{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:49:18Z","timestamp":1760143758540,"version":"build-2065373602"},"reference-count":127,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T00:00:00Z","timestamp":1709078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"],"award-info":[{"award-number":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"],"award-info":[{"award-number":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Vanderbilt Ingram Cancer Center","award":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"],"award-info":[{"award-number":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"]}]},{"name":"Vanderbilt Vision Center","award":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"],"award-info":[{"award-number":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"]}]},{"DOI":"10.13039\/100000002","name":"NIH\/NCRR","doi-asserted-by":"publisher","award":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"],"award-info":[{"award-number":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cancer Center Support Grant","award":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"],"award-info":[{"award-number":["UH3TR002097","RR024975","A68485","DK20593","DK58404","DK59637","1S10OD021630 1","CA68485","EY08126","RR030956","5P30 CA68485"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>The implementation of three-dimensional tissue engineering concurrently with stem cell technology holds great promise for in vitro research in pharmacology and toxicology and modeling cardiac diseases, particularly for rare genetic and pediatric diseases for which animal models, immortal cell lines, and biopsy samples are unavailable. It also allows for a rapid assessment of phenotype\u2013genotype relationships and tissue response to pharmacological manipulation. Mutations in the TSC1 and TSC2 genes lead to dysfunctional mTOR signaling and cause tuberous sclerosis complex (TSC), a genetic disorder that affects multiple organ systems, principally the brain, heart, skin, and kidneys. Here we differentiated healthy (CC3) and tuberous sclerosis (TSP8-15) human induced pluripotent stem cells (hiPSCs) into cardiomyocytes to create engineered cardiac tissue constructs (ECTCs). We investigated and compared their mechano-elastic properties and gene expression and assessed the effects of rapamycin, a potent inhibitor of the mechanistic target of rapamycin (mTOR). The TSP8-15 ECTCs had increased chronotropy compared to healthy ECTCs. Rapamycin induced positive inotropic and chronotropic effects (i.e., increased contractility and beating frequency, respectively) in the CC3 ECTCs but did not cause significant changes in the TSP8-15 ECTCs. A differential gene expression analysis revealed 926 up- and 439 down-regulated genes in the TSP8-15 ECTCs compared to their healthy counterparts. The application of rapamycin initiated the differential expression of 101 and 31 genes in the CC3 and TSP8-15 ECTCs, respectively. A gene ontology analysis showed that in the CC3 ECTCs, the positive inotropic and chronotropic effects of rapamycin correlated with positively regulated biological processes, which were primarily related to the metabolism of lipids and fatty and amino acids, and with negatively regulated processes, which were predominantly associated with cell proliferation and muscle and tissue development. In conclusion, this study describes for the first time an in vitro TSC cardiac tissue model, illustrates the response of normal and TSC ECTCs to rapamycin, and provides new insights into the mechanisms of TSC.<\/jats:p>","DOI":"10.3390\/bioengineering11030234","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T06:14:22Z","timestamp":1709100862000},"page":"234","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Contractile and Genetic Characterization of Cardiac Constructs Engineered from Human Induced Pluripotent Stem Cells: Modeling of Tuberous Sclerosis Complex and the Effects of Rapamycin"],"prefix":"10.3390","volume":"11","author":[{"given":"Veniamin Y.","family":"Sidorov","sequence":"first","affiliation":[{"name":"Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN 37235, USA"},{"name":"Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana N.","family":"Sidorova","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip C.","family":"Samson","sequence":"additional","affiliation":[{"name":"Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN 37235, USA"},{"name":"Department of Physics and Astronomy, Vanderbilt University, Nashville, TN 37212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3786-7893","authenticated-orcid":false,"given":"Ronald S.","family":"Reiserer","sequence":"additional","affiliation":[{"name":"Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN 37235, USA"},{"name":"Department of Physics and Astronomy, Vanderbilt University, Nashville, TN 37212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clayton M.","family":"Britt","sequence":"additional","affiliation":[{"name":"Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN 37235, USA"},{"name":"Department of Physics and Astronomy, Vanderbilt University, Nashville, TN 37212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Diana","family":"Neely","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin C.","family":"Ess","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John P.","family":"Wikswo","sequence":"additional","affiliation":[{"name":"Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN 37235, USA"},{"name":"Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235, USA"},{"name":"Department of Physics and Astronomy, Vanderbilt University, Nashville, TN 37212, USA"},{"name":"Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1177\/1535370217732765","article-title":"Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology","volume":"242","author":"Watson","year":"2017","journal-title":"Exp. 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