delivery methods to support skin regeneration in the hopes of combating the poor engraftment of MSCs after delivery, which is one of the major pitfalls in clinical studies utilizing MSCs.
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Affiliation(s)
- Julia Riedl
- Medical Scientist Training Program (MD/PhD), University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA
| | - Courtney Popp
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Cindy Eide
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Christen Ebens
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.
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31
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Wang LT, Liu KJ, Sytwu HK, Yen ML, Yen BL. Advances in mesenchymal stem cell therapy for immune and inflammatory diseases: Use of cell-free products and human pluripotent stem cell-derived mesenchymal stem cells. Stem Cells Transl Med 2021; 10:1288-1303. [PMID: 34008922 PMCID: PMC8380447 DOI: 10.1002/sctm.21-0021] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/31/2021] [Accepted: 04/20/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID‐19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off‐the‐shelf products. In addition, new products such as cell‐free exosomes and human pluripotent stem cell (hPSC)‐derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications—including graft‐vs‐host‐disease, strongly Th17‐mediated autoimmune diseases, and osteoarthritis—which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.
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Affiliation(s)
- Li-Tzu Wang
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - Ko-Jiunn Liu
- National Institute of Cancer Research, National Health Research Institutes (NHRI), Tainan, Taiwan, Republic of China
| | - Huey-Kang Sytwu
- National Institute of Infectious Diseases & Vaccinology, NHRI, Zhunan, Taiwan, Republic of China.,Department & Graduate Institute of Microbiology & Immunology, National Defense Medical Center, Taipei, Taiwan, Republic of China
| | - Men-Luh Yen
- Department of Obstetrics & Gynecology, National Taiwan University (NTU) Hospital & College of Medicine, NTU, Taipei, Taiwan, Republic of China
| | - B Linju Yen
- Regenerative Medicine Research Group, Institute of Cellular & System Medicine, NHRI, Zhunan, Taiwan, Republic of China
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32
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Gou W, Cui W, Cui Y, Wang H. Minimizing Post-Infusion Portal Vein Bleeding during Intrahepatic Islet Transplantation in Mice. J Vis Exp 2021:10.3791/62530. [PMID: 34028442 PMCID: PMC11094622 DOI: 10.3791/62530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Abstract
Although the liver is currently accepted as the primary transplantation site for human islets in clinical settings, islets are transplanted under the kidney capsule in most rodent preclinical islet transplantation studies. This model is commonly used because murine intrahepatic islet transplantation is technically challenging, and a high percentage of mice could die from surgical complications, especially bleeding from the injection site post-transplantation. In this study, two procedures that can minimize the incidence of post-infusion portal vein bleeding are demonstrated. The first method applies an absorbable hemostatic gelatin sponge to the injection site, and the second method involves penetrating the islet injection needle through the fat tissue first and then into the portal vein by using the fat tissue as a physical barrier to stop bleeding. Both methods could effectively prevent bleeding-induced mouse death. The whole liver section showing islet distribution and evidence of islet thrombosis post-transplantation, a typical feature for intrahepatic islet transplantation, were presented. These improved protocols refine the intrahepatic islet transplantation procedures and may help laboratories set up the procedure to study islet survival and function in pre-clinical settings.
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Affiliation(s)
- Wenyu Gou
- Department of Surgery, Medical University of South Carolina
| | | | | | - Hongjun Wang
- Department of Surgery, Medical University of South Carolina; Ralph H. Johnson Veterans Affairs Medical Center;
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Ma Z, Zhou J, Yang T, Xie W, Song G, Song Z, Chen J. Mesenchymal stromal cell therapy for pancreatitis: Progress and challenges. Med Res Rev 2021; 41:2474-2488. [PMID: 33840113 DOI: 10.1002/med.21801] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 11/17/2020] [Accepted: 03/23/2021] [Indexed: 12/15/2022]
Abstract
Pancreatitis is a common gastrointestinal disease with no effective therapeutic options, particularly for cases of severe acute and chronic pancreatitis (CP). Mesenchymal stromal cells (MSCs) are multipotent cells with diverse biological properties, including directional migration, paracrine, immunosuppressive, and antiinflammatory effects, which are considered an ideal candidate cell type for repairing tissue damage caused by various pathogenies. Several researchers have reported significant therapeutic efficacy of MSCs in animal models of acute and CP. However, the specific underlying mechanisms are yet to be clarified and clinical application of MSCs as pancreatitis therapy has rarely been reported. This review mainly focuses on the potential and challenges in clinical application of MSCs for treatment of acute and CP, along with discussion of the underlying molecular mechanisms.
