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Rout S, Mishra PR, Balamurugan AN, Ravi PK. Islet dimension and its impact on transplant outcome: A systematic review. World J Transplant 2025; 15:102383. [DOI: 10.5500/wjt.v15.i3.102383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 02/19/2025] [Accepted: 02/27/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Not all islet transplants desirably achieve insulin independence. This can be attributed to the microarchitecture and function of the islets influenced by their dimensions. Large islets enhance insulin secretion through paracrine effects but are more susceptible to hypoxic injury post-transplant, while small islets offer better viability and insulin independence. In vivo studies suggest large islets are essential for maintaining euglycemia, though smaller islets are typically preferred in transplantation for better outcomes.
AIM To document the impact of islet dimension on clinical and preclinical transplant outcomes to optimize procedures.
METHODS PubMed, Scopus and EMBASE platforms were searched for relevant literature up to 9 April 2024. Articles reported on either glucose-stimulated insulin-secreting (GSIS) capacity, islet viability and engraftment, or insulin independence based on the islet dimension were included. The risk of bias was measured using the Appraisal Tool for Cross-Sectional Studies. Extracted data was analyzed via a narrative synthesis.
RESULTS Nineteen studies were included in the review. A total of sixteen studies reported the GSIS, of which nine documented the increased insulin secretion in the small islet, where the majority reported insulin secretion per islet equivalent (IEQ). Seven studies documented increased GSIS in large-sized islets that measure insulin secretion per cell or islet. All the articles that compared small and large islets reported poor viability and engraftment of large islets.
CONCLUSION Small islets with a diameter < 125 µm have desired transplantation outcomes due to their better survival following isolation. Large-sized islets receive blood supply directly from arterioles in vivo to meet their higher metabolic demands. The large islet undergoes central necrosis soon after the isolation (devascularization); failing to maintain the viability and glucose stimuli leads to a decline in GSIS and the overall function of the islet. Improved preservation of large islets after islet isolation, enhances the islet yield (IEQ), thereby reducing the likelihood of failed islet isolation and potentially improves transplant outcome.
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Affiliation(s)
- Sipra Rout
- Department of Anatomy, All India Institute of Medical Sciences, Bhubaneswar 751019, Odisha, India
| | - Pravash R Mishra
- Department of Anatomy, All India Institute of Medical Sciences, Bhubaneswar 751019, Odisha, India
| | - Appakalai N Balamurugan
- Wendy Novak Diabetes Institute, Norton Children's Research Institute, Norton Healthcare, Louisville, KY 40202, United States
- Division of Pediatric Endocrinology, Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY 40202, United States
| | - Praveen Kumar Ravi
- Department of Anatomy, All India Institute of Medical Sciences, Bhubaneswar 751019, Odisha, India
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2
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Kieffer TJ, Hoesli CA, Shapiro AMJ. Advances in Islet Transplantation and the Future of Stem Cell-Derived Islets to Treat Diabetes. Cold Spring Harb Perspect Med 2025; 15:a041624. [PMID: 39074874 PMCID: PMC12047745 DOI: 10.1101/cshperspect.a041624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/31/2024]
Abstract
β-Cell replacement for type 1 diabetes (T1D) can restore normal glucose homeostasis, thereby eliminating the need for exogenous insulin and halting the progression of diabetes complications. Success in achieving insulin independence following transplantation of cadaveric islets fueled academic and industry efforts to develop techniques to mass produce β cells from human pluripotent stem cells, and these have now been clinically validated as an alternative source of regulated insulin production. Various encapsulation strategies are being pursued to contain implanted cells in a retrievable format, and different implant sites are being explored with some strategies reaching clinical studies. Stem cell lines, whether derived from embryonic sources or reprogrammed somatic cells, are being genetically modified for designer features, including immune evasiveness to enable implant without the use of chronic immunosuppression. Although hurdles remain in optimizing large-scale manufacturing, demonstrating efficacy, durability, and safety, products containing stem cell-derived β cells promise to provide a potent treatment for insulin-dependent diabetes.
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Affiliation(s)
- Timothy J Kieffer
- Department of Cellular and Physiological Sciences, Life Sciences Institute, School of Biomedical Engineering
- Department of Surgery, The University of British Columbia, Vancouver V6T1Z3, British Columbia, Canada
| | - Corinne A Hoesli
- Department of Chemical Engineering, Department of Biomedical Engineering, McGill University, Montreal H3A 0C5, Québec, Canada
- Associate Member, Department of Biomedical Engineering, McGill University, Montreal H3A 0C5, Québec, Canada
| | - A M James Shapiro
- Clinical Islet Transplant Program, University of Alberta, Edmonton T6G2E1, Alberta, Canada
- Department of Surgery, University of Alberta, Edmonton T6G2E1, Alberta, Canada
- Alberta Diabetes Institute, University of Alberta, Edmonton T6G2E1, Alberta, Canada
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3
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Geng A, Yuan S, Yu QC, Zeng YA. The role of endothelial cells in pancreatic islet development, transplantation and culture. Front Cell Dev Biol 2025; 13:1558137. [PMID: 40330424 PMCID: PMC12052768 DOI: 10.3389/fcell.2025.1558137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/03/2025] [Indexed: 05/08/2025] Open
Abstract
Endothelial cells (ECs) play pivotal roles in the development and maintenance of tissue homeostasis. During development, vasculature actively involves in organ morphogenesis and functional maturation, through the secretion of angiocrine factors and extracellular matrix components. Islets of Langerhans, essential functional units of glucose homeostasis, are embedded in a dense endothelial capillary network. Islet vasculature not only supplies nutrients and oxygen to endocrine cells but also facilitate the rapid delivery of pancreatic hormones to target tissues, thereby ensuring precise glucose regulation. Diabetes mellitus is a major disease burden and is caused by islet dysfunction or depletion, often accompanied by vessel loss and dysregulation. Therefore, elucidating the regulatory mechanisms of ECs within islets hold profound implications for diabetes therapy. This review provides an overview of recent research advancements on the functional roles of ECs in islet biology, transplantation, and in vitro islet organoid culture.
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Affiliation(s)
- Ajun Geng
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Shubo Yuan
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Qing Cissy Yu
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yi Arial Zeng
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- New Cornerstone Science Laboratory, Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
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4
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Bal T. Scaffold-free endocrine tissue engineering: role of islet organization and implications in type 1 diabetes. BMC Endocr Disord 2025; 25:107. [PMID: 40259265 PMCID: PMC12010671 DOI: 10.1186/s12902-025-01919-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 01/17/2025] [Indexed: 04/23/2025] Open
Abstract
Type 1 diabetes (T1D) is a chronic hyperglycemia disorder emerging from beta-cell (insulin secreting cells of the pancreas) targeted autoimmunity. As the blood glucose levels significantly increase and the insulin secretion is gradually lost, the entire body suffers from the complications. Although various advances in the insulin analogs, blood glucose monitoring and insulin application practices have been achieved in the last few decades, a cure for the disease is not obtained. Alternatively, pancreas/islet transplantation is an attractive therapeutic approach based on the patient prognosis, yet this treatment is also limited mainly by donor shortage, life-long use of immunosuppressive drugs and risk of disease transmission. In research and clinics, such drawbacks are addressed by the endocrine tissue engineering of the pancreas. One arm of this engineering is scaffold-free models which often utilize highly developed cell-cell junctions, soluble factors and 3D arrangement of islets with the cellular heterogeneity to prepare the transplant formulations. In this review, taking T1D as a model autoimmune disease, techniques to produce so-called pseudoislets and their applications are studied in detail with the aim of understanding the role of mimicry and pointing out the promising efforts which can be translated from benchside to bedside to achieve exogenous insulin-free patient treatment. Likewise, these developments in the pseudoislet formation are tools for the research to elucidate underlying mechanisms in pancreas (patho)biology, as platforms to screen drugs and to introduce immunoisolation barrier-based hybrid strategies.
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Affiliation(s)
- Tugba Bal
- Department of Bioengineering, Faculty of Engineering and Natural Sciences, Uskudar University, Istanbul, 34662, Turkey.
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5
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Kim M, Cho S, Hwang DG, Shim IK, Kim SC, Jang J, Jang J. Bioprinting of bespoke islet-specific niches to promote maturation of stem cell-derived islets. Nat Commun 2025; 16:1430. [PMID: 39920133 PMCID: PMC11805982 DOI: 10.1038/s41467-025-56665-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 01/27/2025] [Indexed: 02/09/2025] Open
Abstract
Pancreatic islets are densely packed cellular aggregates containing various hormonal cell types essential for blood glucose regulation. Interactions among these cells markedly affect the glucoregulatory functions of islets along with the surrounding niche and pancreatic tissue-specific geometrical organization. However, stem cell (SC)-derived islets generated in vitro often lack the three-dimensional extracellular microenvironment and peri-vasculature, which leads to the immaturity of SC-derived islets, reducing their ability to detect glucose fluctuations and insulin release. Here, we bioengineer the in vivo-like pancreatic niches by optimizing the combination of pancreatic tissue-specific extracellular matrix and basement membrane proteins and utilizing bioprinting-based geometrical guidance to recreate the spatial pattern of islet peripheries. The bioprinted islet-specific niche promotes coordinated interactions between islets and vasculature, supporting structural and functional features resembling native islets. Our strategy not only improves SC-derived islet functionality but also offers significant potential for advancing research on islet development, maturation, and diabetic disease modeling, with future implications for translational applications.
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Affiliation(s)
- Myungji Kim
- Division of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Seungyeun Cho
- Center for 3D Organ Printing and Stem Cells, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Dong Gyu Hwang
- Center for 3D Organ Printing and Stem Cells, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - In Kyong Shim
- Asan Institute for Life Science, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
| | - Song Cheol Kim
- Asan Institute for Life Science, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
- Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea
| | - Jiwon Jang
- Center for 3D Organ Printing and Stem Cells, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Jinah Jang
- Division of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Center for 3D Organ Printing and Stem Cells, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Department of Mechanical Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Department of Convergence IT Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Institute for Convergence Research and Education in Advanced Technology, Yonsei University, Seoul, Republic of Korea.
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6
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Kim Y, Kang M, Mamo MG, Adisasmita M, Huch M, Choi D. Liver organoids: Current advances and future applications for hepatology. Clin Mol Hepatol 2025; 31:S327-S348. [PMID: 39722609 PMCID: PMC11925438 DOI: 10.3350/cmh.2024.1040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Revised: 12/13/2024] [Accepted: 12/24/2024] [Indexed: 12/28/2024] Open
Abstract
The creation of self-organizing liver organoids represents a significant, although modest, step toward addressing the ongoing organ shortage crisis in allogeneic liver transplantation. However, researchers have recognized that achieving a fully functional whole liver remains a distant goal, and the original ambition of organoid-based liver generation has been temporarily put on hold. Instead, liver organoids have revolutionized the field of hepatology, extending their influence into various domains of precision and molecular medicine. These 3D cultures, capable of replicating key features of human liver function and pathology, have opened new avenues for human-relevant disease modeling, CRISPR gene editing, and high-throughput drug screening that animal models cannot accomplish. Moreover, advancements in creating more complex systems have led to the development of multicellular assembloids, dynamic organoid-on-chip systems, and 3D bioprinting technologies. These innovations enable detailed modeling of liver microenvironments and complex tissue interactions. Progress in regenerative medicine and transplantation applications continues to evolve and strives to overcome the obstacles of biocompatibility and tumorigenecity. In this review, we examine the current state of liver organoid research by offering insights into where the field currently stands, and the pivotal developments that are shaping its future.
