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Zhao Y, Ye C, Wang H, Chen C, Lu Y, Yang C, Xu T, Zhou Y, Wu Z, Song X, Zhu Z, Yang Z, Chen X. Loading tea polyphenols enhances the repair of human umbilical cord mesenchymal stem cell sheet after spinal cord injury. Stem Cell Res Ther 2025; 16:264. [PMID: 40437527 PMCID: PMC12121034 DOI: 10.1186/s13287-025-04376-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 05/02/2025] [Indexed: 06/01/2025] Open
Abstract
BACKGROUND Spinal cord injury (SCI) is a devastating central nervous system disorder that remains a global health challenge. SCI-induced oxidative stress in the postinjury microenvironment limits tissue repair by provoking the excessive production of reactive oxygen species (ROS). Tea polyphenols (TP), as a natural plant polyphenol, could effectively reduce ROS. In recent years, stem cell-based therapy combined with cell sheet technology has been widely used in the treatment of SCI. Therefore, we constructed human umbilical cord mesenchymal stem cell sheet loaded with TP (CS-TP) and evaluated their therapeutic effects and mechanisms both in vitro and in vivo in SCI rats. METHODS Human umbilical cord mesenchymal stem cell sheet (CS) were prepared by temperature-responsive cell culture method and successfully loaded with TP. The protective effect of CS and CS-TP on cells against oxidative stress was tested by Live/Dead cell staining and CCK-8 assay. CS and CS-TP were co-cultured with PC12 cells and human umbilical vein endothelial cells (HUVECs), respectively, and their effects on reducing ROS production were evaluated using flow cytometry and ROS fluorescence assays. Immune fluorescence (IF) and Western blot analysis of the mechanism by which CS-TP affects PC12 cells and HUVECs in vitro. Wound healing assay, transwell Chamber invasion experiment and tube formation assay were performed to evaluate the effects of CS and CS-TP on the biological behaviors of HUVECs. (Basso-Beattie-Bresnahan) BBB scores and gait analysis were performed to assess the recovery of motor function in rats. Molecular modeling is used to study the affinity between the main active ingredient epigallocatechin gallate (EGCG) in TP and target proteins. Western blot analyzes the mechanism of action of CS and CS-TP in SCI animals and the expression levels of antioxidant proteins. Tissue IF staining was used to evaluate angiogenesis, neuron regeneration and axonal extension. RESULTS Compared with CS, CS-TP could effectively reduce cellular ROS production and increase cell viability under high oxidative stress conditions and significantly enhance its biological activity. In vitro, CS-TP can significantly activate the Keap-1/Nrf2/HO-1 pathway, thereby affecting PC12 cells and HUVECs. After transplantation in SCI rats, CS-TP also activates the Keap-1/Nrf2/HO-1 pathway, influencing the repair of SCI and upregulating the expression of SOD1 and SOD2. CS-TP can more effectively promote angiogenesis, neuronal regeneration, and axonal extension in injured spinal cords, greatly improving the motor function of the rats. CONCLUSION CS-TP not only significantly enhances the resistance of CS to ROS, activates the Keap-1/Nrf2/HO-1 pathway, and regulates the level of antioxidant proteins in the body. Compared to CS, it can also more effectively increase the number of new blood vessels, promote neuron regeneration and axon extension, thereby more effectively repairing SCI.
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Affiliation(s)
- Yulin Zhao
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Cong Ye
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Heng Wang
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Cheng Chen
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Yang Lu
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Changwei Yang
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Tao Xu
- Medical School of Nantong University, Nantong, China
| | - Yuchen Zhou
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Zhengchao Wu
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Xianrui Song
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Zhenyang Zhu
- Medical School of Nantong University, Nantong, China
| | - Zongze Yang
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China
- Medical School of Nantong University, Nantong, China
| | - Xiaoqing Chen
- Department of Spine Surgery, Affiliated Hospital of Nantong University, Nantong, China.
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Kaur SD, Choudhary S, Sen S, Pemmaraju DB, Singh SK, Kapoor DN. Microneedle patches: the next frontier in cardiovascular care. Drug Deliv Transl Res 2025:10.1007/s13346-025-01802-2. [PMID: 39881106 DOI: 10.1007/s13346-025-01802-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2025] [Indexed: 01/31/2025]
Abstract
Myocardial infarction is a condition where the heart muscle is damaged due to clogged coronary arteries. There are limited treatment options for treating myocardial infarction. Microneedle patches have recently become popular as a possibly viable therapy for myocardial. By adhering to the surface of the heart, these microneedle patches provide mechanical support, regenerative medicines, or cells directly to the injured tissue allowing for targeted treatment. These microneedle patches resolve the drawbacks of systemic therapy by facilitating targeted administration and integration with the goal of restoring damaged heart function. Recent advances in fabrication methods and current perspectives on the therapeutic advantages of cardiac microneedles patches used in the treatment of myocardial infarction are summarized in this review. Although the data is less in this area this review provides an avenue for the formulation scientist working in biomedical science to develop such microneedle patches for clinical applications in cardiology.
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Affiliation(s)
- Simran Deep Kaur
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, 173229, India
| | - Shivanshu Choudhary
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, 173229, India
| | - Santimoy Sen
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Guwahati, Assam, 781101, India
| | - Deepak B Pemmaraju
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Guwahati, Assam, 781101, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi Gt Road, Phagwara, Punjab, 144411, India
| | - Deepak N Kapoor
- School of Pharmaceutical Sciences, Shoolini University of Biotechnology and Management Sciences, Solan, 173229, India.
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Li YL, Chen EG, Ren BB. Umbilical cord-derived mesenchymal stromal cells: Promising therapy for heart failure. World J Cardiol 2025; 17:101153. [PMID: 39866217 PMCID: PMC11755126 DOI: 10.4330/wjc.v17.i1.101153] [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: 09/05/2024] [Revised: 11/06/2024] [Accepted: 12/02/2024] [Indexed: 01/21/2025] Open
Abstract
Heart failure (HF) is a complex syndrome characterized by the reduced capacity of the heart to adequately fill or eject blood. Currently, HF remains a leading cause of morbidity and mortality worldwide, imposing a substantial burden on global healthcare systems. Recent advancements have highlighted the therapeutic potential of mesenchymal stromal cells (MSCs) in managing HF. Notably, umbilical cord-derived MSCs (UC-MSCs) have demonstrated superior clinical potential compared to traditional bone marrow-derived MSCs; this is evident in their non-invasive collection process, higher proliferation efficacy, and lower immunogenicity and tumorigenicity, as substantiated by preclinical studies. Although the feasibility and safety of UC-MSCs have been tested in animal models, the application of UC-MSCs in HF treatment remains challenged by issues such as inaccurate targeted migration and low survival rates of UC-MSCs. Therefore, further research and clinical trials are imperative to advance the clinical application of UC-MSCs.
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Affiliation(s)
- Ya-Lun Li
- Department of Pulmonary and Critical Care Medicine, Regional Medical Center for National Institute of Respiratory Disease, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
- Medical College, Zhejiang University, Hangzhou 310063, Zhejiang Province, China
| | - En-Guo Chen
- Department of Pulmonary and Critical Care Medicine, Regional Medical Center for National Institute of Respiratory Disease, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China
| | - Bing-Bing Ren
- Department of Pulmonary and Critical Care Medicine, Regional Medical Center for National Institute of Respiratory Disease, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310016, Zhejiang Province, China.
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Ma Z, Li M, Guo R, Tian Y, Zheng Y, Huang B, You Y, Xu Q, Cui M, Shen L, Lan F, Yang H, Liu R, Yang T, Wan F, He Q, Huo X, Bi Y, Zhang Y, Ling Y. Treating myocardial infarction via a nano-ultrasonic contrast agent-mediated high-efficiency drug delivery system targeting macrophages. SCIENCE ADVANCES 2025; 11:eadp7126. [PMID: 39752485 PMCID: PMC11698097 DOI: 10.1126/sciadv.adp7126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 11/06/2024] [Indexed: 01/06/2025]
Abstract
Following myocardial infarction (MI), the accumulation of CD86-positive macrophages in the ischemic injury zone leads to secondary myocardial damage. Precise pharmacological intervention targeting this process remains challenging. This study engineered a nanotherapeutic delivery system with CD86-positive macrophage-specific targeting and ultrasound-responsive release capabilities. A folic acid (FA)-modified ultrasound-responsive gene/drug delivery system, assembled from DOTAP, DSPE-PEG2000-FA, cholesterol, and perfluorohexane (PFH)-termed FA-PNBs-was developed to codeliver small interfering RNA of STAT1 (siSTAT1) and the small-molecule nitro-oleic acid (OA-NO2) into CD86-positive macrophages. Upon irradiation with low-intensity focused ultrasound, FA-PNBs release siSTAT1 and OA-NO2 at the ischemic injury zone. The results demonstrated the system's precise targeting and efficient delivery capabilities. The combined modulation of OA-NO2 and siSTAT1 optimizes the immune microenvironment in the infarcted region, alleviates ventricular remodeling, preserves cardiac function, and holds promise for clinical intervention strategies after MI.
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Affiliation(s)
- Zhen Ma
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Joint International Research Center of Translational and Clinical Research, Beijing 100142, China
- State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery System, and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Ming Li
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Ultrasound Medical Center, Lanzhou University Second Hospital, Gansu Province Clinical Research Center for Ultrasonography, Gansu Province Medical Engineering Research Center for Intelligence Ultrasound, Lanzhou 730000, China
| | - Rui Guo
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Joint International Research Center of Translational and Clinical Research, Beijing 100142, China
- State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery System, and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Yu Tian
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Yongbin Zheng
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Bingxin Huang
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Joint International Research Center of Translational and Clinical Research, Beijing 100142, China
- State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery System, and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Yi You
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Qing Xu
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Ming Cui
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Department of Cardiology, Peking University Third Hospital, Beijing 100191, China
| | - Li Shen
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China
| | - Feng Lan
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Hang Yang
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
| | - Rucong Liu
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Department of Biomedical Informatics, State Key Laboratory of Vascular Homeostasis and Remodeling, School of Basic Medical Sciences, Peking University, Beijing 100191, China
| | - Tao Yang
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Institute for Carbon Neutrality, Beijing Advanced Innovation Center for Materials Genome Engineering, University of Science and Technology Beijing, Beijing 100083, China
| | - Feng Wan
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Department of Cardiac and Vascular Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China
| | - Qihua He
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery System, and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
| | - Xiao Huo
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Youkun Bi
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Institute of Biophysics Chinese Academy of Sciences, Beijing 100101, China
| | - Yingying Zhang
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- School of Medical Imaging, Xuzhou Medical University, Xuzhou 221006, China
| | - Yunpeng Ling
- Department of Cardiac Surgery, Peking University Third Hospital, Beijing 100191, China
- Joint International Research Center of Translational and Clinical Research, Beijing 100142, China
- State Key Laboratory of Natural and Biomimetic Drugs, Beijing Key Laboratory of Molecular Pharmaceutics and Drug Delivery System, and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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Rampin A, Caravaggi CMF, Troisi L, Spinetti G. Macromolecular Crowding Supports the Generation of Basal Membrane-Rich Pericyte-Based Cell Sheets Useful for Cell Therapy of Diabetic Wounds. Cell Transplant 2025; 34:9636897241309698. [PMID: 40071575 PMCID: PMC11898230 DOI: 10.1177/09636897241309698] [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: 08/22/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 03/15/2025] Open
Abstract
Diabetic foot ulcers (DFUs) are associated with a high risk of amputations and a 50% 5-year survival rate due at least in part to the limited angiogenic and wound healing capacity of patients with diabetes. Cell therapy via intramuscular injection of peripheral blood mononuclear cells showed encouraging but limited results. Such limitations may arise from the limited ability of therapeutic cells to adhere to the target tissue. The development of a methodology able to support the targeted delivery of viable angiogenic cells would improve cell therapy outcomes in DFU. Here, we optimized a protocol for the production of autologous extracellular matrix (ECM)-rich pericyte-based cell sheets for cell delivery. Pericytes were isolated from skeletal muscle biopsies of DFU patients and non-diabetic controls and characterized by flow cytometry and immunofluorescence. Human umbilical vein endothelial cells used for the optimization of collagen IV deposition showed a positive correlation with seeding density and a negative one with sub-culture passaging (P < 0.05). Macromolecular crowding significantly increased collagen IV deposition both in human umbilical vein endothelial cells and in patient-derived pericytes (P < 0.01) without affecting proliferation (P > 0.05). Finally, DFU patient-derived pericytes effectively deposited ECM supporting their use for autologous cell sheet production.
