Long noncoding RNA BCYRN1 promotes cardioprotection by enhancing human and murine regulatory T cell dynamics
Ke Liao, … , Ahmed G.E. Ibrahim, Eduardo Marbán
Ke Liao, … , Ahmed G.E. Ibrahim, Eduardo Marbán
Published March 25, 2025
Citation Information: J Clin Invest. 2025;135(9):e179262. https://doi.org/10.1172/JCI179262.
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Research Article Cardiology

Long noncoding RNA BCYRN1 promotes cardioprotection by enhancing human and murine regulatory T cell dynamics

Abstract

Regulatory T cells (Tregs) modulate immune responses and attenuate inflammation. Extracellular vesicles from human cardiosphere-derived cells (CDC-EVs) enhance Treg proliferation and IL-10 production, but the mechanisms remain unclear. Here, we focused on BCYRN1, a long noncoding RNA (lncRNA) highly abundant in CDC-EVs, and its role in Treg function. BCYRN1 acts as a “microRNA sponge,” inhibiting miR-138, miR-150, and miR-98. Suppression of these miRs leads to increased Treg proliferation via ATG7-dependent autophagy, CCR6-dependent Treg migration, and enhanced Treg IL-10 production. In a mouse model of myocardial infarction, CDC-EVs, particularly those overexpressing BCYRN1, were cardioprotective, reducing infarct size and troponin I levels even when administered after reperfusion. Underlying the cardioprotection, we verified that CDC-EVs overexpressing BCYRN1 increased cardiac Treg infiltration, proliferation, and IL-10 production in vivo. These salutary effects were negated when BCYRN1 levels were reduced in CDC-EVs or when Tregs were depleted systemically. Thus, we have identified BCYRN1 as a booster of Treg number and bioactivity, rationalizing its cardioprotective efficacy. While we studied BCYRN1 overexpression in the context of ischemic injury here, the same approach merits testing in other disease processes (e.g., autoimmunity or transplant rejection) where increased Treg activity is a recognized therapeutic goal.

Authors

Ke Liao, Jiayi Yu, Akbarshakh Akhmerov, Zahra Mohammadigoldar, Liang Li, Weixin Liu, Natasha Anders, Ahmed G.E. Ibrahim, Eduardo Marbán

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Figure 5

CDC-EV BCYRN1 induces Treg migration by competitively binding miR-150 to regulate CCR6 expression.

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CDC-EV BCYRN1 induces Treg migration by competitively binding miR-150 to...
(A) Human iTregs were exposed to CDC-EVs or were not treated (ctrl). The expression of CCR6 was assessed by qPCR. (B) Human Tregs were exposed to ctrl-CDC-EVs or si-BCYRN1 CDC-EVs (EV with BCYRN1 knockdown) or were not treated (ctrl). The expression of CCR6 was assessed by qPCR. (C) Human Tregs were transfected with vector or OE-BCYRN1 lenti-vector, followed by assessment of CCR6 by qPCR. (D) Biotin-labeled BCYRN1 probe was used to pull down BCYRN1-associated RNAs, followed by assessment of miR-150, negative control (U6 and GAPDH), and positive control (BCYRN1) expression by qPCR. (E) The top panels putative lncRNA BCYRN1 binding sites in miR-150. The bottom panel shows human iTregs that were cotransfected with WT or mutant luciferase reporters and mimic miR-150 into HEK-293T cells, followed by the assessment of relative luciferase activity. (F and G). Cotransfection of miR-150 and BCYRN1 in Tregs followed by assessments of CCR6 by WB (F) and cellular migration by trans-well migration assay (G). One-way ANOVA followed by Bonferroni’s post hoc test was used to determine statistical significance. All data are presented as mean ± SEM of 3 or 4individual experiments (biological replicates). **P < 0.01, ***P < 0.001 versus control group. ###P < 0.001 versus miR-150 group.