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Affiliation(s)
- Zhilong Ma
- Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jia Zhou
- Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Tingsong Yang
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wangcheng Xie
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Guodong Song
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Zhenshun Song
- Department of General Surgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ji Chen
- Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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He J, Kong D, Yang Z, Guo R, Amponsah AE, Feng B, Zhang X, Zhang W, Liu A, Ma J, O’Brien T, Cui H. Clinical efficacy on glycemic control and safety of mesenchymal stem cells in patients with diabetes mellitus: Systematic review and meta-analysis of RCT data. PLoS One 2021; 16:e0247662. [PMID: 33705413 PMCID: PMC7951834 DOI: 10.1371/journal.pone.0247662] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 02/10/2021] [Indexed: 12/26/2022] Open
Abstract
Background Diabetes mellitus as a chronic metabolic disease is threatening human health seriously. Although numerous clinical trials have been registered for the treatment of diabetes with stem cells, no articles have been published to summarize the efficacy and safety of mesenchymal stem cells (MSCs) in randomized controlled trials (RCTs). Methods and findings The aim of this study was to systematically review the evidence from RCTs and, where possible, conduct meta-analyses to provide a reliable numerical summary and the most comprehensive assessment of therapeutic efficacy and safety with MSCs in diabetes. PubMed, Web of Science, Ovid, the Cochrane Library and CNKI were searched. The retrieval time was from establishment of these databases to January 4, 2020. Seven RCTs were eligible for analysis, including 413 participants. Meta-analysis results showed that there were no significant differences in the reduction of fasting plasma glucose (FPG) compared to the baseline [mean difference (MD) = -1.05, 95% confidence interval (CI) (-2.26,0.16), P<0.01, I2 = 94%] and the control group [MD = -0.62, 95%CI (-1.46,0.23), P<0.01, I2 = 87%]. The MSCs treatment group showed a significant decrease in hemoglobin (Hb) A1c [random-effects, MD = -1.32, 95%CI (-2.06, -0.57), P<0.01, I2 = 90%] after treatment. Additionally, HbA1c reduced more significantly in MSC treatment group than in control group [random-effects, MD = -0.87, 95%CI (-1.53, -0.22), P<0.01, I2 = 82%] at the end of follow-up. However, as for fasting C-peptide levels, the estimated pooled MD showed that there was no significant increase [MD = -0.07, 95%CI (-0.30, 0.16), P<0.01, I2 = 94%] in MSCs treatment group compared with that in control group. Notably, there was no significant difference in the incidence of adverse events between MSCs treatment group and control group [relative risk (RR) = 0.98, 95%CI (0.72, 1.32), P = 0.02, I2 = 70%]. The most commonly observed adverse reaction in the MSC treatment group was hypoglycemia (29.95%). Conclusions This meta-analysis revealed MSCs therapy may be an effective and safe intervention in subjects with diabetes. However, due to the limited studies, a number of high-quality as well as large-scale RCTs should be performed to confirm these conclusions.
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Affiliation(s)
- Jingjing He
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei Province, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei Province, China
| | - Desheng Kong
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei Province, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei Province, China
| | - Zhifen Yang
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Ruiyun Guo
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei Province, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei Province, China
| | - Asiamah Ernest Amponsah
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei Province, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei Province, China
| | - Baofeng Feng
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei Province, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei Province, China
| | - Xiaolin Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Wei Zhang
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei Province, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei Province, China
| | - Aijing Liu
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei Province, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei Province, China
- Second Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China
| | - Jun Ma
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei Province, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei Province, China
- Human Anatomy Department, Hebei Medical University, Shijiazhuang, Hebei Province, China
- * E-mail: (JM); (TO); (HC)
| | - Timothy O’Brien
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei Province, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei Province, China
- Regenerative Medicine Institute, School of Medicine, National University of Ireland Galway, Galway, Ireland
- * E-mail: (JM); (TO); (HC)
| | - Huixian Cui
- Hebei Medical University-National University of Ireland Galway Stem Cell Research Center, Hebei Medical University, Shijiazhuang, Hebei Province, China
- Hebei Research Center for Stem Cell Medical Translational Engineering, Shijiazhuang, Hebei Province, China
- Human Anatomy Department, Hebei Medical University, Shijiazhuang, Hebei Province, China
- * E-mail: (JM); (TO); (HC)
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Khatri R, Petry SF, Linn T. Intrapancreatic MSC transplantation facilitates pancreatic islet regeneration. Stem Cell Res Ther 2021; 12:121. [PMID: 33579357 PMCID: PMC7881671 DOI: 10.1186/s13287-021-02173-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
