Background

Cardiosphere derived stem cells (CDSCs) are signified as a valued source of stem cell therapeutics for treating a gamut of cardiovascular ailments. However, challenges in the cardiogenic differentiation process culminate in stem cell transplantation failure. Hence, it is imperative to understand the comprehensive mechanisms and the role of endogenous factors in cardiac differentiation.

Objectives

Objective of the current study is to check the effect of 15-epi-lipoxin A₄ (15E-LXA4)—a stable analogue of lipoxin A4, a pro-resolving agonist—on miR-499 (a cardiac-specific microRNA)-induced differentiation of CDSCs.

Methods

CDSCs were transfected with lentiviral vectors bearing miR-499 and subjected to 15E-LXA4 treatment. Then, the treatment effects on surface markers (c-kit and CD105), cardiogenic gene markers (NKX2.5, GATA4, and cTnI), Wnt/β-catenin signaling (Wnt3a and phosphorylated/dephosphorylated β-catenin ratio) and TGFβ/SMAD signaling (TGFβ1 and SMAD3) were evaluated.

Results

15E-LXA4 treatment repressed miR-499 over-expression induced cardiac differentiation, manifested by enhanced expression of surface markers, Wnt/β-catenin and TGFβ/SMAD signaling parameters and reduced expression cardiogenic gene markers, plausibly through activation of estrogen receptor (ERα).

Conclusions

These findings give reason to understand the role of endogenous resolution factors like 15E-LXA4, as it displayed reciprocal effect on miR-499 induced cardiac differentiation in CDSCs.

中文翻译：

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分辨率因子 15-epi-Lipoxin A4 通过双重抑制 Wnt/β-catenin 和 TGFβ/SMAD 信号轴来调节 miRNA-499 诱导的心脏球源性干细胞分化

背景

心源性干细胞 (CDSC) 被认为是治疗各种心血管疾病的干细胞疗法的重要来源。然而，心源性分化过程中的挑战最终导致干细胞移植失败。因此，了解内源性因素在心脏分化中的综合机制和作用势在必行。

目标

本研究的目的是检查 15-epi-lipoxin A ₄ (15E-LXA4)——一种脂氧素 A4 的稳定类似物，一种促分解激动剂——对 miR-499（一种心脏特异性 microRNA）诱导的CDSCs 的分化。

方法

用携带 miR-499 的慢病毒载体转染 CDSCs 并进行 15E-LXA4 处理。然后，治疗对表面标志物（c-kit 和 CD105）、心源性基因标志物（NKX2.5、GATA4 和 cTnI）、Wnt/β-catenin 信号（Wnt3a 和磷酸化/去磷酸化 β-catenin 比率）和 TGFβ/评估了 SMAD 信号（TGFβ1 和 SMAD3）。

结果

15E-LXA4 治疗抑制了 miR-499 过表达诱导的心脏分化，表现为表面标志物、Wnt/β-catenin 和 TGFβ/SMAD 信号参数的表达增强和心源性基因标志物的表达降低，这可能是通过激活雌激素受体 (ERα) .

结论

这些发现为了解内源性分辨因子（如 15E-LXA4）的作用提供了理由，因为它显示出对 miR-499 诱导的 CDSC 心脏分化的相互影响。