Cell-mediated delivery of VEGF modified mRNA enhances blood vessel regeneration and ameliorates murine critical limb ischemia

Yu, Ziyou; Witman, Nevin; Wang, Wenbo; Liu, Dong; Yan, Bingqian; Deng, Mingwu; Wang, Xiangsheng; Wang, Huijing; Zhou, Guangdong; Liu, Wei; Sahara, Makoto; Cao, Yilin; Fritsche‐Danielson, Regina; Zhang, Wenjie; Fu, Wei; Chien, Kenneth R.

doi:10.1016/j.jconrel.2019.08.014

Cited by 43 publications

(52 citation statements)

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“…(*p † < 0.05, **p † < 0.01) exhibit burst-like therapeutic expression levels of VEGF protein in vivo before the loss of transplanted cells caused by initial ischemia, which has been reported ( Fig. 1g and 4b) [23,56].…”

Section: Discussionsupporting

confidence: 62%

“…For example, the delivery and expression kinetics of modRNAs are met with high biocompatibility and low immunogenicity (Figs. 1and 2) [20,23]. In addition, modRNA constructs are synthetically derived and can therefore be produced quickly and in large-scale format for applied and pre-clinical research in animal models of disease [57,58].…”

Section: Discussionmentioning

confidence: 99%

“…modRNA synthesis and formulation modRNA was synthesized in vitro using T7 RNA polymerase-mediated transcription from a linearized DNA template, which incorporated generic 5′ and 3′ UTRs and a poly-A tail, as previously described [23,28,29]. During the in vitro transcription reaction, we fully replaced uridine with N1-methylpseudouridine.…”

Section: Isolation and Culture Of Human Adipose-derived Stem Cells (Hmentioning

confidence: 99%

“…All experimental protocols were approved by the Animal Care and Experiment Committee of the Shanghai Ninth People's Hospital. Three mice were used for the implantation of Matrigel plugs as previously described [23]. In brief, ice-cold Matrigel (BD Biosciences, San Jose, CA, USA) (200 μL per plug) was mixed with 50 μL PBS or hADSCs (1 × 10 6 cells in 50 μL PBS) and then injected subcutaneously into the dorsal region of mice (each mouse received three plugs in total from the different groups).…”

Section: Matrigel Plug Assaymentioning

confidence: 99%

“…Moreover, a recent clinical study also suggested that intradermal injection of VEGF modRNA (modVEGF) was well tolerated in men with type 2 diabetes mellitus (T2DM), where the delivery induced local functional VEGF protein expression leading to increased dermal blood flow [22]. More recently, Yu et al applied a cell-mediated modVEGF delivery system employing human fibroblasts to treat critical limb ischemia (CLI) [23]. In this aforementioned study by Yu et al, a cell-mediated approach for protein delivery through modRNAs revealed enhanced tissue regeneration when compared to the naked delivery of mod-VEGF alone by extending the window of expression and increasing the therapeutic potency of the protein, ultimately giving rise to healthier blood vessels.…”

Section: Introductionmentioning

confidence: 99%

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Human adipose-derived stem cells enriched with VEGF-modified mRNA promote angiogenesis and long-term graft survival in a fat graft transplantation model

Witman

Yan

et al. 2020

Stem Cell Res Ther

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Background Fat grafting, as a standard treatment for numerous soft tissue defects, remains unpredictable and technique-dependent. Human adipose-derived stem cells (hADSCs) are promising candidates for cell-assisted therapy to improve graft survival. As free-living fat requires nutritional and respiratory sources to thrive, insufficient and unstable vascularization still impedes hADSC-assisted therapy. Recently, cytotherapy combined with modified mRNA (modRNA) encoding vascular endothelial growth factor (VEGF) has been applied for the treatment of ischemia-related diseases. Herein, we hypothesized that VEGF modRNA (modVEGF)-engineered hADSCs could robustly enhance fat survival in a fat graft transplantation model. Methods hADSCs were acquired from lipoaspiration and transfected with modRNAs. Transfection efficiency and expression kinetics of modRNAs in hADSCs were first evaluated in vitro. Next, we applied an in vivo Matrigel plug assay to assess the viability and angiogenic potential of modVEGF-engineered hADSCs at 1 week post-implantation. Finally, modVEGF-engineered hADSCs were co-transplanted with human fat in a murine model to analyze the survival rate, re-vascularization, proliferation, fibrosis, apoptosis, and necrosis of fat grafts over long-term follow-up. Results Transfections of modVEGF in hADSCs were highly tolerable as the modVEGF-engineered hADSCs facilitated burst-like protein production of VEGF in both our in vitro and in vivo models. modVEGF-engineered hADSCs induced increased levels of cellular proliferation and proangiogenesis when compared to untreated hADSCs in both ex vivo and in vivo assays. In a fat graft transplantation model, we provided evidence that modVEGF-engineered hADSCs promote the optimal potency to preserve adipocytes, especially in the long-term post-transplantation phase. Detailed histological analysis of fat grafts harvested at 15, 30, and 90 days following in vivo grafting suggested the release of VEGF protein from modVEGF-engineered hADSCs significantly improved neo-angiogenesis, vascular maturity, and cell proliferation. The modVEGF-engineered hADSCs also significantly mitigated the presence of fibrosis, apoptosis, and necrosis of grafts when compared to the control groups. Moreover, modVEGF-engineered hADSCs promoted graft survival and cell differentiation abilities, which also induced an increase in vessel formation and the number of surviving adipocytes after transplantation. Conclusion This current study demonstrates the employment of modVEGF-engineered hADSCs as an advanced alternative to the clinical treatment involving soft-tissue reconstruction and rejuvenation.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Section: Isolation and Culture Of Human Adipose-derived Stem Cells (Hmentioning