Background Type 1 diabetes mellitus (T1D) is characterized by the autoimmune destruction of the pancreatic β cells. The transplantation of mesenchymal stromal/stem cells (MSC) was reported to rescue the damaged pancreatic niche. However, there is an ongoing discussion on whether direct physical contact between MSC and pancreatic islets results in a superior outcome as opposed to indirect effects of soluble factors released from the MSC entrapped in the lung microvasculature after systemic administration. Hence, MSC were studied in direct contact (DC) and indirect contact (IDC) with murine pancreatic β cell line MIN6-cells damaged by nitrosourea derivative streptozotocin (STZ) in vitro. Further, the protective and antidiabetic outcome of MSC transplantation was evaluated through the intrapancreatic route (IPR) and intravenous route (IVR) in STZ-induced diabetic NMRI nude mice. Methods MSC were investigated in culture with STZ-damaged MIN6-cells, either under direct contact (DC) or separated through a semi-permeable membrane (IDC). Moreover, multiple low doses of STZ were administered to NMRI nude mice for the induction of hyperglycemia. 0.5 × 106 adipose-derived mesenchymal stem cells (ADMSC) were transferred through direct injection into the pancreas (IPR) or the tail vein (IVR), respectively. Bromodeoxyuridine (BrdU) was injected for the detection of proliferating islet cells in vivo, and real-time polymerase chain reaction (RT-PCR) was employed for the measurement of the expression of growth factor and immunomodulatory genes in the murine pancreas and human MSC. Phosphorylation of AKT and ERK was analyzed with Western blotting. Results The administration of MSC through IPR ameliorated hyperglycemia in contrast to IVR, STZ, and non-diabetic control in a 30-day window. IPR resulted in a higher number of replicating islet cells, number of islets, islet area, growth factor (EGF), and balancing of the Th1/Th2 response in vivo. Physical contact also provided a superior protection to MIN6-cells from STZ through the AKT and ERK pathway in vitro in comparison with IDC. Conclusion Our study suggests that the physical contact between MSC and pancreatic islet cells is required to fully unfold their protective potential. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02173-4.
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Affiliation(s)
- Rahul Khatri
- Clinical Research Unit, Centre of Internal Medicine, Faculty of Medicine, Justus Liebig University Giessen, Friedrichstrasse. 20/ Aulweg 123, 35392, Giessen, Germany
| | - Sebastian Friedrich Petry
- Clinical Research Unit, Centre of Internal Medicine, Faculty of Medicine, Justus Liebig University Giessen, Friedrichstrasse. 20/ Aulweg 123, 35392, Giessen, Germany
| | - Thomas Linn
- Clinical Research Unit, Centre of Internal Medicine, Faculty of Medicine, Justus Liebig University Giessen, Friedrichstrasse. 20/ Aulweg 123, 35392, Giessen, Germany.
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36
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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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Atkinson SP. A preview of selected articles. Stem Cells Transl Med 2021; 10:160-163. [PMID: 33522152 PMCID: PMC7848349 DOI: 10.1002/sctm.20-0565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 12/31/2020] [Indexed: 11/29/2022] Open
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Song L, Gou W, Wang J, Wei H, Lee J, Strange C, Wang H. Overexpression of alpha-1 antitrypsin in mesenchymal stromal cells improves their intrinsic biological properties and therapeutic effects in nonobese diabetic mice. Stem Cells Transl Med 2021; 10:320-331. [PMID: 32945622 PMCID: PMC7848369 DOI: 10.1002/sctm.20-0122] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 06/28/2020] [Accepted: 07/15/2020] [Indexed: 02/06/2023] Open
Abstract
Islet/β cell dysfunction and death caused by autoimmune-mediated injuries are major features of type 1 diabetes (T1D). Mesenchymal stromal cells (MSCs) have been used for the treatment of T1D in animal models and clinical trials. Based on the anti-inflammatory effects of alpha-1 antitrypsin (AAT), we generated human AAT engineered MSCs (hAAT-MSCs) by infecting human bone marrow-derived MSCs with the pHAGE CMV-a1aT-UBC-GFP-W lentiviral vector. We compared the colony forming, differentiation, and migration capacity of empty virus-treated MSCs (hMSC) and hAAT-MSCs and tested their protective effects in the prevention of onset of T1D in nonobese diabetic (NOD) mice. hAAT-MSCs showed increased self-renewal, better migration and multilineage differentiation abilities compared to hMSCs. In addition, polymerase chain reaction array for 84 MSC-related genes showed that 23 genes were upregulated, and 3 genes were downregulated in hAAT-MSCs compared to hMSCs. Upregulated genes include those critical for the stemness (ie, Wnt family member 3A [WNT3A], kinase insert domain receptor [KDR]), migration (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion protein 1 [VICAM-1], matrix metalloproteinase-2 [MMP2]), and survival (insulin-like growth factor 1 [IGF-1]) of MSCs. Pathway analysis showed that changed genes were related to growth factor activity, positive regulation of cell migration, and positive regulation of transcription. In vivo, a single intravenous infusion of hAAT-MSCs significantly limited inflammatory infiltration into islets and delayed diabetes onset in the NOD mice compared with those receiving vehicle or hMSCs. Taken together, overexpression of hAAT in MSCs improved intrinsic biological properties of MSCs needed for cellular therapy for the treatment of T1D.
