Transient secretion of VEGF protein from transplanted hiPSC-CMs enhances engraftment and improves rat heart function post MI

Ai, Xuefeng; Yan, Bingqian; Witman, Nevin; Gong, Yiqi; Li, Yang; Tan, Yong; Chen, Ying; Liu, Minglu; Lu, Tingting; Luo, Runjiao; Wang, Huijing; Chien, Kenneth R.; Wang, Wei; Fu, Wei

doi:10.1016/j.ymthe.2022.08.012

Cited by 26 publications

(26 citation statements)

References 71 publications

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“…Ideal carriers should have the ability to deliver modRNA to specific cell types and permit significant transgene expression for a specified duration in order to attain a satisfactory therapeutic effect, while avoiding activation from host immune responses, and/or by exhibiting ‘stealth’ features for optimal safety. A common delivery agent of choice for many RNA studies has been lipid nanoparticles (such as commercial transfection reagents RNAiMAX and MessengerMAX), which effectively express exogenous genes with high efficiency [ 20 , 26 , 53 , 54 , 55 ]. However, cytotoxic side effects of lipid nanoparticle delivery systems are common.…”

Section: Resultsmentioning

confidence: 99%

Safe and Effective Delivery of mRNA Using Modified PEI-Based Lipopolymers

Wang

Liu

et al. 2023

Pharmaceutics

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Chemically modified mRNA (modRNA) has proven to be a versatile tool for the treatment of various cancers and infectious diseases due to recent technological advancements. However, a safe and effective delivery system to overcome the complex extracellular and intracellular barriers is required in order to achieve higher therapeutic efficacy and broaden clinical applications. Here, we explored All-Fect and Leu-Fect C as novel transfection reagents derived from lipopolymers, which demonstrated excellent biocompatibility, efficient delivery capabilities, and a robust ability to escape the lysosomes. These properties directly increase mRNA stability by preventing mRNA degradation by nucleases and simultaneously promote efficient gene translation in vitro and in vivo. The modRNA delivered with lipopolymer vectors sustained effective transfection in mouse hearts following direct intramyocardial injection, as well as in major organs (liver and spleen) after systemic administration. No observable immune reactions or systemic toxicity were detected following the systemic administration of lipopolymer-mRNA complexes to additional solid organs. This study identified commercial reagents for the effective delivery of modRNA and may help facilitate the advancement of gene-based interventions involving the safe and effective delivery of nucleic acid drug substances.

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Section: Resultsmentioning

confidence: 99%

Safe and Effective Delivery of mRNA Using Modified PEI-Based Lipopolymers

Wang

Liu

et al. 2023

Pharmaceutics

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“… 34,35 In our previous studies, we incorporated m1ψ as a substitute for uridine‐5‐triphosphate in the mRNA molecules. These modifications have been demonstrated to enhance mRNA stability and improve protein secretion in various mRNA molecules 30,36–38 . Subsequently, we aimed to assess the efficiency of lipid‐mediated transfection of modRNA molecules encoding TGF‐β3, and IL‐10 (modGFP, modTGF‐β3, and modIL‐10) in hADSCs.…”

Section: Resultsmentioning

confidence: 99%

“…In recent studies, our team has documented the advantageous outcomes of a cell‐based mRNA delivery platform for enhancing therapeutic applications in limb ischemia, myocardial infarction, bone defects, corneal injury, and improvement of fat grafting. These studies have yielded promising results 30,36–38,50 . As an exploration in the field of scar‐less healing, we developed ADSCs dual , which can continuously express IL‐10 and TGF‐β3 using liposomal transient transfection of modRNA IL‐10 and TGF‐β3.…”

Section: Discussionmentioning

confidence: 99%

Adipose‐derived stem cells enriched with therapeutic mRNA TGF‐β3 and IL‐10 synergistically promote scar‐less wound healing in preclinical models

