Ultrasound-Responsive Micelle-Encapsulated Mesenchymal Stem Cell-Derived EVs for the Treatment of Lower Limb Microcirculation Disease

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Abstract

Lower limb microcirculatory ischemic disease is a vascular disorder primarily characterized by limb pain, gangrene, and potential amputation. It can be caused by various factors, such as hyperglycemia, atherosclerosis, and infection. Due to the extremely narrow luminal diameter in lower limb microcirculatory ischemic lesions, both surgical and medical interventions face challenges in achieving satisfactory therapeutic outcomes within the microvessels. Extracellular vesicles derived from mesenchymal stem cells (MSCs-EVs) exhibit promising potential in the treatment of microcirculation ischemic lesions due to their small size and ability to promote angiogenesis. After undergoing substantial losses during the process of EVs transportation, only a minimal fraction of EVs can effectively reach the site of microcirculatory lesions, thereby compromising the therapeutic efficacy for microcirculatory disorders. Herein, an ultrasound-responsive system utilizing 2-(dimethylamino)ethyl methacrylate- b-2-tetrahydropyranyl methacrylate (DMAEMA- b-THPMA) micelles to encapsulate MSCs-EVs has been successfully constructed, with the aim of achieving localized and targeted release of EVs at the site of microcirculatory lesions. The reversible addition–fragmentation chain transfer (RAFT) polymerization method facilitates the successful synthesis of diblock copolymers comprising monomer 2-(dimethylamino)ethyl methacrylate (DMAEMA) and monomer 2-tetrahydropyranyl methacrylate (THPMA). The DMAEMA- b-THPMA micelles exhibit a nanoscale structure, reliable biocompatibility, ultrasound responsiveness, and conspicuous protection of EVs. Furthermore, the implementation of low-energy-density ultrasound can enhance angiogenesis by upregulating the levels of the vascular endothelial growth factor (VEGF). In in vivo experiments, the ultrasound-responsive system of the DMAEMA- b-THPMA micelles and MSCs-EVs synergistically enhances therapeutic efficacy by promoting angiogenesis, improving vascular permeability, and optimizing vascular. In conclusion, this work demonstrates bioapplication of an ultrasound-responsive micellar nanosystem loaded with EVs for the treatment of lower limb microcirculatory ischemic disorders.

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Most cited references 57

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Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model

Shi-Cong Tao, TING YUAN, Yue-Lei Zhang … (2017)

OBJECTIVES: Osteoarthritis (OA) is the most common joint disease throughout the world. Exosomes derived from miR-140-5p-overexpressing synovial mesenchymal stem cells (SMSC-140s) may be effective in treating OA. We hypothesized that exosomes derived from SMSC-140 (SMSC-140-Exos) would enhance the proliferation and migration abilities of articular chondrocytes (ACs) without harming extracellular matrix (ECM) secretion. METHODS: SMSCs were transfected with or without miR-140-5p. Exosomes derived from SMSCs or SMSC-140s (SMSC-Exos or SMSC-140-Exos) were isolated and identified. Proliferation, migration and ECM secretion were measured in vitro and compared between groups. The mechanism involving alternative Wnt signalling and activation of Yes-associated protein (YAP) was investigated using lentivirus, oligonucleotides or chemical drugs. The preventative effect of exosomes in vivo was measured using Safranin-O and Fast green staining and immunohistochemical staining. RESULTS: Wnt5a and Wnt5b carried by exosomes activated YAP via the alternative Wnt signalling pathway and enhanced proliferation and migration of chondrocytes with the side-effect of significantly decreasing ECM secretion. Highly-expressed miR-140-5p blocked this side-effect via RalA. SMSC-140-Exos enhanced the proliferation and migration of ACs without damaging ECM secretion in vitro, while in vivo, SMSC-140-Exos successfully prevented OA in a rat model. CONCLUSIONS: These findings highlight the promising potential of SMSC-140-Exos in preventing OA. We first found a potential source of exosomes and studied their merits and shortcomings. Based on our understanding of the molecular mechanism, we overcame the shortcomings by modifying the exosomes. Such exosomes derived from modified cells hold potential as future therapeutic strategies.

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Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling.

Johnathon Anderson, Henrik Johansson, Calvin S Graham … (2016)

Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.

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Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery

Sophia G Antimisiaris, Spyridon Mourtas, Antonia Marazioti (2018)

The similarities between exosomes and liposomes, together with the high organotropism of several types of exosomes, have recently prompted the development of engineered-exosomes or exosome-mimetics, which may be artificial (liposomal) or cell-derived vesicles, as advanced platforms for targeted drug delivery. Here, we provide the current state-of-the-art of using exosome or exosome-inspired systems for drug delivery. We review the various approaches investigated and the shortcomings of each approach. Finally the challenges which have been identified to date in this field are summarized.

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Author and article information

Journal

Journal ID (nlm-ta): ACS Omega

Journal ID (iso-abbrev): ACS Omega

Journal ID (publisher-id): ao

Journal ID (coden): acsodf

Title: ACS Omega

Publisher: American Chemical Society

ISSN (Electronic): 2470-1343

Publication date (Electronic): 11 December 2023

Publication date Collection: 26 December 2023

Volume: 8

Issue: 51

Pages: 49406-49419

Affiliations

[† ]The Fifth Affiliated Hospital of Zhengzhou University , Zhengzhou 450001, Henan, China

[‡ ]College of Materials and Chemical Engineering, West Anhui University , Luan 237012, Anhui, China

[§ ]The First Affiliated Hospital of Lanzhou University , Lanzhou 730000, Gansu, China

Author notes

[* ]Email: hnxgwk@ 123456126.com .

Author information

Peng Guo https://orcid.org/0009-0002-2573-9920

Article

DOI: 10.1021/acsomega.3c08133

PMC ID: 10753545

SO-VID: f79276d7-6f1b-4b2c-ad3c-f1c4e9a2e8dd

License:

Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 17 October 2023

Date accepted : 27 November 2023

Date revision received : 25 November 2023

Funding

Funded by: University Natural Science Research Project of Anhui Province, doi 10.13039/501100009558;

Award ID: KJ2021A0942

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document-id-old-9 ao3c08133

document-id-new-14 ao3c08133

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