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Affiliation(s)
- Lili Song
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Wenyu Gou
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Jingjing Wang
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Hua Wei
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Jennifer Lee
- Academic Magnet High SchoolNorth CharlestonSouth CarolinaUSA
| | - Charlie Strange
- Department of MedicineMedical University of South CarolinaCharlestonSouth CarolinaUSA
| | - Hongjun Wang
- Department of SurgeryMedical University of South CarolinaCharlestonSouth CarolinaUSA
- Ralph H. Johnson Veterans Affairs Medical CenterCharlestonSouth CarolinaUSA
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Keshtkar S, Kaviani M, Jabbarpour Z, Sabet Sarvestani F, Ghahremani MH, Esfandiari E, Hossein Aghdaei M, Nikeghbalian S, Shamsaeefar A, Geramizadeh B, Azarpira N. Hypoxia-Preconditioned Wharton's Jelly-Derived Mesenchymal Stem Cells Mitigate Stress-Induced Apoptosis and Ameliorate Human Islet Survival and Function in Direct Contact Coculture System. Stem Cells Int 2020; 2020:8857457. [PMID: 33381188 PMCID: PMC7759420 DOI: 10.1155/2020/8857457] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 11/08/2020] [Accepted: 11/30/2020] [Indexed: 12/17/2022] Open
Abstract
Protection of isolated pancreatic islets against hypoxic and oxidative damage-induced apoptosis is essential during a pretransplantation culture period. A beneficial approach to maintain viable and functional islets is the coculture period with mesenchymal stem cells (MSCs). Hypoxia preconditioning of MSCs (Hpc-MSCs) for a short time stimulates the expression and secretion of antiapoptotic, antioxidant, and prosurvival factors. The aim of the present study was to evaluate the survival and function of human islets cocultured with Hpc-MSCs. Wharton's jelly-derived MSCs were subjected to hypoxia (5% O2: Hpc) or normoxia (20% O2: Nc) for 24 hours and then cocultured with isolated human islets in direct and indirect systems. Assays of viability and apoptosis, along with the production of reactive oxygen species (ROS), hypoxia-inducible factor 1-alpha (HIF-1α), apoptotic pathway markers, and vascular endothelial growth factor (VEGF) in the islets, were performed. Insulin and C-peptide secretions as islet function were also evaluated. Hpc-MSCs and Nc-MSCs significantly reduced the ROS production and HIF-1α protein aggregation, as well as downregulation of proapoptotic proteins and upregulation of antiapoptotic marker along with increment of VEGF secretion in the cocultured islet. However, the Hpc-MSCs groups were better than Nc-MSCs cocultured islets. Hpc-MSCs in both direct and indirect coculture systems improved the islet survival, while promotion of function was only significant in the direct cocultured cells. Hpc potentiated the cytoprotective and insulinotropic effects of MSCs on human islets through reducing stressful markers, inhibiting apoptosis pathway, enhancing prosurvival factors, and promoting insulin secretion, especially in direct coculture system, suggesting the effective strategy to ameliorate the islet quality for better transplantation outcomes.
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Affiliation(s)
- Somayeh Keshtkar
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maryam Kaviani
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Jabbarpour
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mohammad Hossein Ghahremani
- Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Elaheh Esfandiari
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Saman Nikeghbalian
- Shiraz Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Alireza Shamsaeefar
- Shiraz Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Negar Azarpira
- Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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Razavi M, Ren T, Zheng F, Telichko A, Wang J, Dahl JJ, Demirci U, Thakor AS. Facilitating islet transplantation using a three-step approach with mesenchymal stem cells, encapsulation, and pulsed focused ultrasound. Stem Cell Res Ther 2020; 11:405. [PMID: 32948247 PMCID: PMC7501701 DOI: 10.1186/s13287-020-01897-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 07/06/2020] [Accepted: 08/24/2020] [Indexed: 01/23/2023] Open
Abstract
BACKGROUND The aim of this study was to examine the effect of a three-step approach that utilizes the application of adipose tissue-derived mesenchymal stem cells (AD-MSCs), encapsulation, and pulsed focused ultrasound (pFUS) to help the engraftment and function of transplanted islets. METHODS In step 1, islets were co-cultured with AD-MSCs to form a coating of AD-MSCs on islets: here, AD-MSCs had a cytoprotective effect on islets; in step 2, islets coated with AD-MSCs were conformally encapsulated in a thin layer of alginate using a co-axial air-flow method: here, the capsule enabled AD-MSCs to be in close proximity to islets; in step 3, encapsulated islets coated with AD-MSCs were treated with pFUS: here, pFUS enhanced the secretion of insulin from islets as well as stimulated the cytoprotective effect of AD-MSCs. RESULTS Our approach was shown to prevent islet death and preserve islet functionality in vitro. When 175 syngeneic encapsulated islets coated with AD-MSCs were transplanted beneath the kidney capsule of diabetic mice, and then followed every 3 days with pFUS treatment until day 12 post-transplantation, we saw a significant improvement in islet function with diabetic animals re-establishing glycemic control over the course of our study (i.e., 30 days). In addition, our approach was able to enhance islet engraftment by facilitating their revascularization and reducing inflammation. CONCLUSIONS This study demonstrates that our clinically translatable three-step approach is able to improve the function and viability of transplanted islets.