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Affiliation(s)
- Yohan Kim
- Department of MetaBioHealth, Sungkyunkwan University, Suwon, Korea
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, Korea
- Biomedical Institute for Convergence at SKKU, Sungkyunkwan University, Suwon, Korea
| | - Minseok Kang
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
| | - Michael Girma Mamo
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
| | - Michael Adisasmita
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
| | - Meritxell Huch
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Dongho Choi
- Department of Surgery, Hanyang University College of Medicine, Seoul, Korea
- Research Institute of Regenerative Medicine and Stem Cells, Hanyang University, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
- Department of HY-KIST Bio-convergence, Hanyang University, Seoul, Korea
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7
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Yoneyama Y, Wu Y, Mori K, Takebe T. In toto biological framework: Modeling interconnectedness during human development. Dev Cell 2025; 60:8-20. [PMID: 39765224 DOI: 10.1016/j.devcel.2024.09.027] [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: 08/30/2023] [Revised: 04/21/2024] [Accepted: 09/20/2024] [Indexed: 05/24/2025]
Abstract
Recent advancements in pluripotent stem cell and synthetic tissue technology have brought significant breakthroughs in studying early embryonic development, particularly within the first trimester of development in humans. However, during fetal stage development, investigating further biological events represents a major challenge, partly due to the evolving complexity and continued interaction across multiple organ systems. To bridge this gap, we propose an "in toto" biological framework that leverages a triad of technologies: synthetic tissues, intravital microscopy, and computer vision to capture in vivo cellular morphodynamics, conceptualized as single-cell choreography. This perspective will discuss the inherent challenges in capturing such complexities and explore engineering technologies to delve into the less-explored phase of human development. We also propose reframing the organ-centric to a system-centric paradigm, as such a framework broadens the value of the in vivo-embedded synthetic-tissue-based approach for interrogating the multifaceted interplay of human developmental processes during this crucial stage.
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Affiliation(s)
- Yosuke Yoneyama
- Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Graduate School of Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan; Human Biology Research Unit, Institute of Integrated Research, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Yunheng Wu
- Graduate School of Informatics, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
| | - Kensaku Mori
- Graduate School of Informatics, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Information Technology Center, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Research Center for Medical Bigdata, National Institute of Informatics, Tokyo 100-0003, Japan
| | - Takanori Takebe
- Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe), Graduate School of Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, Japan; Human Biology Research Unit, Institute of Integrated Research, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Divisions of Gastroenterology, Hepatology & Nutrition, and Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
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8
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Werschler N, Quintard C, Nguyen S, Penninger J. Engineering next generation vascularized organoids. Atherosclerosis 2024; 398:118529. [PMID: 39304390 DOI: 10.1016/j.atherosclerosis.2024.118529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/31/2024] [Accepted: 06/21/2024] [Indexed: 09/22/2024]
Abstract
Organoids are self-organizing 3D cell culture models that are valuable for studying the mechanisms underlying both development and disease in multiple species, particularly, in humans. These 3D engineered tissues can mimic the structure and function of human organs in vitro. Methods to generate organoids have substantially improved to better resemble, in various ways, their in vivo counterpart. One of the major limitations in current organoid models is the lack of a functional vascular compartment. Here we discuss methodological approaches to generating perfusable blood vessel networks in organoid systems. Inclusion of perfused vascular compartments markedly enhances the physiological relevance of organoid systems and is a critical step in the establishment of next generation, higher-complexity in vitro systems for use in developmental, clinical, and drug-development settings.
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Affiliation(s)
- Nicolas Werschler
- University of British Columbia, Life Sciences Institute, Vancouver, Canada; University of British Columbia, School of Biomedical Engineering, Vancouver, Canada.
| | - Clement Quintard
- University of British Columbia, Life Sciences Institute, Vancouver, Canada; University of British Columbia, Medical Genetics, Vancouver, Canada
| | - Stephanie Nguyen
- University of British Columbia, School of Biomedical Engineering, Vancouver, Canada
| | - Josef Penninger
- University of British Columbia, Life Sciences Institute, Vancouver, Canada; University of British Columbia, School of Biomedical Engineering, Vancouver, Canada; University of British Columbia, Medical Genetics, Vancouver, Canada; Helmholtz Centre for Infection Research, Germany; Eric Kandel Institute, Department of Laboratory Medicine, Medical University of Vienna, Austria; IMBA Institute of Molecular Biotechnology, Vienna, Austria
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9
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Migliorini A, Nostro MC. Vascular and immune interactions in islets transplantation and 3D islet models. Curr Opin Genet Dev 2024; 88:102237. [PMID: 39111229 DOI: 10.1016/j.gde.2024.102237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 07/14/2024] [Accepted: 07/18/2024] [Indexed: 09/11/2024]
Abstract
The aim of regenerative medicine is to restore specific functions to damaged cells or tissues. A crucial aspect of success lies in effectively reintegrating these cells or tissues within the recipient organism. This is particularly pertinent for diabetes, where islet function relies on the close connection of beta cells to the bloodstream for glucose sensing and insulin release. Central to this approach is the need to establish a fast connection with the host's vascular system. In this review, we explore the intricate relationships between endocrine, vascular, and immune cell interactions in transplantation outcomes. We also delve into recent strategies aimed at enhancing engraftment, along with the utilization of in vitro platforms to model cellular interactions.
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Affiliation(s)
- Adriana Migliorini
- McEwen Stem Cell Institute, University Health Network, Toronto M5G 1L7, Ontario, Canada. https://twitter.com/@AdrianaMiglior1
| | - M Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, Toronto M5G 1L7, Ontario, Canada; Ajmera Transplant Centre, Toronto General Hospital Research Institute, University Health Network, Toronto, Canada; Department of Physiology, University of Toronto, Toronto M5S 1A8, Ontario, Canada.
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10
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Carolina E, Kuse Y, Okumura A, Aoshima K, Tadokoro T, Matsumoto S, Kanai E, Okumura T, Kasai T, Yamabe S, Nishikawa Y, Yamaguchi K, Furukawa Y, Tanimizu N, Taniguchi H. Generation of human iPSC-derived 3D bile duct within liver organoid by incorporating human iPSC-derived blood vessel. Nat Commun 2024; 15:7424. [PMID: 39198465 PMCID: PMC11358266 DOI: 10.1038/s41467-024-51487-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 08/06/2024] [Indexed: 09/01/2024] Open
Abstract
In fetal development, tissue interaction such as the interplay between blood vessel (BV) and epithelial tissue is crucial for organogenesis. Here we recapitulate the spatial arrangement between liver epithelial tissue and the portal vein to observe the formation of intrahepatic bile ducts (BDs) from human induced pluripotent stem cells (hiPSC). We co-culture hiPSC-liver progenitors on the artificial BV consisting of immature smooth muscle cells and endothelial cells, both derived from hiPSCs. After 3 weeks, liver progenitors within hiPSC-BV-incorporated liver organoids (BVLO) differentiate to cholangiocytes and acquire epithelial characteristics, including intercellular junctions, microvilli on the apical membrane, and secretory functions. Furthermore, liver surface transplanted-BVLO temporarily attenuates cholestatic injury symptoms. Single cell RNA sequence analysis suggests that BD interact with the BV in BVLO through TGFβ and Notch pathways. Knocking out JAG1 in hiPSC-BV significantly attenuates bile duct formation, highlighting BVLO potential as a model for Alagille syndrome, a congenital biliary disease. Overall, we develop a novel 3D co-culture method that successfully establishes functional human BDs by emulating liver epithelial-BV interaction.
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Affiliation(s)
- Erica Carolina
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Yoshiki Kuse
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Ayumu Okumura
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Kenji Aoshima
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Tomomi Tadokoro
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Shinya Matsumoto
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Eriko Kanai
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Takashi Okumura
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Toshiharu Kasai
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Souichiro Yamabe
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Yuji Nishikawa
- Division of Tumor Pathology, Department of Pathology, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Kiyoshi Yamaguchi
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yoichi Furukawa
- Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Naoki Tanimizu
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Hideki Taniguchi
- Division of Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- Department of Regenerative Medicine, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
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11
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Li Y, Xu M, Chen J, Huang J, Cao J, Chen H, Zhang J, Luo Y, Wang Y, Sun J. Ameliorating and refining islet organoids to illuminate treatment and pathogenesis of diabetes mellitus. Stem Cell Res Ther 2024; 15:188. [PMID: 38937834 PMCID: PMC11210168 DOI: 10.1186/s13287-024-03780-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 06/01/2024] [Indexed: 06/29/2024] Open
Abstract
Diabetes mellitus, a significant global public health challenge, severely impacts human health worldwide. The organoid, an innovative in vitro three-dimensional (3D) culture model, closely mimics tissues or organs in vivo. Insulin-secreting islet organoid, derived from stem cells induced in vitro with 3D structures, has emerged as a potential alternative for islet transplantation and as a possible disease model that mirrors the human body's in vivo environment, eliminating species difference. This technology has gained considerable attention for its potential in diabetes treatment. Despite advances, the process of stem cell differentiation into islet organoid and its cultivation demonstrates deficiencies, prompting ongoing efforts to develop more efficient differentiation protocols and 3D biomimetic materials. At present, the constructed islet organoid exhibit limitations in their composition, structure, and functionality when compared to natural islets. Consequently, further research is imperative to achieve a multi-tissue system composition and improved insulin secretion functionality in islet organoid, while addressing transplantation-related safety concerns, such as tumorigenicity, immune rejection, infection, and thrombosis. This review delves into the methodologies and strategies for constructing the islet organoid, its application in diabetes treatment, and the pivotal scientific challenges within organoid research, offering fresh perspectives for a deeper understanding of diabetes pathogenesis and the development of therapeutic interventions.
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Affiliation(s)
- Yushan Li
- Department of Endocrinology, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Meiqi Xu
- Department of Biomedical Engineering, Shanxi Medical University, Taiyuan, Shanxi, 030001, China
| | - Jiali Chen
- Department of Endocrinology, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jiansong Huang
- Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jiaying Cao
- Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Huajing Chen
- Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Jiayi Zhang
- Nanfang Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yukun Luo
- Department of Endocrinology, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yazhuo Wang
- Tsinghua-Peking Center for Life Sciences, School of Basic Medical Sciences, Tsinghua University, Beijing, China.
| | - Jia Sun
- Department of Endocrinology, Zhujiang Hospital, The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China.
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12
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Kado T, Tomimaru Y, Kobayashi S, Harada A, Sasaki K, Iwagami Y, Yamada D, Noda T, Takahashi H, Kita S, Shimomura I, Miyagawa S, Doki Y, Eguchi H. Skeletal Myoblast Cells Enhance the Function of Transplanted Islets in Diabetic Mice. J Diabetes Res 2024; 2024:5574968. [PMID: 38800586 PMCID: PMC11126349 DOI: 10.1155/2024/5574968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/05/2024] [Accepted: 04/23/2024] [Indexed: 05/29/2024] Open
Abstract
Islet transplantation (ITx) is an established and safe alternative to pancreas transplantation for type 1 diabetes mellitus (T1DM) patients. However, most ITx recipients lose insulin independence by 3 years after ITx due to early graft loss, such that multiple donors are required to achieve insulin independence. In the present study, we investigated whether skeletal myoblast cells could be beneficial for promoting angiogenesis and maintaining the differentiated phenotypes of islets. In vitro experiments showed that the myoblast cells secreted angiogenesis-related cytokines (vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and stromal-derived factor-1α (SDF-1α)), contributed to maintenance of differentiated islet phenotypes, and enhanced islet cell insulin secretion capacity. To verify these findings in vivo, we transplanted islets alone or with myoblast cells under the kidney capsule of streptozotocin-induced diabetic mice. Compared with islets alone, the group bearing islets with myoblast cells had a significantly lower average blood glucose level. Histological examination revealed that transplants with islets plus myoblast cells were associated with a significantly larger insulin-positive area and significantly higher number of CD31-positive microvessels compared to islets alone. Furthermore, islets cotransplanted with myoblast cells showed JAK-STAT signaling activation. Our results suggest two possible mechanisms underlying enhancement of islet graft function with myoblast cells cotransplantation: "indirect effects" mediated by angiogenesis and "direct effects" of myoblast cells on islets via the JAK-STAT cascade. Overall, these findings suggest that skeletal myoblast cells enhance the function of transplanted islets, implying clinical potential for a novel ITx procedure involving myoblast cells for patients with diabetes.