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Affiliation(s)
- Andrea Rampin
- Cardiovascular Research Unit, IRCCS MultiMedica, Milan, Italy
| | | | - Luigi Troisi
- Reconstructive Microsurgery Service – Department of Hand Surgery & Rehabilitation-IRCCS MultiMedica, Milan, Italy
| | - Gaia Spinetti
- Cardiovascular Research Unit, IRCCS MultiMedica, Milan, Italy
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Zhao Y, Wu Z, Zhou Y, Chen C, Lu Y, Wang H, Xu T, Yang C, Chen X. Cell Sheets Formation Enhances Therapeutic Effects of Human Umbilical Cord Mesenchymal Stem Cells on Spinal Cord Injury. CNS Neurosci Ther 2024; 30:e70163. [PMID: 39670537 PMCID: PMC11638885 DOI: 10.1111/cns.70163] [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: 07/20/2024] [Revised: 10/04/2024] [Accepted: 11/15/2024] [Indexed: 12/14/2024] Open
Abstract
BACKGROUND In recent years, the utilization of stem cell therapy and cell sheet technology has emerged as a promising approach for addressing spinal cord injury (SCI). However, the most appropriate cell type and mechanism of action remain unclear at this time. This study sought to develop an SCI rat model and evaluate the therapeutic effects of human umbilical cord mesenchymal stem cell (hUC-MSC) sheets in this model. Furthermore, the mechanisms underlying the vascular repair effect of hUC-MSC sheets following SCI were investigated. METHODS A temperature-responsive cell culture method was employed for the preparation of hUC-MSC sheets. The extracellular matrix (ECM) produced by hUC-MSCs serves two distinct yet interrelated purposes. Firstly, it acts as a biologically active scaffold for transplanted cells, facilitating their attachment and proliferation. Secondly, it provides mechanical support and bridges spinal cord stumps, thereby facilitating the restoration of spinal cord function. The formation of the cavity within the spinal cord was evaluated using the Hematoxylin and Eosin (H&E) staining method. Subsequently, endothelial cells were cultivated with the conditioned medium (CM) obtained from hUC-MSCs or hUC-MSC sheets. The pro-angiogenic impact of the conditioned medium of hUC-MSCs (MSC-CM) and the conditioned medium of hUC-MSC sheets (CS-CM) was evaluated through the utilization of the CCK-8 assay, endothelial wound healing assay, and tube formation assay in an in vitro context. The development of glial scars, blood vessels, neurons, and axons in hUC-MSCs and hUC-MSC sheets was assessed through immunofluorescence staining. RESULTS In comparison to hUC-MSCs, hUC-MSC sheets demonstrated a more pronounced capacity to facilitate vascular formation and induce the regeneration of newborn neurons at the SCI site, while also reducing glial scar formation and significantly enhancing motor function in SCI rats. Notably, under identical conditions, the formation of cell sheets has been associated with a paracrine increase in the ability of the cells themselves to secrete pro-angiogenic growth factors. During the course of the experiment, it was observed that the secretion of uPAR was the most pronounced among the pro-angiogenic factors present in MSC-CM and CS-CM. This finding was subsequently corroborated in subsequent experiments, wherein uPAR was demonstrated to promote angiogenesis via the PI3K/Akt signaling pathway. CONCLUSION The creation of cell sheets not only significantly enhances the biological function of hUC-MSCs but also effectively retains the cells locally in spinal cord injury. Therefore, the transplantation of hUC-MSC sheets can maximize the function of hUC-MSCs, greatly reducing glial scar formation, enhancing vascular formation, and promoting the regeneration of neurons and axons. Additionally, the research findings prove that hUC-MSC sheets activate the PI3K/Akt signaling pathway through uPAR secretion to enhance angiogenesis. The transfer of the entire extracellular matrix by hUC-MSC sheets, in the absence of the introduction of additional exogenous or synthetic biomaterials, serves to further augment their potential for clinical application.
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Affiliation(s)
- Yulin Zhao
- Department of Spine SurgeryAffiliated Hospital of Nantong UniversityNantongChina
- Medical School of Nantong UniversityNantongChina
| | - Zhengchao Wu
- Department of Spine SurgeryAffiliated Hospital of Nantong UniversityNantongChina
- Medical School of Nantong UniversityNantongChina
| | - Yuchen Zhou
- Department of Spine SurgeryAffiliated Hospital of Nantong UniversityNantongChina
- Medical School of Nantong UniversityNantongChina
| | - Cheng Chen
- Department of Spine SurgeryAffiliated Hospital of Nantong UniversityNantongChina
| | - Yang Lu
- Department of Spine SurgeryAffiliated Hospital of Nantong UniversityNantongChina
| | - Heng Wang
- Department of Spine SurgeryAffiliated Hospital of Nantong UniversityNantongChina
| | - Tao Xu
- Medical School of Nantong UniversityNantongChina
| | - Changwei Yang
- Department of Spine SurgeryAffiliated Hospital of Nantong UniversityNantongChina
| | - Xiaoqing Chen
- Department of Spine SurgeryAffiliated Hospital of Nantong UniversityNantongChina
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Zhang Z, Du H, Gao W, Zhang D. Engineered macrophages: an "Intelligent Repair" cellular machine for heart injury. CELL REGENERATION (LONDON, ENGLAND) 2024; 13:25. [PMID: 39592532 PMCID: PMC11599506 DOI: 10.1186/s13619-024-00209-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 10/22/2024] [Accepted: 11/06/2024] [Indexed: 11/28/2024]
Abstract
Macrophages are crucial in the heart's development, function, and injury. As part of the innate immune system, they act as the first line of defense during cardiac injury and repair. After events such as myocardial infarction or myocarditis, numerous macrophages are recruited to the affected areas of the heart to clear dead cells and facilitate tissue repair. This review summarizes the roles of resident and recruited macrophages in developing cardiovascular diseases. We also describe how macrophage phenotypes dynamically change within the cardiovascular disease microenvironment, exhibiting distinct pro-inflammatory and anti-inflammatory functions. Recent studies reveal the values of targeting macrophages in cardiovascular diseases treatment and the novel bioengineering technologies facilitate engineered macrophages as a promising therapeutic strategy. Engineered macrophages have strong natural tropism and infiltration for cardiovascular diseases aiming to reduce inflammatory response, inhibit excessive fibrosis, restore heart function and promote heart regeneration. We also discuss recent studies highlighting therapeutic strategies and new approaches targeting engineered macrophages, which can aid in heart injury recovery.
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Affiliation(s)
- Zhuo Zhang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, 430062, China
- Stem Cells and Tissue Engineering Manufacture Center, School of Life Sciences, Hubei University, Wuhan, 430062, China
| | - Hetian Du
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, 430062, China
- Stem Cells and Tissue Engineering Manufacture Center, School of Life Sciences, Hubei University, Wuhan, 430062, China
| | - Weijie Gao
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, 430062, China.
- Stem Cells and Tissue Engineering Manufacture Center, School of Life Sciences, Hubei University, Wuhan, 430062, China.
| | - Donghui Zhang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, 430062, China.
- Stem Cells and Tissue Engineering Manufacture Center, School of Life Sciences, Hubei University, Wuhan, 430062, China.
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Yin W, Chen Y, Wang W, Guo M, Tong L, Zhang M, Wang Z, Yuan H. Macrophage-mediated heart repair and remodeling: A promising therapeutic target for post-myocardial infarction heart failure. J Cell Physiol 2024; 239:e31372. [PMID: 39014935 DOI: 10.1002/jcp.31372] [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: 03/04/2024] [Revised: 06/06/2024] [Accepted: 06/25/2024] [Indexed: 07/18/2024]
Abstract
Heart failure (HF) remains prevalent in patients who survived myocardial infarction (MI). Despite the accessibility of the primary percutaneous coronary intervention and medications that alleviate ventricular remodeling with functional improvement, there is an urgent need for clinicians and basic scientists to further reveal the mechanisms behind post-MI HF as well as investigate earlier and more efficient treatment after MI. Growing numbers of studies have highlighted the crucial role of macrophages in cardiac repair and remodeling following MI, and timely intervention targeting the immune response via macrophages may represent a promising therapeutic avenue. Recently, technology such as single-cell sequencing has provided us with an updated and in-depth understanding of the role of macrophages in MI. Meanwhile, the development of biomaterials has made it possible for macrophage-targeted therapy. Thus, an overall and thorough understanding of the role of macrophages in post-MI HF and the current development status of macrophage-based therapy will assist in the further study and development of macrophage-targeted treatment for post-infarction cardiac remodeling. This review synthesizes the spatiotemporal dynamics, function, mechanism and signaling of macrophages in the process of HF after MI, as well as discusses the emerging bio-materials and possible therapeutic agents targeting macrophages for post-MI HF.
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Affiliation(s)
- Wenchao Yin
- Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
| | - Yong Chen
- Department of Emergency, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Wenjun Wang
- Department of Intensive Care Unit, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Mengqi Guo
- Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Lingjun Tong
- Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Mingxiang Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research, Department of Cardiology, Chinese Ministry of Education and Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, Shandong, China
| | - Zhaoyang Wang
- Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Haitao Yuan
- Department of Cardiology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, China
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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Wang J, Zhan H, Wang Y, Zhao L, Huang Y, Wu R. Current advances in understanding endometrial epithelial cell biology and therapeutic applications for intrauterine adhesion. Stem Cell Res Ther 2024; 15:379. [PMID: 39456113 PMCID: PMC11515228 DOI: 10.1186/s13287-024-03989-6] [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: 04/25/2024] [Accepted: 10/09/2024] [Indexed: 10/28/2024] Open
Abstract
The human endometrium is a highly regenerative tissue capable of undergoing scarless repair during the menstruation and postpartum phases. This process is mediated by endometrial adult stem/progenitor cells. During the healing of endometrial injuries, swift reepithelization results in the rapid covering of the wound surface and facilitates subsequent endometrial restoration. The involvement of endogenous endometrial epithelial stem cells, stromal cells, and bone marrow-derived cells in the regeneration of the endometrial epithelium has been a subject of prolonged debate. Increasing evidence suggests that the regeneration of the endometrial epithelium mainly relies on epithelial stem cells rather than stromal cells and bone marrow-derived cells. Currently, no consensus has been established on the identity of epithelial stem cells in the epithelial compartment. Several markers, including stage-specific embryonic antigen-1 (SSEA-1), sex-determining region Y-box 9 (SOX9), neural-cadherin (N-cadherin), leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5), CD44, axis inhibition protein 2 (Axin2), and aldehyde dehydrogenase 1A1 (ALDH1A1), have been suggested as potential candidate markers for endometrial epithelial stem cells. The identification of endometrial epithelial stem cells contributes to our understanding of endometrial regeneration and offers new therapeutic insights into diseases characterized by regenerative defects in the endometrium, such as intrauterine adhesion. This review explores different perspectives on the origins of human and mouse endometrial epithelial cells. It summarizes the potential markers, locations, and hierarchies of epithelial stem cells in both human and mouse endometrium. It also discusses epithelial cell-based treatments for intrauterine adhesion, hoping to inspire further research and clinical application of endometrial epithelial stem cells.
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Affiliation(s)
- Jia Wang
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China
| | - Hong Zhan
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China
| | - Yinfeng Wang
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China
| | - Li Zhao
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China
| | - Yunke Huang
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China
| | - Ruijin Wu
- Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou, 310006, Zhejiang, People's Republic of China.
- Zhejiang Key Laboratory of Maternal and Infant Health, Hangzhou, People's Republic of China.
- Zhejiang Provincial Clinical Research Center for Obstetrics and Gynecology, Hangzhou, People's Republic of China.
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10
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Sun S, Wang L, Tang Q, Yi J, Yu X, Cao Y, Jiang L, Liu J. Myocardial infarction in rats was alleviated by MSCs derived from the maternal segment of the human umbilical cord. Front Cell Dev Biol 2024; 12:1469541. [PMID: 39479514 PMCID: PMC11521943 DOI: 10.3389/fcell.2024.1469541] [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: 07/24/2024] [Accepted: 09/25/2024] [Indexed: 11/02/2024] Open
Abstract
Background Mesenchymal stem cells (MSCs) are safe and effective in treating myocardial infarction (MI) and have broad application prospects. However, the heterogeneity of MSCs may affect their therapeutic effect on the disease. We recently found that MSCs derived from different segments of the same umbilical cord (UC) showed significant difference in the expression of genes that are related to heart development and injury repair. We therefore hypothesized that those MSCs with high expression of above genes are more effective to treat MI and tested it in this study. Methods MSCs were isolated from 3 cm-long segments of the maternal, middle and fetal segments of the UC (maternal-MSCs, middle-MSCs and fetal-MSCs, respectively). RNA-seq was used to analyze and compare the transcriptomes. We verified the effects of MSCs on oxygen-glucose deprivation (OGD)-induced cardiomyocyte apoptosis in vitro. In vivo, a rat MI model was established by ligating the left anterior descending coronary artery, and MSCs were injected into the myocardium surrounding the MI site. The therapeutic effects of MSCs derived from different segments of the UC were evaluated by examining cardiac function, histopathology, cardiomyocyte apoptosis, and angiogenesis. Results Compared to fetal-MSCs and middle-MSCs, maternal-MSCs exhibited significantly higher expression of genes that are associated with heart development, such as GATA-binding protein 4 (GATA4), and myocardin (MYOCD). Coculture with maternal-MSCs reduced OGD-induced cardiomyocyte apoptosis. In rats with MI, maternal-MSCs significantly restored cardiac contractile function and reduced the infarct size. Mechanistic experiments revealed that maternal-MSCs exerted cardioprotective effects by decreasing cardiomyocyte apoptosis, and promoting angiogenesis. Conclusion Our data demonstrated that maternal segment-derived MSCs were a superior cell source for regenerative repair after MI. Segmental localization of the entire UC when isolating hUCMSCs was necessary to improve the effectiveness of clinical applications.
