Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy

Yu, Yang; Liao, Li; Shao, Bingyi; Su, Xiaoxia; Yi, Siyan; Wang, Han; Shang, Fengqing; Zhou, Zhifei; Yang, Deqin; Jin, Yan

doi:10.1016/j.ymthe.2016.11.015

Cited by 41 publications

(51 citation statements)

References 59 publications

(82 reference statements)

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“…MicroRNAs (miRNAs), a class of small noncoding RNAs, play a central role in various biological functions, such as cell proliferation, differentiation, apoptosis, and metabolism 1. Increasing evidence demonstrates that aberrant expression of miRNAs is closely related to human cancers; and thus, by regulating the expression of critical cancer‐related genes, miRNAs are capable of essentially inhibiting the tumor growth and angiogenesis 2.…”

Section: Introductionmentioning

confidence: 99%

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

et al. 2017

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Efficient microRNAs (miRNA) delivery into cells is a promising strategy for disease therapy, but is a major challenge because the available conventional nonviral vectors have significant drawbacks. In particular, after these vectors are entrapped in lysosomes, the escape efficiency of genes from lysosomes into the cytosol is less than 2%. Here, a novel approach for lethal‐7a (let‐7a) replacement therapy using rod‐shaped active pure drug nanoparticles (≈130 nm in length, PNPs) with a dramatically high drug‐loading of ≈300% as vectors is reported. Importantly, unlike other vectors, the developed PNPs/let‐7a complexes (≈178 nm, CNPs) can enter cells and bypass the lysosomal route to localize to the cytosol, achieving efficient intracellular delivery of let‐7a and a 50% reduction in expression of the target protein (KRAS). Also, CNPs prolong the t 1/2 of blood circulation by ≈threefold and increase tumor accumulation by ≈1.5–2‐fold, resulting in significantly improved antitumor efficacies. Additionally, no damage to normal organs is observed following systemic injection of CNPs. In conclusion, rod‐shaped active PNPs enable efficient and safe delivery of miRNA with synergistic treatment for disease. This nanoplatform would also offer a viable strategy for the potent delivery of proteins and peptides in vitro and in vivo.

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Section: Introductionmentioning

confidence: 99%

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

et al. 2017

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“…Post‐transcriptional regulation by miRNAs—apopulation of small, noncoding RNAs—is essential for BMSC function and bone remodeling (28, 29). Our recent work confirmed that let‐7a, one of the most conservative and abundant miRNAs in BMSCs, targets both Fas and FasI mRNA to suppress their expression (18); therefore, we focused on let‐7a. Real‐time RT‐PCR demonstrated that let‐7a expression increased in OVX BMSCs (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Let‐7a is highly expressed in BMSCs and suppresses both Fas and FasL expression (18); therefore, let‐7a is a crucial regulator of the immunoregulatory properties of BMSCs. In this study, we found that TNF‐α treatment promoted the expression of let‐7a in BMSCs.…”

Section: Discussionmentioning

confidence: 99%

“…BMSCs that were isolated from C57BL/6 or BALB/c mouse femurs and tibias were cultured as previously described (18). BMSCs were passaged 2‐3 times and received routine characterization—surface marker identification, self‐renew assay, and multipotent differentiation assay.…”

Section: Methodsmentioning

confidence: 99%

“…T‐cell migration assay was performed as previously reported (18). In brief, 2 × 10 5 BMSCs that were labeled with a PKH26 Red Fluorescent Cell Linker Kit (5 μM; Sigma‐Aldrich) were seeded on the lower chamber of a 12‐well culture plate for 24 h.…”

Section: Methodsmentioning

confidence: 99%

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Redundant let‐7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis

Liao

Shao

et al. 2018

FASEB j.

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Bone marrow-derived mesenchymal stem cell (BMSC) cytotherapy has emerged as a promising treatment strategy for refractory immune diseases; however, the influence of the pathologic conditions of donors on the immunomodulatory properties of BMSCs is still poorly understand. Here, we found that BMSCs that were derived from donors with osteoporosis were ineffective as cytotherapy for patients with experimental colitis and graft- vs.-host disease (GVHD). In vivo and in vitro assays revealed that the capacity of osteoporotic BMSCs to induce T-cell apoptosis declined as a result of decreased Fas and FasL protein. Additional analysis revealed that let-7a, a microRNA induced by TNF-α in osteoporosis, inhibited the expression of the Fas/FasL system via post-transcriptional regulation. By knocking down let-7a expression, we successfully recovered the immunosuppressive capacity of osteoporotic BMSCs and improved their therapy for experimental colitis and GVHD. Taken together, our study demonstrates that the immunomodulatory properties of BMSCs are suppressed in osteoporosis and illustrates the molecular mechanism that underlies this suppression. These findings might have important implications for the development of targeted strategies to improve BMSC cytotherapy.-Liao, L., Yu, Y., Shao, B., Su, X., Wang, H., Kuang, H., Jing, H., Shuai, Y., Yang, D., Jin, Y. Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis.

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Correlation of microRNA expression profile with clinical response to tumor necrosis factor inhibitor in treating rheumatoid arthritis patients: A prospective cohort study

Liu

Han

et al. 2019

Clinical Laboratory Analysis

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: This study aimed to explore the correlation of circulating microRNA (miRNA) expression profile with clinical response to tumor necrosis factor (TNF) inhibitor in treating rheumatoid arthritis (RA) patients. Methods: Baseline PBMC samples from eight responders and eight non-responders after 24-week TNF inhibitor (etanercept) treatment were subjected to miRNA microarray. Then, top 10 dysregulated miRNAs were selected and further validated by quantitative polymerase chain reaction (qPCR) in baseline PBMC samples from 92 RA patients treated with 24-week TNF inhibitor (etanercept). Responders and nonresponders were divided referring to the decline in disease activity score in 28 joints.Results: In microarray assay, total 59 upregulated and 78 downregulated miRNAs were identified in responders compared to non-responders, which were mainly enriched in regulating immune-and inflammation-related biological processes and pathways. The top 10 dysregulated miRNAs were as follows: miR-192-5p, miR-146a-5p, miR-19b-3p, miR-320c, miR-335-5p, miR-149-3p, miR-766-3p, let-7a-5p, miR-24-3p, and miR-1226-5p. In qPCR validation, miR-146a-5p was increased, while let-7a-5p was decreased in responders compared with non-responders. Multivariate logistic analysis illuminated that miR-146a-5p and CRP independently correlated with higher clinical response, while let-7a-5p and biologics history independently associated with lower clinical response. Subsequently, receiver operating characteristic curve showed that combination of these four independent factors presented with a great predictive value for clinical response with area under curve: 0.863, 95% CI 0.781-0.945.Conclusion: miRNA expression profile is closely implicated in the treatment efficacy of TNF inhibitor, and combined measurement of miR-146a-5p, let-7a-5p, CRP, and biologics history disclosed a great predictive value for clinical response to TNF inhibitor in RA patients. How to cite this article: Liu Y, Han Y, Qu H, Fang J, Ye M, Yin W. Correlation of microRNA expression profile with clinical response to tumor necrosis factor inhibitor in treating rheumatoid arthritis patients: A prospective cohort study.

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Knockdown of MicroRNA Let-7a Improves the Functionality of Bone Marrow-Derived Mesenchymal Stem Cells in Immunotherapy

Cited by 41 publications

References 59 publications

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

Rod‐Shaped Active Drug Particles Enable Efficient and Safe Gene Delivery

Redundant let‐7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis

Correlation of microRNA expression profile with clinical response to tumor necrosis factor inhibitor in treating rheumatoid arthritis patients: A prospective cohort study

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