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Affiliation(s)
- Takeshi Kado
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Akima Harada
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shunbun Kita
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
- Department of Adipose Management, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
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13
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Osonoi S, Takebe T. Organoid-guided precision hepatology for metabolic liver disease. J Hepatol 2024; 80:805-821. [PMID: 38237864 PMCID: PMC11828489 DOI: 10.1016/j.jhep.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 12/28/2023] [Accepted: 01/02/2024] [Indexed: 03/09/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease affects millions of people worldwide. Progress towards a definitive cure has been incremental and treatment is currently limited to lifestyle modification. Hepatocyte-specific lipid accumulation is the main trigger of lipotoxic events, driving inflammation and fibrosis. The underlying pathology is extraordinarily heterogenous, and the manifestations of steatohepatitis are markedly influenced by metabolic communications across non-hepatic organs. Synthetic human tissue models have emerged as powerful platforms to better capture the mechanistic diversity in disease progression, while preserving person-specific genetic traits. In this review, we will outline current research efforts focused on integrating multiple synthetic tissue models of key metabolic organs, with an emphasis on organoid-based systems. By combining functional genomics and population-scale en masse profiling methodologies, human tissues derived from patients can provide insights into personalised genetic, transcriptional, biochemical, and metabolic states. These collective efforts will advance our understanding of steatohepatitis and guide the development of rational solutions for mechanism-directed diagnostic and therapeutic investigation.
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Affiliation(s)
- Sho Osonoi
- Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, 036-8562, Japan
| | - Takanori Takebe
- Center for Stem Cell and Organoid Medicine (CuSTOM), Division of Gastroenterology, Hepatology and Nutrition, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; WPI Premium Institute for Human Metaverse Medicine (WPI-PRIMe) and Department of Genome Biology, Graduate School of Medicine, Osaka University, Osaka, 565-0871, Japan; Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan; Communication Design Center, Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan.
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14
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Park S, Cho SW. Bioengineering toolkits for potentiating organoid therapeutics. Adv Drug Deliv Rev 2024; 208:115238. [PMID: 38447933 DOI: 10.1016/j.addr.2024.115238] [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: 09/26/2023] [Revised: 01/28/2024] [Accepted: 02/27/2024] [Indexed: 03/08/2024]
Abstract
Organoids are three-dimensional, multicellular constructs that recapitulate the structural and functional features of specific organs. Because of these characteristics, organoids have been widely applied in biomedical research in recent decades. Remarkable advancements in organoid technology have positioned them as promising candidates for regenerative medicine. However, current organoids still have limitations, such as the absence of internal vasculature, limited functionality, and a small size that is not commensurate with that of actual organs. These limitations hinder their survival and regenerative effects after transplantation. Another significant concern is the reliance on mouse tumor-derived matrix in organoid culture, which is unsuitable for clinical translation due to its tumor origin and safety issues. Therefore, our aim is to describe engineering strategies and alternative biocompatible materials that can facilitate the practical applications of organoids in regenerative medicine. Furthermore, we highlight meaningful progress in organoid transplantation, with a particular emphasis on the functional restoration of various organs.
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Affiliation(s)
- Sewon Park
- Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea
| | - Seung-Woo Cho
- Department of Biotechnology, Yonsei University, Seoul 03722, Republic of Korea; Center for Nanomedicine, Institute for Basic Science (IBS), Seoul 03722, Republic of Korea; Graduate Program of Nano Biomedical Engineering (NanoBME), Advanced Science Institute, Yonsei University, Seoul 03722, Republic of Korea.
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15
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Azad A, Altunbas HA, Manguoglu AE. From islet transplantation to beta-cell regeneration: an update on beta-cell-based therapeutic approaches in type 1 diabetes. Expert Rev Endocrinol Metab 2024; 19:217-227. [PMID: 38693782 DOI: 10.1080/17446651.2024.2347263] [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: 05/16/2023] [Accepted: 03/06/2024] [Indexed: 05/03/2024]
Abstract
INTRODUCTION Type 1 diabetes (T1D) mellitus is an autoimmune disease in which immune cells, predominantly effector T cells, destroy insulin-secreting beta-cells. Beta-cell destruction led to various consequences ranging from retinopathy and nephropathy to neuropathy. Different strategies have been developed to achieve normoglycemia, including exogenous glucose compensation, whole pancreas transplantation, islet transplantation, and beta-cell replacement. AREAS COVERED The last two decades of experience have shown that indigenous glucose compensation through beta-cell regeneration and protection is a peerless method for T1D therapy. Tremendous studies have tried to find an unlimited source for beta-cell regeneration, on the one hand, and beta-cell protection against immune attack, on the other hand. Recent advances in stem cell technology, gene editing methods, and immune modulation approaches provide a unique opportunity for both beta-cell regeneration and protection. EXPERT OPINION Pluripotent stem cell differentiation into the beta-cell is considered an unlimited source for beta-cell regeneration. Devising engineered pancreas-specific regulatory T cells using Chimeric Antigen Receptor (CAR) technology potentiates an effective immune tolerance induction for beta-cell protection. Beta-cell regeneration using pluripotent stem cells and beta-cell protection using pancreas-specific engineered regulatory T cells promises to develop a curative protocol in T1D.
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Affiliation(s)
- Asef Azad
- Department of Medical Biology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Hasan Ali Altunbas
- Department of Endocrinology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
| | - Ayse Esra Manguoglu
- Department of Medical Biology, Faculty of Medicine, Akdeniz University, Antalya, Turkey
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16
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Nashimoto Y, Konno A, Imaizumi T, Nishikawa K, Ino K, Hori T, Kaji H, Shintaku H, Goto M, Shiku H. Microfluidic vascular formation model for assessing angiogenic capacities of single islets. Biotechnol Bioeng 2024; 121:1050-1059. [PMID: 38131167 DOI: 10.1002/bit.28631] [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: 05/26/2023] [Revised: 09/12/2023] [Accepted: 12/07/2023] [Indexed: 12/23/2023]
Abstract
Pancreatic islet transplantation presents a promising therapy for individuals suffering from type 1 diabetes. To maintain the function of transplanted islets in vivo, it is imperative to induce angiogenesis. However, the mechanisms underlying angiogenesis triggered by islets remain unclear. In this study, we introduced a microphysiological system to study the angiogenic capacity and dynamics of individual islets. The system, which features an open-top structure, uniquely facilitates the inoculation of islets and the longitudinal observation of vascular formation in in vivo like microenvironment with islet-endothelial cell communication. By leveraging our system, we discovered notable islet-islet heterogeneity in the angiogenic capacity. Transcriptomic analysis of the vascularized islets revealed that islets with high angiogenic capacity exhibited upregulation of genes related to insulin secretion and downregulation of genes related to angiogenesis and fibroblasts. In conclusion, our microfluidic approach is effective in characterizing the vascular formation of individual islets and holds great promise for elucidating the angiogenic mechanisms that enhance islet transplantation therapy.
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Affiliation(s)
- Yuji Nashimoto
- Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Frontier Research Institute for Interdisciplinary Sciences (FRIS), Tohoku University, Miyagi, Japan
- Graduate School of Engineering, Tohoku University, Miyagi, Japan
- Graduate School of Environmental Studies, Tohoku University, Miyagi, Japan
- Cluster for Pioneering Research, RIKEN, Saitama, Japan
| | - An Konno
- Graduate School of Environmental Studies, Tohoku University, Miyagi, Japan
| | - Takuto Imaizumi
- Graduate School of Environmental Studies, Tohoku University, Miyagi, Japan
| | | | - Kosuke Ino
- Graduate School of Engineering, Tohoku University, Miyagi, Japan
| | - Takeshi Hori
- Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hirokazu Kaji
- Institute of Biomaterials and Bioengineering (IBB), Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hirofumi Shintaku
- Cluster for Pioneering Research, RIKEN, Saitama, Japan
- Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan
| | - Masafumi Goto
- Division of Transplantation and Regenerative Medicine, Graduate School of Medicine, Tohoku University, Miyagi, Japan
| | - Hitoshi Shiku
- Graduate School of Engineering, Tohoku University, Miyagi, Japan
- Graduate School of Environmental Studies, Tohoku University, Miyagi, Japan
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17
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Li H, Li J, Wang T, Sun K, Huang G, Cao Y, Wu F, Xu A. Hepatobiliary organoids differentiated from hiPSCs relieve cholestasis-induced liver fibrosis in nonhuman primates. Int J Biol Sci 2024; 20:1160-1179. [PMID: 38385067 PMCID: PMC10878143 DOI: 10.7150/ijbs.90441] [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: 09/23/2023] [Accepted: 01/07/2024] [Indexed: 02/23/2024] Open
Abstract
There is an urgent need for novel therapies to treat end-stage liver disease due to the shortage of available organs. Although cell transplantation holds considerable promise, its availability is limited due to the low engrafted cell mass and lack of unifying cell transplantation strategies. Here, we optimally established human induced pluripotent stem cell-derived functional hepatobiliary organoids (HBOs) based on our previous research and transplanted them into a monkey model via liver subcapsular and submesenteric transplantation routes to assess their potential clinical application. Our study revealed that HBO transplantation could safely and effectively improve hepatoprotection effects by antiapoptotic and antifibrotic agents. In addition, we also discovered that while multiple HBO transplantation pathways may have a shared effector mechanism, their respective treatment approaches have distinct advantages. Transplantation of HBOs could promote the high expression of CTSV in hepatic sinusoid endothelial cells, which might halt the progression of hepatic sinusoidal capillarization and liver fibrosis. Liver subcapsular transplants had stronger pro-CTSV upregulation than HBO submesenteric transplants, which could be attributed to naturally high CTSV expression in HBOs. Interestingly, both transplantation routes of HBOs were targeted the injured liver and triggered a new pattern of ductular reaction to alleviate the degree of liver fibrosis by surrounding the area with CK19-positive labeled cells. These residing, homing and repairing effects might be related to the high expression of MMP family genes. By promoting a unique pattern of ductular reactions, submesenteric HBO transplantation has a more representative antifibrotic impact than liver subcapsular transplantation. Altogether, our data strongly imply that the treatment of severe liver diseases with liver subcapsular and submesenteric transplantation of HBOs may be clinically effective and safe. These findings provide new insight into HBOs for further experimental and clinical validation.
