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Yu JL, Yang C, Liu L, Lin A, Guo SJ, Tian WD. Optimal good manufacturing practice-compliant production of dental follicle stem cell sheet and its application in Sprague-Dawley rat periodontitis. World J Stem Cells 2025; 17:104116. [DOI: 10.4252/wjsc.v17.i5.104116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 02/27/2025] [Accepted: 04/18/2025] [Indexed: 05/26/2025] Open
Abstract
BACKGROUND Dental follicle stem cell (DFSC) sheets demonstrate strong extracellular secretion capabilities and efficacy in periodontal regeneration. However, existing methods for producing DFSC sheets lack a comprehensive discussion on the most efficient and cost-effective approaches at the good manufacturing practice (GMP) level.
AIM To investigate the culture condition of GMP-compliant DFSC sheets and to compare the properties of DFSC sheets and cell suspensions.
METHODS This study explored the optimal conditions for culturing GMP-compliant DFSC sheets, focusing on four key factors: Cell passage, cell concentration, L-ascorbic acid content, and culture duration. We evaluated the characteristics of the cell sheets under varying culture conditions, including cell viability, cell count, appearance, osteogenesis, chondrogenesis, odontogenesis, aging, relative telomere length, and extracellular matrix secretion. A comparison was also made between the periodontal regeneration, osteogenesis, and paracrine capacity of cell sheets cultured under optimal conditions and those of the cell suspensions.
RESULTS The GMP-compliant DFSC sheets cultured from passage 4 cells exhibited the highest viability (≥ 99%, P < 0.05) and optimal osteogenic differentiation capacity (optical density ≥ 0.126, P < 0.05). When cultured for 10 days, DFSC sheets demonstrated maximal expression of osteogenic, chondrogenic and periostin genes [alkaline phosphatase, Runt-related transcription factor 2, collagen type I, osteopontin, cartilage associated protein, and PERIOSTN (P < 0.001); osteocalcin (P < 0.01)]. Concurrently, they showed the lowest senescent cell count (P < 0.01) with no progression to late-stage senescence. At a seeding density of 2500 cells/cm2, GMP-compliant DFSC sheets achieved better osteogenic differentiation (P < 0.01) and maximal osteogenic, chondrogenic and periostin gene expression (P < 0.001), coupled with the highest hydroxyproline secretion (P < 0.001) and moderate sulfated glycosaminoglycan production. No statistically significant difference in senescent cell count was observed compared to DFSC sheets at a seeding density of 5000 cells/cm2. Supplementation with 25 μg/mL L-ascorbic acid significantly enhanced osteogenic gene expression (P < 0.001) and elevated hydroxyproline (P < 0.01) and sulfated glycosaminoglycan secretion to high ranges. Compared with the cell suspension, the cell sheet demonstrated improved osteogenic, paracrine, and periodontal regenerative capacities in Sprague-Dawley rats. The optimized DFSC sheets demonstrated significantly higher levels of vascular endothelial growth factor and angiopoietin-1 (P < 0.001) compared to DFSC suspensions, along with enhanced osteogenic induction outcomes (optical density = 0.1333 ± 0.01270 vs 0.1007 ± 0.0005774 in suspensions, P < 0.05). Following implantation into the rat periodontal defect model, micro-computed tomography analysis revealed superior bone regeneration metrics in the cell sheet group compared to both the cell suspension group and control group (percent bone volume, trabecular thickness, trabecular number), while trabecular spacing exhibited an inverse pattern.
CONCLUSION Optimized DFSC sheets cultured under the identified conditions outperform DFSC suspensions. This study contributes to the industrial-scale production of DFSC sheets and establishes a foundation for cell therapy applications.