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Affiliation(s)
- Shuifen Sun
- Regenerative Medicine Research Center, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
- Cell Therapy Engineering Research Center for Cardiovascular Diseases in Yunnan Province, Kunming, Yunnan, China
- Key Laboratory of Innovative Application for Traditional Chinese Medicine in Yunnan Province, Kunming, Yunnan, China
| | - Linping Wang
- Regenerative Medicine Research Center, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
- Cell Therapy Engineering Research Center for Cardiovascular Diseases in Yunnan Province, Kunming, Yunnan, China
- Key Laboratory of Innovative Application for Traditional Chinese Medicine in Yunnan Province, Kunming, Yunnan, China
| | - Qisheng Tang
- Regenerative Medicine Research Center, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
- Cell Therapy Engineering Research Center for Cardiovascular Diseases in Yunnan Province, Kunming, Yunnan, China
- Key Laboratory of Innovative Application for Traditional Chinese Medicine in Yunnan Province, Kunming, Yunnan, China
| | - Jialian Yi
- Regenerative Medicine Research Center, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
- Cell Therapy Engineering Research Center for Cardiovascular Diseases in Yunnan Province, Kunming, Yunnan, China
- Key Laboratory of Innovative Application for Traditional Chinese Medicine in Yunnan Province, Kunming, Yunnan, China
| | - Xin Yu
- Medicine School, Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Yu Cao
- Cell Therapy Engineering Research Center for Cardiovascular Diseases in Yunnan Province, Kunming, Yunnan, China
- Key Laboratory of Innovative Application for Traditional Chinese Medicine in Yunnan Province, Kunming, Yunnan, China
- Department of Cardiovascular Surgery, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Lihong Jiang
- Regenerative Medicine Research Center, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
- Cell Therapy Engineering Research Center for Cardiovascular Diseases in Yunnan Province, Kunming, Yunnan, China
- Key Laboratory of Innovative Application for Traditional Chinese Medicine in Yunnan Province, Kunming, Yunnan, China
- Department of Cardiovascular Surgery, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
| | - Jie Liu
- Regenerative Medicine Research Center, NHC Key Laboratory of Healthy Birth and Birth Defect Prevention in Western China, The First People’s Hospital of Yunnan Province, Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China
- Cell Therapy Engineering Research Center for Cardiovascular Diseases in Yunnan Province, Kunming, Yunnan, China
- Key Laboratory of Innovative Application for Traditional Chinese Medicine in Yunnan Province, Kunming, Yunnan, China
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11
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Xu C, Xie Y, Wang B. Genetically modified mesenchymal stromal cells: a cell-based therapy offering more efficient repair after myocardial infarction. Stem Cell Res Ther 2024; 15:323. [PMID: 39334266 PMCID: PMC11438184 DOI: 10.1186/s13287-024-03942-7] [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: 06/27/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Myocardial infarction (MI) is a serious complication of coronary artery disease. This condition is common worldwide and has a profound impact on patients' lives and quality of life. Despite significant advances in the treatment of heart disease in modern medicine, the efficient treatment of MI still faces a number of challenges. Problems such as scar formation and loss of myocardial function after a heart attack still limit patients' recovery. Therefore, the search for a new therapeutic tool that can promote repair and regeneration of myocardial tissue has become crucial. In this context, mesenchymal stromal cells (MSCs) have attracted much attention as a potential therapeutic tool. MSCs are a class of adult stem cells with multidirectional differentiation potential, derived from bone marrow, fat, placenta and other tissues, and possessing properties such as self-renewal and immunomodulation. The application of MSCs may provide a new direction for the treatment of MI. These stem cells have the potential to differentiate into cardiomyocytes and vascular endothelial cells in damaged tissue and to repair and protect myocardial tissue through anti-inflammatory, anti-fibrotic and pro-neovascularization mechanisms. However, the clinical results of MSCs transplantation for the treatment of MI are less satisfactory due to the limitations of the native function of MSCs. Genetic modification has overcome problems such as the low survival rate of transplanted MSCs in vivo and enhanced their functions of promoting neovascularization and differentiation into cardiomyocytes, paving the way for them to become an effective tool for repair therapy after MI. In previous studies, MSCs have shown some therapeutic potential in experimental animals and preliminary clinical trials. This review aims to provide readers with a comprehensive and in-depth understanding to promote the wider application of engineering MSCs in the field of MI therapy, offering new hope for recovery and improved survival of cardiac patients.
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Affiliation(s)
- Congwang Xu
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese, Medicine321 Zhongshan Road, Nanjing, 210008, People's Republic of China
| | - Yuanyuan Xie
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, People's Republic of China
| | - Bin Wang
- Clinical Stem Cell Center, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese, Medicine321 Zhongshan Road, Nanjing, 210008, People's Republic of China.
- Clinical Stem Cell Center, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, 210000, People's Republic of China.
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12
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Sousa AR, Cunha AF, Santos-Coquillat A, Estrada BH, Spiller KL, Barão M, Rodrigues AF, Simões S, Vilaça A, Ferreira L, Oliveira MB, Mano JF. Shape-Versatile Fixed Cellular Materials for Multiple Target Immunomodulation. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2405367. [PMID: 38739450 PMCID: PMC11272431 DOI: 10.1002/adma.202405367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Indexed: 05/16/2024]
Abstract
Therapeutic cells are usually administered as living agents, despite the risks of undesired cell migration and acquisition of unpredictable phenotypes. Additionally, most cell-based therapies rely on the administration of single cells, often associated with rapid in vivo clearance. 3D cellular materials may be useful to prolong the effect of cellular therapies and offer the possibility of creating structural volumetric constructs. Here, the manufacturing of shape-versatile fixed cell-based materials with immunomodulatory properties is reported. Living cell aggregates with different shapes (spheres and centimeter-long fibers) are fixed using a method compatible with maintenance of structural integrity, robustness, and flexibility of 3D constructs. The biological properties of living cells can be modulated before fixation, rendering an in vitro anti-inflammatory effect toward human macrophages, in line with a decreased activation of the nuclear factor kappa B (NF-κB) pathway that preponderantly correlated with the surface area of the materials. These findings are further corroborated in vivo in mouse skin wounds. Contact with fixed materials also reduces the proliferation of activated primary T lymphocytes, while promoting regulatory populations. The fixation of cellular constructs is proposed as a versatile phenotypic stabilization method that can be easily implemented to prepare immunomodulatory materials with therapeutic potential.
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Affiliation(s)
- Ana Rita Sousa
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, Aveiro, 3810-193, Portugal
| | - Ana F Cunha
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, Aveiro, 3810-193, Portugal
| | - Ana Santos-Coquillat
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, Aveiro, 3810-193, Portugal
| | - Beatriz Hernaez Estrada
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA, 19104, USA
| | - Kara L Spiller
- School of Biomedical Engineering, Science, and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA, 19104, USA
| | - Marta Barão
- CNC-Center for Neurosciences and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, 3004-517, Portugal
| | - Artur Filipe Rodrigues
- CNC-Center for Neurosciences and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, 3004-517, Portugal
| | - Susana Simões
- CNC-Center for Neurosciences and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, 3004-517, Portugal
| | - Andreia Vilaça
- CNC-Center for Neurosciences and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, 3004-517, Portugal
| | - Lino Ferreira
- CNC-Center for Neurosciences and Cell Biology, CIBB-Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, 3004-517, Portugal
- FMUC-Faculty of Medicine, University of Coimbra, Coimbra, 3004-517, Portugal
| | - Mariana B Oliveira
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, Aveiro, 3810-193, Portugal
| | - João F Mano
- Department of Chemistry, CICECO - Aveiro Institute of Materials, University of Aveiro, Aveiro, 3810-193, Portugal
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13
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Zhang J, Li J, Qu X, Liu Y, Sun L, Harada A, Hua Y, Sougawa N, Tabata A, Liu L, Miyagawa S. Development of composite functional tissue sheets using hiPSC-CMs and hADSCs to improve the cardiac function after myocardial infarction. Bioact Mater 2024; 37:533-548. [PMID: 38689657 PMCID: PMC11058078 DOI: 10.1016/j.bioactmat.2024.03.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 02/28/2024] [Accepted: 03/21/2024] [Indexed: 05/02/2024] Open
Abstract
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in therapy of ischemic heart disease. However, there are still remaining issues that limit the therapeutic efficacy, such as immune rejection and low retention of hiPSC-CMs. Human adipose mesenchymal stromal cells (hADSCs) have been reported to be able to regulate the immune response, promote angiogenesis and promote the maturation of hiPSC-CMs. In this study, we co-cultured these two types of cells on fiber scaffold made of biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) polymer for several days to develop a composited 3D cardiac tissue sheet. As expected, the cells formed 231.00 ± 15.14 μm thickness tissue, with improved organization, alignment, ECM condition, contractile ability, and paracrine function compared to culture hiPSC-CMs only on PLGA fiber. Furthermore, the composited 3D cardiac tissue sheet significantly promoted the engraftment and survival after transplantation. The composited 3D cardiac tissue sheet also increased cardiac function, attenuated ventricular remodeling, decreased fibrosis, and enhanced angiogenesis in rat myocardial infarction model, indicating that this strategy wound be a promising therapeutic option in the clinical scenario.
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Affiliation(s)
- Jingbo Zhang
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Junjun Li
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
- Department of Applied Physics Osaka University, Osaka University, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Xiang Qu
- Frontier of Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan
| | - Yuting Liu
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Lifu Sun
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Akima Harada
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Ying Hua
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Nagako Sougawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
- Department of Physiology, Osaka Dental University, 8-1 Kuzuha Hanazono-cho, Hirakata, 573-1121, Japan
| | - Akiko Tabata
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Li Liu
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
- Department of Applied Physics Osaka University, Osaka University, 2-2 Yamada-oka, Osaka, 565-0871, Japan
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Osaka, 565-0871, Japan
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14
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Liu T, Hao Y, Zhang Z, Zhou H, Peng S, Zhang D, Li K, Chen Y, Chen M. Advanced Cardiac Patches for the Treatment of Myocardial Infarction. Circulation 2024; 149:2002-2020. [PMID: 38885303 PMCID: PMC11191561 DOI: 10.1161/circulationaha.123.067097] [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] [Indexed: 06/20/2024]
Abstract
Myocardial infarction is a cardiovascular disease characterized by a high incidence rate and mortality. It leads to various cardiac pathophysiological changes, including ischemia/reperfusion injury, inflammation, fibrosis, and ventricular remodeling, which ultimately result in heart failure and pose a significant threat to global health. Although clinical reperfusion therapies and conventional pharmacological interventions improve emergency survival rates and short-term prognoses, they are still limited in providing long-lasting improvements in cardiac function or reversing pathological progression. Recently, cardiac patches have gained considerable attention as a promising therapy for myocardial infarction. These patches consist of scaffolds or loaded therapeutic agents that provide mechanical reinforcement, synchronous electrical conduction, and localized delivery within the infarct zone to promote cardiac restoration. This review elucidates the pathophysiological progression from myocardial infarction to heart failure, highlighting therapeutic targets and various cardiac patches. The review considers the primary scaffold materials, including synthetic, natural, and conductive materials, and the prevalent fabrication techniques and optimal properties of the patch, as well as advanced delivery strategies. Last, the current limitations and prospects of cardiac patch research are considered, with the goal of shedding light on innovative products poised for clinical application.
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Affiliation(s)
- Tailuo Liu
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases (T.L., Y.H., H.Z., S.P., D.Z., Y.C., M.C.), West China Hospital, Sichuan University, Chengdu, PR China
- Department of Cardiology (T.L., S.P., D.Z., M.C.), West China Hospital, Sichuan University, Chengdu, PR China
- Medicine and Engineering Interdisciplinary Research Laboratory of Nursing & Materials, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, PR China (T.L., K.L., Y.C.)
| | - Ying Hao
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases (T.L., Y.H., H.Z., S.P., D.Z., Y.C., M.C.), West China Hospital, Sichuan University, Chengdu, PR China
| | - Zixuan Zhang
- West China School of Public Health/West China Fourth Hospital, Sichuan University, Chengdu, PR China (Z.Z.)
| | - Hao Zhou
- Laboratory of Cardiac Structure and Function, Institute of Cardiovascular Diseases (T.L., Y.H., H.Z., S.P., D.Z., Y.C., M.C.), West China Hospital, Sichuan University, Chengdu, PR China
| | - Shiqin Peng
- Department of Cardiology (T.L., S.P., D.Z., M.C.), West China Hospital, Sichuan University, Chengdu, PR China
| | - Dingyi Zhang
- Department of Cardiology (T.L., S.P., D.Z., M.C.), West China Hospital, Sichuan University, Chengdu, PR China
| | - Ka Li
- Medicine and Engineering Interdisciplinary Research Laboratory of Nursing & Materials, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, PR China (T.L., K.L., Y.C.)
| | - Yuwen Chen
- Medicine and Engineering Interdisciplinary Research Laboratory of Nursing & Materials, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, PR China (T.L., K.L., Y.C.)
| | - Mao Chen
- Department of Cardiology (T.L., S.P., D.Z., M.C.), West China Hospital, Sichuan University, Chengdu, PR China
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15
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Razavi ZS, Soltani M, Mahmoudvand G, Farokhi S, Karimi-Rouzbahani A, Farasati-Far B, Tahmasebi-Ghorabi S, Pazoki-Toroudi H, Afkhami H. Advancements in tissue engineering for cardiovascular health: a biomedical engineering perspective. Front Bioeng Biotechnol 2024; 12:1385124. [PMID: 38882638 PMCID: PMC11176440 DOI: 10.3389/fbioe.2024.1385124] [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: 02/17/2024] [Accepted: 05/13/2024] [Indexed: 06/18/2024] Open
Abstract
Myocardial infarction (MI) stands as a prominent contributor to global cardiovascular disease (CVD) mortality rates. Acute MI (AMI) can result in the loss of a large number of cardiomyocytes (CMs), which the adult heart struggles to replenish due to its limited regenerative capacity. Consequently, this deficit in CMs often precipitates severe complications such as heart failure (HF), with whole heart transplantation remaining the sole definitive treatment option, albeit constrained by inherent limitations. In response to these challenges, the integration of bio-functional materials within cardiac tissue engineering has emerged as a groundbreaking approach with significant potential for cardiac tissue replacement. Bioengineering strategies entail fortifying or substituting biological tissues through the orchestrated interplay of cells, engineering methodologies, and innovative materials. Biomaterial scaffolds, crucial in this paradigm, provide the essential microenvironment conducive to the assembly of functional cardiac tissue by encapsulating contracting cells. Indeed, the field of cardiac tissue engineering has witnessed remarkable strides, largely owing to the application of biomaterial scaffolds. However, inherent complexities persist, necessitating further exploration and innovation. This review delves into the pivotal role of biomaterial scaffolds in cardiac tissue engineering, shedding light on their utilization, challenges encountered, and promising avenues for future advancement. By critically examining the current landscape, we aim to catalyze progress toward more effective solutions for cardiac tissue regeneration and ultimately, improved outcomes for patients grappling with cardiovascular ailments.
