Extracellular vesicle-mimetic nanovesicles transport LncRNA-H19 as competing endogenous RNA for the treatment of diabetic wounds

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Abstract

Diabetic wounds, one of the most enervating complications of diabetes mellitus, affect millions of people worldwide annually. Vascular insufficiency, caused by hyperglycemia, is one of the primary causes and categories of diabetic impaired wound healing. Recently, long noncoding RNA (LncRNA)-H19, which is significantly decreased in diabetes and may be crucial in triggering angiogenesis, has attracted increasing interest. The possible relationship between the decrease of LncRNA-H19 and the impairment of angiogenesis in diabetes could involve impairment of the insulin–phosphatidylinositol 3-kinase (PI3K)–Akt pathway via the interdiction of LncRNA-H19. Thus, a therapeutic strategy utilizing LncRNA-H19 delivery is feasible. In this study, we investigated the possibility of using high-yield extracellular vesicle-mimetic nanovesicles (EMNVs) as an effective nano-drug delivery system for LncRNA, and studied the function of EMNVs with a high content of LncRNA-H19 ( ^H19EMNVs). The results, which were exciting, showed that ^H19EMNVs had a strong ability to neutralize the regeneration-inhibiting effect of hyperglycemia, and could remarkably accelerate the healing processes of chronic wounds. Our results suggest that bioengineered EMNVs can serve as a powerful instrument to effectively deliver LncRNA and will be an extremely promising multifunctional drug delivery system in the immediate future.

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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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Role of Akt signaling in vascular homeostasis and angiogenesis.

Ichiro Shiojima, Kenneth Walsh (2002)

Akt is a serine/threonine protein kinase that is activated by a number of growth factors and cytokines in a phosphatidylinositol-3 kinase-dependent manner. Although antiapoptotic activity of Akt is well known, it also regulates other aspects of cellular functions, including migration, glucose metabolism, and protein synthesis. In this review, Akt signaling in endothelial cells and its critical roles in the regulation of vascular homeostasis and angiogenesis will be discussed.

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Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway

Jieyuan Zhang, Xiaolin Liu, Haiyan Li … (2016)

Background Recently, accumulating evidence has shown that exosomes, the naturally secreted nanocarriers of cells, can exert therapeutic effects in various disease models in the absence of parent cells. However, application of exosomes in bone defect repair and regeneration has been rarely reported, and little is known regarding their underlying mechanisms. Methods Exosomes derived from human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPS-MSC-Exos) were combined with tricalcium phosphate (β-TCP) to repair critical-sized calvarial bone defects, and the efficacy was assessed by histological examination. We evaluated the in vitro effects of hiPSC-MSC-Exos on the proliferation, migration, and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) by cell-counting, scratch assays, and qRT-PCR, respectively. Gene expression profiling and bioinformatics analyses were also used to identify the underlying mechanisms in the repair. Results We found that the exosome/β-TCP combination scaffolds could enhance osteogenesis as compared to pure β-TCP scaffolds. In vitro assays showed that the exosomes could release from β-TCP and could be internalized by hBMSCs. In addition, the internalization of exosomes into hBMSCs could profoundly enhance the proliferation, migration, and osteogenic differentiation of hBMSCs. Furthermore, gene expression profiling and bioinformatics analyses demonstrated that exosome/β-TCP combination scaffolds significantly altered the expression of a network of genes involved in the PI3K/Akt signaling pathway. Functional studies further confirmed that the PI3K/Akt signaling pathway was the critical mediator during the exosome-induced osteogenic responses of hBMSCs. Conclusions We propose that the exosomes can enhance the osteoinductivity of β-TCP through activating the PI3K/Akt signaling pathway of hBMSCs, which means that the exosome/β-TCP combination scaffolds possess better osteogenesis activity than pure β-TCP scaffolds. These results indicate that naturally secreted nanocarriers-exosomes can be used as a bioactive material to improve the bioactivity of the biomaterials, and that hiPS-MSC-Exos combined with β-TCP scaffolds can be potentially used for repairing bone defects. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0391-3) contains supplementary material, which is available to authorized users.

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Author and article information

Journal

Journal ID (nlm-ta): Drug Deliv

Journal ID (iso-abbrev): Drug Deliv

Journal ID (publisher-id): IDRD

Journal ID (publisher-id): idrd20

Title: Drug Delivery

Publisher: Taylor & Francis

ISSN (Print): 1071-7544

ISSN (Electronic): 1521-0464

Publication date Collection: 2018

Publication date (Electronic): 15 January 2018

Volume: 25

Issue: 1

Pages: 241-255

Affiliations

[a ]Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital , Shanghai, China;

[b ]Department of Pharmacy, Shanghai Tenth People’s Hospital of Tongji University , Shanghai, China;

[c ]Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital , Shanghai, China

Author notes

[*]

Co-first authors: These authors contributed equally to this work.

Supplemental data for this article can be accessed here .

CONTACT Shang-Chun Guo achuni@ 123456126.com Institute of Microsurgery on Extremities, Shanghai Jiao Tong University Affiliated Sixth People's Hospital , 600 Yishan Road, Shanghai200233, China;

Yang Zhang zy_benjamin@ 123456163.com Department of Pharmacy, Shanghai Tenth People's Hospital of Tongji University , 301 Yanchang Road, Shanghai200072, China

Article

Publisher ID: 1425774

DOI: 10.1080/10717544.2018.1425774

PMC ID: 6058500

PubMed ID: 29334272

SO-VID: 0b2de45b-18d6-4398-a982-2dbe1aacb371

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 20 October 2017

Date revision received : 26 December 2017

Date accepted : 05 January 2018

Page count

Pages: 15, Words: 9954

Funding

Funded by: National Natural Science Foundation of China 10.13039/501100001809

Award ID: 81301589

Award ID: 81272003

Award ID: 81472066

Award ID: 2014ZYJB0301

Award ID: 201402016

This work was supported by the National Natural Science Foundation of China [Grant No.81301589, 81272003 and 81472066]. This work was also supported by Joint Project Funding for Major Diseases in Shanghai [Grant No.2014ZYJB0301] and the NHFPC Special Fund for Health Scientific Research in the Public Welfare (NO. 201402016).

Extracellular vesicle-mimetic nanovesicles transport LncRNA-H19 as competing endogenous RNA for the treatment of diabetic wounds

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RNA drug delivery

Most cited references 52

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

Role of Akt signaling in vascular homeostasis and angiogenesis.

Exosomes/tricalcium phosphate combination scaffolds can enhance bone regeneration by activating the PI3K/Akt signaling pathway

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