confidence: 99%

Section: Matrigel Plug Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human adipose-derived stem cells enriched with VEGF-modified mRNA promote angiogenesis and long-term graft survival in a fat graft transplantation model

Witman

Yan

et al. 2020

Stem Cell Res Ther

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ROS‐Responsive Injectable Hydrogel Loaded with SLC7A11‐modRNA Inhibits Ferroptosis and Mitigates Intervertebral Disc Degeneration in Rats

Gao,

Xu,

et al. 2024

Adv Healthcare Materials

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Intervertebral disc degeneration (IVDD) is the primary cause of low back pain, with oxidative stress being a recognized factor that causes its development. Presently, low back pain imposes a significant global economic burden. However, the effectiveness of treatments for IVDD remains extremely limited. Therefore, this study aims to explore innovative and effective IVDD treatments by focusing on oxidative stress as a starting point. In this study, an injectable reactive oxygen species‐responsive hydrogel (PVA‐tsPBA@SLC7A11 modRNA) is developed, designed to achieve rapid loading and selective release of chemically synthesized modified mRNA (modRNA). SLC7A11 modRNA is specifically used to upregulate the expression of the ferroptosis marker SLC7A11. The local injection of PVA‐tsPBA@SLC7A11 modRNA into the degenerated intervertebral disc results in the cleavage of PVA‐tsPBA, leading to the release of enclosed SLC7A11 modRNA. The extent of SLC7A11 modRNA release is directly proportional to the severity of IVDD, ultimately ameliorating IVDD by inhibiting ferroptosis in nucleus pulposus cells. This study proposes an innovative system of PVA‐tsPBA hydrogel‐encapsulated modRNA, representing a potential novel treatment strategy for patients with early‐stage IVDD.This article is protected by copyright. All rights reserved

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Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery

Huang,

Deng,

Wang

et al. 2023

Advanced Materials

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Messenger RNA (mRNA)‐based therapy has emerged as a powerful, safe, and rapidly scalable therapeutic approach that involves technologies for both mRNA itself and the delivery vehicle. Although there are some unique challenges for different applications of mRNA therapy, a common challenge for all mRNA therapeutics is the transport of mRNA into the target cell cytoplasm for sufficient protein expression. This review is focused on the behaviors at the cellular level of nanotechnology‐mediated mRNA delivery systems, which have not been comprehensively reviewed yet. First, the four main therapeutic applications of mRNA are introduced, including immunotherapy, protein replacement therapy, genome editing, and cellular reprogramming. Second, common types of mRNA cargos and mRNA delivery systems are summarized. Third, strategies to enhance mRNA delivery efficiency during the cellular trafficking process are highlighted, including accumulation to the cell, internalization into the cell, endosomal escape, release of mRNA from the nanocarrier, and translation of mRNA into protein. Finally, the challenges and opportunities for the development of nanotechnology‐mediated mRNA delivery systems are presented. This review can provide new insights into the future fabrication of mRNA nanocarriers with desirable cellular trafficking performance.

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Cell-mediated delivery of VEGF modified mRNA enhances blood vessel regeneration and ameliorates murine critical limb ischemia

Cited by 43 publications

References 43 publications

Human adipose-derived stem cells enriched with VEGF-modified mRNA promote angiogenesis and long-term graft survival in a fat graft transplantation model

Human adipose-derived stem cells enriched with VEGF-modified mRNA promote angiogenesis and long-term graft survival in a fat graft transplantation model

ROS‐Responsive Injectable Hydrogel Loaded with SLC7A11‐modRNA Inhibits Ferroptosis and Mitigates Intervertebral Disc Degeneration in Rats

Cellular Trafficking of Nanotechnology‐Mediated mRNA Delivery

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