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可编程编辑初级 MicroRNA 开关可调节干细胞分化，促进组织再生。

Programmable editing of primary MicroRNA switches stem cell differentiation and improves tissue regeneration.

机构信息

Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan.

Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Linkou, Taiwan.

出版信息

Nat Commun. 2024 Sep 27;15(1):8358. doi: 10.1038/s41467-024-52707-6.

DOI:10.1038/s41467-024-52707-6
PMID:39333549
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11436717/
Abstract

Programmable RNA editing is harnessed for modifying mRNA. Besides mRNA, miRNA also regulates numerous biological activities, but current RNA editors have yet to be exploited for miRNA manipulation. To engineer primary miRNA (pri-miRNA), the miRNA precursor, we present a customizable editor REPRESS (RNA Editing of Pri-miRNA for Efficient Suppression of miRNA) and characterize critical parameters. The optimized REPRESS is distinct from other mRNA editing tools in design rationale, hence enabling editing of pri-miRNAs that are not editable by other RNA editing systems. We edit various pri-miRNAs in different cells including adipose-derived stem cells (ASCs), hence attenuating mature miRNA levels without disturbing host gene expression. We further develop an improved REPRESS (iREPRESS) that enhances and prolongs pri-miR-21 editing for at least 10 days, with minimal perturbation of transcriptome and miRNAome. iREPRESS reprograms ASCs differentiation, promotes in vitro cartilage formation and augments calvarial bone regeneration in rats, thus implicating its potentials for engineering miRNA and applications such as stem cell reprogramming and tissue regeneration.

摘要

可编程 RNA 编辑被用于修饰 mRNA。除了 mRNA，miRNA 还调节着众多的生物活动，但目前的 RNA 编辑工具尚未被用于 miRNA 的操作。为了对初级 miRNA（pri-miRNA，miRNA 的前体）进行工程改造，我们提出了一种可定制的编辑器 REPRESS（用于高效抑制 miRNA 的 pri-miRNA 编辑），并对关键参数进行了表征。与其他的 mRNA 编辑工具不同，优化后的 REPRESS 在设计原理上有所不同，因此能够编辑其他 RNA 编辑系统无法编辑的 pri-miRNAs。我们在不同的细胞中编辑了各种 pri-miRNAs，包括脂肪来源的干细胞（ASCs），从而在不干扰宿主基因表达的情况下降低成熟 miRNA 的水平。我们进一步开发了一种改进的 REPRESS（iREPRESS），它增强和延长了 pri-miR-21 的编辑至少 10 天，对转录组和 miRNA 组的干扰最小。iREPRESS 重编程了 ASCs 的分化，促进了体外软骨的形成，并增强了大鼠颅骨骨再生，从而为 miRNA 的工程设计以及干细胞重编程和组织再生等应用提供了潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/646da3a9b9eb/41467_2024_52707_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/adf341c93570/41467_2024_52707_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/88e7b732d2e9/41467_2024_52707_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/351267bf4958/41467_2024_52707_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/6a1e3e9eb66d/41467_2024_52707_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/07e4982f9888/41467_2024_52707_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/646da3a9b9eb/41467_2024_52707_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/adf341c93570/41467_2024_52707_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/88e7b732d2e9/41467_2024_52707_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/351267bf4958/41467_2024_52707_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/6a1e3e9eb66d/41467_2024_52707_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/07e4982f9888/41467_2024_52707_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edcc/11436717/646da3a9b9eb/41467_2024_52707_Fig6_HTML.jpg

相似文献

[1]
Programmable editing of primary MicroRNA switches stem cell differentiation and improves tissue regeneration.

Nat Commun. 2024-9-27

[2]
The role of miR-31-modified adipose tissue-derived stem cells in repairing rat critical-sized calvarial defects.

Biomaterials. 2013-6-13

[3]
Frequency and fate of microRNA editing in human brain.

Nucleic Acids Res. 2008-9

[4]
A signal-amplification circuit between miR-218 and Wnt/β-catenin signal promotes human adipose tissue-derived stem cells osteogenic differentiation.

Bone. 2013-9-30

[5]
Osteogenic differentiation of adipose-derived stem cells and calvarial defect repair using baculovirus-mediated co-expression of BMP-2 and miR-148b.

Biomaterials. 2014-3-24

[6]
RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex.

EMBO Rep. 2007-8

[7]
Enhanced Calvarial Bone Repair Using ASCs Engineered with RNA-Guided Split dCas12a System that Co-Activates Sox 5, Sox6, and Long Non-Coding RNA H19.

Small. 2024-5

[8]
A-to-I editing of microRNAs in the mammalian brain increases during development.

Genome Res. 2012-5-29

[9]
The Notch signalling pathway and miRNA regulation play important roles in the differentiation of Schwann cells from adipose-derived stem cells.

Lab Invest. 2022-3

[10]
Enhancement of bone regeneration using osteogenic-induced adipose-derived stem cells combined with demineralized bone matrix in a rat critically-sized calvarial defect model.

Curr Stem Cell Res Ther. 2012-5

引用本文的文献

[1]
Intramolecular DNA Wheel Construction for Highly Sensitive Electrochemical Detection of miRNA.

Nano Lett. 2025-1-29

[2]
Investigating the biology of microRNA links to ALDH1A1 reveals candidates for preclinical testing in acute myeloid leukemia.

Int J Oncol. 2024-12

本文引用的文献

[1]
A strategy for Cas13 miniaturization based on the structure and AlphaFold.

Nat Commun. 2023-9-8

[2]
Advances in MicroRNA Therapy for Heart Failure: Clinical Trials, Preclinical Studies, and Controversies.

Cardiovasc Drugs Ther. 2025-2

[3]
MicroRNA: trends in clinical trials of cancer diagnosis and therapy strategies.

Exp Mol Med. 2023-7

[4]
Shoot the messenger: RNA editing is here.

Nat Biotechnol. 2023-3

[5]
RNA editing: Expanding the potential of RNA therapeutics.

Mol Ther. 2023-6-7

[6]
An RNA-targeting CRISPR-Cas13d system alleviates disease-related phenotypes in Huntington's disease models.

Nat Neurosci. 2023-1

[7]
Programmable RNA base editing with a single gRNA-free enzyme.

Nucleic Acids Res. 2022-9-9

[8]
Pre-existing adaptive immunity to the RNA-editing enzyme Cas13d in humans.

Nat Med. 2022-7

[9]
Endogenous ADAR-mediated RNA editing in non-human primates using stereopure chemically modified oligonucleotides.

Nat Biotechnol. 2022-7

[10]
Engineered circular ADAR-recruiting RNAs increase the efficiency and fidelity of RNA editing in vitro and in vivo.

Nat Biotechnol. 2022-6

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