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Affiliation(s)
- Hongmei Li
- School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
- Beizhong Jingyuan Biotechnology (Beijing) Limited, Beijing, People's Republic of China
| | - Jingyi Li
- School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
| | - Ting Wang
- School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
| | - Ke Sun
- School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
| | - Guangrui Huang
- School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
- Beizhong Jingyuan Biotechnology (Beijing) Limited, Beijing, People's Republic of China
| | - Yulin Cao
- Beizhong Jingyuan Biotechnology (Beijing) Limited, Beijing, People's Republic of China
- Tangyi Holdings (Shenzhen) Limited, Shenzhen, People's Republic of China
| | - Fenfang Wu
- Shenzhen Hospital, Beijing University of Chinese Medicine, Shenzhen 518116, People's Republic of China
| | - Anlong Xu
- School of Life Science, Beijing University of Chinese Medicine, Beijing 100029, People's Republic of China
- State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Pharmaceutical Functional Genes, College of Life Sciences, Sun Yat-Sen University, Guangzhou, Guangdong 510006, People's Republic of China
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18
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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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19
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Juste-Lanas Y, Hervas-Raluy S, García-Aznar JM, González-Loyola A. Fluid flow to mimic organ function in 3D in vitro models. APL Bioeng 2023; 7:031501. [PMID: 37547671 PMCID: PMC10404142 DOI: 10.1063/5.0146000] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 06/20/2023] [Indexed: 08/08/2023] Open
Abstract
Many different strategies can be found in the literature to model organ physiology, tissue functionality, and disease in vitro; however, most of these models lack the physiological fluid dynamics present in vivo. Here, we highlight the importance of fluid flow for tissue homeostasis, specifically in vessels, other lumen structures, and interstitium, to point out the need of perfusion in current 3D in vitro models. Importantly, the advantages and limitations of the different current experimental fluid-flow setups are discussed. Finally, we shed light on current challenges and future focus of fluid flow models applied to the newest bioengineering state-of-the-art platforms, such as organoids and organ-on-a-chip, as the most sophisticated and physiological preclinical platforms.
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Affiliation(s)
| | - Silvia Hervas-Raluy
- Department of Mechanical Engineering, Engineering Research Institute of Aragón (I3A), University of Zaragoza, Zaragoza, Spain
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20
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沈 钧, 欧阳 智, 钟 健, 龙 怡, 孙 誉, 曾 烨. [Research progress on vascularization of organoids]. SHENG WU YI XUE GONG CHENG XUE ZA ZHI = JOURNAL OF BIOMEDICAL ENGINEERING = SHENGWU YIXUE GONGCHENGXUE ZAZHI 2023; 40:625-631. [PMID: 37666751 PMCID: PMC10477383 DOI: 10.7507/1001-5515.202211011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 02/21/2023] [Indexed: 09/06/2023]
Abstract
Organoids are three-dimensional structures formed by self-organizing growth of cells in vitro, which own many structures and functions similar with those of corresponding in vivo organs. Although the organoid culture technologies are rapidly developed and the original cells are abundant, the organoid cultured by current technologies are rather different with the real organs, which limits their application. The major challenges of organoid cultures are the immature tissue structure and restricted growth, both of which are caused by poor functional vasculature. Therefore, how to develop the vascularization of organoids has become an urgent problem. We presently reviewed the progresses on the original cells of organoids and the current methods to develop organoids vascularization, which provide clues to solve the above-mentioned problems.
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Affiliation(s)
- 钧怡 沈
- 四川大学 华西基础医学与法医学院 生物医学工程研究室（成都 610041）Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, P. R. China
| | - 智 欧阳
- 四川大学 华西基础医学与法医学院 生物医学工程研究室（成都 610041）Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, P. R. China
| | - 健 钟
- 四川大学 华西基础医学与法医学院 生物医学工程研究室（成都 610041）Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, P. R. China
| | - 怡岑 龙
- 四川大学 华西基础医学与法医学院 生物医学工程研究室（成都 610041）Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, P. R. China
| | - 誉珈 孙
- 四川大学 华西基础医学与法医学院 生物医学工程研究室（成都 610041）Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, P. R. China
| | - 烨 曾
- 四川大学 华西基础医学与法医学院 生物医学工程研究室（成都 610041）Institute of Biomedical Engineering, West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Chengdu 610041, P. R. China
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21
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Jeon S, Lee YS, Oh SR, Jeong J, Lee DH, So KH, Hwang NS. Recent advances in endocrine organoids for therapeutic application. Adv Drug Deliv Rev 2023; 199:114959. [PMID: 37301512 DOI: 10.1016/j.addr.2023.114959] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/21/2023] [Accepted: 06/05/2023] [Indexed: 06/12/2023]
Abstract
The endocrine system, consisting of the hypothalamus, pituitary, endocrine glands, and hormones, plays a critical role in hormone metabolic interactions. The complexity of the endocrine system is a significant obstacle to understanding and treating endocrine disorders. Notably, advances in endocrine organoid generation allow a deeper understanding of the endocrine system by providing better comprehension of molecular mechanisms of pathogenesis. Here, we highlight recent advances in endocrine organoids for a wide range of therapeutic applications, from cell transplantation therapy to drug toxicity screening, combined with development in stem cell differentiation and gene editing technologies. In particular, we provide insights into the transplantation of endocrine organoids to reverse endocrine dysfunctions and progress in developing strategies for better engraftments. We also discuss the gap between preclinical and clinical research. Finally, we provide future perspectives for research on endocrine organoids for the development of more effective treatments for endocrine disorders.
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Affiliation(s)
- Suwan Jeon
- Interdisciplinary Program for Biochemical Engineering and Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
| | - Young-Sun Lee
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea
| | - Seh Ri Oh
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea
| | - Jinseong Jeong
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea
| | - Dong-Hyun Lee
- Interdisciplinary Program for Biochemical Engineering and Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
| | - Kyoung-Ha So
- School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea; Bio-MAX/N-Bio Institute, Institute of Bio-Engineering, Seoul National University, Seoul 08826, Republic of Korea.
| | - Nathaniel S Hwang
- Interdisciplinary Program for Biochemical Engineering and Biotechnology, Seoul National University, Seoul 08826, Republic of Korea; School of Chemical and Biological Engineering, Institute of Chemical Processes, Seoul National University, Seoul 08826, Republic of Korea; Bio-MAX/N-Bio Institute, Institute of Bio-Engineering, Seoul National University, Seoul 08826, Republic of Korea; Institute of Engineering Research, Seoul National University, Seoul, 08826, Republic of Korea.
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22
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Tan C, Ding M, Zheng YW. The Values and Perspectives of Organoids in the Field of Metabolic Syndrome. Int J Mol Sci 2023; 24:8125. [PMID: 37175830 PMCID: PMC10179392 DOI: 10.3390/ijms24098125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 04/21/2023] [Accepted: 04/29/2023] [Indexed: 05/15/2023] Open
Abstract
Metabolic syndrome (MetS) has become a global health problem, and the prevalence of obesity at all stages of life makes MetS research increasingly important and urgent. However, as a comprehensive and complex disease, MetS has lacked more appropriate research models. The advent of organoids provides an opportunity to address this issue. However, it should be noted that organoids are still in their infancy. The main drawbacks are a lack of maturity, complexity, and the inability to standardize large-scale production. Could organoids therefore be a better choice for studying MetS than other models? How can these limitations be overcome? Here, we summarize the available data to present current progress on pancreatic and hepatobiliary organoids and to answer these open questions. Organoids are of human origin and contain a variety of human cell types necessary to mimic the disease characteristics of MetS in their development. Taken together with the discovery of hepatobiliary progenitors in situ, the dedifferentiation of beta cells in diabetes, and studies on hepatic macrophages, we suggest that promoting endogenous regeneration has the potential to prevent the development of end-stage liver and pancreatic lesions caused by MetS and outline the direction of future research in this field.
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Affiliation(s)
- Chen Tan
- Institute of Regenerative Medicine, Department of Dermatology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang 212001, China; (C.T.); (M.D.)
| | - Min Ding
- Institute of Regenerative Medicine, Department of Dermatology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang 212001, China; (C.T.); (M.D.)
| | - Yun-Wen Zheng
- Institute of Regenerative Medicine, Department of Dermatology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang 212001, China; (C.T.); (M.D.)
- Department of Medicinal and Life Sciences, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
- School of Medicine, Yokohama City University, Yokohama 234-0006, Japan
- Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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Beydag-Tasöz BS, Yennek S, Grapin-Botton A. Towards a better understanding of diabetes mellitus using organoid models. Nat Rev Endocrinol 2023; 19:232-248. [PMID: 36670309 PMCID: PMC9857923 DOI: 10.1038/s41574-022-00797-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2022] [Indexed: 01/22/2023]
Abstract
Our understanding of diabetes mellitus has benefited from a combination of clinical investigations and work in model organisms and cell lines. Organoid models for a wide range of tissues are emerging as an additional tool enabling the study of diabetes mellitus. The applications for organoid models include studying human pancreatic cell development, pancreatic physiology, the response of target organs to pancreatic hormones and how glucose toxicity can affect tissues such as the blood vessels, retina, kidney and nerves. Organoids can be derived from human tissue cells or pluripotent stem cells and enable the production of human cell assemblies mimicking human organs. Many organ mimics relevant to diabetes mellitus are already available, but only a few relevant studies have been performed. We discuss the models that have been developed for the pancreas, liver, kidney, nerves and vasculature, how they complement other models, and their limitations. In addition, as diabetes mellitus is a multi-organ disease, we highlight how a merger between the organoid and bioengineering fields will provide integrative models.
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Affiliation(s)
- Belin Selcen Beydag-Tasöz
- The Novo Nordisk Foundation Center for Stem Cell Biology, Copenhagen, Denmark
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Siham Yennek
- The Novo Nordisk Foundation Center for Stem Cell Biology, Copenhagen, Denmark
| | - Anne Grapin-Botton
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
- Paul Langerhans Institute Dresden, Dresden, Germany.
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24
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Cell Replacement Therapy for Type 1 Diabetes Patients: Potential Mechanisms Leading to Stem-Cell-Derived Pancreatic β-Cell Loss upon Transplant. Cells 2023; 12:cells12050698. [PMID: 36899834 PMCID: PMC10000642 DOI: 10.3390/cells12050698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/09/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
Cell replacement therapy using stem-cell-derived insulin-producing β-like cells (sBCs) has been proposed as a practical cure for patients with type one diabetes (T1D). sBCs can correct diabetes in preclinical animal models, demonstrating the promise of this stem cell-based approach. However, in vivo studies have demonstrated that most sBCs, similarly to cadaveric human islets, are lost upon transplantation due to ischemia and other unknown mechanisms. Hence, there is a critical knowledge gap in the current field concerning the fate of sBCs upon engraftment. Here we review, discuss effects, and propose additional potential mechanisms that could contribute toward β-cell loss in vivo. We summarize and highlight some of the literature on phenotypic loss in β-cells under both steady, stressed, and diseased diabetic conditions. Specifically, we focus on β-cell death, dedifferentiation into progenitors, trans-differentiation into other hormone-expressing cells, and/or interconversion into less functional β-cell subtypes as potential mechanisms. While current cell replacement therapy efforts employing sBCs carry great promise as an abundant cell source, addressing the somewhat neglected aspect of β-cell loss in vivo will further accelerate sBC transplantation as a promising therapeutic modality that could significantly enhance the life quality of T1D patients.
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25
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Vascularized Tissue Organoids. Bioengineering (Basel) 2023; 10:bioengineering10020124. [PMID: 36829618 PMCID: PMC9951914 DOI: 10.3390/bioengineering10020124] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/09/2023] [Accepted: 01/10/2023] [Indexed: 01/19/2023] Open
Abstract
Tissue organoids hold enormous potential as tools for a variety of applications, including disease modeling and drug screening. To effectively mimic the native tissue environment, it is critical to integrate a microvasculature with the parenchyma and stroma. In addition to providing a means to physiologically perfuse the organoids, the microvasculature also contributes to the cellular dynamics of the tissue model via the cells of the perivascular niche, thereby further modulating tissue function. In this review, we discuss current and developing strategies for vascularizing organoids, consider tissue-specific vascularization approaches, discuss the importance of perfusion, and provide perspectives on the state of the field.