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Affiliation(s)
- Mehdi Razavi
- Department of Radiology, Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94304, USA
- Biionix™ (Bionic Materials, Implants & Interfaces) Cluster, Department of Internal Medicine, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
- Department of Materials Science and Engineering, University of Central Florida, Orlando, FL, 32816, USA
| | - Tanchen Ren
- Department of Radiology, Bio-Acoustic MEMS in Medicine Laboratory (BAMM), Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Fengyang Zheng
- Department of Radiology, Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94304, USA
| | - Arsenii Telichko
- Department of Radiology, Dahl Ultrasound Laboratory, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Jing Wang
- Department of Radiology, Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94304, USA
| | - Jeremy J Dahl
- Department of Radiology, Dahl Ultrasound Laboratory, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Utkan Demirci
- Department of Radiology, Bio-Acoustic MEMS in Medicine Laboratory (BAMM), Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Avnesh S Thakor
- Department of Radiology, Interventional Regenerative Medicine and Imaging Laboratory, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA, 94304, USA.
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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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Kale VP. Transforming growth factor-β boosts the functionality of human bone marrow-derived mesenchymal stromal cells. Cell Biol Int 2020; 44:2293-2306. [PMID: 32749730 DOI: 10.1002/cbin.11437] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 07/17/2020] [Accepted: 08/02/2020] [Indexed: 12/19/2022]
Abstract
Transforming growth factor β1 (TGFβ1) is a negative regulator of hematopoiesis, and yet, it is frequently found at the active sites of hematopoiesis. Here, we show for the first time that bone marrow-derived mononuclear cells (BM MNCs) secrete TGFβ1 in response to erythropoietin (EPO). We further show that human bone marrow-derived mesenchymal stromal cells (BMSCs) briefly exposed to the conditioned medium of EPO-primed MNCs, or purified TGFβ1, gain significantly increased hematopoiesis-supportive ability. Mechanistically, we show that this phenomenon involves TGFβ1-mediated activation of nitric oxide (NO) signalling pathway in the BMSCs. The data suggest that EPO-MNC-TGFβ1 could be one of the regulatory axes operative in the bone marrow microenvironment involved in maintaining the functionality of the resident BMSCs.
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Affiliation(s)
- Vaijayanti P Kale
- Symbiosis Centre for Stem Cell Research, Symbiosis International University, Pune, India
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El-Kersh AOFO, El-Akabawy G, Al-Serwi RH. Transplantation of human dental pulp stem cells in streptozotocin-induced diabetic rats. Anat Sci Int 2020; 95:523-539. [PMID: 32476103 DOI: 10.1007/s12565-020-00550-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 05/20/2020] [Indexed: 12/11/2022]
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic β-cells. Human dental pulp stem cells represent a promising source for cell-based therapies, owing to their easy, minimally invasive surgical access, and high proliferative capacity. It was reported that human dental pulp stem cells can differentiate into a pancreatic cell lineage in vitro; however, few studies have investigated their effects on diabetes. Our study aimed to investigate the therapeutic potential of intravenous and intrapancreatic transplantation of human dental pulp stem cells in a rat model of streptozotocin-induced type 1 diabetes. Forty Sprague Dawley male rats were randomly categorized into four groups: control, diabetic (STZ), intravenous treatment group (IV), and intrapancreatic treatment group (IP). Human dental pulp stem cells (1 × 106 cells) or vehicle were injected into the pancreas or tail vein 7 days after streptozotocin injection. Fasting blood glucose levels were monitored weekly. Glucose tolerance test, rat and human serum insulin and C-peptide, pancreas histology, and caspase-3, vascular endothelial growth factor, and Ki67 expression in pancreatic tissues were assessed 28 days post-transplantation. We found that both IV and IP transplantation of human dental pulp stem cells reduced blood glucose and increased levels of rat and human serum insulin and C-peptide. The cells engrafted and survived in the streptozotocin-injured pancreas. Islet-like clusters and scattered human dental pulp stem cells expressing insulin were observed in the pancreas of diabetic rats with some difference in the distribution pattern between the two injection routes. RT-PCR analyses revealed the expression of the human-specific pancreatic β-cell genes neurogenin 3 (NGN3), paired box 4 (PAX4), glucose transporter 2 (GLUT2), and insulin in the pancreatic tissues of both the IP and IV groups. In addition, the transplanted cells downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and Ki67, suggesting that the injected cells exerted pro-angiogenetic and antiapoptotic effects, and promoted endogenous β-cell replication. Our study is the first to show that human dental pulp stem cells can migrate and survive within streptozotocin-injured pancreas, and induce antidiabetic effects through the differentiation and replacement of lost β-cells and paracrine-mediated pancreatic regeneration. Thus, human dental pulp stem cells may have therapeutic potential to treat patients with long term T1DM.
