TMEM182 inhibits myocardial differentiation of human iPS cells by maintaining the activated state of Wnt/β-catenin signaling through an increase in ILK expression

IF 2.5 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY FASEB bioAdvances Pub Date : 2024-10-14 DOI:10.1096/fba.2024-00086
Hirofumi Morihara, Shunichi Yokoe, Shigeo Wakabayashi, Shinji Takai
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Abstract

Transmembrane protein 182 (TMEM182) is notably abundant in muscle and adipose tissue, but its role in the heart remains unknown. This study examined the contribution of TMEM182 in the differentiation of human induced pluripotent stem cells (hiPSCs) into cardiomyocytes. For this, we generated hiPSCs overexpressing TMEM182 in a doxycycline-inducible manner and induced their differentiation into cardiomyocytes. On Day 12 of differentiation, expression of the cardiomyocyte markers, TNNT2 and MYH6, was significantly decreased in TMEM182-overexpressing cells. Additionally, we found that phosphorylation of GSK-3β (Ser9) and β-catenin (Ser552) was increased during TMEM182 overexpression, suggesting activation of Wnt/β-catenin signaling. We further focused on integrin-linked kinase (ILK) as the mechanism by which TMEM182 activates Wnt/β-catenin signaling. Evaluation showed that ILK expression was increased in cells overexpressing TMEM182. These results suggest that TMEM182 maintains Wnt/β-catenin signaling in an activated state after mesoderm formation by increasing ILK expression, thereby suppressing hiPSCs differentiation into cardiomyocytes.

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TMEM182 通过增加 ILK 的表达维持 Wnt/β-catenin 信号的激活状态,从而抑制人 iPS 细胞的心肌分化
跨膜蛋白182(TMEM182)在肌肉和脂肪组织中含量显著丰富,但其在心脏中的作用仍不清楚。本研究考察了TMEM182在人类诱导多能干细胞(hiPSCs)向心肌细胞分化过程中的作用。为此,我们以多西环素诱导的方式生成了过表达 TMEM182 的 hiPSCs,并诱导其分化为心肌细胞。在分化的第 12 天,TMEM182-过表达细胞中心肌细胞标志物 TNNT2 和 MYH6 的表达明显下降。此外,我们发现在过表达 TMEM182 的过程中,GSK-3β(Ser9)和β-catenin(Ser552)的磷酸化增加,这表明 Wnt/β-catenin 信号被激活。我们进一步研究了整合素连接激酶(ILK)作为TMEM182激活Wnt/β-catenin信号的机制。评估显示,在过表达 TMEM182 的细胞中,ILK 的表达增加。这些结果表明,TMEM182通过增加ILK的表达,使Wnt/β-catenin信号在中胚层形成后保持激活状态,从而抑制了hiPSCs向心肌细胞的分化。
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来源期刊
FASEB bioAdvances
FASEB bioAdvances Multiple-
CiteScore
5.40
自引率
3.70%
发文量
56
审稿时长
10 weeks
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