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26
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Moeinvaziri F, Zarkesh I, Pooyan P, Nunez DA, Baharvand H. Inner ear organoids: progress and outlook, with a focus on the vascularization. FEBS J 2022; 289:7368-7384. [PMID: 34331740 DOI: 10.1111/febs.16146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 06/11/2021] [Accepted: 07/30/2021] [Indexed: 01/13/2023]
Abstract
The inner ear is a complex organ that encodes sound, motion, and orientation in space. Given the complexity of the inner ear, it is not surprising that treatments are relatively limited despite the fact that, in 2015, hearing loss was the fourth leading cause of years lived with disability worldwide. Inner ear organoid models are a promising tool to advance the study of multiple aspects of the inner ear to aid the development of new treatments and validate drug-based therapies. The blood supply of the inner ear plays a pivotal role in growth, maturation, and survival of inner ear tissues and their physiological functions. This vasculature cannot be ignored in order to achieve a truly in vivo-like model that mimics the microenvironment and niches of organ development. However, this aspect of organoid development has remained largely absent in the generation of inner ear organoids. The current review focuses on three-dimensional inner ear organoid and how recent technical progress in generating in vitro vasculature can enhance the next generation of these models.
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Affiliation(s)
- Farideh Moeinvaziri
- Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Ibrahim Zarkesh
- Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Paria Pooyan
- Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
| | - Desmond A Nunez
- Division of Otolaryngology, Department of Surgery, University of British Columbia, Vancouver, Canada
| | - Hossein Baharvand
- Department of Developmental Biology, School of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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27
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Heaton ES, Jin S. Importance of multiple endocrine cell types in islet organoids for type 1 diabetes treatment. Transl Res 2022; 250:68-83. [PMID: 35772687 PMCID: PMC11554285 DOI: 10.1016/j.trsl.2022.06.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/08/2022] [Accepted: 06/21/2022] [Indexed: 11/21/2022]
Abstract
Almost 50 years ago, scientists developed the bi-hormonal abnormality hypothesis, stating that diabetes is not caused merely by the impaired insulin signaling. Instead, the presence of inappropriate level of glucagon is a prerequisite for the development of type 1 diabetes (T1D). It is widely understood that the hormones insulin and glucagon, secreted by healthy β and α cells respectively, operate in a negative feedback loop to maintain the body's blood sugar levels. Despite this fact, traditional T1D treatments rely solely on exogenous insulin injections. Furthermore, research on cell-based therapies and stem-cell derived tissues tends to focus on the replacement of β cells alone. In vivo, the pancreas is made up of 4 major endocrine cell types, that is, insulin-producing β cells, glucagon-producing α cells, somatostatin-producing δ cells, and pancreatic polypeptide-producing γ cells. These distinct cell types are involved synergistically in regulating islet functions. Therefore, it is necessary to produce a pancreatic islet organoid in vitro consisting of all these cell types that adequately replaces the function of the native islets. In this review, we describe the unique function of each pancreatic endocrine cell type and their interactions contributing to the maintenance of normoglycemia. Furthermore, we detail current sources of whole islets and techniques for their long-term expansion and culture. In addition, we highlight a vast potential of the pancreatic islet organoids for transplantation and diabetes research along with updated new approaches for successful transplantation using stem cell-derived islet organoids.
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Affiliation(s)
- Emma S Heaton
- Department of Biomedical Engineering, Thomas J. Watson School of Engineering and Applied Sciences, State University of New York at Binghamton, Binghamton, New York
| | - Sha Jin
- Department of Biomedical Engineering, Thomas J. Watson School of Engineering and Applied Sciences, State University of New York at Binghamton, Binghamton, New York; Center of Biomanufacturing for Regenerative Medicine, State University of New York at Binghamton, Binghamton, New York.
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28
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Rojek K, Ćwiklińska M, Kuczak J, Guzowski J. Microfluidic Formulation of Topological Hydrogels for Microtissue Engineering. Chem Rev 2022; 122:16839-16909. [PMID: 36108106 PMCID: PMC9706502 DOI: 10.1021/acs.chemrev.1c00798] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Indexed: 02/07/2023]
Abstract
Microfluidics has recently emerged as a powerful tool in generation of submillimeter-sized cell aggregates capable of performing tissue-specific functions, so-called microtissues, for applications in drug testing, regenerative medicine, and cell therapies. In this work, we review the most recent advances in the field, with particular focus on the formulation of cell-encapsulating microgels of small "dimensionalities": "0D" (particles), "1D" (fibers), "2D" (sheets), etc., and with nontrivial internal topologies, typically consisting of multiple compartments loaded with different types of cells and/or biopolymers. Such structures, which we refer to as topological hydrogels or topological microgels (examples including core-shell or Janus microbeads and microfibers, hollow or porous microstructures, or granular hydrogels) can be precisely tailored with high reproducibility and throughput by using microfluidics and used to provide controlled "initial conditions" for cell proliferation and maturation into functional tissue-like microstructures. Microfluidic methods of formulation of topological biomaterials have enabled significant progress in engineering of miniature tissues and organs, such as pancreas, liver, muscle, bone, heart, neural tissue, or vasculature, as well as in fabrication of tailored microenvironments for stem-cell expansion and differentiation, or in cancer modeling, including generation of vascularized tumors for personalized drug testing. We review the available microfluidic fabrication methods by exploiting various cross-linking mechanisms and various routes toward compartmentalization and critically discuss the available tissue-specific applications. Finally, we list the remaining challenges such as simplification of the microfluidic workflow for its widespread use in biomedical research, bench-to-bedside transition including production upscaling, further in vivo validation, generation of more precise organ-like models, as well as incorporation of induced pluripotent stem cells as a step toward clinical applications.
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Affiliation(s)
- Katarzyna
O. Rojek
- Institute of Physical Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
| | - Monika Ćwiklińska
- Institute of Physical Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
| | - Julia Kuczak
- Institute of Physical Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
| | - Jan Guzowski
- Institute of Physical Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
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29
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Terrassoux L, Claux H, Bacari S, Meignan S, Furlan A. A Bloody Conspiracy. Blood Vessels and Immune Cells in the Tumor Microenvironment. Cancers (Basel) 2022; 14:cancers14194581. [PMID: 36230504 PMCID: PMC9558972 DOI: 10.3390/cancers14194581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/10/2022] [Accepted: 09/15/2022] [Indexed: 11/29/2022] Open
Abstract
Simple Summary The tumor microenvironment has risen over the last years as a significant contributor to the failure of antitumoral strategies due to its numerous pro-tumorigenic activities. In this review, we focused on two features of this microenvironment, namely angiogenesis and immunity, which have been the targets of therapies to tackle tumors via its microenvironmental part over the last decade. Increasing our knowledge of the complex interactions within this ecosystem is mandatory to optimize these therapeutic approaches. The development of innovative experimental models is of great help in reaching this goal. Abstract Cancer progression occurs in concomitance with a profound remodeling of the cellular microenvironment. Far from being a mere passive event, the re-orchestration of interactions between the various cell types surrounding tumors highly contributes to the progression of the latter. Tumors notably recruit and stimulate the sprouting of new blood vessels through a process called neo-angiogenesis. Beyond helping the tumor cope with an increased metabolic demand associated with rapid growth, this also controls the metastatic dissemination of cancer cells and the infiltration of immune cells in the tumor microenvironment. To decipher this critical interplay for the clinical progression of tumors, the research community has developed several valuable models in the last decades. This review offers an overview of the various instrumental solutions currently available, including microfluidic chips, co-culture models, and the recent rise of organoids. We highlight the advantages of each technique and the specific questions they can address to better understand the tumor immuno-angiogenic ecosystem. Finally, we discuss this development field’s fundamental and applied perspectives.
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Affiliation(s)
- Lisa Terrassoux
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
| | - Hugo Claux
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
| | - Salimata Bacari
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
| | - Samuel Meignan
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
| | - Alessandro Furlan
- Univ. Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, F-59000 Lille, France
- Tumorigenesis and Resistance to Treatment Unit, Centre Oscar Lambret, F-59000 Lille, France
- Correspondence:
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30
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Wieland F, Schumacher A, Roumans N, van Blitterswijk C, LaPointe V, Rademakers T. Methodological approaches in aggregate formation and microscopic analysis to assess pseudoislet morphology and cellular interactions. OPEN RESEARCH EUROPE 2022; 2:87. [PMID: 37645341 PMCID: PMC10446072 DOI: 10.12688/openreseurope.14894.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/14/2022] [Indexed: 08/31/2023]
Abstract
Microscopy has revolutionised our view on biology and has been vital for many discoveries since its invention around 200 years ago. Recent developments in cell biology have led to a strong interest in generating spheroids and organoids that better represent tissue. However, the current challenge faced by many researchers is the culture and analysis of these three-dimensional (3D) cell cultures. With the technological improvements in reconstructing volumetric datasets by optical sections, it is possible to quantify cells, their spatial arrangement, and the protein distribution without destroying the physical organization. We assessed three different microwell culture plates and four analysis tools for 3D imaging data for their applicability for the analysis of 3D cultures. A key advantage of microwell plates is their potential to perform high-throughput experiments in which cell cultures are generated and analysed in one single system. However, it was shown that this potential could be impacted by the material composition and microwell structure. For example, antibody staining was not possible in a hydrogel microwell, and truncated pyramid-structured microwells had increased background fluorescence due to their structure. Regarding analysis tools, four different software, namely CellProfiler, Fiji/ImageJ, Nikon GA3 and Imaris, were compared for their accuracy and applicability in analysing datasets from 3D cultures. The results showed that the open-access software, CellProfiler and Fiji, could quantify nuclei and cells, yet with varying results compared to manual counting, and may require post-processing optimisation. On the other hand, the GA3 and Imaris software packages showed excellent versatility in usage and accuracy in the quantification of nuclei and cells, and could classify cell localisation. Together these results provide critical considerations for microscopic imaging and analysis of 3D cell cultures.
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Affiliation(s)
- Fredrik Wieland
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Anika Schumacher
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Nadia Roumans
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Clemens van Blitterswijk
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Vanessa LaPointe
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
| | - Timo Rademakers
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, The Netherlands
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31
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Ma X, Li H, Zhu S, Hong Z, Kong W, Yuan Q, Wu R, Pan Z, Zhang J, Chen Y, Wang X, Wang K. Angiorganoid: vitalizing the organoid with blood vessels. VASCULAR BIOLOGY (BRISTOL, ENGLAND) 2022; 4:R44-R57. [PMID: 35994010 PMCID: PMC9513648 DOI: 10.1530/vb-22-0001] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 08/22/2022] [Indexed: 11/08/2022]
Abstract
The emergence of the organoid simulates the native organs and this mini organ offers an excellent platform for probing multicellular interaction, disease modeling and drug discovery. Blood vessels constitute the instructive vascular niche which is indispensable for organ development, function and regeneration. Therefore, it is expected that the introduction of infiltrated blood vessels into the organoid might further pump vitality and credibility into the system. While the field is emerging and growing with new concepts and methodologies, this review aims at presenting various sources of vascular ingredients for constructing vascularized organoids and the paired methodology including de- and recellularization, bioprinting and microfluidics. Representative vascular organoids corresponding to specific tissues are also summarized and discussed to elaborate on the next generation of organoid development.