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Affiliation(s)
- Jia-Lu Yu
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Chao Yang
- Department of Product Development, Chengdu Shiliankangjian Biotechnology Co., Ltd, Chengdu 610041, Sichuan Province, China
| | - Li Liu
- Engineering Research Center of Oral Translational Medicine, National Clinical Research Center for Oral Diseases, Departments of 5 Periodontics and 6 Oral and Maxillofacial Surgery, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - An Lin
- State Key Laboratory of Oral Diseases, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shu-Juan Guo
- Department of Periodontics, West China School of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wei-Dong Tian
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Engineering Research Center of Oral Translational Medicine, National Engineering Laboratory for Oral Regenerative Medicine, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan Province, China
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Pinheiro-Machado E, de Haan BJ, Engelse MA, Smink AM. Secretome Analysis of Human and Rat Pancreatic Islets Co-Cultured with Adipose-Derived Stromal Cells Reveals a Signature with Enhanced Regenerative Capacities. Cells 2025; 14:302. [PMID: 39996773 PMCID: PMC11854805 DOI: 10.3390/cells14040302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/06/2025] [Accepted: 02/14/2025] [Indexed: 02/26/2025] Open
Abstract
Pancreatic islet transplantation (PIT) is a promising treatment for type 1 diabetes (T1D) but faces challenges pre- and post-transplantation. Co-transplantation with mesenchymal stromal cells (MSCs), known for their regenerative properties, has shown potential in improving PIT outcomes. This study examined the secretome of islets cultured alone compared to the secretomes of islets co-cultured with adipose-derived stromal cells (ASCs), a subtype of MSCs, under transplantation-relevant stressors: normoxia, cytokines, high glucose, hypoxia, and combined hypoxia and high glucose. Islet co-culture with ASCs significantly altered the proteome, affecting pathways related to energy metabolism, angiogenesis, extracellular matrix organization, and immune modulation. Key signaling molecules (e.g., VEGF, PDGF, bFGF, Collagen I alpha 1, IL-1α, and IL-10) were differentially regulated depending on culture conditions and ASC presence. Functional assays demonstrated that the co-culture secretome could enhance angiogenesis, collagen deposition, and immune modulation, depending on the stress conditions. These findings highlight possible mechanisms through which ASCs may support islet survival and function, offering insights into overcoming PIT challenges. Moreover, this work contributes to identifying biomarkers of the post-transplantation microenvironment, advancing therapeutic strategies for T1D and regenerative medicine.
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Affiliation(s)
- Erika Pinheiro-Machado
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Bart J. de Haan
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
| | - Marten A. Engelse
- Leiden Transplant Center, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Alexandra M. Smink
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
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Endo Kumata Y, Inagaki A, Nakamura Y, Imura T, Saito R, Katano T, Suzuki S, Tokodai K, Kamei T, Unno M, Watanabe K, Tabata Y, Goto M. A novel method of pancreatic islet transplantation at the liver surface using a gelatin hydrogel nonwoven fabric. Cell Transplant 2025; 34:9636897251328419. [PMID: 40264358 PMCID: PMC12035123 DOI: 10.1177/09636897251328419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 02/12/2025] [Accepted: 02/19/2025] [Indexed: 04/24/2025] Open
Abstract
Considering the limitations of intraportal transplantation (Tx), we sought to establish an alternative approach for it-transplanting islets onto the liver surface (LS) by optimizing adipose tissue-derived stem cell (ADSC) co-Tx procedures with a gelatin hydrogel nonwoven fabric (GHNF). In the in vivo study, we examined the use of the GHNF, the effectiveness of islet covering materials, and preferred procedures for ADSC co-Tx using a syngeneic rat model. Immunohistochemical staining was performed to evaluate the extracellular matrix (ECM) expression and angiogenesis. In the in vitro study, we analyzed the culture supernatants to identify crucial factors secreted from ADSCs in different ADSC co-Tx procedures. It was shown that the GHNF should be used to cover the islets but not to embed internally (encapsulate) them. Utilization of the GHNF in LS Tx resulted in significantly better glucose changes (P = 0.0002) and cure rate of diabetic recipients (P = 0.0003) than the use of a common adhesion barrier. Although neovascularization was comparable among groups, ECM reconstitution tended to be higher when the GHNF was used. ADSC co-Tx further enhanced ECM reconstitution only when ADSCs were cultured in the GHNF before islet Tx. Leptin, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and several chemokines were identified as candidate factors for enhancing ECM reconstitution (P < 0.001). The inhibition assay using antagonist suggested that leptin might be at least in part responsible for the difference in transplant efficiency in distinct ADSC co-Tx methods. This study showed that the GHNF effectively improved the outcomes of LS islet Tx, mainly due to ECM reconstitution around the islets. Furthermore, we established a novel method of LS islet Tx by combining a GHNF with ADSCs, which is equally effective as intraportal Tx.