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Affiliation(s)
| | - Gehan El-Akabawy
- Department of Basic Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia. .,Department of Anatomy and Embryology, Faculty of Medicine, Menoufia University, Menoufia, Egypt.
| | - Rasha H Al-Serwi
- Basic Dental Sciences, College of Dentistry, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.,Oral Biology Department, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
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Black LA, Zorina T. Genetic profile considerations for induction of allogeneic chimerism as a therapeutic approach for type 1 diabetes mellitus. Drug Discov Today 2020; 25:1293-1297. [PMID: 32445668 DOI: 10.1016/j.drudis.2020.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2020] [Revised: 04/26/2020] [Accepted: 05/05/2020] [Indexed: 11/28/2022]
Abstract
The major therapeutic modality for type 1 diabetes mellitus (T1DM) remains sustaining euglycemia by exogenous administration of insulin. Based on a new understanding of bone marrow structural and functional dynamics, a conditioning-free bone marrow transplantation (BMT), with reduced adverse effects, opens the possibility for evaluating β cell regeneration and restoration of euglycemia by induction of allogeneic chimerism in patients T1DM, as shown in a mouse model. With this therapeutic modality, donor bone marrow (BM) selection based on T1DM-predisposing and preventive phenotypes will improve treatment outcomes by limiting the risk of exacerbating the autoimmune processes in the BM recipient.
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Affiliation(s)
- Labe A Black
- Thomas Jefferson University, Jefferson College of Health Professions, Department of Medical Laboratory Science and Biotechnology, Philadelphia, PA, USA.
| | - Tatiana Zorina
- Thomas Jefferson University, Jefferson College of Health Professions, Department of Medical Laboratory Science and Biotechnology, Philadelphia, PA, USA.
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Yu CP, Juang JH, Lin YJ, Kuo CW, Hsieh LH, Huang CC. Enhancement of Subcutaneously Transplanted β Cell Survival Using 3D Stem Cell Spheroids with Proangiogenic and Prosurvival Potential. ACTA ACUST UNITED AC 2020; 4:e1900254. [PMID: 32293147 DOI: 10.1002/adbi.201900254] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/08/2020] [Indexed: 01/20/2023]
Abstract
Islet transplantation has been demonstrated to be a promising therapy for type 1 diabetes mellitus. Although it is a minimally invasive operating procedure and provides easy access for graft monitoring, subcutaneous transplantation of the islet only has limited therapeutic outcomes, owing to the poor capacity of skin tissue to foster revascularization in a short period. Herein, 3D cell spheroids of clinically accessible umbilical cord blood mesenchymal stem cells and human umbilical vein endothelial cells are formed and employed for codelivery with β cells subcutaneously. The 3D stem cell spheroids, which can secrete multiple proangiogenic and prosurvival growth factors, induce robust angiogenesis and prevent β cell graft death, as indicated by the results of in vivo bioluminescent tracking and histological analysis. These experimental data highlight the efficacy of the 3D stem cell spheroids that are fabricated using translationally applicable cell types in promoting the survival and function of subcutaneously transplanted β cells.