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Affiliation(s)
- Xiaojing Ma
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Hongfei Li
- Department of Biological Sciences, Mount Holyoke College, South Hadley, Massachusetts, USA
| | - Shuntian Zhu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Zixuan Hong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Weijing Kong
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Qihang Yuan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Runlong Wu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Zihang Pan
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
| | - Jing Zhang
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Yahong Chen
- Department of Pulmonary and Critical Care Medicine, Peking University Third Hospital, Beijing, China
| | - Xi Wang
- Department of Biological and Environmental Engineering, Cornell University, Ithaca, New York, USA
| | - Kai Wang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing, China
- Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, China
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32
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Günther C, Winner B, Neurath MF, Stappenbeck TS. Organoids in gastrointestinal diseases: from experimental models to clinical translation. Gut 2022; 71:1892-1908. [PMID: 35636923 PMCID: PMC9380493 DOI: 10.1136/gutjnl-2021-326560] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 05/13/2022] [Indexed: 12/12/2022]
Abstract
We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases. In the lab, organoids have emerged as powerful systems to model molecular and cellular processes orchestrating natural and pathophysiological human tissue formation in remarkable detail. Preclinical studies have impressively demonstrated that these organs-in-a-dish can be used to model immunological, neoplastic, metabolic or infectious GI disorders by taking advantage of patient-derived material. Technological breakthroughs now allow to study cellular communication and molecular mechanisms of interorgan cross-talk in health and disease including communication along for example, the gut-brain axis or gut-liver axis. Despite considerable success in culturing classical 3D organoids from various parts of the GI tract, some challenges remain to develop these systems to best help patients. Novel platforms such as organ-on-a-chip, engineered biomimetic systems including engineered organoids, micromanufacturing, bioprinting and enhanced rigour and reproducibility will open improved avenues for tissue engineering, as well as regenerative and personalised medicine. This review will highlight some of the established methods and also some exciting novel perspectives on organoids in the fields of gastroenterology. At present, this field is poised to move forward and impact many currently intractable GI diseases in the form of novel diagnostics and therapeutics.
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Affiliation(s)
- Claudia Günther
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Beate Winner
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
- Department of Stem Cell Biology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Center of Rare Diseases Erlangen (ZSEER), University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Thaddeus S Stappenbeck
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Pignatelli C, Campo F, Neroni A, Piemonti L, Citro A. Bioengineering the Vascularized Endocrine Pancreas: A Fine-Tuned Interplay Between Vascularization, Extracellular-Matrix-Based Scaffold Architecture, and Insulin-Producing Cells. Transpl Int 2022; 35:10555. [PMID: 36090775 PMCID: PMC9452644 DOI: 10.3389/ti.2022.10555] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 08/11/2022] [Indexed: 11/23/2022]
Abstract
Intrahepatic islet transplantation is a promising β-cell replacement strategy for the treatment of type 1 diabetes. Instant blood-mediated inflammatory reactions, acute inflammatory storm, and graft revascularization delay limit islet engraftment in the peri-transplant phase, hampering the success rate of the procedure. Growing evidence has demonstrated that islet engraftment efficiency may take advantage of several bioengineering approaches aimed to recreate both vascular and endocrine compartments either ex vivo or in vivo. To this end, endocrine pancreas bioengineering is an emerging field in β-cell replacement, which might provide endocrine cells with all the building blocks (vascularization, ECM composition, or micro/macro-architecture) useful for their successful engraftment and function in vivo. Studies on reshaping either the endocrine cellular composition or the islet microenvironment have been largely performed, focusing on a single building block element, without, however, grasping that their synergistic effect is indispensable for correct endocrine function. Herein, the review focuses on the minimum building blocks that an ideal vascularized endocrine scaffold should have to resemble the endocrine niche architecture, composition, and function to foster functional connections between the vascular and endocrine compartments. Additionally, this review highlights the possibility of designing bioengineered scaffolds integrating alternative endocrine sources to overcome donor organ shortages and the possibility of combining novel immune-preserving strategies for long-term graft function.
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Affiliation(s)
- Cataldo Pignatelli
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Francesco Campo
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Alessia Neroni
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Lorenzo Piemonti
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Università Vita-Salute San Raffaele, Milan, Italy
| | - Antonio Citro
- San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
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34
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Sun W, Liu J, Zhao R, Yang T, Zheng Z, Zhang T, Wang G. Knockdown of IFNAR2 reduces the inflammatory response in mouse model of type 1 diabetes. Biochem Biophys Res Commun 2022; 619:9-14. [PMID: 35728283 DOI: 10.1016/j.bbrc.2022.06.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/08/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND and Purpose: To investigate the biological role of interferon α/β receptor 2 (IFNAR2) in type 1 diabetes (T1D). METHODS First, IFNAR2 mRNA and protein expression levels in serum of T1D patients and healthy controls were detected by RT-qPCR and Western blot. For experimental studies, 80 male C57BL/6 mice were randomly divided into 4 groups with 20 mice in each group: the control group, the T1D group, the T1D + ad-con group and the T1D + ad-si-IFNAR2 group. The T1D mouse model was generated by multiple intraperitoneal injections of small doses of streptozotocin (STZ). Body weight and blood glucose levels were measured weekly until 6 weeks. After 6 weeks, all mice were sacrificed and the levels of insulin (Ins), tumor necrosis factor α (TNF-α), interleukin 4 (IL-4), IL-6, and type I interferon γ (IFN-γ), IFNAR2 protein expression, the number of dendritic cells (DCs), and changes in islet β cells were assessed. RESULTS IFNAR2 mRNA and protein expression levels in serum of T1D patients were significantly higher than those in healthy controls (P < 0.05). Furthermore, IFNAR2 protein expression, number of DCs, and IFNAR2 mRNA, blood glucose, TNF-α, and IFN-γ levels were significantly upregulated in T1D mice compared with the control group (P < 0.05), while weight, and Ins, IL-6, and IL-4 levels were decreased (P < 0.05). However, knockdown of IFNAR2 reversed these trends. There was no significant difference in markers between the T1D + ad-con group and the T1D group (P > 0.05). CONCLUSIONS Knockdown of IFNAR2 reduced the inflammatory response and improved islet function of T1D mice.
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Affiliation(s)
- Wei Sun
- Department of Clinical Laboratory, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, The Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, JiangSu, 222061, China
| | - Jing Liu
- Management of Hospital Infection, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, The Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, JiangSu, 222061, China
| | - Renhao Zhao
- Department of Endocrinology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, The Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, JiangSu, 222061, China
| | - Teng Yang
- Department of Endocrinology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, The Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, JiangSu, 222061, China
| | - Zhichen Zheng
- Department of Endocrinology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, The Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, JiangSu, 222061, China
| | - Tongyu Zhang
- Department of Endocrinology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, The Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, JiangSu, 222061, China
| | - Guofeng Wang
- Department of Endocrinology, The Affiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, The Affiliated Hospital of Kangda College of Nanjing Medical University, Lianyungang, JiangSu, 222061, China.
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35
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Patel SN, Mathews CE, Chandler R, Stabler CL. The Foundation for Engineering a Pancreatic Islet Niche. Front Endocrinol (Lausanne) 2022; 13:881525. [PMID: 35600597 PMCID: PMC9114707 DOI: 10.3389/fendo.2022.881525] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 03/30/2022] [Indexed: 12/01/2022] Open
Abstract
Progress in diabetes research is hindered, in part, by deficiencies in current experimental systems to accurately model human pathophysiology and/or predict clinical outcomes. Engineering human-centric platforms that more closely mimic in vivo physiology, however, requires thoughtful and informed design. Summarizing our contemporary understanding of the unique and critical features of the pancreatic islet can inform engineering design criteria. Furthermore, a broad understanding of conventional experimental practices and their current advantages and limitations ensures that new models address key gaps. Improving beyond traditional cell culture, emerging platforms are combining diabetes-relevant cells within three-dimensional niches containing dynamic matrices and controlled fluidic flow. While highly promising, islet-on-a-chip prototypes must evolve their utility, adaptability, and adoptability to ensure broad and reproducible use. Here we propose a roadmap for engineers to craft biorelevant and accessible diabetes models. Concurrently, we seek to inspire biologists to leverage such tools to ask complex and nuanced questions. The progenies of such diabetes models should ultimately enable investigators to translate ambitious research expeditions from benchtop to the clinic.
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Affiliation(s)
- Smit N. Patel
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Clayton E. Mathews
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, United States
- Diabetes Institute, University of Florida, Gainesville, FL, United States
| | - Rachel Chandler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Cherie L. Stabler
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
- Diabetes Institute, University of Florida, Gainesville, FL, United States
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36
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Tremmel DM, Sackett SD, Feeney AK, Mitchell SA, Schaid MD, Polyak E, Chlebeck PJ, Gupta S, Kimple ME, Fernandez LA, Odorico JS. A human pancreatic ECM hydrogel optimized for 3-D modeling of the islet microenvironment. Sci Rep 2022; 12:7188. [PMID: 35504932 PMCID: PMC9065104 DOI: 10.1038/s41598-022-11085-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 04/04/2022] [Indexed: 02/07/2023] Open
Abstract
Extracellular matrix (ECM) plays a multitude of roles, including supporting cells through structural and biochemical interactions. ECM is damaged in the process of isolating human islets for clinical transplantation and basic research. A platform in which islets can be cultured in contact with natural pancreatic ECM is desirable to better understand and support islet health, and to recapitulate the native islet environment. Our study demonstrates the derivation of a practical and durable hydrogel from decellularized human pancreas that supports human islet survival and function. Islets embedded in this hydrogel show increased glucose- and KCl-stimulated insulin secretion, and improved mitochondrial function compared to islets cultured without pancreatic matrix. In extended culture, hydrogel co-culture significantly reduced levels of apoptosis compared to suspension culture and preserved controlled glucose-responsive function. Isolated islets displayed altered endocrine and non-endocrine cell arrangement compared to in situ islets; hydrogel preserved an islet architecture more similar to that observed in situ. RNA sequencing confirmed that gene expression differences between islets cultured in suspension and hydrogel largely fell within gene ontology terms related to extracellular signaling and adhesion. Natural pancreatic ECM improves the survival and physiology of isolated human islets.
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Affiliation(s)
- Daniel M Tremmel
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
| | - Sara Dutton Sackett
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
| | - Austin K Feeney
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Samantha A Mitchell
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Michael D Schaid
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.,William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | - Erzsebet Polyak
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Peter J Chlebeck
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Sakar Gupta
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Michelle E Kimple
- Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.,William S. Middleton Memorial Veterans Hospital, Madison, WI, USA
| | | | - Jon S Odorico
- Division of Transplantation, Department of Surgery, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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37
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Methods for vascularization and perfusion of tissue organoids. Mamm Genome 2022; 33:437-450. [PMID: 35333952 DOI: 10.1007/s00335-022-09951-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 03/10/2022] [Indexed: 12/17/2022]
Abstract
Tissue organoids or "mini organs" can be invaluable tools for understanding health and disease biology, modeling tissue dynamics, or screening potential drug candidates. Effective vascularization of these models is critical for truly representing the in vivo tissue environment. Not only is the formation of a vascular network, and ultimately a microcirculation, essential for proper distribution and exchange of oxygen and nutrients throughout larger organoids, but vascular cells dynamically communicate with other cells to modulate overall tissue behavior. Additionally, interstitial fluid flow, mediated by a perfused microvasculature, can have profound influences on tissue biology. Thus, a truly functionally and biologically relevant organoid requires a vasculature. Here, we review existing strategies for fabricating and incorporating vascular elements and perfusion within tissue organoids.