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Affiliation(s)
- Yukiko Endo Kumata
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akiko Inagaki
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiro Nakamura
- Division of Pathology, Graduate School of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Takehiro Imura
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ryusuke Saito
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takumi Katano
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shoki Suzuki
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuaki Tokodai
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kimiko Watanabe
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yasuhiko Tabata
- Plastic and Reconstructive Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masafumi Goto
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
- Division of Transplantation and Regenerative Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
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4
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Benchaprathanphorn K, Muangman P, Chinaroonchai K, Namviriyachote N, Ampawong S, Angkhasirisap W, Kengkoom K, Viravaidya-Pasuwat K. Translational application of human keratinocyte-fibroblast cell sheets for accelerated wound healing in a clinically relevant type 2 diabetic rat model. Cytotherapy 2024; 26:360-371. [PMID: 38363247 DOI: 10.1016/j.jcyt.2024.01.003] [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: 08/09/2023] [Revised: 12/27/2023] [Accepted: 01/20/2024] [Indexed: 02/17/2024]
Abstract
BACKGROUND AIMS Despite advancements in wound care, wound healing remains a challenge, especially in individuals with type 2 diabetes. Cell sheet technology has emerged as an efficient and promising therapy for tissue regeneration and wound repair. Among these, bilayered human keratinocyte-fibroblast cell sheets constructed using temperature-responsive culture surfaces have been shown to mimic a normal tissue-like structure and secrete essential cytokines and growth factors that regulate the wound healing process. METHODS This study aimed to evaluate the safety and therapeutic potential of human skin cell sheets to treat full-thickness skin defects in a rat model of type 2 diabetes. RESULTS Our findings demonstrate that diabetic wounds transplanted with bilayered cell sheets resulted in accelerated re-epithelialization, increased angiogenesis, enhanced macrophage polarization and regeneration of tissue that closely resembled healthy skin. In contrast, the control group that did not receive cell sheet transplantation presented characteristic symptoms of impaired and delayed wound healing associated with type 2 diabetes. CONCLUSIONS The secretory cytokines and the upregulation of Nrf2 expression in response to cell sheet transplantation are believed to have played a key role in the improved wound healing observed in diabetic rats. Our study suggests that human keratinocyte-fibroblast cell sheets hold great potential as a therapeutic alternative for diabetic ulcers.
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Affiliation(s)
- Kanokaon Benchaprathanphorn
- Biological Engineering Program, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand
| | - Pornprom Muangman
- Trauma Surgery Division, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Kusuma Chinaroonchai
- Trauma Surgery Division, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nantaporn Namviriyachote
- Trauma Surgery Division, Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Sumate Ampawong
- Department of Tropical Pathology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Wannee Angkhasirisap
- Research and Academic Support Office, National Laboratory Animal Center, Mahidol University, Nakorn Pathom, Thailand
| | - Kanchana Kengkoom
- Research and Academic Support Office, National Laboratory Animal Center, Mahidol University, Nakorn Pathom, Thailand
| | - Kwanchanok Viravaidya-Pasuwat
- Biological Engineering Program, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand; Chemical Engineering, Faculty of Engineering, King Mongkut's University of Technology Thonburi, Bangkok, Thailand.
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5
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Zhao J, Lu F, Dong Z. Strategies for Constructing Tissue-Engineered Fat for Soft Tissue Regeneration. Tissue Eng Regen Med 2024; 21:395-408. [PMID: 38032533 PMCID: PMC10987464 DOI: 10.1007/s13770-023-00607-z] [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: 05/28/2023] [Revised: 09/17/2023] [Accepted: 10/05/2023] [Indexed: 12/01/2023] Open
Abstract
BACKGROUND Repairing soft tissue defects caused by inflammation, tumors, and trauma remains a major challenge for surgeons. Adipose tissue engineering (ATE) provides a promising way to solve this problem. METHODS This review summarizes the current ATE strategies for soft tissue reconstruction, and introduces potential construction methods for ATE. RESULTS Scaffold-based and scaffold-free strategies are the two main approaches in ATE. Although several of these methods have been effective clinically, both scaffold-based and scaffold-free strategies have limitations. The third strategy is a synergistic tissue engineering strategy and combines the advantages of scaffold-based and scaffold-free strategies. CONCLUSION Personalized construction, stable survival of reconstructed tissues and functional recovery of organs are future goals of building tissue-engineered fat for ATE.
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Affiliation(s)
- Jing Zhao
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
- Department of Plastic Surgery and Burn Center, Second Affiliated Hospital, Plastic Surgery Institute of Shantou University Medical College, Shantou, 515063, Guangdong, China
| | - Feng Lu
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
| | - Ziqing Dong
- Department of Plastic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
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6
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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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7
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Abadpour S, Niemi EM, Orrhult LS, Hermanns C, de Vries R, Nogueira LP, Haugen HJ, Josefsen D, Krauss S, Gatenholm P, van Apeldoorn A, Scholz H. Adipose-Derived Stromal Cells Preserve Pancreatic Islet Function in a Transplantable 3D Bioprinted Scaffold. Adv Healthc Mater 2023; 12:e2300640. [PMID: 37781993 PMCID: PMC11469278 DOI: 10.1002/adhm.202300640] [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: 02/27/2023] [Revised: 09/07/2023] [Indexed: 10/03/2023]
Abstract
Intra-portal islet transplantation is currently the only clinically approved beta cell replacement therapy, but its outcome is hindered by limited cell survival due to a multifactorial reaction against the allogeneic tissue in liver. Adipose-derived stromal cells (ASCs) can potentially improve the islet micro-environment by their immunomodulatory action. The challenge is to combine both islets and ASCs in a relatively easy and consistent long-term manner in a deliverable scaffold. Manufacturing the 3D bioprinted double-layered scaffolds with primary islets and ASCs using a mix of alginate/nanofibrillated cellulose (NFC) bioink is reported. The diffusion properties of the bioink and the supportive effect of human ASCs on islet viability, glucose sensing, insulin secretion, and reducing the secretion of pro-inflammatory cytokines are demonstrated. Diabetic mice transplanted with islet-ASC scaffolds reach normoglycemia seven days post-transplantation with no significant difference between this group and the group received islets under the kidney capsules. In addition, animals transplanted with islet-ASC scaffolds stay normoglycemic and show elevated levels of C-peptide compared to mice transplanted with islet-only scaffolds. The data present a functional 3D bioprinted scaffold for islets and ASCs transplanted to the extrahepatic site and suggest a possible role of ASCs on improving the islet micro-environment.
