Mesenchymal Stromal Cells-derived Extracellular Vesicles Reprogramme Macrophages in ARDS Models Through the MiR-181a-5p-PTEN-pSTAT5-SOCS1 Axis

Overview

Journal Thorax

Date 2022 Aug 10

PMID 35948417

Authors

Yue Su

Johnatas Dutra Silva

Declan Doherty

David A Simpson

Daniel J Weiss

Sara Rolandsson-Enes

Daniel F McAuley

Cecilia M OKane

Derek P Brazil

Anna D Krasnodembskaya

Affiliations

Soon will be listed here.

Abstract

Rationale: A better understanding of the mechanism of action of mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) is needed to support their use as novel therapies for acute respiratory distress syndrome (ARDS). Macrophages are important mediators of ARDS inflammatory response. Suppressor of cytokine signalling (SOCS) proteins are key regulators of the macrophage phenotype switch. We therefore investigated whether SOCS proteins are involved in mediation of the MSC effect on human macrophage reprogramming.

Methods: Human monocyte-derived macrophages (MDMs) were stimulated with lipopolysaccharide (LPS) or plasma samples from patients with ARDS (these samples were previously classified into hypo-inflammatory and hyper-inflammatory phenotype) and treated with MSC conditioned medium (CM) or EVs. Protein expression was measured by Western blot. EV micro RNA (miRNA) content was determined by miRNA sequencing. In vivo: LPS-injured C57BL/6 mice were given EVs isolated from MSCs in which miR-181a had been silenced by miRNA inhibitor or overexpressed using miRNA mimic.

Results: EVs were the key component of MSC CM responsible for anti-inflammatory modulation of human macrophages. EVs significantly reduced secretion of tumour necrosis factor-α and interleukin-8 by LPS-stimulated or ARDS plasma-stimulated MDMs and this was dependent on SOCS1. Transfer of miR-181a in EVs downregulated phosphatase and tensin homolog (PTEN) and subsequently activated phosphorylated signal transducer and activator of transcription 5 (pSTAT5) leading to upregulation of SOCS1 in macrophages. In vivo, EVs alleviated lung injury and upregulated pSTAT5 and SOCS1 expression in alveolar macrophages in a miR181-dependent manner. Overexpression of miR-181a in MSCs significantly enhanced therapeutic efficacy of EVs in this model.

Conclusion: miR-181a-PTEN-pSTAT5-SOCS1 axis is a novel pathway responsible for immunomodulatory effect of MSC EVs in ARDS.

Citing Articles

Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies.

Ma W, Tang S, Yao P, Zhou T, Niu Q, Liu P Signal Transduct Target Ther. 2025; 10(1):75.

PMID: 40050633 PMC: 11885678. DOI: 10.1038/s41392-025-02127-9.

Recent advances in the role of mesenchymal stem cells as modulators in autoinflammatory diseases.

Chen B, Chen Z, He M, Zhang L, Yang L, Wei L Front Immunol. 2025; 15:1525380.

PMID: 39759531 PMC: 11695405. DOI: 10.3389/fimmu.2024.1525380.

Therapeutic prospects of microRNAs derived from mesenchymal stem cell extracellular vesicles in rheumatoid arthritis: a comprehensive overview.

Akbarzadeh A, Gerami M, Farrokhi M, Shapoori S, Jafarinia M Mol Cell Biochem. 2024; 480(3):1275-1286.

PMID: 39105963 DOI: 10.1007/s11010-024-05082-1.

Mesenchymal stem cell-derived extracellular vesicles accelerate diabetic wound healing by inhibiting NET-induced ferroptosis of endothelial cells.

Lu W, Li X, Wang Z, Zhao C, Li Q, Zhang L Int J Biol Sci. 2024; 20(9):3515-3529.

PMID: 38993565 PMC: 11234223. DOI: 10.7150/ijbs.97150.

Mesenchymal stromal cell-based therapy in lung diseases; from research to clinic.

Yuan D, Bao Y, El-Hashash A Am J Stem Cells. 2024; 13(2):37-58.

PMID: 38765802 PMC: 11101986. DOI: 10.62347/JAWM2040.

References

Matthay M, Arabi Y, Siegel E, Ware L, Bos L, Sinha P . Phenotypes and personalized medicine in the acute respiratory distress syndrome. Intensive Care Med. 2020; 46(12):2136-2152. PMC: 7673253. DOI: 10.1007/s00134-020-06296-9. View

Sinha P, Delucchi K, McAuley D, OKane C, Matthay M, Calfee C . Development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: a secondary analysis of randomised controlled trials. Lancet Respir Med. 2020; 8(3):247-257. PMC: 7543720. DOI: 10.1016/S2213-2600(19)30369-8. View

Nishioka C, Ikezoe T, Yang J, Yokoyama A . Long-term exposure of leukemia cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene. Leukemia. 2010; 24(9):1631-40. DOI: 10.1038/leu.2010.145. View