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Affiliation(s)
- Zahra-Sadat Razavi
- Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Madjid Soltani
- Department of Mechanical Engineering, K. N. Toosi University of Technology, Tehran, Iran
- Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, ON, Canada
- Centre for Sustainable Business, International Business University, Toronto, ON, Canada
| | - Golnaz Mahmoudvand
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Simin Farokhi
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Arian Karimi-Rouzbahani
- Student Research Committee, USERN Office, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Bahareh Farasati-Far
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran
| | - Samaneh Tahmasebi-Ghorabi
- Master of Health Education, Research Expert, Clinical Research Development Unit, Emam Khomeini Hospital, Ilam University of Medical Sciences, Ilam, Iran
| | | | - Hamed Afkhami
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
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16
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Li G, Wang Q, Liu H, Yang Z, Wu Y, He L, Deng X. Fabricating Composite Cell Sheets for Wound Healing: Cell Sheets Based on the Communication Between BMSCs and HFSCs Facilitate Full-Thickness Cutaneous Wound Healing. Tissue Eng Regen Med 2024; 21:421-435. [PMID: 37995084 PMCID: PMC10987453 DOI: 10.1007/s13770-023-00614-0] [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: 07/04/2023] [Revised: 10/26/2023] [Accepted: 10/29/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Insufficient angiogenesis and the lack of skin appendages are critical challenges in cutaneous wound healing. Stem cell-fabricated cell sheets have become a promising strategy, but cell sheets constructed by a single cell type are inadequate to provide a comprehensive proregenerative microenvironment for wound tissue. METHODS Based on the communication between cells, in this study, bone marrow mesenchymal stem cells (BMSCs) and hair follicle stem cells (HFSCs) were cocultured to fabricate a composite cell sheet (H/M-CS) for the treatment of full-thickness skin wounds in mice. RESULTS Experiments confirmed that there is cell-cell communication between BMSCs and HFSCs, which enhances the cell proliferation and migration abilities of both cell types. Cell-cell talk also upregulates the gene expression of pro-angiogenic-related cytokines in BMSCs and pro-hair follicle-related cytokines in HFSCs, as well as causing changes in the properties of secreted extracellular matrix components. CONCLUSIONS Therefore, the composite cell sheet is more conducive for cutaneous wound healing and promoting the regeneration of blood vessels and hair follicles.
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Affiliation(s)
- Gongjian Li
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics and Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Qin Wang
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics and Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Hao Liu
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics and Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Zuojun Yang
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics and Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Yuhan Wu
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics and Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Li He
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics and Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, China
| | - Xiaoyuan Deng
- MOE Key Laboratory of Laser Life Science and Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
- Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics and Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, China.
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Chen W, Nie M, Gan J, Xia N, Wang D, Sun L. Tailoring cell sheets for biomedical applications. SMART MEDICINE 2024; 3:e20230038. [PMID: 39188516 PMCID: PMC11235941 DOI: 10.1002/smmd.20230038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 01/04/2024] [Indexed: 08/28/2024]
Abstract
Cell sheet technology has emerged as a novel scaffold-free approach for cell-based therapies in regenerative medicine. Techniques for harvesting cell sheets are essential to preserve the integrity of living cell sheets. This review provides an overview of fundamental technologies to fabricate cell sheets and recent advances in cell sheet-based tissue engineering. In addition to the commonly used temperature-responsive systems, we introduce alternative approaches, such as ROS-induced, magnetic-controlled, and light-induced cell sheet technologies. Moreover, we discuss the modification of the cell sheet to improve its function, including stacking, genetic modification, and vascularization. With the significant advances in cell sheet technology, cell sheets have been widely applied in various tissues and organs, including but not limited to the lung, cornea, cartilage, periodontium, heart, and liver. This review further describes both the preclinical and clinical applications of cell sheets. We believe that the progress in cell sheet technology would further propel its biomedical applications.
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Affiliation(s)
- Weiwei Chen
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Min Nie
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Jingjing Gan
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Nan Xia
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Dandan Wang
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
| | - Lingyun Sun
- Department of Rheumatology and ImmunologyNanjing Drum Tower HospitalMedical SchoolNanjing UniversityNanjingChina
- Department of Rheumatology and ImmunologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
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18
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Li Y, Deng T, Aili D, Chen Y, Zhu W, Liu Q. Cell Sheet Technology: An Emerging Approach for Tendon and Ligament Tissue Engineering. Ann Biomed Eng 2024; 52:141-152. [PMID: 37731091 DOI: 10.1007/s10439-023-03370-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 09/09/2023] [Indexed: 09/22/2023]
Abstract
Tendon and ligament injuries account for a substantial proportion of disorders in the musculoskeletal system. While non-operative and operative treatment strategies have advanced, the restoration of native tendon and ligament structures after injury is still challenging due to its innate limited regenerative ability. Cell sheet technology is an innovative tool for tissue fabrication and cell transplantation in regenerative medicine. In this review, we first summarize different harvesting procedures and advantages of cell sheet technology, which preserves intact cell-to-cell connections and extracellular matrix. We then describe the recent progress of cell sheet technology from preclinical studies, focusing on the application of stem cell-derived sheets in treating tendon and ligament injuries, as well as highlighting its effects on mitigating inflammation and promoting tendon/graft-bone interface healing. Finally, we discuss several prerequisites for future clinical translation including the selection of appropriate cell source, optimization of preparation process, establishment of suitable animal model, and the fabrication of vascularized complex tissue. We believe this review could potentially provoke new ideas and drive the development of more functional biomimetic tissues using cell sheet technology to meet the needs of clinical patients.
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Affiliation(s)
- Yexin Li
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Ting Deng
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Dilihumaer Aili
- Department of Orthopedic Surgery, Affiliated Hospital of Traditional Chinese Medicine, Xinjiang Medical University, Ürümqi, People's Republic of China
| | - Yang Chen
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Weihong Zhu
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Qian Liu
- Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China.
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19
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Noh S, Lee SJ, Yoo JJ, Jin YJ, Yun HW, Min BH, Park JY, Park DY. Synovium-Derived Mesenchymal Stem Cell-Based Scaffold-Free Fibrocartilage Engineering for Bone-Tendon Interface Healing in an Anterior Cruciate Ligament Reconstruction Model. Tissue Eng Regen Med 2024; 21:341-351. [PMID: 37856071 PMCID: PMC10825091 DOI: 10.1007/s13770-023-00593-2] [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: 06/23/2023] [Revised: 08/21/2023] [Accepted: 08/27/2023] [Indexed: 10/20/2023] Open
Abstract
BACKGROUND Current tendon and ligament reconstruction surgeries rely on scar tissue healing which differs from native bone-to-tendon interface (BTI) tissue. We aimed to engineer Synovium-derived mesenchymal stem cells (Sy-MSCs) based scaffold-free fibrocartilage constructs and investigate in vivo bone-tendon interface (BTI) healing efficacy in a rat anterior cruciate ligament (ACL) reconstruction model. METHODS Sy-MSCs were isolated from knee joint of rats. Scaffold-free sy-MSC constructs were fabricated and cultured in differentiation media including TGF-β-only, CTGF-only, and TGF-β + CTGF. Collagenase treatment on tendon grafts was optimized to improve cell-to-graft integration. The effects of fibrocartilage differentiation and collagenase treatment on BTI integration was assessed by conducting histological staining, cell adhesion assay, and tensile testing. Finally, histological and biomechanical analyses were used to evaluate in vivo efficacy of fibrocartilage construct in a rat ACL reconstruction model. RESULTS Fibrocartilage-like features were observed with in the scaffold-free sy-MSC constructs when applying TGF-β and CTGF concurrently. Fifteen minutes collagenase treatment increased cellular attachment 1.9-fold compared to the Control group without affecting tensile strength. The failure stress was highest in the Col + D + group (22.494 ± 13.74 Kpa) compared to other groups at integration analysis in vitro. The ACL Recon + FC group exhibited a significant 88% increase in estimated stiffness (p = 0.0102) compared to the ACL Recon group at the 4-week postoperative period. CONCLUSION Scaffold-free, fibrocartilage engineering together with tendon collagenase treatment enhanced fibrocartilaginous BTI healing in ACL reconstruction.
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Affiliation(s)
- Sujin Noh
- Department of Biomedical Sciences, Graduate School of Ajou University, 206 World Cup-Ro, Yeongtong-Gu, Suwon, Republic of Korea
| | - Sang Jin Lee
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - James J Yoo
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Yong Jun Jin
- Department of Orthopedic Surgery, School of Medicine, Ajou University, Suwon, Republic of Korea
| | - Hee-Woong Yun
- Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea
| | - Byoung-Hyun Min
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA
| | - Jae-Young Park
- Department of Orthopedics Surgery, CHA University Bundang Medical Center, Bundang-Gu, Seongnam-Si, Gyeonggi-Do, Republic of Korea
| | - Do Young Park
- Department of Biomedical Sciences, Graduate School of Ajou University, 206 World Cup-Ro, Yeongtong-Gu, Suwon, Republic of Korea.
- Department of Orthopedic Surgery, School of Medicine, Ajou University, Suwon, Republic of Korea.
- Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea.
- Leading Convergence of Healthcare and Medicine, Institute of Science & Technology (ALCHeMIST), Ajou University, Suwon, Republic of Korea.
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20
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Li M, Liu Y, Huang B, Zhou G, Pan M, Jin J, Wang F, Wang Y, Ren X, Xu B, Hu B, Gu N. A Self-Homing and Traceable Cardiac Patch Leveraging Ferumoxytol for Spatiotemporal Therapeutic Delivery. ACS NANO 2024; 18:3073-3086. [PMID: 38227475 DOI: 10.1021/acsnano.3c08346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
Mesenchymal stem cell (MSC)-based cardiac patches are envisioned to be a promising treatment option for patients with myocardial infarction. However, their therapeutic efficacy and duration are hampered due to their limited retention on the epicardium. We engineered a scaffold-free MSC sheet with an inherent ability to migrate into the infarcted myocardium, a strategy enabled by actively establishing a sustained intracellular hypoxic environment through the endocytosis of our FDA-approved ferumoxytol. This iron oxide nanoparticle stabilized hypoxia-induced factor-1α, triggering upregulation of the CXC chemokine receptor and subsequent MSC chemotaxis. Thus, MSCs integrated into 2/3 depth of the left ventricular anterior wall in a rat model of acute myocardial infarction and persisted for at least 28 days. This led to spatiotemporal delivery of paracrine factors by MSCs, enhancing cardiac regeneration and function. Ferumoxytol also facilitated the noninvasive MRI tracking of implanted MSCs. Our approach introduces a strategy for mobilizing MSC migration, holding promise for rapid clinical translation in myocardial infarction treatment.
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Affiliation(s)
- Mei Li
- Key Laboratory for Bio-Electromagnetic Environment and Advanced Medical Theranostics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
- National Demonstration Center for Experimental Basic Medical Education, Nanjing Medical University, Nanjing 211166, China
| | - Yiyi Liu
- Key Laboratory for Bio-Electromagnetic Environment and Advanced Medical Theranostics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
| | - Bin Huang
- Key Laboratory for Bio-Electromagnetic Environment and Advanced Medical Theranostics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
| | - Gaoxin Zhou
- Key Laboratory for Bio-Electromagnetic Environment and Advanced Medical Theranostics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
| | - Mingfei Pan
- Key Laboratory for Bio-Electromagnetic Environment and Advanced Medical Theranostics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
| | - Juan Jin
- Key Laboratory for Bio-Electromagnetic Environment and Advanced Medical Theranostics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
| | - Feng Wang
- Department of Analytical & Testing Center, Nanjing Medical University, Nanjing 211166, China
| | - Yipin Wang
- National Demonstration Center for Experimental Basic Medical Education, Nanjing Medical University, Nanjing 211166, China
| | - Xueyang Ren
- Key Laboratory for Bio-Electromagnetic Environment and Advanced Medical Theranostics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
| | - Biao Xu
- Department of Cardiology, Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing 210008, China
| | - Benhui Hu
- Key Laboratory for Bio-Electromagnetic Environment and Advanced Medical Theranostics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
| | - Ning Gu
- Key Laboratory for Bio-Electromagnetic Environment and Advanced Medical Theranostics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211166, China
- Medical School, Nanjing University, Nanjing 210093, China
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21
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Zhang J, Li J, Qu X, Liu Y, Harada A, Hua Y, Yoshida N, Ishida M, Tabata A, Sun L, Liu L, Miyagawa S. Development of a thick and functional human adipose-derived stem cell tissue sheet for myocardial infarction repair in rat hearts. Stem Cell Res Ther 2023; 14:380. [PMID: 38124195 PMCID: PMC10734106 DOI: 10.1186/s13287-023-03560-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 11/03/2023] [Indexed: 12/23/2023] Open
Abstract
BACKGROUND Heart failure (HF) is a major cause of death worldwide. The most effective treatment for HF is heart transplantation, but its use is limited by the scarcity of donor hearts. Recently, stem cell-based therapy has emerged as a promising approach for treating myocardial infarction. Our research group has been investigating the use of human induced pluripotent stem cell-derived cardiomyocyte patches as a potential therapeutic candidate. We have successfully conducted eight cases of clinical trials and demonstrated the safety and effectiveness of this approach. However, further advancements are necessary to overcome immune rejection and enhance therapeutic efficacy. In this study, we propose a novel and efficient technique for constructing mesenchymal stem cell (MSC) tissue sheets, which can be transplanted effectively for treating myocardial infarction repair. METHODS We applied a one-step method to construct the human adipose-derived mesenchymal stem cell (hADSC) tissue sheet on a poly(lactic-co-glycolic acid) fiber scaffold. Histology, immunofluorescence, and paracrine profile assessment were used to determine the organization and function of the hADSC tissue sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, fibrosis area, angiogenesis, and left ventricular remodeling. RESULTS In vitro, the hADSC tissue sheet showed great organization, abundant ECM expression, and increased paracrine secretion than single cells. In vivo, the hADSC tissue sheet group demonstrated improved cardiac functional recovery, less ventricular remodeling, decreased fibrosis, and enhanced angiogenesis than the MI group. CONCLUSIONS We developed thick and functional hADSC tissue sheets via the one-step strategy. The hADSC tissue sheet showed excellent performance in treating myocardial infarction in the rat model.
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Affiliation(s)
- Jingbo Zhang
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Junjun Li
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
- Frontier of Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Xiang Qu
- Frontier of Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Yuting Liu
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Akima Harada
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Ying Hua
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Noriko Yoshida
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Masako Ishida
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Akiko Tabata
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Lifu Sun
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan
| | - Li Liu
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
- Frontier of Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
| | - Shigeru Miyagawa
- Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-Oka, Suita, Osaka, 565-0871, Japan.
