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

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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