• Costamagna, Domiziana
• Caluwé, Ellen
• Duelen, Robin
• Ekhteraeitousi, Samaneh
• Wu, Ming
• Sampaolesi, Maurilio
• Malgrange, Brigitte
• Janssens, Stefan
• Gillijns, Hilde
• Zhang, Jianyi J.
• Jacobs, Johanna
• Devriendt, Koenraad
• Roderick, Llewelyn

Abstract

<jats:p><jats:bold>Introduction:</jats:bold>Cardiomyopathies are a prominent cause of heart failure and affect millions worldwide. Mutation in the<jats:italic>Alström syndrome 1 (ALMS1)</jats:italic>gene causing<jats:bold>Alström syndrome (ALMS)</jats:bold>, reported an extremely rare type of dilated cardiomyopathy - called<jats:bold>mitogenic cardiomyopathy</jats:bold>- leading to neonatal heart failure and death in early infancy due to delayed postnatal cardiomyocyte (CM) cell cycle arrest.</jats:p><jats:p><jats:bold>Methods:</jats:bold><jats:bold>Induced pluripotent stem cells (iPSCs)</jats:bold>from ALMS patients with or without mitogenic cardiomyopathy were used to generate ALMS patient-specific<jats:bold>cardiomyocytes (iPSC-CMs)</jats:bold>. The iPSC-CMs were divided into two main groups based on the presence or absence of the mitogenic phenotype. After transcriptome sequencing, differentially expressed genes (FDR &lt; 0.05, logFC &gt; 0.5 | &lt; -0.5) were found by testing (QL F-test) a robust fitted linear model (edgeR). Harnessing recent advances in stem cell differentiation and tissue engineering, we aimed at creating a human engineered heart tissue model as an unprecedented<jats:italic>in vitro</jats:italic>disease system to study mechanisms responsible for persistent CM proliferation.</jats:p><jats:p><jats:bold>Results:</jats:bold>ALMS1-deficient mitogenic iPSC-CMs exhibited an impaired ability to undergo cell cycle arrest, evidenced by a higher cell percentage in the G2/M phase (19.3% in mitogenic<jats:italic>vs</jats:italic>. 7.5% in non-mitogenic iPSC-CMs). Furthermore, increased extracellular matrix levels of the fibroblast-derived protein periostin (POSTN) were observed in co-cultures of ALMS1-deficient iPSC-CMs and ALMS1 fibroblasts. Finally, we found preliminary evidence of dysregulation of the Hippo signaling pathway, observing altered cellular localization of its key downstream effector Yes-associated protein (YAP) and dysregulated ratio between phosphor and total YAP protein levels that in combination with transcript alteration of<jats:italic>PPIC, SH3BP4, NTN4, LRIG3</jats:italic>suggest perturbations in YAP signaling in ALMS patients.</jats:p><jats:p><jats:bold>Conclusion:</jats:bold>ALMS1-deficient mitogenic iPSC-CMs recapitulate postnatal proliferation, observed in ALMS patients with mitogenic cardiomyopathy. Preliminary molecular analyses in these<jats:italic>in vitro</jats:italic>(multicellular) models point to an important role for altered YAP signaling and provide novel cues to enhance CM proliferation, a much-sought objective in cardiac repair.</jats:p>

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