TY - JOUR
T1 - Demystifying the long noncoding RNA landscape of small EVs derived from human mesenchymal stromal cells
AU - Lee, Chien Wei
AU - Chen, Yi Fan
AU - Hsiao, Allen Wei Ting
AU - Wang, Amanda Yu Fan
AU - Shen, Oscar Yuan Jie
AU - Wang, Belle Yu Hsuan
AU - Ho, Lok Wai Cola
AU - Lin, Wei Ting
AU - Choi, Chung Hang Jonathan
AU - Lee, Oscar Kuang Sheng
N1 - Funding Information:
This work was supported by the Hong Kong Government Research Grant Council, General Research Fund (Reference no. 14104620) to CW Lee and by China Medical University Hospital (Reference no. DMR-110-226) to OK Lee. The authors also thank Prof. HH Cheung at the School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong for the generous gift of human skin fibroblasts (GM08429). Fig. 1 is created with materials from BioRender.com.
Funding Information:
This work was supported by the Hong Kong Government Research Grant Council, General Research Fund (Reference no. 14104620) to CW Lee and by China Medical University Hospital (Reference no. DMR-110-226) to OK Lee. The authors also thank Prof. HH Cheung at the School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong for the generous gift of human skin fibroblasts (GM08429). Fig. 1 is created with materials from BioRender.com.
Publisher Copyright:
© 2021
PY - 2022
Y1 - 2022
N2 - Introduction: The regenerative capacity of mesenchymal stromal cells or medicinal signaling cells (MSCs) is largely mediated by their secreted small extracellular vesicles (sEVs), and the therapeutic efficacy of sEVs can be enhanced by licensing approaches (e.g., cytokines, hypoxia, chemicals, and genetic modification). Noncoding RNAs within MSC-derived sEVs (MSC-sEVs) have been demonstrated to be responsible for tissue regeneration. However, unlike miRNA fingerprints, which have been explored, the landscape of long noncoding RNAs (lncRNAs) in MSC-sEVs remains to be described. Objectives: To characterize lncRNA signatures in sEVs of human adipose-derived MSCs with or without inflammatory cytokine licensing and depict MSC-sEV-specific and MSC-enriched lncRNA repertoires. Methods: sEVs were isolated from MSCs with or without TNF-α and IFN-γ (20 ng/mL) stimulation. High-throughput lncRNA sequencing and an in silico approach were employed to analyze the profile of lncRNAs in sEVs and predict lncRNA-protein interactomes. Results: sEVs derived from human MSCs and fibroblasts carried a unique landscape of lncRNAs distinct from the lncRNAs inside these cells. Compared with fibroblast-derived sEVs (F-sEVs), 194 MSC-sEV-specific and 8 upregulated lncRNAs in MSC-sEVs were considered “medicinal signaling lncRNAs”; inflammatory cytokines upregulated 27 lncRNAs in MSC-sEVs, which were considered “licensing-responsive lncRNAs”. Based on lncRNA-protein interactome prediction and enrichment analysis, we found that the proteins interacting with medicinal signaling lncRNAs or licensing-responsive lncRNAs have a tight interaction network involved in chromatin remodeling, SWI/SNF superfamily type complexes, and histone binding. Conclusion: In summary, our study depicts the landscape of lncRNAs in MSC-sEVs and predicts their potential functions via the lncRNA-protein interactome. Elucidation of the lncRNA landscape of MSC-sEVs will facilitate defining the therapeutic potency of MSC-sEVs and the development of sEV-based therapeutics.
AB - Introduction: The regenerative capacity of mesenchymal stromal cells or medicinal signaling cells (MSCs) is largely mediated by their secreted small extracellular vesicles (sEVs), and the therapeutic efficacy of sEVs can be enhanced by licensing approaches (e.g., cytokines, hypoxia, chemicals, and genetic modification). Noncoding RNAs within MSC-derived sEVs (MSC-sEVs) have been demonstrated to be responsible for tissue regeneration. However, unlike miRNA fingerprints, which have been explored, the landscape of long noncoding RNAs (lncRNAs) in MSC-sEVs remains to be described. Objectives: To characterize lncRNA signatures in sEVs of human adipose-derived MSCs with or without inflammatory cytokine licensing and depict MSC-sEV-specific and MSC-enriched lncRNA repertoires. Methods: sEVs were isolated from MSCs with or without TNF-α and IFN-γ (20 ng/mL) stimulation. High-throughput lncRNA sequencing and an in silico approach were employed to analyze the profile of lncRNAs in sEVs and predict lncRNA-protein interactomes. Results: sEVs derived from human MSCs and fibroblasts carried a unique landscape of lncRNAs distinct from the lncRNAs inside these cells. Compared with fibroblast-derived sEVs (F-sEVs), 194 MSC-sEV-specific and 8 upregulated lncRNAs in MSC-sEVs were considered “medicinal signaling lncRNAs”; inflammatory cytokines upregulated 27 lncRNAs in MSC-sEVs, which were considered “licensing-responsive lncRNAs”. Based on lncRNA-protein interactome prediction and enrichment analysis, we found that the proteins interacting with medicinal signaling lncRNAs or licensing-responsive lncRNAs have a tight interaction network involved in chromatin remodeling, SWI/SNF superfamily type complexes, and histone binding. Conclusion: In summary, our study depicts the landscape of lncRNAs in MSC-sEVs and predicts their potential functions via the lncRNA-protein interactome. Elucidation of the lncRNA landscape of MSC-sEVs will facilitate defining the therapeutic potency of MSC-sEVs and the development of sEV-based therapeutics.
KW - Cytokine priming
KW - Exosomes
KW - lncRNAs
KW - MSCs
KW - protein–RNA interaction predictions
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U2 - 10.1016/j.jare.2021.11.003
DO - 10.1016/j.jare.2021.11.003
M3 - Article
AN - SCOPUS:85120736962
SN - 2090-1232
VL - 39
SP - 73
EP - 88
JO - Journal of Advanced Research
JF - Journal of Advanced Research
ER -