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Affiliation(s)
- Chih-Ping Yu
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Jyuhn-Huarng Juang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan.,Center for Tissue Engineering, Chang Gung Memorial Hospital, Taoyuan, 33305, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan
| | - Yu-Jie Lin
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Ching-Wen Kuo
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan.,Department of Chemical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Li-Hung Hsieh
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan
| | - Chieh-Cheng Huang
- Institute of Biomedical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan
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Coppin LCF, Smets F, Ambroise J, Sokal EEM, Stéphenne X. Infusion-related thrombogenesis by liver-derived mesenchymal stem cells controlled by anticoagulant drugs in 11 patients with liver-based metabolic disorders. Stem Cell Res Ther 2020; 11:51. [PMID: 32028991 PMCID: PMC7006410 DOI: 10.1186/s13287-020-1572-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 12/17/2019] [Accepted: 01/26/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Mesenchymal stem cell (MSC) transplantation is a fast-developing therapy in regenerative medicine. However, some concerns have been raised regarding their safety and the infusion-related pro-coagulant activity. The aim of this study is to analyze the induced thrombogenic risk and the safety of adding anticoagulants during intraportal infusions of liver-derived MSCs (HepaStem), in patients with Crigler-Najjar (CN) and urea cycle disorders (UCD). METHODS Eleven patients (6 CN and 5 UCD patients) were included in this partially randomized phase 1/2 study. Three cell doses of HepaStem were investigated: low (12.5 × 106 cells/kg), intermediate (50 × 106 cells/kg), and high doses (200 × 106 cells/kg). A combination of anticoagulants, heparin (10 I.U./5 × 106cells), and bivalirudin (1.75 mg/kg/h) were added during cell infusions. The infusion-related thrombogenic risk and anticoagulation were evaluated by clinical monitoring, blood sampling (platelet and D-dimer levels, activated clotting time, etc.) and liver Doppler ultrasound. Mixed effects linear regression models were used to assess statistically significant differences. RESULTS One patient presented a thrombogenic event such as a partial portal vein thrombus after 6 infusions. Minor adverse effects such as petechiae, epistaxis, and cutaneous hemorrhage at the site of catheter placement were observed in four patients. A significant decrease in platelet and increase in D-dimer levels were observed at the end of the infusion cycle, normalizing spontaneously after 7 days. No significant and clinically relevant increase in portal vein pressure could be observed once the infusion cycle was completed. CONCLUSIONS The safety- and the infusion-related pro-coagulant activity remains a concern in MSC transplantation. In our study, a combination of heparin and bivalirudin was added to prevent the thrombogenic risk induced by HepaStem infusions in 11 patients. A significant decrease in platelet and increase in D-dimer levels were observed, suggesting the activation of coagulation in these patients; however, this was spontaneously reversible in time. We can conclude that adding this combination of anticoagulants is safe and limits infusion-related thrombogenesis to subclinical signs in most of the patients. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01765283-January 10, 2013.
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Affiliation(s)
- Louise C F Coppin
- Service de Gastro-Entérologie et Hépatologie Pédiatrique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Av Hippocrate 10, B-1200, Brussels, Belgium.
| | - Françoise Smets
- Service de Gastro-Entérologie et Hépatologie Pédiatrique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Av Hippocrate 10, B-1200, Brussels, Belgium
| | - Jérome Ambroise
- Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium
| | - Etienne E M Sokal
- Service de Gastro-Entérologie et Hépatologie Pédiatrique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Av Hippocrate 10, B-1200, Brussels, Belgium
| | - Xavier Stéphenne
- Service de Gastro-Entérologie et Hépatologie Pédiatrique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Av Hippocrate 10, B-1200, Brussels, Belgium
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Black L, Zorina T. Cell-based immunomodulatory therapy approaches for type 1 diabetes mellitus. Drug Discov Today 2020; 25:380-391. [DOI: 10.1016/j.drudis.2019.11.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 11/11/2019] [Accepted: 11/30/2019] [Indexed: 12/14/2022]
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Wang H, Gou W, Strange C, Wang J, Nietert PJ, Cloud C, Owzarski S, Shuford B, Duke T, Luttrell L, Lesher A, Papas KK, Herold KC, Clark P, Usmani-Brown S, Kitzmann J, Crosson C, Adams DB, Morgan KA. Islet Harvest in Carbon Monoxide-Saturated Medium for Chronic Pancreatitis Patients Undergoing Islet Autotransplantation. Cell Transplant 2019; 28:25S-36S. [PMID: 31885286 PMCID: PMC7016471 DOI: 10.1177/0963689719890596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 10/21/2019] [Accepted: 10/31/2019] [Indexed: 12/13/2022] Open
Abstract
Stresses encountered during human islet isolation lead to unavoidable β-cell death after transplantation. This reduces the chance of insulin independence in chronic pancreatitis patients undergoing total pancreatectomy and islet autotransplantation. We tested whether harvesting islets in carbon monoxide-saturated solutions is safe and can enhance islet survival and insulin independence after total pancreatectomy and islet autotransplantation. Chronic pancreatitis patients who consented to the study were randomized into carbon monoxide (islets harvested in a carbon monoxide-saturated medium) or control (islets harvested in a normal medium) groups. Islet yield, viability, oxygen consumption rate, β-cell death (measured by unmethylated insulin DNA), and serum cytokine levels were measured during the peri-transplantation period. Adverse events, metabolic phenotypes, and islet function were measured prior and at 6 months post-transplantation. No adverse events directly related to the infusion of carbon monoxide islets were observed. Carbon monoxide islets showed significantly higher viability before transplantation. Subjects receiving carbon monoxide islets had less β-cell death, decreased CCL23, and increased CXCL12 levels at 1 or 3 days post transplantation compared with controls. Three in 10 (30%) of the carbon monoxide subjects and none of the control subjects were insulin independent. This pilot trial showed for the first time that harvesting human islets in carbon monoxide-saturated solutions is safe for total pancreatectomy and islet autotransplantation patients.