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Affiliation(s)
- Shadab Abadpour
- Department of Transplant MedicineOslo University HospitalOslo0372Norway
- Institute for Surgical ResearchOslo University HospitalOslo0372Norway
- Hybrid Technology Hub – Centre of ExcellenceInstitute of Basic Medical SciencesUniversity of OsloOslo0372Norway
| | - Essi M. Niemi
- Institute for Surgical ResearchOslo University HospitalOslo0372Norway
- Hybrid Technology Hub – Centre of ExcellenceInstitute of Basic Medical SciencesUniversity of OsloOslo0372Norway
- Department of Vascular SurgeryAker HospitalOslo University HospitalOslo0586Norway
| | - Linnea Strid Orrhult
- 3D Bioprinting CenterWWSCDepartment of Chemistry and Chemical EngineeringChalmers University of TechnologyGothenburg41296Sweden
| | - Carolin Hermanns
- MERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityMaastricht6229The Netherlands
| | - Rick de Vries
- MERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityMaastricht6229The Netherlands
| | | | | | - Dag Josefsen
- Section for Cellular TherapyRadiumhospitaletOslo University HospitalOslo0379Norway
| | - Stefan Krauss
- Hybrid Technology Hub – Centre of ExcellenceInstitute of Basic Medical SciencesUniversity of OsloOslo0372Norway
- Department of Immunology and Transfusion MedicineOslo University HospitalOslo0372Norway
| | - Paul Gatenholm
- 3D Bioprinting CenterWWSCDepartment of Chemistry and Chemical EngineeringChalmers University of TechnologyGothenburg41296Sweden
- CELLHEAL ASSandvika1337Norway
| | - Aart van Apeldoorn
- MERLN Institute for Technology‐Inspired Regenerative MedicineMaastricht UniversityMaastricht6229The Netherlands
| | - Hanne Scholz
- Department of Transplant MedicineOslo University HospitalOslo0372Norway
- Institute for Surgical ResearchOslo University HospitalOslo0372Norway
- Hybrid Technology Hub – Centre of ExcellenceInstitute of Basic Medical SciencesUniversity of OsloOslo0372Norway
- Section for Cellular TherapyRadiumhospitaletOslo University HospitalOslo0379Norway
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Zhou X, Xu Z, You Y, Yang W, Feng B, Yang Y, Li F, Chen J, Gao H. Subcutaneous device-free islet transplantation. Front Immunol 2023; 14:1287182. [PMID: 37965322 PMCID: PMC10642112 DOI: 10.3389/fimmu.2023.1287182] [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: 09/01/2023] [Accepted: 10/04/2023] [Indexed: 11/16/2023] Open
Abstract
Diabetes mellitus is a chronic metabolic disease, characterized by high blood sugar levels; it affects more than 500 million individuals worldwide. Type 1 diabetes mellitus (T1DM) is results from insufficient insulin secretion by islets; its treatment requires lifelong use of insulin injections, which leads to a large economic burden on patients. Islet transplantation may be a promising effective treatment for T1DM. Clinically, this process currently involves directly infusing islet cells into the hepatic portal vein; however, transplantation at this site often elicits immediate blood-mediated inflammatory and acute immune responses. Subcutaneous islet transplantation is an attractive alternative to islet transplantation because it is simpler, demonstrates lower surgical complication risks, and enables graft monitoring and removal. In this article, we review the current methods of subcutaneous device-free islet transplantation. Recent subcutaneous islet transplantation techniques with high success rate have involved the use of bioengineering technology and biomaterial cotransplantation-including cell and cell growth factor co-transplantation and hydrogel- or simulated extracellular matrix-wrapped subcutaneous co-transplantation. In general, current subcutaneous device-free islet transplantation modalities can simplify the surgical process and improve the posttransplantation graft survival rate, thus aiding effective T1DM management.