Fergie N, Todd N, McClements L, McAuley D, OKane C, Krasnodembskaya A . Hypercapnic acidosis induces mitochondrial dysfunction and impairs the ability of mesenchymal stem cells to promote distal lung epithelial repair. FASEB J. 2019; 33(4):5585-5598. PMC: 6436662. DOI: 10.1096/fj.201802056R. View

Pineros Alvarez A, Glosson-Byers N, Brandt S, Wang S, Wong H, Sturgeon S . SOCS1 is a negative regulator of metabolic reprogramming during sepsis. JCI Insight. 2017; 2(13). PMC: 5499360. DOI: 10.1172/jci.insight.92530. View

Saito H, Morita Y, Fujimoto M, Narazaki M, Naka T, Kishimoto T . IFN regulatory factor-1-mediated transcriptional activation of mouse STAT-induced STAT inhibitor-1 gene promoter by IFN-gamma. J Immunol. 2000; 164(11):5833-43. DOI: 10.4049/jimmunol.164.11.5833. View

Kim H, Jang S, Lee W, Kim K, Sohn H, Hwang S . PTEN drives Th17 cell differentiation by preventing IL-2 production. J Exp Med. 2017; 214(11):3381-3398. PMC: 5679178. DOI: 10.1084/jem.20170523. View

Wheeler A, Bernard G . Acute lung injury and the acute respiratory distress syndrome: a clinical review. Lancet. 2007; 369(9572):1553-1564. DOI: 10.1016/S0140-6736(07)60604-7. View

Whyte C, Bishop E, Ruckerl D, Gaspar-Pereira S, Barker R, Allen J . Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function. J Leukoc Biol. 2011; 90(5):845-54. DOI: 10.1189/jlb.1110644. View

10.

Craig T, Duffy M, Shyamsundar M, McDowell C, OKane C, Elborn J . A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). Am J Respir Crit Care Med. 2010; 183(5):620-6. DOI: 10.1164/rccm.201003-0423OC. View

11.

Ghazawi F, Faller E, Parmar P, El-Salfiti A, MacPherson P . Suppressor of cytokine signaling (SOCS) proteins are induced by IL-7 and target surface CD127 protein for degradation in human CD8 T cells. Cell Immunol. 2016; 306-307:41-52. DOI: 10.1016/j.cellimm.2016.07.002. View

12.

Dong R, Xie L, Zhao K, Zhang Q, Zhou M, He P . Cigarette smoke-induced lung inflammation in COPD mediated via LTB4/BLT1/SOCS1 pathway. Int J Chron Obstruct Pulmon Dis. 2016; 11:31-41. PMC: 4694688. DOI: 10.2147/COPD.S96412. View

13.

Phinney D, Di Giuseppe M, Njah J, Sala E, Shiva S, St Croix C . Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015; 6:8472. PMC: 4598952. DOI: 10.1038/ncomms9472. View

14.

Laffey J, Kavanagh B . Negative trials in critical care: why most research is probably wrong. Lancet Respir Med. 2018; 6(9):659-660. DOI: 10.1016/S2213-2600(18)30279-0. View

15.

Reddy K, Sinha P, OKane C, Gordon A, Calfee C, McAuley D . Subphenotypes in critical care: translation into clinical practice. Lancet Respir Med. 2020; 8(6):631-643. DOI: 10.1016/S2213-2600(20)30124-7. View

16.

Duncan S, Baganizi D, Sahu R, Singh S, Dennis V . SOCS Proteins as Regulators of Inflammatory Responses Induced by Bacterial Infections: A Review. Front Microbiol. 2018; 8:2431. PMC: 5733031. DOI: 10.3389/fmicb.2017.02431. View

17.

Famous K, Delucchi K, Ware L, Kangelaris K, Liu K, Thompson B . Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy. Am J Respir Crit Care Med. 2016; 195(3):331-338. PMC: 5328179. DOI: 10.1164/rccm.201603-0645OC. View

18.

Rolandsson Enes S, Krasnodembskaya A, English K, Santos C, Weiss D . Research Progress on Strategies that can Enhance the Therapeutic Benefits of Mesenchymal Stromal Cells in Respiratory Diseases With a Specific Focus on Acute Respiratory Distress Syndrome and Other Inflammatory Lung Diseases. Front Pharmacol. 2021; 12:647652. PMC: 8089479. DOI: 10.3389/fphar.2021.647652. View

19.

Silva J, Su Y, Calfee C, Delucchi K, Weiss D, McAuley D . Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS. Eur Respir J. 2020; 58(1). PMC: 8318599. DOI: 10.1183/13993003.02978-2020. View

20.

Schembri F, Sridhar S, Perdomo C, Gustafson A, Zhang X, Ergun A . MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium. Proc Natl Acad Sci U S A. 2009; 106(7):2319-24. PMC: 2650144. DOI: 10.1073/pnas.0806383106. View