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22
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Jiang Y, Zhang LL, Zhang F, Bi W, Zhang P, Yu XJ, Rao SL, Wang SH, Li Q, Ding C, Jin Y, Liu ZM, Yang HT. Dual human iPSC-derived cardiac lineage cell-seeding extracellular matrix patches promote regeneration and long-term repair of infarcted hearts. Bioact Mater 2023; 28:206-226. [PMID: 37274446 PMCID: PMC10236375 DOI: 10.1016/j.bioactmat.2023.05.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 05/21/2023] [Accepted: 05/22/2023] [Indexed: 06/06/2023] Open
Abstract
Human pluripotent stem cell-derived cardiovascular progenitor cells (hCVPCs) and cardiomyocytes (hCMs) possess therapeutic potential for infarcted hearts; however, their efficacy needs to be enhanced. Here we tested the hypotheses that the combination of decellularized porcine small intestinal submucosal extracellular matrix (SIS-ECM) with hCVPCs, hCMs, or dual of them (Mix, 1:1) could provide better therapeutic effects than the SIS alone, and dual hCVPCs with hCMs would exert synergic effects in cardiac repair. The data showed that the SIS patch well supported the growth of hCVPCs and hCMs. Epicardially implanted SIS-hCVPC, SIS-hCM, or SIS-Mix patches at 7-day post-myocardial infarction significantly ameliorated functional worsening, ventricular dilation and scar formation at 28- and 90-day post-implantation in C57/B6 mice, whereas the SIS only mildly improved function at 90-day post-implantation. Moreover, the SIS and SIS-cell patches improved vascularization and suppressed MI-induced cardiomyocyte hypertrophy and expression of Col1 and Col3, but only the SIS-hCM and the SIS-Mix patches increased the ratio of collagen III/I fibers in the infarcted hearts. Further, the SIS-cell patches stimulated cardiomyocyte proliferation via paracrine action. Notably, the SIS-Mix had better improvements in cardiac function and structure, engraftments, and cardiomyocyte proliferation. Proteomic analysis showed distinct biological functions of exclusive proteins secreted from hCVPCs and hCMs, and more exclusive proteins secreted from co-cultivated hCVPCs and hCMs than mono-cells involving in various functional processes essential for infarct repair. These findings are the first to demonstrate the efficacy and mechanisms of mono- and dual-hCVPC- and hCM-seeding SIS-ECM for repair of infarcted hearts based on the side-by-side comparison.
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Affiliation(s)
- Yun Jiang
- Translational Medical Center for Stem Cell Therapy & Institute for Heart Failure and Regenerative Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China
| | - Ling-Ling Zhang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China
| | - Fan Zhang
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Wei Bi
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China
| | - Peng Zhang
- Translational Medical Center for Stem Cell Therapy & Institute for Heart Failure and Regenerative Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China
| | - Xiu-Jian Yu
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China
| | - Sen-Le Rao
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China
| | - Shi-Hui Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China
| | - Qiang Li
- Translational Medical Center for Stem Cell Therapy & Institute for Heart Failure and Regenerative Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China
| | - Chen Ding
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Human Phenome Institute, Zhongshan Hospital, Fudan University, Shanghai, 200433, China
| | - Yin Jin
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China
| | - Zhong-Min Liu
- Translational Medical Center for Stem Cell Therapy & Institute for Heart Failure and Regenerative Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
| | - Huang-Tian Yang
- Translational Medical Center for Stem Cell Therapy & Institute for Heart Failure and Regenerative Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences (CAS), CAS, Shanghai, 200031, PR China
- Institute for Stem Cell and Regeneration, CAS, Beijing, 100101, PR China
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23
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Bernava G, Iop L. Advances in the design, generation, and application of tissue-engineered myocardial equivalents. Front Bioeng Biotechnol 2023; 11:1247572. [PMID: 37811368 PMCID: PMC10559975 DOI: 10.3389/fbioe.2023.1247572] [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: 06/26/2023] [Accepted: 08/29/2023] [Indexed: 10/10/2023] Open
Abstract
Due to the limited regenerative ability of cardiomyocytes, the disabling irreversible condition of myocardial failure can only be treated with conservative and temporary therapeutic approaches, not able to repair the damage directly, or with organ transplantation. Among the regenerative strategies, intramyocardial cell injection or intravascular cell infusion should attenuate damage to the myocardium and reduce the risk of heart failure. However, these cell delivery-based therapies suffer from significant drawbacks and have a low success rate. Indeed, cardiac tissue engineering efforts are directed to repair, replace, and regenerate native myocardial tissue function. In a regenerative strategy, biomaterials and biomimetic stimuli play a key role in promoting cell adhesion, proliferation, differentiation, and neo-tissue formation. Thus, appropriate biochemical and biophysical cues should be combined with scaffolds emulating extracellular matrix in order to support cell growth and prompt favorable cardiac microenvironment and tissue regeneration. In this review, we provide an overview of recent developments that occurred in the biomimetic design and fabrication of cardiac scaffolds and patches. Furthermore, we sift in vitro and in situ strategies in several preclinical and clinical applications. Finally, we evaluate the possible use of bioengineered cardiac tissue equivalents as in vitro models for disease studies and drug tests.
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Affiliation(s)
| | - Laura Iop
- Department of Cardiac Thoracic Vascular Sciences and Public Health, Padua Medical School, University of Padua, Padua, Italy
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24
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Wei X, Wang L, Duan C, Chen K, Li X, Guo X, Chen P, Liu H, Fan Y. Cardiac patches made of brown adipose-derived stem cell sheets and conductive electrospun nanofibers restore infarcted heart for ischemic myocardial infarction. Bioact Mater 2023; 27:271-287. [PMID: 37122901 PMCID: PMC10130885 DOI: 10.1016/j.bioactmat.2023.03.023] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 03/26/2023] [Accepted: 03/30/2023] [Indexed: 05/02/2023] Open
Abstract
Cell sheet engineering has been proven to be a promising strategy for cardiac remodeling post-myocardial infarction. However, insufficient mechanical strength and low cell retention lead to limited therapeutic efficiency. The thickness and area of artificial cardiac patches also affect their therapeutic efficiency. Cardiac patches prepared by combining cell sheets with electrospun nanofibers, which can be transplanted and sutured to the surface of the infarcted heart, promise to solve this problem. Here, we fabricated a novel cardiac patch by stacking brown adipose-derived stem cells (BADSCs) sheet layer by layer, and then they were combined with multi-walled carbon nanotubes (CNTs)-containing electrospun polycaprolactone/silk fibroin nanofibers (CPSN). The results demonstrated that BADSCs tended to generate myocardium-like structures seeded on CPSN. Compared with BADSCs suspension-containing electrospun nanofibers, the transplantation of the CPSN-BADSCs sheets (CNBS) cardiac patches exhibited accelerated angiogenesis and decreased inflammation in a rat myocardial infarction model. In addition, the CNBS cardiac patches could regulate macrophage polarization and promote gap junction remodeling, thus restoring cardiac functions. Overall, the hybrid cardiac patches made of electrospun nanofibers and cell sheets provide a novel solution to cardiac remodeling after ischemic myocardial infarction.
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Affiliation(s)
- Xinbo Wei
- Key Laboratory for Biomechanics and Mechanobiology (Beihang University) of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, PR China
| | - Li Wang
- Key Laboratory for Biomechanics and Mechanobiology (Beihang University) of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, PR China
| | - Cuimi Duan
- Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences, Beijing, 100850, PR China
| | - Kai Chen
- Key Laboratory for Biomechanics and Mechanobiology (Beihang University) of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, PR China
| | - Xia Li
- Beijing Citident Stomatology Hospital, Beijing, 100032, PR China
| | - Ximin Guo
- Department of Advanced Interdisciplinary Studies, Institute of Basic Medical Sciences, Beijing, 100850, PR China
| | - Peng Chen
- Department of Ultrasound, The Third Medical Center, Chinese PLA General Hospital, Beijing, PR China
| | - Haifeng Liu
- Key Laboratory for Biomechanics and Mechanobiology (Beihang University) of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, PR China
| | - Yubo Fan
- Key Laboratory for Biomechanics and Mechanobiology (Beihang University) of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, PR China
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25
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Bui TQ, Binh NT, Pham TLB, Le Van T, Truong NH, Nguyen DPH, Luu TTT, Nguyen-Xuan Pham T, Cam Tran T, Nguyen HTT, Thuy-Trinh N, Tran PA. The Efficacy of Transplanting Human Umbilical Cord Mesenchymal Stem Cell Sheets in the Treatment of Myocardial Infarction in Mice. Biomedicines 2023; 11:2187. [PMID: 37626684 PMCID: PMC10452263 DOI: 10.3390/biomedicines11082187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/17/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023] Open
Abstract
The transplantation of mesenchymal stem cell (MSC) sheets derived from human umbilical cords (hUCs) was investigated in this study as a potential application in treating myocardial infarction (MI). Two groups of hUC-MSC sheets were formed by populating LunaGelTM, which are 3D scaffolds of photo-crosslinkable gelatin-based hydrogel with two different cell densities. An MI model was created by ligating the left anterior descending coronary artery of healthy BALB/c mice. After two weeks, the cell sheets were applied directly to the MI area and the efficacy of the treatment was evaluated over the next two weeks by monitoring the mice's weight, evaluating the left ventricle ejection fraction, and assessing the histology of the heart tissue at the end of the experiment. Higher cell density showed significantly greater efficiency in MI mice treatment in terms of weight gain and the recovery of ejection fraction. The heart tissue of the groups receiving cell sheets showed human-CD44-positive staining and reduced fibrosis and apoptosis. In conclusion, the hUC-MSC sheets ameliorated heart MI injury in mice and the efficacy of the cell sheets improved as the number of cells increased.
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Affiliation(s)
| | - Nguyen Trong Binh
- Biotechnology Center of Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam; (T.L.-B.P.); (D.P.-H.N.); (T.N.-X.P.)
| | - Truc Le-Buu Pham
- Biotechnology Center of Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam; (T.L.-B.P.); (D.P.-H.N.); (T.N.-X.P.)
- Faculty of Biotechnology, Ho Chi Minh City Open University, Ho Chi Minh City 700000, Vietnam
| | - Trinh Le Van
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.L.V.); (N.H.T.)
- Vietnam National University, Ho Chi Minh City 700000, Vietnam;
| | - Nhung Hai Truong
- Laboratory of Stem Cell Research and Application, University of Science, Ho Chi Minh City 700000, Vietnam; (T.L.V.); (N.H.T.)
- Vietnam National University, Ho Chi Minh City 700000, Vietnam;
| | - Dang Phu-Hai Nguyen
- Biotechnology Center of Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam; (T.L.-B.P.); (D.P.-H.N.); (T.N.-X.P.)
| | - Thao Thi-Thu Luu
- Histology-Embryology-Pathology Department, Faculty of Medicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam;
| | - Trang Nguyen-Xuan Pham
- Biotechnology Center of Ho Chi Minh City, Ho Chi Minh City 700000, Vietnam; (T.L.-B.P.); (D.P.-H.N.); (T.N.-X.P.)
| | - Tu Cam Tran
- Institute of Tropical Biology, Ho Chi Minh City 700000, Vietnam;
| | - Huyen Thuong-Thi Nguyen
- Divison of Human and Animal Physiology, HCMC University of Education, Ho Chi Minh City 700000, Vietnam;
| | - Nhu Thuy-Trinh
- Vietnam National University, Ho Chi Minh City 700000, Vietnam;
- School of Biomedical Engineering, International University, Ho Chi Minh City 700000, Vietnam
| | - Phong Anh Tran
- Interface Science and Materials Engineering Group, School of Mechanical, Medical and Process Engineering, Faculty of Engineering, Queensland University of Technology, Brisbane City, QLD 4000, Australia;
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26
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Chang D, Yang X, Fan S, Fan T, Zhang M, Ono M. Engineering of MSCs sheet for the prevention of myocardial ischemia and for left ventricle remodeling. Stem Cell Res Ther 2023; 14:102. [PMID: 37098611 PMCID: PMC10127056 DOI: 10.1186/s13287-023-03322-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 03/29/2023] [Indexed: 04/27/2023] Open
Abstract
Tissue engineering combines cell biology and material science to construct tissues or organs for disease modeling, drug testing, and regenerative medicine. The cell sheet is a newly developed tissue engineering technology that has brought about scaffold-free tissue and shows great application potential. In this review, we summarized recent progress and future possibilities in preclinical research into and clinical applications of cell sheets fabricated by differing cell types from various sources for cardiac tissue repair, and the manufacturing strategies and promising application potential of 3D cell-dense tissue constructed from cell sheets. Special attention was paid to the mechanisms of mesenchymal stem cell (MSC) sheets in the prevention of myocardial ischemia and left ventricle remodeling. Comparing MSCs sheets with other types of cell sheets and 3D cardiac tissues, engineering tissues' potential safety and effectiveness concerns were also discussed.
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Affiliation(s)
- Dehua Chang
- Department of Cell Therapy in Regenerative Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Xiaotong Yang
- BOE Regenerative Medicine Technology Co., Ltd., No. 9 JiuXianQiao North Road, Beijing, 100015, China
| | - Siyang Fan
- Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China
| | - Taibing Fan
- Children Heart Center, Fuwai Central China Cardiovascular Hospital, No. 1 Fuwai Road, Zhengzhou, 450018, China
| | - Mingkui Zhang
- Heart Center, First Hospital of Tsinghua University, No. 6 JiuXianQiao 1st Road, Beijing, 10016, China
| | - Minoru Ono
- Department of Cardiac Surgery, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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27
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Wu Y, Shang H, Lai S, Di Y, Sun X, Qiao N, Han L, Zhao Z, Lu Y. Preparation and evaluation of controllable drug delivery system: A light responsive nanosphere based on β-cyclodextrin/mesoporous silica. Chin J Chem Eng 2023. [DOI: 10.1016/j.cjche.2023.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/05/2023]
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28
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Abdolahzadeh H, Rad NK, Shpichka A, Golroo R, Rahi K, Timashev P, Hassan M, Vosough M. Progress and promise of cell sheet assisted cardiac tissue engineering in regenerative medicine. Biomed Mater 2023; 18. [PMID: 36758240 DOI: 10.1088/1748-605x/acbad4] [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: 09/26/2022] [Accepted: 02/09/2023] [Indexed: 02/11/2023]
Abstract
Cardiovascular diseases (CVDs) are the most common leading causes of premature deaths in all countries. To control the harmful side effects of CVDs on public health, it is necessary to understand the current and prospective strategies in prevention, management, and monitoring CVDs.In vitro,recapitulating of cardiac complex structure with its various cell types is a challenging topic in tissue engineering. Cardiac tissue engineering (CTE) is a multi-disciplinary strategy that has been considered as a novel alternative approach for cardiac regenerative medicine and replacement therapies. In this review, we overview various cell types and approaches in cardiac regenerative medicine. Then, the applications of cell-sheet-assisted CTE in cardiac diseases were discussed. Finally, we described how this technology can improve cardiac regeneration and function in preclinical and clinical models.