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38
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Rodríguez-Comas J, Ramón-Azcón J. Islet-on-a-chip for the study of pancreatic β-cell function. IN VITRO MODELS 2022; 1:41-57. [PMID: 39872972 PMCID: PMC11749753 DOI: 10.1007/s44164-021-00005-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/25/2021] [Accepted: 11/08/2021] [Indexed: 01/30/2025]
Abstract
Diabetes mellitus is a significant public health problem worldwide. It encompasses a group of chronic disorders characterized by hyperglycemia, resulting from pancreatic islet dysfunction or as a consequence of insulin-producing β-cell death. Organ-on-a-chip platforms have emerged as technological systems combining cell biology, engineering, and biomaterial technological advances with microfluidics to recapitulate a specific organ's physiological or pathophysiological environment. These devices offer a novel model for the screening of pharmaceutical agents and to study a particular disease. In the field of diabetes, a variety of microfluidic devices have been introduced to recreate native islet microenvironments and to understand pancreatic β-cell kinetics in vitro. This kind of platforms has been shown fundamental for the study of the islet function and to assess the quality of these islets for subsequent in vivo transplantation. However, islet physiological systems are still limited compared to other organs and tissues, evidencing the difficulty to study this "organ" and the need for further technological advances. In this review, we summarize the current state of islet-on-a-chip platforms that have been developed so far. We recapitulate the most relevant studies involving pancreatic islets and microfluidics, focusing on the molecular and cellular-scale activities that underlie pancreatic β-cell function.
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Affiliation(s)
- Júlia Rodríguez-Comas
- Biosensors for Bioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac, 10-12, 08028 Barcelona, Spain
| | - Javier Ramón-Azcón
- Biosensors for Bioengineering Group, Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac, 10-12, 08028 Barcelona, Spain
- ICREA-Institució Catalana de Recerca i Estudis Avançats, 08010 Barcelona, Spain
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39
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Papoz A, Clément F, Laporte C, Tubbs E, Gidrol X, Pitaval A. [Generating pancreatic islets organoids: Langerhanoids]. Med Sci (Paris) 2022; 38:52-58. [PMID: 35060887 DOI: 10.1051/medsci/2021244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The extension of islet transplantation to a wider number of Type 1 diabetic patients is compromised by the scarcity of donors, the reduced ex vivo survival of pancreatic islets and the use of immunosuppressive treatments. Islets of Langerhans isolated from brain-dead donors are currently the only cell source for transplantation. Thus, it is crucial to find an alternative and an abundant source of functional insulin secreting cells not only for clinical use but also for the development of research dedicated to the screening of drugs and to the development of new therapeutic targets. Several groups around the world, including ours, develop 3D culture models as Langerhanoids that closely mimick human pancreatic islets physiology. In this review, we describe recent advances to mimic the pancreatic niche (extracellular matrix, vascularization, microfluidics) allowing better functionality of Langerhanoids.
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Affiliation(s)
- Anastasia Papoz
- Univ. Grenoble Alpes, CEA, Inserm, IRIG, Biomics, F-38000, Grenoble, France
| | - Flora Clément
- Univ. Grenoble Alpes, CEA, Inserm, IRIG, Biomics, F-38000, Grenoble, France
| | - Camille Laporte
- Univ. Grenoble Alpes, CEA, Leti, Division for biology and healthcare technologies, Microfluidic systems and bioengineering Lab, F-38000, Grenoble, France
| | - Emily Tubbs
- Univ. Grenoble Alpes, CEA, Inserm, IRIG, Biomics, F-38000, Grenoble, France - Univ. Grenoble Alpes, LBFA et BEeSy, Inserm U1055, F-38000, Grenoble, France
| | - Xavier Gidrol
- Univ. Grenoble Alpes, CEA, Inserm, IRIG, Biomics, F-38000, Grenoble, France
| | - Amandine Pitaval
- Univ. Grenoble Alpes, CEA, Inserm, IRIG, Biomics, F-38000, Grenoble, France
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40
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Jiang L, Shen Y, Liu Y, Zhang L, Jiang W. Making human pancreatic islet organoids: Progresses on the cell origins, biomaterials and three-dimensional technologies. Theranostics 2022; 12:1537-1556. [PMID: 35198056 PMCID: PMC8825586 DOI: 10.7150/thno.66670] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 12/27/2021] [Indexed: 11/05/2022] Open
Abstract
Diabetes is one of the most socially challenging health concerns. Even though islet transplantation has shown promise for insulin-dependent diabetes, there is still no effective method for curing diabetes due to the severe shortage of transplantable donors. In recent years, organoid technology has attracted lots of attention as organoid can mirror the human organ in vivo to the maximum extent in vitro, thus bridging the gap between cellular- and tissue/organ-level biological models. Concurrently, human pancreatic islet organoids are expected to be a considerable source of islet transplantation. To construct human islet-like organoids, the seeding cells, biomaterials and three-dimensional structure are three key elements. Herein, this review summarizes current progresses about the cell origins, biomaterials and advanced technology being applied to make human islet organoids, and discusses the advantages, shortcomings, and future challenges of them as well. We hope this review can offer a cross-disciplinary perspective to build human islet organoids and provide insights for tissue engineering and regenerative medicine.
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Affiliation(s)
- Lai Jiang
- Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Yiru Shen
- College of Life Sciences, Wuhan University, Wuhan 430071, China
| | - Yajing Liu
- Asia Regenerative Medicine Ltd., Shenzhen 518110, China
| | - Lei Zhang
- Asia Regenerative Medicine Ltd., Shenzhen 518110, China
| | - Wei Jiang
- Department of Biological Repositories, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
- Human Genetics Resource Preservation Center of Wuhan University, Wuhan 430071, China
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
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41
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Caleffi JT, Aal MCE, Gallindo HDOM, Caxali GH, Crulhas BP, Ribeiro AO, Souza GR, Delella FK. Magnetic 3D cell culture: State of the art and current advances. Life Sci 2021; 286:120028. [PMID: 34627776 DOI: 10.1016/j.lfs.2021.120028] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 09/24/2021] [Accepted: 10/02/2021] [Indexed: 02/07/2023]
Abstract
Cell culture is an important tool for the understanding of cell biology and behavior. In vitro cultivation has been increasingly indispensable for biomedical, pharmaceutical, and biotechnology research. Nevertheless, with the demand for in vitro experimentation strategies more representative of in vivo conditions, tridimensional (3D) cell culture models have been successfully developed. Although these 3D models are efficient and address critical questions from different research areas, there are considerable differences between the existing techniques regarding both elaboration and cost. In light of this, this review describes the construction of 3D spheroids using magnetization while bringing the most recent updates in this field. Magnetic 3D cell culture consists of magnetizing cells using an assembly of gold and iron oxide nanoparticles cross-linked with poly-l-lysine nanoparticles. Then, 3D culture formation in special plates with the assistance of magnets for levitation or bioprinting. Here, we discuss magnetic 3D cell culture advancements, including tumor microenvironment, tissue reconstruction, blood vessel engineering, toxicology, cytotoxicity, and 3D culture of cardiomyocytes, bronchial and pancreatic cells.
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Affiliation(s)
- Juliana Trindade Caleffi
- São Paulo State University (UNESP), Institute of Biosciences, Department of Structural and Functional Biology, Botucatu, São Paulo, Brazil
| | - Mirian Carolini Esgoti Aal
- São Paulo State University (UNESP), Institute of Biosciences, Department of Structural and Functional Biology, Botucatu, São Paulo, Brazil
| | | | - Gabriel Henrique Caxali
- São Paulo State University (UNESP), Institute of Biosciences, Department of Structural and Functional Biology, Botucatu, São Paulo, Brazil
| | | | - Amanda Oliveira Ribeiro
- São Paulo State University (UNESP), Institute of Biosciences, Department of Structural and Functional Biology, Botucatu, São Paulo, Brazil
| | - Glauco R Souza
- University of Texas Health Sciences Center at Houston, Houston, TX, USA
| | - Flávia Karina Delella
- São Paulo State University (UNESP), Institute of Biosciences, Department of Structural and Functional Biology, Botucatu, São Paulo, Brazil.
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42
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Ghezelayagh Z, Zabihi M, Kazemi Ashtiani M, Ghezelayagh Z, Lynn FC, Tahamtani Y. Recapitulating pancreatic cell-cell interactions through bioengineering approaches: the momentous role of non-epithelial cells for diabetes cell therapy. Cell Mol Life Sci 2021; 78:7107-7132. [PMID: 34613423 PMCID: PMC11072828 DOI: 10.1007/s00018-021-03951-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 09/09/2021] [Accepted: 09/23/2021] [Indexed: 12/11/2022]
Abstract
Over the past few years, extensive efforts have been made to generate in-vitro pancreatic micro-tissue, for disease modeling or cell replacement approaches in pancreatic related diseases such as diabetes mellitus. To obtain these goals, a closer look at the diverse cells participating in pancreatic development is necessary. Five major non-epithelial pancreatic (pN-Epi) cell populations namely, pancreatic endothelium, mesothelium, neural crests, pericytes, and stellate cells exist in pancreas throughout its development, and they are hypothesized to be endogenous inducers of the development. In this review, we discuss different pN-Epi cells migrating to and existing within the pancreas and their diverse effects on pancreatic epithelium during organ development mediated via associated signaling pathways, soluble factors or mechanical cell-cell interactions. In-vivo and in-vitro experiments, with a focus on N-Epi cells' impact on pancreas endocrine development, have also been considered. Pluripotent stem cell technology and multicellular three-dimensional organoids as new approaches to generate pancreatic micro-tissues have also been discussed. Main challenges for reaching a detailed understanding of the role of pN-Epi cells in pancreas development in utilizing for in-vitro recapitulation have been summarized. Finally, various novel and innovative large-scale bioengineering approaches which may help to recapitulate cell-cell interactions and are crucial for generation of large-scale in-vitro multicellular pancreatic micro-tissues, are discussed.
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Affiliation(s)
- Zahra Ghezelayagh
- Department of Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Zabihi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Genetics, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
| | - Mohammad Kazemi Ashtiani
- Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Zeinab Ghezelayagh
- Department of Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
- Department of Embryology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Francis C Lynn
- Diabetes Research Group, BC Children's Hospital Research Institute, Vancouver, BC, Canada
- Department of Surgery and School of Biomedical Engineering , University of British Columbia, Vancouver, BC, Canada
| | - Yaser Tahamtani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
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Kim M, Jang J. Construction of 3D hierarchical tissue platforms for modeling diabetes. APL Bioeng 2021; 5:041506. [PMID: 34703970 PMCID: PMC8530538 DOI: 10.1063/5.0055128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 09/27/2021] [Indexed: 12/14/2022] Open
Abstract
Diabetes mellitus (DM) is one of the most serious systemic diseases worldwide, and the majority of DM patients face severe complications. However, many of underlying disease mechanisms related to these complications are difficult to understand with the use of currently available animal models. With the urgent need to fundamentally understand DM pathology, a variety of 3D biomimetic platforms have been generated by the convergence of biofabrication and tissue engineering strategies for the potent drug screening platform of pre-clinical research. Here, we suggest key requirements for the fabrication of physiomimetic tissue models in terms of recapitulating the cellular organization, creating native 3D microenvironmental niches for targeted tissue using biomaterials, and applying biofabrication technologies to implement tissue-specific geometries. We also provide an overview of various in vitro DM models, from a cellular level to complex living systems, which have been developed using various bioengineering approaches. Moreover, we aim to discuss the roadblocks facing in vitro tissue models and end with an outlook for future DM research.
