期刊
NATURE CELL BIOLOGY
卷 18, 期 10, 页码 1031-1042出版社
NATURE PORTFOLIO
DOI: 10.1038/ncb3411
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资金
- Neuroscience Microscopy Service (NMS)
- FACS Core at the Institute for Stem Cell Biology and Regenerative Medicine, Stanford University
- Uehara Memorial Foundation Research Fellowship
- American Heart Association [15POST25160016, 15POST22940013]
- NIH [K99HL130416, K18 HL11708301, R01 HL113006, R01 HL130020, R01 126527, R01 128170, R01 HL123968, R24 HL117756]
- Ministry of Education, Culture, Sports, Science and Technology in Japan
- National Institutes of Health [P01 GM099130]
- Children's Cardiomyopathy Foundation
- AHA Established Investigator Award
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 this was associated with perturbed transforming growth factor beta (TGF-beta) signalling. LVNC iPSC-CMs have decreased proliferative capacity due to abnormal activation of TGF-beta signalling, TBX20 regulates the expression of TGF-beta signalling modifiers including one known to be a genetic cause of LVNC, PRDM16, and genome editing of PRDM16 caused proliferation defects in iPSC-CMs. Inhibition of TGF-beta signalling 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.
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