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Affiliation(s)
- Hadis Abdolahzadeh
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Niloofar Khoshdel Rad
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Anastasia Shpichka
- World-Class Research Center 'Digital Biodesign and Personalized Healthcare', Sechenov University, Moscow, Russia.,Institute for Regenerative Medicine, Sechenov University, Moscow, Russia.,Chemistry Department, Lomonosov Moscow State University, Moscow, Russia
| | - Reihaneh Golroo
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Kosar Rahi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Peter Timashev
- World-Class Research Center 'Digital Biodesign and Personalized Healthcare', Sechenov University, Moscow, Russia.,Institute for Regenerative Medicine, Sechenov University, Moscow, Russia.,Chemistry Department, Lomonosov Moscow State University, Moscow, Russia
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.,Chemistry Department, Lomonosov Moscow State University, Moscow, Russia.,Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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29
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Wang X, Chen J, Tian W. Strategies of cell and cell-free therapies for periodontal regeneration: the state of the art. Stem Cell Res Ther 2022; 13:536. [PMID: 36575471 PMCID: PMC9795760 DOI: 10.1186/s13287-022-03225-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Accepted: 12/19/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Periodontitis often causes irrevocable destruction of tooth-supporting tissues and eventually leads to tooth loss. Currently, stem cell-based tissue engineering has achieved a favorable result in regenerating periodontal tissues. Moreover, cell-free therapies that aim to facilitate the recruitment of resident repair cell populations to injured sites by promoting cell mobilization and homing have become alternative options to cell therapy. MAIN TEXT Cell aggregates (e.g., cell sheets) retain a large amount of extracellular matrix which can improve cell viability and survival rates after implantation in vivo. Electrostatic spinning and 3D bioprinting through fabricating specific alignments and interactions scaffold structures have made promising outcomes in the construction of a microenvironment conducive to periodontal regeneration. Cell-free therapies with adding biological agents (growth factors, exosomes and conditioned media) to promote endogenous regeneration have somewhat addressed the limitations of cell therapy. CONCLUSION Hence, this article reviews the progress of stem cell-based tissue engineering and advanced strategies for endogenous regeneration based on stem cell derivatives in periodontal regeneration.
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Affiliation(s)
- Xiuting Wang
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, People’s Republic of China ,grid.13291.380000 0001 0807 1581National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu, People’s Republic of China ,grid.13291.380000 0001 0807 1581Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China
| | - Jinlong Chen
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, People’s Republic of China ,grid.13291.380000 0001 0807 1581National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu, People’s Republic of China ,grid.13291.380000 0001 0807 1581Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China
| | - Weidong Tian
- grid.13291.380000 0001 0807 1581State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China School of Stomatology, Sichuan University, Chengdu, People’s Republic of China ,grid.13291.380000 0001 0807 1581National Engineering Laboratory for Oral Regenerative Medicine, West China School of Stomatology, Sichuan University, Chengdu, People’s Republic of China ,grid.13291.380000 0001 0807 1581Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041 People’s Republic of China
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30
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Huang JN, Cao H, Liang KY, Cui LP, Li Y. Combination therapy of hydrogel and stem cells for diabetic wound healing. World J Diabetes 2022; 13:949-961. [PMID: 36437861 PMCID: PMC9693739 DOI: 10.4239/wjd.v13.i11.949] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 09/25/2022] [Accepted: 11/02/2022] [Indexed: 11/11/2022] Open
Abstract
Diabetic wounds (DWs) are a common complication of diabetes mellitus; DWs have a low cure rate and likely recurrence, thus affecting the quality of patients’ lives. As traditional therapy cannot effectively improve DW closure, DW has become a severe clinical medical problem worldwide. Unlike routine wound healing, DW is difficult to heal because of its chronically arrested inflammatory phase. Although mesenchymal stem cells and their secreted cytokines can alleviate oxidative stress and stimulate angiogenesis in wounds, thereby promoting wound healing, the biological activity of mesenchymal stem cells is compromised by direct injection, which hinders their therapeutic effect. Hydro-gels form a three-dimensional network that mimics the extracellular matrix, which can provide shelter for stem cells in the inflammatory microenvironment with reactive oxygen species in DW, and maintains the survival and viability of stem cells. This review summarizes the mechanisms and applications of stem cells and hydrogels in treating DW; additionally, it focuses on the different applications of therapy combining hydrogel and stem cells for DW treatment.
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Affiliation(s)
- Jia-Na Huang
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Hao Cao
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Kai-Ying Liang
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
| | - Li-Ping Cui
- Endocrinology Department, Panyu Central Hospital, Guangzhou 511400, Guangdong Province, China
| | - Yan Li
- School of Biomedical Engineering, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument, Sun Yat-sen University, Guangzhou 510006, Guangdong Province, China
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31
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Smart surface-based cell sheet engineering for regenerative medicine. TRENDS IN CHEMISTRY 2022. [DOI: 10.1016/j.trechm.2022.11.001] [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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32
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Ling L, Hou J, Wang Y, Shu H, Huang Y. Effects of Low-Intensity Pulsed Ultrasound on the Migration and Homing of Human Amnion-Derived Mesenchymal Stem Cells to Ovaries in Rats With Premature Ovarian Insufficiency. Cell Transplant 2022; 31:9636897221129171. [PMID: 36282038 PMCID: PMC9608022 DOI: 10.1177/09636897221129171] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Premature ovarian insufficiency (POI) can cause multiple sequelae and is currently incurable. Mesenchymal stem cell (MSC) transplantation might provide an effective treatment method for POI. However, the clinical application of systemic MSC transplantation is limited by the low efficiency of cell homing to target tissue in vivo, including systemic MSC transplantation for POI treatment. Thus, exploration of methods to promote MSC homing is necessary. This study was to investigate the effects of low-intensity pulsed ultrasound (LIPUS) on the migration and homing of transplanted human amnion–derived MSCs (hAD-MSCs) to ovaries in rats with chemotherapy-induced POI. For LIPUS treatment, hAD-MSCs were exposed to LIPUS or sham irradiation. Chemokine receptor expressions in hAD-MSCs were detected by polymerase chain reaction (PCR), Western blot, and immunofluorescence assays. hAD-MSC migration was detected by wound healing and transwell migration assays. Cyclophosphamide-induced POI rat models were established to evaluate the effects of LIPUS on the homing of systemically transplanted hAD-MSCs to chemotherapy-induced POI ovaries in vivo. We found that hAD-MSCs expressed chemokine receptors. The LIPUS promoted the expression of chemokine receptors, especially CXCR4, in hAD-MSCs. SDF-1 induced hAD-MSC migration. The LIPUS promoted hAD-MSC migration induced by SDF-1 through SDF-1/CXCR4 axis. SDF-1 levels significantly increased in ovaries induced by chemotherapy in POI rats. Pretreating hAD-MSCs with LIPUS increased the number of hAD-MSCs homing to ovaries in rats with chemotherapy-induced POI to some extent. However, the difference was not significant. Both hAD-MSC and LIPUS-pretreated hAD-MSC transplantation reduced ovarian injuries and improved ovarian function in rats with chemotherapy-induced POI. CXCR4 antagonist significantly reduced the number of hAD-MSCs- and LIPUS-pretreated hAD-MSCs homing to POI ovaries, and further reduced their efficacy in POI treatment. According to these findings, pretreating MSCs with LIPUS before transplantation might provide a novel, convenient, and safe technique to explore for improving the homing of systemically transplanted MSCs to target tissue.
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Affiliation(s)
- Li Ling
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China,Li Ling, Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, No. 74, Linjiang Road, Chongqing 400010, China.
| | - Jiying Hou
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Wang
- State Key Laboratory of Ultrasound Engineering in Medicine Co-founded by Chongqing and the Ministry of Science and Technology, Chongqing Key Laboratory of Biomedical Engineering, College of Biomedical Engineering, Chongqing Medical University, Chongqing, China
| | - Han Shu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yubin Huang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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33
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Saleem A, Abbas MK, Wang Y, Lan F. hPSC gene editing for cardiac disease therapy. Pflugers Arch 2022; 474:1123-1132. [PMID: 36163402 DOI: 10.1007/s00424-022-02751-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 08/09/2022] [Accepted: 09/18/2022] [Indexed: 11/26/2022]
Abstract
Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide. However, the lack of human cardiomyocytes with proper genetic backgrounds limits the study of disease mechanisms. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have significantly advanced the study of these conditions. Moreover, hPSC-CMs made it easy to study CVDs using genome-editing techniques. This article discusses the applications of these techniques in hPSC for studying CVDs. Recently, several genome-editing systems have been used to modify hPSCs, including zinc finger nucleases, transcription activator-like effector nucleases, and clustered regularly interspaced short palindromic repeat-associated protein 9 (CRISPR/Cas9). We focused on the recent advancement of genome editing in hPSCs, which dramatically improved the efficiency of the cell-based mechanism study and therapy for cardiac diseases.
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Affiliation(s)
- Amina Saleem
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Research Institute Building, Beijinj Anzhen Hospital, Capital Medical University, Room 319, 2 Anzhen Road, Chaoyang District, Beijing, Beijing, 100029, China
| | - Muhammad Khawar Abbas
- BHMS Department, University College of Conventional Medicine, Faculty of Medicine and Allied Health Sciences, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Yongming Wang
- The State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, 200438, China
- The Key Lab of Reproduction Regulation of NPFPC in SIPPR, Institute of Reproduction & Development in Obstetrics & Gynecology Hospital, Fudan University, Shanghai, 200011, China
| | - Feng Lan
- Beijing Laboratory for Cardiovascular Precision Medicine, MOE Key Laboratory of Medical Engineering for Cardiovascular Diseases, MOE Key Laboratory of Remodeling Related Cardiovascular Disease, Beijing Collaborative Innovation Center for Cardiovascular Disorders, Research Institute Building, Beijinj Anzhen Hospital, Capital Medical University, Room 319, 2 Anzhen Road, Chaoyang District, Beijing, Beijing, 100029, China.
- Fuwai Hospital Chinese Academy of Medical Sciences, Shenzhen, Shenzhen Key Laboratory of Cardiovascular Disease, State Key Laboratory of Cardiovascular Disease, Key Laboratory of Pluripotent Stem Cells in Cardiac Repair and Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Beijing, 100029, China.
- National Health Commission Key Laboratory of Cardiovascular Regenerative Medicine, Fuwai Central-China Hospital, Central-China Branch of National Center for Cardiovascular Diseases, Zhengzhou, Beijing, 100037, China.
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34
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Basara G, Bahcecioglu G, Ozcebe SG, Ellis BW, Ronan G, Zorlutuna P. Myocardial infarction from a tissue engineering and regenerative medicine point of view: A comprehensive review on models and treatments. BIOPHYSICS REVIEWS 2022; 3:031305. [PMID: 36091931 PMCID: PMC9447372 DOI: 10.1063/5.0093399] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/08/2022] [Indexed: 05/12/2023]
Abstract
In the modern world, myocardial infarction is one of the most common cardiovascular diseases, which are responsible for around 18 million deaths every year or almost 32% of all deaths. Due to the detrimental effects of COVID-19 on the cardiovascular system, this rate is expected to increase in the coming years. Although there has been some progress in myocardial infarction treatment, translating pre-clinical findings to the clinic remains a major challenge. One reason for this is the lack of reliable and human representative healthy and fibrotic cardiac tissue models that can be used to understand the fundamentals of ischemic/reperfusion injury caused by myocardial infarction and to test new drugs and therapeutic strategies. In this review, we first present an overview of the anatomy of the heart and the pathophysiology of myocardial infarction, and then discuss the recent developments on pre-clinical infarct models, focusing mainly on the engineered three-dimensional cardiac ischemic/reperfusion injury and fibrosis models developed using different engineering methods such as organoids, microfluidic devices, and bioprinted constructs. We also present the benefits and limitations of emerging and promising regenerative therapy treatments for myocardial infarction such as cell therapies, extracellular vesicles, and cardiac patches. This review aims to overview recent advances in three-dimensional engineered infarct models and current regenerative therapeutic options, which can be used as a guide for developing new models and treatment strategies.
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Affiliation(s)
- Gozde Basara
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, USA
| | - Gokhan Bahcecioglu
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, Indiana 46556, USA
| | - S. Gulberk Ozcebe
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, Indiana 46556, USA
| | - Bradley W Ellis
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, Indiana 46556, USA
| | - George Ronan
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, Indiana 46556, USA
| | - Pinar Zorlutuna
- Present address: 143 Multidisciplinary Research Building, University of Notre Dame, Notre Dame, IN 46556. Author to whom correspondence should be addressed:. Tel.: +1 574 631 8543. Fax: +1 574 631 8341
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35
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Manufacture and Quality Control of Human Umbilical Cord-Derived Mesenchymal Stem Cell Sheets for Clinical Use. Cells 2022; 11:cells11172732. [PMID: 36078137 PMCID: PMC9454431 DOI: 10.3390/cells11172732] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/28/2022] [Accepted: 08/30/2022] [Indexed: 11/17/2022] Open
Abstract
Human umbilical cord-derived mesenchymal stem cell (UC−MSC) sheets have attracted much attention in cell therapy. However, the culture media and coating matrix used for the preparation of UC−MSC sheets have not been safe enough to comply with current clinical drug standards. Moreover, the UC−MSC sheet preservation systems developed before did not comply with Good Manufacturing Practice (GMP) regulations. In this study, the culture medium and coating matrix were developed for UC−MSC sheet production to comply with clinical drug standards. Additionally, the GMP-compliant preservation solution and method for the UC−MSC sheet were developed. Then, quality standards of the UC−MSC sheet were formulated according to national and international regulations for drugs. Finally, the production process of UC−MSC sheets on a large scale was standardized, and three batches of trial production were conducted and tested to meet the established quality standards. This research provides the possibility for clinical trials of UC−MSC sheet products in the development stage of new drugs and lays the foundation for industrial large-scale production after the new drug is launched.
