iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy.
iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy.
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DOI：
10.1038/ncb3411
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发表时间：
2016-10
影响因子：
21.3
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中科院分区：
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左心室致密化不全(LVNC)是儿童常见的第三大心肌病，其发病机制与胚胎心肌发育缺陷有关。我们发现，从携带心脏转录因子Tbx20突变的慢性病毒性心肌炎患者中产生的患者特异性诱导多能干细胞来源的心肌细胞(IPSC-CM)在单细胞水平上概括了病理表型的一个关键方面，并与干扰的转化生长因子β(β)信号有关。LVNCIPSC-CMS由于转化生长因子β信号异常激活，细胞增殖能力下降。Tbx20调节转化生长因子β信号修饰物的表达，包括已知的LVNC的遗传原因PRDM16，以及PRDM16的基因组编辑引起的IPSC-CMS的增殖缺陷。抑制转化生长因子β信号转导和Tbx20突变的基因组纠正足以逆转该病的表型。我们的研究表明，IPSC-CMS是一种有用的工具，可用于探索包括LVNC在内的鲜为人知的心肌病的病理机制。
Left ventricular non-compaction (LVNC) is the third most prevalent cardiomyopathy in children and its pathogenesis has been associated with the developmental defect of the embryonic myocardium. We show that patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from LVNC patients carrying a mutation in the cardiac transcription factor TBX20 recapitulate a key aspect of the pathological phenotype at the single-cell level and was associated with perturbed transforming growth factor beta (TGFβ) signaling. LVNC iPSC-CMs have decreased proliferative capacity due to abnormal activation of TGFβ signaling. TBX20 regulates the expression of TGFβ signaling modifiers including a known genetic cause of LVNC, PRDM16, and genome editing of PRDM16 caused proliferation defects in iPSC-CMs. Inhibition of TGFβ signaling and genome correction of the TBX20 mutation were sufficient to reverse the disease phenotype. Our study demonstrates that iPSC-CMs are a useful tool for the exploration of pathological mechanisms underlying poorly understood cardiomyopathies including LVNC.