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Affiliation(s)
| | - Zhiran Xu
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Yanqiu You
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Wangrong Yang
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - BingZheng Feng
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Yuwei Yang
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Fujun Li
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Jibing Chen
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
| | - Hongjun Gao
- Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine, Nanning, China
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9
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Pham CHL, Zuo Y, Chen Y, Tran NM, Nguyen DT, Dang TT. Waffle-inspired hydrogel-based macrodevice for spatially controlled distribution of encapsulated therapeutic microtissues and pro-angiogenic endothelial cells. Bioeng Transl Med 2023; 8:e10495. [PMID: 37206238 PMCID: PMC10189477 DOI: 10.1002/btm2.10495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 12/26/2022] [Accepted: 01/13/2023] [Indexed: 03/17/2023] Open
Abstract
Macro-encapsulation systems for delivery of cellular therapeutics in diabetes treatment offer major advantages such as device retrievability and high cell packing density. However, microtissue aggregation and absence of vasculature have been implicated in the inadequate transfer of nutrients and oxygen to the transplanted cellular grafts. Herein, we develop a hydrogel-based macrodevice to encapsulate therapeutic microtissues positioned in homogeneous spatial distribution to mitigate their aggregation while concurrently supporting an organized intra-device network of vascular-inductive cells. Termed Waffle-inspired Interlocking Macro-encapsulation (WIM) device, this platform comprises two modules with complementary topography features that fit together in a lock-and-key configuration. The waffle-inspired grid-like micropattern of the "lock" component effectively entraps insulin-secreting microtissues in controlled locations while the interlocking design places them in a co-planar spatial arrangement with close proximity to vascular-inductive cells. The WIM device co-laden with INS-1E microtissues and human umbilical vascular endothelial cells (HUVECs) maintains desirable cellular viability in vitro with the encapsulated microtissues retaining their glucose-responsive insulin secretion while embedded HUVECs express pro-angiogenic markers. Furthermore, a subcutaneously implanted alginate-coated WIM device encapsulating primary rat islets achieves blood glucose control for 2 weeks in chemically induced diabetic mice. Overall, this macrodevice design lays foundation for a cell delivery platform, which has the potential to facilitate nutrients and oxygen transport to therapeutic grafts and thereby might lead to improved disease management outcome.
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Affiliation(s)
- Chi H. L. Pham
- School of Chemical and Biomedical EngineeringNanyang Technological University (NTU)SingaporeSingapore
| | - Yicong Zuo
- School of Chemical and Biomedical EngineeringNanyang Technological University (NTU)SingaporeSingapore
| | - Yang Chen
- School of Chemical and Biomedical EngineeringNanyang Technological University (NTU)SingaporeSingapore
| | - Nam M. Tran
- School of Chemical and Biomedical EngineeringNanyang Technological University (NTU)SingaporeSingapore
| | - Dang T. Nguyen
- School of Chemical and Biomedical EngineeringNanyang Technological University (NTU)SingaporeSingapore
| | - Tram T. Dang
- School of Chemical and Biomedical EngineeringNanyang Technological University (NTU)SingaporeSingapore
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10
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Hu D, Li X, Li J, Tong P, Li Z, Lin G, Sun Y, Wang J. The preclinical and clinical progress of cell sheet engineering in regenerative medicine. Stem Cell Res Ther 2023; 14:112. [PMID: 37106373 PMCID: PMC10136407 DOI: 10.1186/s13287-023-03340-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Cell therapy is an accessible method for curing damaged organs or tissues. Yet, this approach is limited by the delivery efficiency of cell suspension injection. Over recent years, biological scaffolds have emerged as carriers of delivering therapeutic cells to the target sites. Although they can be regarded as revolutionary research output and promote the development of tissue engineering, the defect of biological scaffolds in repairing cell-dense tissues is apparent. Cell sheet engineering (CSE) is a novel technique that supports enzyme-free cell detachment in the shape of a sheet-like structure. Compared with the traditional method of enzymatic digestion, products harvested by this technique retain extracellular matrix (ECM) secreted by cells as well as cell-matrix and intercellular junctions established during in vitro culture. Herein, we discussed the current status and recent progress of CSE in basic research and clinical application by reviewing relevant articles that have been published, hoping to provide a reference for the development of CSE in the field of stem cells and regenerative medicine.
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Affiliation(s)
- Danping Hu
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
- HANGZHOU CHEXMED TECHNOLOGY CO., LTD, Hangzhou, 310000, China
| | - Xinyu Li
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
| | - Jie Li
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
| | - Pei Tong
- Hospital of Hunan Guangxiu, Medical College of Hunan Normal University, Hunan Normal University, Changsha, 410008, China
| | - Zhe Li
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
| | - Ge Lin
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China
- National Engineering and Research Center of Human Stem Cells, Changsha, 410008, China
- Key Laboratory of Stem Cells and Reproductive Engineering, Ministry of Health, Changsha, 410008, China
| | - Yi Sun
- Institute of Reproductive and Stem Cell Engineering, School of Basic Medical Science, Central South University, Changsha, 410008, China.