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Affiliation(s)
- Hongjun Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Wenyu Gou
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Charlie Strange
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Jingjing Wang
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Paul J. Nietert
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Colleen Cloud
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Stefanie Owzarski
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Betsy Shuford
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Tara Duke
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Louis Luttrell
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Aaron Lesher
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | | | - Kevan C. Herold
- Department of Immunology, Yale University, New Haven, CT, USA
| | - Pamela Clark
- Department of Immunology, Yale University, New Haven, CT, USA
| | | | | | - Craig Crosson
- Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - David B. Adams
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
| | - Katherine A. Morgan
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
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Fadini GP, Albiero M, Bonora BM, Avogaro A. Angiogenic Abnormalities in Diabetes Mellitus: Mechanistic and Clinical Aspects. J Clin Endocrinol Metab 2019; 104:5431-5444. [PMID: 31211371 DOI: 10.1210/jc.2019-00980] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 06/12/2019] [Indexed: 12/25/2022]
Abstract
CONTEXT Diabetes causes severe pathological changes to the microvasculature in many organs and tissues and is at the same time associated with an increased risk of coronary and peripheral macrovascular events. We herein review alterations in angiogenesis observed in human and experimental diabetes and how they contribute to diabetes onset and development of vascular complications. EVIDENCE ACQUISITION The English language medical literature was searched for articles reporting on angiogenesis/vasculogenesis abnormalities in diabetes and their clinical manifestations, mechanistic aspects, and possible therapeutic implications. EVIDENCE SYNTHESIS Angiogenesis is a complex process, driven by a multiplicity of molecular mechanisms and involved in several physiological and pathological conditions. Incompetent angiogenesis is pervasive in diabetic vascular complications, with both excessive and defective angiogenesis observed in various tissues. A striking different angiogenic response typically occurs in the retina vs the myocardium and peripheral circulation, but some commonalities in abnormal angiogenesis can explain the well-known association between microangiopathy and macroangiopathy. Impaired angiogenesis can also affect endocrine islet and adipose tissue function, providing a link to diabetes onset. Exposure to high glucose itself directly affects angiogenic/vasculogenic processes, and the mechanisms include defective responses to hypoxia and proangiogenic factors, impaired nitric oxide bioavailability, shortage of proangiogenic cells, and loss of pericytes. CONCLUSIONS Dissecting the molecular drivers of tissue-specific alterations of angiogenesis/vasculogenesis is an important challenge to devise new therapeutic approaches. Angiogenesis-modulating therapies should be carefully evaluated in view of their potential off-target effects. At present, glycemic control remains the most reasonable therapeutic strategy to normalize angiogenesis in diabetes.
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Affiliation(s)
- Gian Paolo Fadini
- Department of Medicine, University of Padova, Padova, Italy
- Venetian Institute of Molecular Medicine, Padova, Italy
| | - Mattia Albiero
- Department of Medicine, University of Padova, Padova, Italy
- Venetian Institute of Molecular Medicine, Padova, Italy
| | - Benedetta Maria Bonora
- Department of Medicine, University of Padova, Padova, Italy
- Venetian Institute of Molecular Medicine, Padova, Italy
| | - Angelo Avogaro
- Department of Medicine, University of Padova, Padova, Italy
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Coppin L, Sokal E, Stéphenne X. Thrombogenic Risk Induced by Intravascular Mesenchymal Stem Cell Therapy: Current Status and Future Perspectives. Cells 2019; 8:cells8101160. [PMID: 31569696 PMCID: PMC6829440 DOI: 10.3390/cells8101160] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 09/20/2019] [Accepted: 09/25/2019] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are currently studied and used in numerous clinical trials. Nevertheless, some concerns have been raised regarding the safety of these infusions and the thrombogenic risk they induce. MSCs express procoagulant activity (PCA) linked to the expression of tissue factor (TF) that, when in contact with blood, initiates coagulation. Some even describe a dual activation of both the coagulation and the complement pathway, called Instant Blood-Mediated Inflammatory Reaction (IBMIR), explaining the disappointing results and low engraftment rates in clinical trials. However, nowadays, different approaches to modulate the PCA of MSCs and thus control the thrombogenic risk after cell infusion are being studied. This review summarizes both in vitro and in vivo studies on the PCA of MSC of various origins. It further emphasizes the crucial role of TF linked to the PCA of MSCs. Furthermore, optimization of MSC therapy protocols using different methods to control the PCA of MSCs are described.
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Affiliation(s)
- Louise Coppin
- Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
| | - Etienne Sokal
- Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
| | - Xavier Stéphenne
- Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain (UCLouvain), 1200 Brussels, Belgium.
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