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36
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Munderere R, Kim SH, Kim C, Park SH. The Progress of Stem Cell Therapy in Myocardial-Infarcted Heart Regeneration: Cell Sheet Technology. Tissue Eng Regen Med 2022; 19:969-986. [PMID: 35857259 DOI: 10.1007/s13770-022-00467-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022] Open
Abstract
Various tissues, including the heart, cornea, bone, esophagus, bladder and liver, have been vascularized using the cell sheet technique. It overcomes the limitations of existing techniques by allowing small layers of the cell sheet to generate capillaries on their own, and it can also be used to vascularize tissue-engineered transplants. Cell sheets eliminate the need for traditional tissue engineering procedures such as isolated cell injections and scaffold-based technologies, which have limited applicability. While cell sheet engineering can eliminate many of the drawbacks, there are still a few challenges that need to be addressed. The number of cell sheets that can be layered without triggering core ischemia or hypoxia is limited. Even when scaffold-based technologies are disregarded, strategies to tackle this problem remain a substantial impediment to the efficient regeneration of thick, living three-dimensional cell sheets. In this review, we summarize the cell sheet technology in myocardial infarcted tissue regeneration.
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Affiliation(s)
- Raissa Munderere
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan, Republic of Korea.,The Center for Marine Integrated Biomedical Technology (BK21 PLUS), Pukyong National University, Busan, Republic of Korea
| | - Seon-Hwa Kim
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan, Republic of Korea.,The Center for Marine Integrated Biomedical Technology (BK21 PLUS), Pukyong National University, Busan, Republic of Korea
| | - Changsu Kim
- Department of Orthopedics Surgery, Kosin University Gospel Hospital, Busan, Republic of Korea
| | - Sang-Hyug Park
- Industry 4.0 Convergence Bionics Engineering, Pukyong National University, Busan, Republic of Korea. .,The Center for Marine Integrated Biomedical Technology (BK21 PLUS), Pukyong National University, Busan, Republic of Korea. .,Major of Biomedical Engineering, Division of Smart Healthcare, College of Information Technology and Convergence, Pukyong National University, 45 Yongso-ro, Nam-gu, Busan, 48513, Republic of Korea.
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37
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Qi Z, Yan Z, Wang Y, Ji N, Yang X, Zhang A, Li M, Xu F, Zhang J. Ginsenoside Rh2 Inhibits NLRP3 Inflammasome Activation and Improves Exosomes to Alleviate Hypoxia-Induced Myocardial Injury. Front Immunol 2022; 13:883946. [PMID: 35865525 PMCID: PMC9294352 DOI: 10.3389/fimmu.2022.883946] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 06/09/2022] [Indexed: 11/18/2022] Open
Abstract
The inflammatory microenvironment after acute myocardial infarction (MI) is a key limiting factor in the clinical application of stem cell transplantation and paracrine exosome therapy. Qishen Yiqi Pills contain a saponin ingredient called Ginsenoside Rh2 (Rh2) which exhibits a certain therapeutic effect on MI. However, the mechanism by which Rh2 alleviates the inflammatory microenvironment and improves the therapeutic efficiency of exosomes remains enigmatic. Here, we found that Rh2 attenuated the adverse effect of oxygen-glucose deprivation (OGD)-induced cellular injury, an in vitro pathological model of MI. Confocal microscopy revealed that DiI-labeled BMSCs-derived exosomes exhibited an increased homing ability of cardiomyocytes, which, in turn, inhibited the nuclear translocation of NF-κB p65 and NLRP3 inflammasome activation, thereby alleviating the inflammatory microenvironment and further facilitating the homing of exosomes to cardiomyocytes by forming a feed-forward enhancement loop. Additionally, we found that Rh2 could regulate the HMGB1/NF-κB signaling pathway to improve the OGD environment of cardiomyocytes, increasing the efficiency of the feed-forward loop. In conclusion, we found that Rh2 can improve the inflammatory microenvironment by enhancing the protection of exosomes against myocardial injury, providing new insights into the indirect modification of exosomes by Rh2 in MI treatment.
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Affiliation(s)
- Zhongwen Qi
- Postdoctoral Research Station of China Academy of Chinese Medical Sciences, Institute of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhipeng Yan
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yueyao Wang
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Nan Ji
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaoya Yang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ao Zhang
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Meng Li
- Institute of Hypertension, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Fengqin Xu
- Postdoctoral Research Station of China Academy of Chinese Medical Sciences, Institute of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Junping Zhang
- Medical Experiment Center, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Gao S, Jin Y, Ma J, Wang J, Wang J, Shao Z, Fan T, Zhang M, Chang D. Preclinical study of human umbilical cord mesenchymal stem cell sheets for the recovery of ischemic heart tissue. Stem Cell Res Ther 2022; 13:252. [PMID: 35690871 PMCID: PMC9188245 DOI: 10.1186/s13287-022-02919-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 05/03/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Human umbilical cord mesenchymal stem cells (hUC-MSCs) have been widely used due to their multipotency, a broad range of sources, painless collection, and compliance with standard amplification. Cell sheet technology is a tissue engineering methodology requiring scaffolds free, and it provides an effective method for cell transplantation. To improve the therapeutic efficacy, we combined hUC-MSCs with cell sheet technology to evaluate the safety and efficacy of hUC-MSC sheets in preclinical studies using appropriate animal models. METHODS hUC-MSC sheets were fabricated by hUC-MSCs from a cell bank established by a standard operation process and quality control. Cytokine secretion, immunoregulation, and angiopoiesis were evaluated in vitro. Oncogenicity and cell diffusion assays of hUC-MSC sheets were conducted to verify the safety of hUC-MSCs sheet transplantation in mice. To provide more meaningful animal experimental data for clinical trials, porcine myocardial infarction (MI) models were established by constriction of the left circumflex, and hUC-MSC sheets were transplanted onto the ischemic area of the heart tissue. Cardiac function was evaluated and compared between the experimental and MI groups. RESULTS The in vitro results showed that hUC-MSC sheets could secrete multiple cellular factors, including VEGF, HGF, IL-6, and IL-8. Peripheral blood mononuclear cells had a lower proliferation rate and lower TNF-α secretion when co-cultured with hUC-MSC sheets. TH1 cells had a smaller proportion after activation. In vivo safety results showed that the hUC-MSCs sheet had no oncogenicity and was mainly distributed on the surface of the ischemic myocardial tissue. Echocardiography showed that hUC-MSC sheets effectively improved the left ventricular ejection fraction (LVEF), and the LVEF significantly changed (42.25 ± 1.23% vs. 66.9 ± 1.10%) in the hUC-MSC transplantation group compared with the MI group (42.52 ± 0.65% vs. 39.55 ± 1.97%) at 9 weeks. The infarct ratio of the hUC-MSCs sheet transplantation groups was also significantly reduced (14.2 ± 4.53% vs. 4.00 ± 2.00%) compared with that of the MI group. CONCLUSION Allogeneic source and cell bank established by the standard operation process and quality control make hUC-MSCs sheet possible to treat MI by off-the-shelf drug with universal quality instead of individualized medical technology.
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Affiliation(s)
- Shuang Gao
- BOE Regenerative Medicine Technology Co., Ltd., No. 9 JiuXianQiao North Road, Beijing, 100015, China
| | - Yongqiang Jin
- Heart Center, First Hospital of Tsinghua University, No. 6 JiuXianQiao 1st Road, Beijing, 10016, China
| | - Jianlin Ma
- BOE Regenerative Medicine Technology Co., Ltd., No. 9 JiuXianQiao North Road, Beijing, 100015, China
| | - Juan Wang
- BOE Regenerative Medicine Technology Co., Ltd., No. 9 JiuXianQiao North Road, Beijing, 100015, China
| | - Jing Wang
- BOE Regenerative Medicine Technology Co., Ltd., No. 9 JiuXianQiao North Road, Beijing, 100015, China
| | - Zehua Shao
- Heart Center of Henan Provincial People's Hospital, Zhengzhou University People's Hospital, No. 7 Weiwu Road, Zhengzhou, 450003, China
| | - Taibing Fan
- Children Heart Center, Fuwai Central China Cardiovascular Hospital, No. 1 Fuwai Road, Zhengzhou, 450018, China
| | - Mingkui Zhang
- Heart Center, First Hospital of Tsinghua University, No. 6 JiuXianQiao 1st Road, Beijing, 10016, China
| | - Dehua Chang
- Department of Cell Therapy in Regenerative Medicine, The University of Tokyo Hospital, 7-3-1 Honggo, Bunkyo-ku, Tokyo, 113-8655, Japan.
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Liu J, Liang X, Li M, Lin F, Ma X, Xin Y, Meng Q, Zhuang R, Zhang Q, Han W, Gao L, He Z, Zhou X, Liu Z. Intramyocardial injected human umbilical cord-derived mesenchymal stem cells (HucMSCs) contribute to the recovery of cardiac function and the migration of CD4 + T cells into the infarcted heart via CCL5/CCR5 signaling. Stem Cell Res Ther 2022; 13:247. [PMID: 35690805 PMCID: PMC9188247 DOI: 10.1186/s13287-022-02914-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/25/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Human umbilical cord-derived mesenchymal stem cells (HucMSCs) have been recognized as a promising cell for treating myocardial infarction (MI). Inflammatory response post MI is critical in determining the cardiac function and subsequent adverse left ventricular remodeling. However, the local inflammatory effect of HucMSCs after intramyocardial injection in murine remains unclear. METHODS HucMSCs were cultured and transplanted into the mice after MI surgery. Cardiac function of mice were analyzed among MI-N.S, MI-HucMSC and MI-HucMSC-C-C Motif Chemokine receptor 5 (CCR5) antagonist groups, and angiogenesis, fibrosis and hypertrophy, and immune cells infiltration of murine hearts were evaluated between MI-N.S and MI-HucMSC groups. We detected the expression of inflammatory cytokines and their effects on CD4+ T cells migration. RESULTS HucMSCs treatment can significantly improve the cardiac function and some cells can survive at least 28 days after MI. Intramyocardial administration of HucMSCs also improved angiogenesis and alleviated cardiac fibrosis and hypertrophy. Moreover, we found the much higher numbers of CD4+ T cells and CD4+FoxP3+ regulatory T cells (Tregs) in the heart with HucMSCs than that with N.S treatment on day 7 post MI. In addition, the protein level of C-C Motif Chemokine Ligand 5 (CCL5) greatly increased in HucMSCs treated heart compared to MI-N.S group. In vitro, HucMSCs inhibited CD4+ T cells migration and addition of CCL5 antibody or CCR5 antagonist significantly reversed this effect. In vivo results further showed that addition of CCR5 antagonist can reduce the cardioprotective effect of HucMSCs administration on day 7 post MI injury. CONCLUSION These findings indicated that HucMSCs contributed to cardiac functional recovery and attenuated cardiac remodeling post MI. Intramyocardial injection of HucMSCs upregulated the CD4+FoxP3+ Tregs and contributed to the migration of CD4+ T cells into the injured heart via CCL5/CCR5 pathway.
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Affiliation(s)
- Jing Liu
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Department of Burn and Plastic Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, People's Republic of China
| | - Xiaoting Liang
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, People's Republic of China
| | - Mimi Li
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Fang Lin
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Xiaoxue Ma
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Yuanfeng Xin
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
| | - Qingshu Meng
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Rulin Zhuang
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
| | - Qingliu Zhang
- Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China
| | - Wei Han
- Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China
| | - Ling Gao
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, People's Republic of China
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, People's Republic of China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, People's Republic of China
| | - Xiaohui Zhou
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China.
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China.
| | - Zhongmin Liu
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China.
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China.
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China.
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China.
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Wu Y, Zhang H, Wang S, Li L, Wang R, Jiang S. Human umbilical cord-derived stem cell sheets improve left ventricular function in rat models of ischemic heart failure. Eur J Pharmacol 2022; 925:174994. [PMID: 35513020 DOI: 10.1016/j.ejphar.2022.174994] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 04/06/2022] [Accepted: 04/28/2022] [Indexed: 02/03/2023]
Abstract
INTRODUCTION Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are among the most promising cell therapy sources used to treat ischemic heart disease. Cell sheet engineering has been used to transplant stem cells and improve their therapeutic effectiveness. We aimed to evaluate the effectiveness of UC-MSC sheets in the treatment of chronic ischemic heart failure. METHODS AND RESULTS Flow cytometric analysis showed that UC-MSCs were positive for CD73, CD90, and CD105. UC-MSC sheets were produced from UC-MSCs using temperature-responsive culture dishes. Afterward, these sheets were transplanted onto the epicardial surface at the infarct heart in rat models of chronic ischemic heart failure. At four weeks after the transplantation, echocardiography analysis revealed that the cardiac function of the UC-MSC sheets group was significantly better than that of the suspension and myocardial infarction (MI) only groups. Furthermore, histological examinations revealed that the left ventricular remodeling was attenuated compared with the suspension and MI-only groups. In the UC-MSC slice group, the neovascular den and cell size in the infarct margin region were was significantly improved than in the suspension and MI-only groups. Also, the UC-MSC sheets inhibited the PI3K/AKT/mTOR signaling pathway in chronic ischemic heart failure. CONCLUSIONS UC-MSC sheets can maintain cardiac function and attenuate ventricular remodeling in chronic ischemic heart failure, indicating that this strategy would be a promising therapeutic option in the clinical scenario.