- National Engineering and Research Center of Human Stem Cells, Changsha, 410008, China.
- Key Laboratory of Stem Cells and Reproductive Engineering, Ministry of Health, Changsha, 410008, China.
| | - Juan Wang
- Shanghai Biomass Pharmaceutical Product Evaluation Professional Public Service Platform, Center for Pharmacological Evaluation and Research, China State Institute of Pharmaceutical Industry, Shanghai, 200437, China.
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11
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Thummarati P, Laiwattanapaisal W, Nitta R, Fukuda M, Hassametto A, Kino-oka M. Recent Advances in Cell Sheet Engineering: From Fabrication to Clinical Translation. Bioengineering (Basel) 2023; 10:211. [PMID: 36829705 PMCID: PMC9952256 DOI: 10.3390/bioengineering10020211] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 01/26/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Cell sheet engineering, a scaffold-free tissue fabrication technique, has proven to be an important breakthrough technology in regenerative medicine. Over the past two decades, the field has developed rapidly in terms of investigating fabrication techniques and multipurpose applications in regenerative medicine and biological research. This review highlights the most important achievements in cell sheet engineering to date. We first discuss cell sheet harvesting systems, which have been introduced in temperature-responsive surfaces and other systems to overcome the limitations of conventional cell harvesting methods. In addition, we describe several techniques of cell sheet transfer for preclinical (in vitro and in vivo) and clinical trials. This review also covers cell sheet cryopreservation, which allows short- and long-term storage of cells. Subsequently, we discuss the cell sheet properties of angiogenic cytokines and vasculogenesis. Finally, we discuss updates to various applications, from biological research to clinical translation. We believe that the present review, which shows and compares fundamental technologies and recent advances in cell engineering, can potentially be helpful for new and experienced researchers to promote the further development of tissue engineering in different applications.
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Affiliation(s)
- Parichut Thummarati
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan
- Biosensors and Bioanalytical Technology for Cells and Innovative Testing Device Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Wanida Laiwattanapaisal
- Biosensors and Bioanalytical Technology for Cells and Innovative Testing Device Research Unit, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Rikiya Nitta
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan
| | - Megumi Fukuda
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan
| | - Artchaya Hassametto
- Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Masahiro Kino-oka
- Department of Biotechnology, Graduate School of Engineering, Osaka University, Osaka 565-0871, Japan
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12
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Homma J, Sekine H, Shimizu T. Tricultured Cell Sheets Develop into Functional Pancreatic Islet Tissue with a Vascular Network. Tissue Eng Part A 2023; 29:211-224. [PMID: 36565034 DOI: 10.1089/ten.tea.2022.0167] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Methods to induce islet β-cells from induced pluripotent stem cells or embryonic stem cells have been established. However, islet β-cells are susceptible to apoptosis under hypoxic conditions, so the technique used to transplant β-cells must maintain the viability of cells in vivo. This study describes the development of a tricultured cell sheet, which was made by coculturing islet β-cells, vascular endothelial cells, and mesenchymal stem cells for 1 day. The islet β-cells in the tricultured cell sheet self-organized into islet-like structures surrounded by a dense vascular network in vitro. Triple-layered tricultured cell sheets engrafted well after transplantation in vivo and developed into insulin-secreting tissue with abundant blood vessels and a high density of islet β-cells. We anticipate that the tricultured cell sheet could be used as an in vitro pseudo-islet model for pharmaceutical testing and may have potential for development into transplantable grafts for use in regenerative medicine.
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Affiliation(s)
- Jun Homma
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
| | - Hidekazu Sekine
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
| | - Tatsuya Shimizu
- Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan
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13
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Abstract
BACKGROUND The lack of a suitable transplantation site has become a bottleneck restricting the development of islet transplantation. METHODS In this study, for the first time, a prevascularized sinus tract (PST) for islet transplantation was constructed in a mouse model by temporarily embedding a 4× silk thread between the liver surface and the attached decellularized human amniotic membrane. After which, the characteristics of the PST and the function of the islet graft within the PST were evaluated. RESULTS The results showed that PST was lined with granulation tissue, the blood vessel density of the local tissue increased, and proangiogenic proteins were upregulated, which mimics the microenvironment of the islets in the pancreas to a certain extent. Transplantation of ~200 syngeneic islets into the PST routinely reversed the hyperglycemia of the recipient mice and maintained euglycemia for >100 d until the islet grafts were retrieved. The islet grafts within the PST achieved better results to those in the nonprevascularized control groups and comparable results to those under the kidney capsule with respect to glycemic control and glucose tolerance. CONCLUSIONS By attaching a decellularized human amniotic membrane to the surface of mouse liver and temporarily embedding a 4× silk thread, the PST formed on the liver surface has a favorable local microenvironment and is a potential clinical islet transplantation site.