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Affiliation(s)
- Myungji Kim
- School of Interdisciplinary Bioscience and Bioengineering, POSTECH, 77 Cheongam-ro, Namgu, Pohang, Kyungbuk, 37673, Republic of Korea
| | - Jinah Jang
- Author to whom correspondence should be addressed:
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Aghazadeh Y, Poon F, Sarangi F, Wong FTM, Khan ST, Sun X, Hatkar R, Cox BJ, Nunes SS, Nostro MC. Microvessels support engraftment and functionality of human islets and hESC-derived pancreatic progenitors in diabetes models. Cell Stem Cell 2021; 28:1936-1949.e8. [PMID: 34480863 DOI: 10.1016/j.stem.2021.08.001] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 04/27/2021] [Accepted: 08/04/2021] [Indexed: 12/19/2022]
Abstract
Islet transplantation is a promising treatment for type 1 diabetes (T1D), yet the low donor pool, poor islet engraftment, and life-long immunosuppression prevent it from becoming the standard of care. Human embryonic stem cell (hESC)-derived pancreatic cells could eliminate donor shortages, but interventions to improve graft survival are needed. Here, we enhanced subcutaneous engraftment by employing a unique vascularization strategy based on ready-made microvessels (MVs) isolated from the adipose tissue. This resulted in improved cell survival and effective glucose response of both human islets and hESC-derived pancreatic cells, which ameliorated preexisting diabetes in three mouse models of T1D.
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Affiliation(s)
- Yasaman Aghazadeh
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Frankie Poon
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Farida Sarangi
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Frances T M Wong
- Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Safwat T Khan
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada
| | - Xuetao Sun
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Rupal Hatkar
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Brian J Cox
- Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5G 1E2, Canada
| | - Sara S Nunes
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Laboratory of Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON M5S 3H2, Canada.
| | - M Cristina Nostro
- McEwen Stem Cell Institute, University Health Network, Toronto, ON M5G 1L7, Canada; Deparment of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
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45
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Al Reza H, Okabe R, Takebe T. Organoid transplant approaches for the liver. Transpl Int 2021; 34:2031-2045. [PMID: 34614263 PMCID: PMC8602742 DOI: 10.1111/tri.14128] [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: 06/10/2021] [Revised: 08/13/2021] [Accepted: 08/30/2021] [Indexed: 12/12/2022]
Abstract
Organoid technology is a state-of-the-art cell culture tool that has revolutionized study of development, regeneration, and diseases. Human liver organoids (HLOs) are now derived from either adult stem/progenitors or pluripotent stem cells (PSCs), emulating cellular diversity and structural symphony akin to the human liver. With the rapid rise in decompensated liver disease conditions only treated by liver transplant therapy, HLOs represent an alternate source for transplantation to address the ongoing shortage of grafts. Although ongoing advancements in bioengineering technology have moved the organoid transplant approach to the next level, sustained survival of the transplanted tissue still eludes us toward functional organ replacement. Herein, we review the development of HLOs and discuss promises and challenges on organoid transplant approaches.
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Affiliation(s)
- Hasan Al Reza
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA
- Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA
| | - Ryo Okabe
- Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takanori Takebe
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA
- Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA
- Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan
- Division of Gastroenterology, Hepatology & Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-3039, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Communication Design Center, Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Japan
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In Vitro Disease Models of the Endocrine Pancreas. Biomedicines 2021; 9:biomedicines9101415. [PMID: 34680532 PMCID: PMC8533367 DOI: 10.3390/biomedicines9101415] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/30/2021] [Accepted: 10/05/2021] [Indexed: 12/12/2022] Open
Abstract
The ethical constraints and shortcomings of animal models, combined with the demand to study disease pathogenesis under controlled conditions, are giving rise to a new field at the interface of tissue engineering and pathophysiology, which focuses on the development of in vitro models of disease. In vitro models are defined as synthetic experimental systems that contain living human cells and mimic tissue- and organ-level physiology in vitro by taking advantage of recent advances in tissue engineering and microfabrication. This review provides an overview of in vitro models and focuses specifically on in vitro disease models of the endocrine pancreas and diabetes. First, we briefly review the anatomy, physiology, and pathophysiology of the human pancreas, with an emphasis on islets of Langerhans and beta cell dysfunction. We then discuss different types of in vitro models and fundamental elements that should be considered when developing an in vitro disease model. Finally, we review the current state and breakthroughs in the field of pancreatic in vitro models and conclude with some challenges that need to be addressed in the future development of in vitro models.
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Dellaquila A, Le Bao C, Letourneur D, Simon‐Yarza T. In Vitro Strategies to Vascularize 3D Physiologically Relevant Models. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2100798. [PMID: 34351702 PMCID: PMC8498873 DOI: 10.1002/advs.202100798] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/23/2021] [Indexed: 05/04/2023]
Abstract
Vascularization of 3D models represents a major challenge of tissue engineering and a key prerequisite for their clinical and industrial application. The use of prevascularized models built from dedicated materials could solve some of the actual limitations, such as suboptimal integration of the bioconstructs within the host tissue, and would provide more in vivo-like perfusable tissue and organ-specific platforms. In the last decade, the fabrication of vascularized physiologically relevant 3D constructs has been attempted by numerous tissue engineering strategies, which are classified here in microfluidic technology, 3D coculture models, namely, spheroids and organoids, and biofabrication. In this review, the recent advancements in prevascularization techniques and the increasing use of natural and synthetic materials to build physiological organ-specific models are discussed. Current drawbacks of each technology, future perspectives, and translation of vascularized tissue constructs toward clinics, pharmaceutical field, and industry are also presented. By combining complementary strategies, these models are envisioned to be successfully used for regenerative medicine and drug development in a near future.
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Affiliation(s)
- Alessandra Dellaquila
- Université de ParisINSERM U1148X Bichat HospitalParisF‐75018France
- Elvesys Microfluidics Innovation CenterParis75011France
- Biomolecular PhotonicsDepartment of PhysicsUniversity of BielefeldBielefeld33615Germany
| | - Chau Le Bao
- Université de ParisINSERM U1148X Bichat HospitalParisF‐75018France
- Université Sorbonne Paris NordGalilée InstituteVilletaneuseF‐93430France
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Ghezelayagh Z, Zabihi M, Zarkesh I, Gonçalves CAC, Larsen M, Hagh-Parast N, Pakzad M, Vosough M, Arjmand B, Baharvand H, Larijani B, Grapin-Botton A, Aghayan HR, Tahamtani Y. Improved Differentiation of hESC-Derived Pancreatic Progenitors by Using Human Fetal Pancreatic Mesenchymal Cells in a Micro-scalable Three-Dimensional Co-culture System. Stem Cell Rev Rep 2021; 18:360-377. [PMID: 34586606 DOI: 10.1007/s12015-021-10266-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/16/2021] [Indexed: 01/12/2023]
Abstract
Mesenchymal cells of diverse origins differ in gene and protein expression besides producing varying effects on their organ-matched epithelial cells' maintenance and differentiation capacity. Co-culture with rodent's tissue-specific pancreatic mesenchyme accelerates proliferation, self-renewal, and differentiation of pancreatic epithelial progenitors. Therefore, in our study, the impact of three-dimensional (3D) co-culture of human fetal pancreatic-derived mesenchymal cells (hFP-MCs) with human embryonic stem cell-derived pancreatic progenitors (hESC-PPs) development towards endocrine and beta cells was assessed. Besides, the ability to maintain scalable cultures combining hFP-MCs and hESC-PPs was investigated. hFP-MCs expressed many markers in common with bone marrow-derived mesenchymal stem cells (BM-MSCs). However, they showed higher expression of DESMIN compared to BM-MSCs. After co-culture of hESC-PPs with hFP-MCs, the pancreatic progenitor (PP) spheroids generated in Matrigel had higher expression of NGN3 and INSULIN than BM-MSCs co-culture group, which shows an inductive impact of pancreatic mesenchyme on hESC-PPs beta-cells maturation. Pancreatic aggregates generated by forced aggregation through scalable AggreWell system showed similar features compared to the spheroids. These aggregates, a combination of hFP-MCs and hESC-PPs, can be applied as an appropriate tool for assessing endocrine-niche interactions and developmental processes by mimicking the pancreatic tissue.
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Affiliation(s)
- Zahra Ghezelayagh
- Department of Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mahsa Zabihi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Department of Genetics, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran
| | - Ibrahim Zarkesh
- Department of Cell Engineering, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Carla A C Gonçalves
- The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Michael Larsen
- The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Newsha Hagh-Parast
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mohammad Pakzad
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Babak Arjmand
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Baharvand
- Department of Developmental Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR, Tehran, Iran.,Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Bagher Larijani
- Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Anne Grapin-Botton
- The Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.,Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Hamid Reza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Yaser Tahamtani
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. .,Reproductive Epidemiology Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
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Cell-based therapies for vascular regeneration: Past, present and future. Pharmacol Ther 2021; 231:107976. [PMID: 34480961 DOI: 10.1016/j.pharmthera.2021.107976] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 06/01/2021] [Accepted: 08/05/2021] [Indexed: 12/27/2022]
Abstract
Tissue vascularization remains one of the outstanding challenges in regenerative medicine. Beyond its role in circulating oxygen and nutrients, the vasculature is critical for organ development, function and homeostasis. Importantly, effective vascular regeneration is key in generating large 3D tissues for regenerative medicine applications to enable the survival of cells post-transplantation, organ growth, and integration into the host system. Therefore, the absence of clinically applicable means of (re)generating vessels is one of the main obstacles in cell replacement therapy. In this review, we highlight cell-based vascularization strategies which demonstrate clinical potential, discuss their strengths and limitations and highlight the main obstacles hindering cell-based therapeutic vascularization.
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50
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Wörsdörfer P, Ergün S. The Impact of Oxygen Availability and Multilineage Communication on Organoid Maturation. Antioxid Redox Signal 2021; 35:217-233. [PMID: 33334234 DOI: 10.1089/ars.2020.8195] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Significance: An optimal supply with oxygen is of high importance during embryogenesis and a prerequisite for proper organ development. Different tissues require varying amounts of oxygen, and even within single organs, different phases of development go alongside with either physiological hypoxia or the need for sufficient oxygen supply. Recent Advances: Human induced pluripotent stem cell-derived organoid models are state of the art cell culture platforms for the investigation of developmental processes, disease modeling, and drug testing. Organoids modeling the development of multiple tissues were developed within the past years. Critical Issues: Until now, optimization of oxygen supply and its role during organoid growth, differentiation, and maturation have only rarely been addressed. Recent publications indicate that hypoxia-induced processes play an important role in three-dimensional tissue cultures, triggering multilineage communication between mesenchymal cells, the endothelium, as well as organotypic cells. Later in culture, a sufficient supply with oxygen is of high importance to allow larger organoid sizes. Moreover, cellular stress is reduced and tissue maturation is improved. Therefore, a functional blood vessel network is required. Future Directions: In this review, we will briefly summarize aspects of the role of oxygen during embryonic development and organogenesis, present an update on novel organoid models with a special focus on organoid vascularization, and discuss the importance of complex organoids involving parenchymal cells, mesenchymal cells, inflammatory cells, and functional blood vessels for the generation of mature and fully functional tissues in vitro. Antioxid. Redox Signal. 35, 217-233.
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Affiliation(s)
- Philipp Wörsdörfer
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Würzburg, Würzburg, Germany
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