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Affiliation(s)
- Yuanbin Wu
- Medical School of Chinese PLA, Beijing, 100853, China; Division of Adult Cardiac Surgery, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Huajun Zhang
- Division of Adult Cardiac Surgery, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Shuling Wang
- Division of Adult Cardiac Surgery, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Libing Li
- Division of Adult Cardiac Surgery, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, 100853, China
| | - Rong Wang
- Division of Adult Cardiac Surgery, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
| | - Shengli Jiang
- Division of Adult Cardiac Surgery, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
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Extraembryonic Mesenchymal Stromal/Stem Cells in Liver Diseases: A Critical Revision of Promising Advanced Therapy Medicinal Products. Cells 2022; 11:cells11071074. [PMID: 35406638 PMCID: PMC8997603 DOI: 10.3390/cells11071074] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 02/04/2023] Open
Abstract
Liver disorders have been increasing globally in recent years. These diseases are associated with high morbidity and mortality rates and impose high care costs on the health system. Acute liver failure, chronic and congenital liver diseases, as well as hepatocellular carcinoma have been limitedly treated by whole organ transplantation so far. But novel treatments for liver disorders using cell-based approaches have emerged in recent years. Extra-embryonic tissues, including umbilical cord, amnion membrane, and chorion plate, contain multipotent stem cells. The pre-sent manuscript discusses potential application of extraembryonic mesenchymal stromal/stem cells, focusing on the management of liver diseases. Extra-embryonic MSC are characterized by robust and constitutive anti-inflammatory and anti-fibrotic properties, indicating as therapeutic agents for inflammatory conditions such as liver fibrosis or advanced cirrhosis, as well as chronic inflammatory settings or deranged immune responses.
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Li M, Wu H, Yuan Y, Hu B, Gu N. Recent fabrications and applications of cardiac patch in myocardial infarction treatment. VIEW 2022. [DOI: 10.1002/viw.20200153] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Mei Li
- School of Biomedical Engineering and Informatics Nanjing Medical University Nanjing China
- The Laboratory Center for Basic Medical Sciences Nanjing Medical University Nanjing China
| | - Hao Wu
- School of Biomedical Engineering and Informatics Nanjing Medical University Nanjing China
| | - Yuehui Yuan
- School of Biomedical Engineering and Informatics Nanjing Medical University Nanjing China
| | - Benhui Hu
- School of Biomedical Engineering and Informatics Nanjing Medical University Nanjing China
| | - Ning Gu
- School of Biomedical Engineering and Informatics Nanjing Medical University Nanjing China
- State Key Laboratory of Bioelectronics Jiangsu Key Laboratory for Biomaterials and Devices School of Biological Sciences and Medical Engineering Southeast University Nanjing China
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Yu Q, Qiao GH, Wang M, Yu L, Sun Y, Shi H, Ma TL. Stem Cell-Based Therapy for Diabetic Foot Ulcers. Front Cell Dev Biol 2022; 10:812262. [PMID: 35178389 PMCID: PMC8844366 DOI: 10.3389/fcell.2022.812262] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic foot ulcer has become a worldwide clinical medical challenge as traditional treatments are not effective enough to reduce the amputation rate. Therefore, it is of great social significance to deeply study the pathogenesis and biological characteristics of the diabetic foot, explore new treatment strategies and promote their application. Stem cell-based therapy holds tremendous promise in the field of regenerative medicine, and its mechanisms include promoting angiogenesis, ameliorating neuroischemia and inflammation, and promoting collagen deposition. Studying the specific molecular mechanisms of stem cell therapy for diabetic foot has an important role and practical clinical significance in maximizing the repair properties of stem cells. In addition, effective application modalities are also crucial in order to improve the survival and viability of stem cells at the wound site. In this paper, we reviewed the specific molecular mechanisms of stem cell therapy for diabetic foot and the extended applications of stem cells in recent years, with the aim of contributing to the development of stem cell-based therapy in the repair of diabetic foot ulcers.
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Affiliation(s)
- Qian Yu
- Department of Hepatology, Songjiang Hospital Affiliated to Nanjing Medical University, Shanghai, China
| | - Guo-Hong Qiao
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Min Wang
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Li Yu
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yaoxiang Sun
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
| | - Hui Shi
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China.,Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Institute of Stem Cell, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Tie-Liang Ma
- Department of Clinical Laboratory, The Affiliated Yixing Hospital of Jiangsu University, Yixing, China
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Xiong Y, Tang R, Xu J, Jiang W, Gong Z, Zhang L, Li X, Ning Y, Huang P, Xu J, Chen G, Jin C, Li X, Qian H, Yang Y. Sequential transplantation of exosomes and mesenchymal stem cells pretreated with a combination of hypoxia and Tongxinluo efficiently facilitates cardiac repair. Stem Cell Res Ther 2022; 13:63. [PMID: 35130979 PMCID: PMC8822662 DOI: 10.1186/s13287-022-02736-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 12/17/2021] [Indexed: 02/07/2023] Open
Abstract
Background Bone marrow-derived mesenchymal stem cells (MSCs), which possess immunomodulatory characteristic, are promising candidates for the treatment of acute myocardial infarction (AMI). However, the low retention and survival rate of MSCs in the ischemic heart limit their therapeutic efficacy. Strategies either modifying MSCs or alleviating the inflammatory environment, which facilitates the recruitment and survival of the engrafted MSCs, may solve the problem. Thus, we aimed to explore the therapeutic efficacy of sequential transplantation of exosomes and combinatorial pretreated MSCs in the treatment of AMI. Methods Exosomes derived from MSCs were delivered to infarcted hearts through intramyocardial injection followed by the intravenous infusion of differentially pretreated MSCs on Day 3 post-AMI. Enzyme linked immunosorbent assay (ELISA) was performed to evaluate the inflammation level as well as the SDF-1 levels in the infarcted border zone of the heart. Echocardiography and histological analysis were performed to assess cardiac function, infarct size, collagen area and angiogenesis. Results Sequential transplantation of exosomes and the combinatorial pretreated MSCs significantly facilitated cardiac repair compared to AMI rats treated with exosomes alone. Notably, compared to the other three methods of cotransplantation, combinatorial pretreatment with hypoxia and Tongxinluo (TXL) markedly enhanced the CXCR4 level of MSCs and promoted recruitment, which resulted in better cardiac function, smaller infarct size and enhanced angiogenesis. We further demonstrated that exosomes effectively reduced apoptosis in MSCs in vitro. Conclusion Sequential delivery of exosomes and pretreated MSCs facilitated cardiac repair post-AMI, and combined pretreatment with hypoxia and TXL better enhanced the cardioprotective effects. This method provides new insight into the clinical translation of stem cell-based therapy for AMI.
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Chang D, Fan T, Gao S, Jin Y, Zhang M, Ono M. Application of mesenchymal stem cell sheet to treatment of ischemic heart disease. Stem Cell Res Ther 2021; 12:384. [PMID: 34233729 PMCID: PMC8261909 DOI: 10.1186/s13287-021-02451-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 06/07/2021] [Indexed: 12/29/2022] Open
Abstract
In recent years, mesenchymal stem cells (MSCs) have been used to improve cardiac function and attenuate adverse ventricular remodeling of the ischemic myocardium through paracrine effects and immunoregulation functions. In combination with cell sheet technology, MSCs could be more easily transplanted to the ischemic area. The long-term retention of MSCs in the affected area was realized and significantly improved the curative effect. In this review, we summarized the research and the applications of MSC sheets to the treatment of ischemic heart tissue. At present, many types of MSCs have been considered as multipotent cells in the treatment of heart failure, such as bone marrow-derived mesenchymal stem cells (BM-MSCs), adipose-derived mesenchymal stem cells (AD-MSCs), umbilical cord-derived mesenchymal stem cells (UC-MSCs), and skeletal myoblasts (SMs). Since UC-MSCs have few human leukocyte antigen-II and major histocompatibility complex class I molecules, and are easy to isolate and culture, UC-MSC sheets have been proposed as a candidate for clinical applications to ischemic heart disease.
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Affiliation(s)
- Dehua Chang
- Department of Cell Therapy in Regenerative Medicine, The University of Tokyo Hospital, 7-3-1 Honggo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Taibing Fan
- Children Heart Center, Fuwai Central China Cardiovascular Hospital, No.1 Fuwai Road, Zhengzhou, 450018, China
| | - Shuang Gao
- Research and Development Department, BOE Regenerative Medicine Technology Co., Ltd., NO.9 JiuXianQiao North Road, Beijing, 100015, China
| | - Yongqiang Jin
- Heart Center, First Hospital of Tsinghua University, NO.6 JiuXianQiao 1st Road, Beijing, 10016, China
| | - Mingkui Zhang
- Heart Center, First Hospital of Tsinghua University, NO.6 JiuXianQiao 1st Road, Beijing, 10016, China
| | - Minoru Ono
- Department of Cardiac Surgery, The University of Tokyo Hospital, 7-3-1 Honggo, Bunkyo-ku, Tokyo, 113-8655, Japan
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Fan X, He S, Song H, Yin W, Zhang J, Peng Z, Yang K, Zhai X, Zhao L, Gong H, Ping Y, Jiao X, Zhang S, Yan C, Wang H, Li RK, Xie J. Human endometrium-derived stem cell improves cardiac function after myocardial ischemic injury by enhancing angiogenesis and myocardial metabolism. Stem Cell Res Ther 2021; 12:344. [PMID: 34112245 PMCID: PMC8193887 DOI: 10.1186/s13287-021-02423-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 05/27/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND The human endometrium in premenopausal women is an active site of physiological angiogenesis, with regenerative cells present, suggesting that the endometrium contains adult angiogenic stem cells. In the context of cardiac repair after ischemic injury, angiogenesis is a crucial process to rescue cardiomyocytes. We therefore investigated whether human endometrium-derived stem cells (hEMSCs) can be used for cardiac repair after ischemic injury and their possible underlying mechanisms. METHODS Comparisons were made between hEMSCs successfully isolated from 22 premenopausal women and human bone marrow mesenchymal stem cells (hBMSCs) derived from 25 age-matched patients. Cell proliferation, migration, differentiation, and angiogenesis were evaluated through in vitro experiments, while the ability of hEMSCs to restore cardiac function was examined by in vivo cell transplantation into the infarcted nude rat hearts. RESULTS In vitro data showed that hEMSCs had greater proliferative and migratory capacities, whereas hBMSCs had better adipogenic differentiation ability. Human umbilical cord vein endothelial cells, treated with conditioned medium from hEMSCs, had significantly higher tube formation than that from hBMSCs or control medium, indicating greater angiogenic potentials for hEMSCs. In vivo, hEMSC transplantation preserved cardiac function, decreased infarct size, and improved tissue repair post-injury. Cardiac metabolism, assessed by 18F-FDG uptake, showed that 18F-FDG uptake at the infarction area was significantly higher in both hBMSC and hEMSC groups, compared to the PBS control group, with hEMSCs having the highest uptake, suggesting hEMSC treatment improves cardiomyocyte metabolism and survival after injury. Mechanistic assessment of the angiogenic potential for hEMSCS revealed that angiogenesis-related factors angiopoietin 2, Fms-like tyrosine kinase 1, and FGF9 were significantly upregulated in hEMSC-implanted infarcted hearts, compared to the PBS control group. CONCLUSION hEMSCs, compared to hBMSCs, have greater capacity to induce angiogenesis, and improved cardiac function after ischemic injury.
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Affiliation(s)
- Xuemei Fan
- grid.263452.40000 0004 1798 4018The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China ,grid.263452.40000 0004 1798 4018Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, The Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Sheng He
- grid.263452.40000 0004 1798 4018The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China ,grid.452461.00000 0004 1762 8478The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Huifang Song
- grid.263452.40000 0004 1798 4018The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Wenjuan Yin
- grid.263452.40000 0004 1798 4018The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Jie Zhang
- grid.263452.40000 0004 1798 4018The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Zexu Peng
- grid.263452.40000 0004 1798 4018The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Kun Yang
- grid.263452.40000 0004 1798 4018The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China ,grid.263452.40000 0004 1798 4018Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, The Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiaoyan Zhai
- grid.263452.40000 0004 1798 4018The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Lingxia Zhao
- grid.263452.40000 0004 1798 4018Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, The Third Hospital of Shanxi Medical University, Taiyuan, China
| | - Hui Gong
- grid.263452.40000 0004 1798 4018The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Yi Ping
- grid.452845.aThe Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Xiangying Jiao
- grid.263452.40000 0004 1798 4018The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Sanyuan Zhang
- grid.452461.00000 0004 1762 8478The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Changping Yan
- grid.452461.00000 0004 1762 8478The First Hospital of Shanxi Medical University, Taiyuan, China
| | - Hongliang Wang
- grid.452461.00000 0004 1762 8478The First Hospital of Shanxi Medical University, Taiyuan, China ,grid.263452.40000 0004 1798 4018Key Laboratory of Molecular Imaging, Molecular Imaging Precision Medicine Collaborative Innovation Center, Shanxi Medical University, Taiyuan, China
| | - Ren-Ke Li
- Toronto General Hospital Research Institute, University Health Network, Toronto, Canada.
| | - Jun Xie
- The Laboratory of Stem Cell Regenerative Medicine Research, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Cell Physiology of Ministry of Education, Shanxi Medical University, Taiyuan, China.
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Jiang Z, Li N, Zhu D, Ren L, Shao Q, Yu K, Yang G. Genetically modified cell sheets in regenerative medicine and tissue engineering. Biomaterials 2021; 275:120908. [PMID: 34119885 DOI: 10.1016/j.biomaterials.2021.120908] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 05/16/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023]
Abstract
Genetically modified cell sheet technology is emerging as a promising biomedical tool to deliver therapeutic genes for regenerative medicine and tissue engineering. Virus-based gene transfection and non-viral gene transfection have been used to fabricate genetically modified cell sheets. Preclinical and clinical studies have shown various beneficial effects of genetically modified cell sheets in the regeneration of bone, periodontal tissue, cartilage and nerves, as well as the amelioration of dental implant osseointegration, myocardial infarction, skeletal muscle ischemia and kidney injury. Furthermore, this technology provides a potential treatment option for various hereditary diseases. However, the method has several limitations, such as safety concerns and difficulties in controlling transgene expression. Therefore, recent studies explored efficient and safe gene transfection methods, prolonged and controllable transgene expression and their potential application in personalized and precision medicine. This review summarizes various types of genetically modified cell sheets, preparation procedures, therapeutic applications and possible improvements.
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Affiliation(s)
- Zhiwei Jiang
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China
| | - Na Li
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China
| | - Danji Zhu
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China
| | - Lingfei Ren
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China
| | - Qin Shao
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China
| | - Ke Yu
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China
| | - Guoli Yang
- The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, Zhejiang, 310006, China.
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