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14
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Nagahara AI, Homma J, Ryu B, Sekine H, Higashi Y, Shimizu T, Kawamata T. Networked lymphatic endothelial cells in a transplanted cell sheet contribute to form functional lymphatic vessels. Sci Rep 2022; 12:21698. [PMID: 36522421 PMCID: PMC9755306 DOI: 10.1038/s41598-022-26041-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
This study evaluated whether cell sheets containing a network of lymphatic endothelial cells (LECs) promoted lymphangiogenesis after transplantation in vivo. Cell sheets with a LEC network were constructed by co-culturing LECs and adipose-derived stem cells (ASCs) on temperature-responsive culture dishes. A cell ratio of 3:2 (vs. 1:4) generated networks with more branches and longer branch lengths. LEC-derived lymphatic vessels were observed 2 weeks after transplantation of a three-layered cell sheet construct onto rat gluteal muscle. Lymphatic vessel number, diameter and depth were greatest for a construct comprising two ASC sheets stacked on a LEC/ASC (3:2 ratio) sheet. Transplantation of this construct in a rat model of femoral lymphangiectomy led to the formation of functional lymphatic vessels containing both transplanted and host LECs. Further development of this technique may lead to a new method of promoting lymphangiogenesis.
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Affiliation(s)
- Ayumi Inoue Nagahara
- grid.410818.40000 0001 0720 6587Department of Neurosurgery, Graduate School of Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666 Japan
| | - Jun Homma
- grid.410818.40000 0001 0720 6587Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666 Japan
| | - Bikei Ryu
- grid.488555.10000 0004 1771 2637Department of Neurosurgery, Tokyo Women’s Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666 Japan
| | - Hidekazu Sekine
- grid.410818.40000 0001 0720 6587Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666 Japan
| | - Yuhei Higashi
- grid.410818.40000 0001 0720 6587Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666 Japan ,Tokaihit Co., Ltd., Shizuoka, Japan
| | - Tatsuya Shimizu
- grid.410818.40000 0001 0720 6587Institute of Advanced Biomedical Engineering and Science, TWIns, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666 Japan
| | - Takakazu Kawamata
- grid.488555.10000 0004 1771 2637Department of Neurosurgery, Tokyo Women’s Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666 Japan
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15
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Duman BO, Sariboyaci AE, Karaoz E. Bio-engineering of 3-D cell sheets for diabetic rats: Interaction between mesenchymal stem cells and beta cells in functional islet regeneration system. Tissue Cell 2022; 79:101919. [DOI: 10.1016/j.tice.2022.101919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 07/22/2022] [Accepted: 09/03/2022] [Indexed: 11/15/2022]
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16
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The Potential of Cell Sheet Technology for Beta Cell Replacement Therapy. CURRENT TRANSPLANTATION REPORTS 2022. [DOI: 10.1007/s40472-022-00371-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
Abstract
Purpose of Review
Here, we review the use of cell sheet technology using different cell types and its potential for restoring the extracellular matrix microenvironment, perfusion, and immunomodulatory action on islets and beta cells.
Recent Findings
Cell sheets can be produced with different fabrication techniques ranging from the widely used temperature responsive system to the magnetic system. A variety of cells have been used to produce cell sheets including skin fibroblasts, smooth muscle cells, human umbilical vein endothelial cells, and mesenchymal stem cells.
Summary
CST would allow to recreate the ECM of islets which would provide cues to support islet survival and improvement of islet function. Depending on the used cell type, different additional supporting properties like immunoprotection or cues for better revascularization could be provided. Furthermore, CST offers the possibility to use other implantation sites than inside the liver. Further research should focus on cell sheet thickness and size to generate a potential translational therapy.