Wang,

Chen,

Zhang

et al. 2023

Bioengineering & Transla Med

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Skin wound healing often leads to scar formation, presenting physical and psychological challenges for patients. Advancements in messenger RNA (mRNA) modifications offer a potential solution for pulsatile cytokine delivery to create a favorable wound‐healing microenvironment, thereby preventing cutaneous fibrosis. This study aimed to investigate the effectiveness of human adipose‐derived stem cells (hADSCs) enriched with N1‐methylpseudouridine (m1ψ) modified transforming growth factor‐β3 (TGF‐β3) and interleukin‐10 (IL‐10) mRNA in promoting scar‐free healing in preclinical models. The results demonstrated that the modified mRNA (modRNA)‐loaded hADSCs efficiently and temporarily secreted TGF‐β3 and IL‐10 proteins. In a dorsal injury model, hADSCs loaded with modRNA TGF‐β3 and IL‐10 exhibited multidimensional therapeutic effects, including improved collagen deposition, extracellular matrix organization, and neovascularization. In vitro experiments confirmed the ability of these cells to markedly inhibit the proliferation and migration of keloid fibroblasts, and reverse the myofibroblast phenotype. Finally, collagen degradation mediated by matrix metalloproteinase upregulation was observed in an ex vivo keloid explant culture model. In conclusion, the synergistic effects of the modRNA TGF‐β3, IL‐10, and hADSCs hold promise for establishing a scar‐free wound‐healing microenvironment, representing a robust foundation for the management of wounds in populations susceptible to scar formation.

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“…The potential impact of this study, however, extends beyond the consequences for embryonic development. Stem-cell-based therapies are considered to be one of the possible groundbreaking solutions for degenerative diseases such as type 1 diabetes, Parkinson’s, and heart failure, as they can be differentiated into virtually any somatic cell type [ 64 , 65 , 66 ]. Although great progress is being made in this field, differentiation protocols require further improvements to produce uniform populations of desired cells with high efficiencies.…”

Section: Discussionmentioning

confidence: 99%

Progesterone Receptor Modulates Extraembryonic Mesoderm and Cardiac Progenitor Specification during Mouse Gastrulation

Drozd

Mariani

Guo

et al. 2022

IJMS

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Progesterone treatment is commonly employed to promote and support pregnancy. While maternal tissues are the main progesterone targets in humans and mice, its receptor (PGR) is expressed in the murine embryo, questioning its function during embryonic development. Progesterone has been previously associated with murine blastocyst development. Whether it contributes to lineage specification is largely unknown. Gastrulation initiates lineage specification and generation of the progenitors contributing to all organs. Cells passing through the primitive streak (PS) will give rise to the mesoderm and endoderm. Cells emerging posteriorly will form the extraembryonic mesodermal tissues supporting embryonic growth. Cells arising anteriorly will contribute to the embryonic heart in two sets of distinct progenitors, first (FHF) and second heart field (SHF). We found that PGR is expressed in a posterior–anterior gradient in the PS of gastrulating embryos. We established in vitro differentiation systems inducing posterior (extraembryonic) and anterior (cardiac) mesoderm to unravel PGR function. We discovered that PGR specifically modulates extraembryonic and cardiac mesoderm. Overexpression experiments revealed that PGR safeguards cardiac differentiation, blocking premature SHF progenitor specification and sustaining the FHF progenitor pool. This role of PGR in heart development indicates that progesterone administration should be closely monitored in potential early-pregnancy patients undergoing infertility treatment.

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Transient secretion of VEGF protein from transplanted hiPSC-CMs enhances engraftment and improves rat heart function post MI

Cited by 26 publications

References 71 publications

Safe and Effective Delivery of mRNA Using Modified PEI-Based Lipopolymers

Safe and Effective Delivery of mRNA Using Modified PEI-Based Lipopolymers

Adipose‐derived stem cells enriched with therapeutic mRNA TGF‐β3 and IL‐10 synergistically promote scar‐less wound healing in preclinical models

Progesterone Receptor Modulates Extraembryonic Mesoderm and Cardiac Progenitor Specification during Mouse Gastrulation

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