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      Fabrication of Tβ4-Exosome-releasing artificial stem cells for myocardial infarction therapy by improving coronary collateralization

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          Abstract

          Currently, stem cell transplantations in cardiac repair are limited owing to disadvantages, such as immunological rejection and poor cell viability. Although direct injection of exosomes can have a curative effect similar to that of stem cell transplantation, high clearance hinders its application in clinical practice. Previous reports suggested that induction of coronary collateralization can be a desired method of adjunctive therapy for someone who had missed the optimal operation time to attenuate myocardial ischemia. In this study, to mimic the paracrine and biological activity of stem cells, we developed artificial stem cells that can continuously release Tβ4-exosomes (Tβ4-ASCs) by encapsulating specific exosomes within microspheres using microfluidics technology. The results show that Tβ4-ASCs can greatly promote coronary collateralization in the periphery of the myocardial infarcted area, and its therapeutic effect is superior to that of directly injecting the exosomes. In addition, to better understand how it works, we demonstrated that the Tβ4-ASC-derived exosomes can enhance the angiogenic capacity of coronary endothelial cells (CAECs) via the miR-17-5p/PHD3/Hif-1α pathway. In brief, as artificial stem cells, Tβ4-ASCs can constantly release functional exosomes and stimulate the formation of collateral circulation after myocardial infarction, providing a feasible and alternative method for clinical revascularization.

          Graphical abstract

          Tβ4-ASCs, an artificial stem cells developed by combining microspheres and engineered exosomes, can release Tβ4-exosomes slowly and continuously in myocardial infarcted area. Specific Tβ4-EXOs released constantly from Tβ4-ASCs can enhance the formation of coronary collateralization by promoting the angiogenesis of coronary artery endothelial cells (CAECs), meeting the requirements of precision medicine.

          Highlights

          • •

            Inspired by the paracrine of stem cells, we fabricated artificial stem cells (Tβ4-ASCs) by loading engineered Tβ4-exosomes with microspheres using microfluidics technology.

          • •

            Tβ4-ASCs stimulate the formation of coronary collateralization in myocardial infarcted area through a slowly sustained release of engineered Tβ4-exosomes.

          • •

            Tβ4-ASCs improve coronary collateralization via the miR-17-5p/PHD3/Hif-1α signaling pathway.

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          Glypican-1 identifies cancer exosomes and detects early pancreatic cancer.

          A. Melo, Linda Luecke, Christoph Kahlert … (2015)
          Exosomes are lipid-bilayer-enclosed extracellular vesicles that contain proteins and nucleic acids. They are secreted by all cells and circulate in the blood. Specific detection and isolation of cancer-cell-derived exosomes in the circulation is currently lacking. Using mass spectrometry analyses, we identify a cell surface proteoglycan, glypican-1 (GPC1), specifically enriched on cancer-cell-derived exosomes. GPC1(+) circulating exosomes (crExos) were monitored and isolated using flow cytometry from the serum of patients and mice with cancer. GPC1(+) crExos were detected in the serum of patients with pancreatic cancer with absolute specificity and sensitivity, distinguishing healthy subjects and patients with a benign pancreatic disease from patients with early- and late-stage pancreatic cancer. Levels of GPC1(+) crExos correlate with tumour burden and the survival of pre- and post-surgical patients. GPC1(+) crExos from patients and from mice with spontaneous pancreatic tumours carry specific KRAS mutations, and reliably detect pancreatic intraepithelial lesions in mice despite negative signals by magnetic resonance imaging. GPC1(+) crExos may serve as a potential non-invasive diagnostic and screening tool to detect early stages of pancreatic cancer to facilitate possible curative surgical therapy.
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            Engineering Bioactive Self-Healing Antibacterial Exosomes Hydrogel for Promoting Chronic Diabetic Wound Healing and Complete Skin Regeneration

            Chenggui Wang, Min Wang, Tianzhen Xu … (2019)
            Rationale: Chronic nonhealing diabetic wound therapy and complete skin regeneration remains a critical clinical challenge. The controlled release of bioactive factors from a multifunctional hydrogel was a promising strategy to repair chronic wounds. Methods: Herein, for the first time, we developed an injectable, self-healing and antibacterial polypeptide-based FHE hydrogel (F127/OHA-EPL) with stimuli-responsive adipose-derived mesenchymal stem cells exosomes (AMSCs-exo) release for synergistically enhancing chronic wound healing and complete skin regeneration. The materials characterization, antibacterial activity, stimulated cellular behavior and in vivo full-thickness diabetic wound healing ability of the hydrogels were performed and analyzed. Results: The FHE hydrogel possessed multifunctional properties including fast self-healing process, shear-thinning injectable ability, efficient antibacterial activity, and long term pH-responsive bioactive exosomes release behavior. In vitro, the FHE@exosomes (FHE@exo) hydrogel significantly promoted the proliferation, migration and tube formation ability of human umbilical vein endothelial cells (HUVECs). In vivo, the FHE@exo hydrogel significantly enhanced the healing efficiency of diabetic full-thickness cutaneous wounds, characterized with enhanced wound closure rates, fast angiogenesis, re-epithelization and collagen deposition within the wound site. Moreover, the FHE@exo hydrogel displayed better healing outcomes than those of exosomes or FHE hydrogel alone, suggesting that the sustained release of exosomes and FHE hydrogel can synergistically facilitate diabetic wound healing. Skin appendages and less scar tissue also appeared in FHE@exo hydrogel treated wounds, indicating its potent ability to achieve complete skin regeneration. Conclusion: This work offers a new approach for repairing chronic wounds completely through a multifunctional hydrogel with controlled exosomes release.
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              Acute Myocardial Infarction.

              Jeffrey Anderson, David A Morrow (2017)
              Article 0 comments Cited 303 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Yaobin Wu
                Caiwen Ou
                Minsheng Chen
                Journal
                Journal ID (nlm-ta): Bioact Mater
                Journal ID (iso-abbrev): Bioact Mater
                Title: Bioactive Materials
                Publisher: KeAi Publishing
                ISSN (Electronic): 2452-199X
                Publication date PMC-release: 29 January 2022
                Publication date Collection: August 2022
                Publication date (Electronic): 29 January 2022
                Volume: 14
                Pages: 416-429
                Affiliations
                [a ]Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, Department of Cardiology and Laboratory of Heart Center, Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Zhujiang Hospital, Southern Medical University, Guangzhou, 510280, China
                [b ]Biomaterials Research Center, School of Biomedical Engineering, Southern Medical University, Guangzhou, 510515, China
                [c ]Guangdong Engineering Research Center for Translation of Medical 3D Printing Application, Guangdong Provincial Key Laboratory of Medical Biomechanics, National Key Discipline of Human Anatomy, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China
                Author notes
                [∗ ]Corresponding author. oucaiwen@ 123456smu.edu.cn
                [∗∗ ]Corresponding author. wuyaobin2018@ 123456smu.edu.cn
                [∗∗∗ ]Corresponding author. gzminsheng@ 123456vip.163.com
                Article
                Publisher Item ID: S2452-199X(22)00040-8
                DOI: 10.1016/j.bioactmat.2022.01.029
                PMC ID: 8964820
                PubMed ID: 35386821
                SO-VID: 414340a2-2b3c-41a1-a006-d8355d9996e7
                Copyright © © 2022 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 7 November 2021
                Date revision received : 16 January 2022
                Date accepted : 17 January 2022
                Categories
                Subject: Article

                Keywords: artificial stem cells,exosomes,myocardial infarction,coronary collateralization
                Data availability:
                Keywords: artificial stem cells, exosomes, myocardial infarction, coronary collateralization

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