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17
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A Prevascularized Sinus Tract on the Liver Surface for Islet Transplantation. Transplantation 2022. [DOI: 10.1097/10.1097/tp.0000000000004236] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Fathi I, Imura T, Inagaki A, Nakamura Y, Nabawi A, Goto M. Decellularized Whole-Organ Pre-vascularization: A Novel Approach for Organogenesis. Front Bioeng Biotechnol 2021; 9:756755. [PMID: 34746108 PMCID: PMC8567193 DOI: 10.3389/fbioe.2021.756755] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/04/2021] [Indexed: 01/15/2023] Open
Abstract
Introduction: Whole-organ decellularization is an attractive approach for three-dimensional (3D) organ engineering. However, progress with this approach is hindered by intra-vascular blood coagulation that occurs after in vivo implantation of the re-cellularized scaffold, resulting in a short-term graft survival. In this study, we explored an alternative approach for 3D organ engineering through an axial pre-vascularization approach and examined its suitability for pancreatic islet transplantation. Methods: Whole livers from male Lewis rats were decellularized through sequential arterial perfusion of detergents. The decellularized liver scaffold was implanted into Lewis rats, and an arteriovenous bundle was passed through the scaffold. At the time of implantation, fresh bone marrow preparation (BM; n = 3), adipose-derived stem cells (ADSCs; n = 4), or HBSS (n = 4) was injected into the scaffold through the portal vein. After 5 weeks, around 2,600 islet equivalents (IEQs) were injected through the portal vein of the scaffold. The recipient rats were rendered diabetic by the injection of 65 mg/kg STZ intravenously 1 week before islet transplantation and were followed up after transplantation by measuring the blood glucose and body weight for 30 days. Intravenous glucose tolerance test was performed in the cured animals, and samples were collected for immunohistochemical (IHC) analyses. Micro-computed tomography (CT) images were obtained from one rat in each group for representation. Results: Two rats in the BM group and one in the ADSC group showed normalization of blood glucose levels, while one rat from each group showed partial correction of blood glucose levels. In contrast, no rats were cured in the HBSS group. Micro-CT showed evidence of sprouting from the arteriovenous bundle inside the scaffold. IHC analyses showed insulin-positive cells in all three groups. The number of von-Willebrand factor-positive cells in the islet region was higher in the BM and ADSC groups than in the HBSS group. The number of 5-bromo-2'-deoxyuridine-positive cells was significantly lower in the BM group than in the other two groups. Conclusions: Despite the limited numbers, the study showed the promising potential of the pre-vascularized whole-organ scaffold as a novel approach for islet transplantation. Both BM- and ADSCs-seeded scaffolds were superior to the acellular scaffold.
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Affiliation(s)
- Ibrahim Fathi
- Division of Transplantation and Regenerative Medicine, Tohoku University, Sendai, Japan
- Department of Surgery, University of Alexandria, Alexandria, Egypt
| | - Takehiro Imura
- Division of Transplantation and Regenerative Medicine, Tohoku University, Sendai, Japan
| | - Akiko Inagaki
- Division of Transplantation and Regenerative Medicine, Tohoku University, Sendai, Japan
| | - Yasuhiro Nakamura
- Division of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Ayman Nabawi
- Department of Surgery, University of Alexandria, Alexandria, Egypt
| | - Masafumi Goto
- Division of Transplantation and Regenerative Medicine, Tohoku University, Sendai, Japan
- Department of Surgery, Tohoku University, Sendai, Japan
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Nagaya M, Hasegawa K, Uchikura A, Nakano K, Watanabe M, Umeyama K, Matsunari H, Osafune K, Kobayashi E, Nakauchi H, Nagashima H. Feasibility of large experimental animal models in testing novel therapeutic strategies for diabetes. World J Diabetes 2021; 12:306-330. [PMID: 33889282 PMCID: PMC8040081 DOI: 10.4239/wjd.v12.i4.306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 01/30/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
Diabetes is among the top 10 causes of death in adults and caused approximately four million deaths worldwide in 2017. The incidence and prevalence of diabetes is predicted to increase. To alleviate this potentially severe situation, safer and more effective therapeutics are urgently required. Mice have long been the mainstay as preclinical models for basic research on diabetes, although they are not ideally suited for translating basic knowledge into clinical applications. To validate and optimize novel therapeutics for safe application in humans, an appropriate large animal model is needed. Large animals, especially pigs, are well suited for biomedical research and share many similarities with humans, including body size, anatomical features, physiology, and pathophysiology. Moreover, pigs already play an important role in translational studies, including clinical trials for xenotransplantation. Progress in genetic engineering over the past few decades has facilitated the development of transgenic animals, including porcine models of diabetes. This article discusses features that attest to the attractiveness of genetically modified porcine models of diabetes for testing novel treatment strategies using recent technical advances.
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Affiliation(s)
- Masaki Nagaya
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Department of Immunology, St. Marianna University School of Medicine, Kawasaki 261-8511, Kanagawa, Japan
| | - Koki Hasegawa
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Ayuko Uchikura
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Kazuaki Nakano
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Masahito Watanabe
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Kazuhiro Umeyama
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Research and Development, PorMedTec Co. Ltd, Kawasaki 214-0034, Kanagawa, Japan
| | - Hitomi Matsunari
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
| | - Kenji Osafune
- Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Kyoto, Japan
| | - Eiji Kobayashi
- Department of Organ Fabrication, Keio University School of Medicine, Shinjuku 160-8582, Tokyo, Japan
| | - Hiromitsu Nakauchi
- Institute for Stem Cell Biology and Regenerative Medicine, Department of Genetics, Stanford University School of Medicine, Stanford University, Stanford, CA 94305, United States
- Division of Stem Cell Therapy, Institute of Medical Science, The University of Tokyo, Minato 108-8639, Tokyo, Japan
| | - Hiroshi Nagashima
- Meiji University International Institute for Bio-Resource Research, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
- Laboratory of Medical Bioengineering, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Kanagawa, Japan
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