TY - JOUR
T1 - Coronary artery disease patient-derived iPSC-hepatocytes have distinct miRNA profile that may alter lipid metabolism
AU - Alexanova, Anna
AU - Raitoharju, Emma
AU - Valtonen, Joona
AU - Aalto-Setälä, Katriina
AU - Viiri, Leena E.
N1 - Funding Information:
The authors acknowledge Markus Haponen, Henna Lappi and Merja Lehtinen for general technical support, The Hummingbird diagnostics for performing the microarrays, Juha Kesseli and Reija Autio for support regarding bioinformatics. The authors also thank the Biocenter Finland (BF) and Tampere Imaging Facility (TIF) and the Tampere facility of iPS Cells for their services. The research leading to these results has received funding from the European Union Seventh Framework Programme [FP7-2007-2013] under two grant agreements, HEALTH-F2-2013-602222 ‘Targeting novel lipid pathways for treatment of cardiovascular disease’ (Athero-Flux), and HEALTH.2012-3057392 ‘Personalized diagnostics and treatment for high-risk coronary artery disease’ (RiskyCAD), as well as Pirkanmaa Finnish Cultural Foundation (Pirkanmaan rahasto, Suomen Kulttuurisäätiö), Academy of Finland (330809, 338395), Signe och Ane Gyllenbergs stiftelse, Instrumentarium Science Foundation (Instrumentariumin Tiedesäätiö), The Finnish Medical Foundation (Suomen Lääketieteen Säätiö), Yrjö Jahnsson Foundation (20197212), Päivikki and Sakari Sohlberg Foundation, The Finnish Foundation for Cardiovascular Research, the Tampere University Hospital Medical Funds and Sigrid Juselius Foundation.
Funding Information:
The authors acknowledge Markus Haponen, Henna Lappi and Merja Lehtinen for general technical support, The Hummingbird diagnostics for performing the microarrays, Juha Kesseli and Reija Autio for support regarding bioinformatics. The authors also thank the Biocenter Finland (BF) and Tampere Imaging Facility (TIF) and the Tampere facility of iPS Cells for their services. The research leading to these results has received funding from the European Union Seventh Framework Programme [FP7-2007-2013] under two grant agreements, HEALTH-F2-2013-602222 ‘Targeting novel lipid pathways for treatment of cardiovascular disease’ (Athero-Flux), and HEALTH.2012-3057392 ‘Personalized diagnostics and treatment for high-risk coronary artery disease’ (RiskyCAD), as well as Pirkanmaa Finnish Cultural Foundation (Pirkanmaan rahasto, Suomen Kulttuurisäätiö), Academy of Finland (330809, 338395), Signe och Ane Gyllenbergs stiftelse, Instrumentarium Science Foundation (Instrumentariumin Tiedesäätiö), The Finnish Medical Foundation (Suomen Lääketieteen Säätiö), Yrjö Jahnsson Foundation (20197212), Päivikki and Sakari Sohlberg Foundation, The Finnish Foundation for Cardiovascular Research, the Tampere University Hospital Medical Funds and Sigrid Juselius Foundation.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/1
Y1 - 2023/1
N2 - Metabolic dysfunction, partly driven by altered liver function, predisposes to coronary artery disease (CAD), but the role of liver in vulnerable atherosclerotic plaque development remains unclear. Here we produced hepatocyte-like cells (HLCs) from 27 induced pluripotent stem cell (iPSC) lines derived from 15 study subjects with stable CAD (n = 5), acute CAD (n = 5) or healthy controls (n = 5). We performed a miRNA microarray screening throughout the differentiation, as well as compared iPSC-HLCs miRNA profiles of the patient groups to identify miRNAs involved in the development of CAD. MicroRNA profile changed during differentiation and started to resemble that of the primary human hepatocytes. In the microarray, 35 and 87 miRNAs were statistically significantly deregulated in the acute and stable CAD patients, respectively, compared to controls. Down-regulation of miR-149-5p, -92a-3p and -221-3p, and up-regulation of miR-122-5p was verified in the stable CAD patients when compared to other groups. The predicted targets of deregulated miRNAs were enriched in pathways connected to insulin signalling, inflammation and lipid metabolism. The iPSC-HLCs derived from stable CAD patients with extensive lesions had a distinct genetic miRNA profile possibly linked to metabolic dysfunction, potentially explaining the susceptibility to developing CAD. The iPSC-HLCs from acute CAD patients with only the acute rupture in otherwise healthy coronaries did not present a distinct miRNA profile, suggesting that hepatic miRNAs do not explain susceptibility to plaque rupture.
AB - Metabolic dysfunction, partly driven by altered liver function, predisposes to coronary artery disease (CAD), but the role of liver in vulnerable atherosclerotic plaque development remains unclear. Here we produced hepatocyte-like cells (HLCs) from 27 induced pluripotent stem cell (iPSC) lines derived from 15 study subjects with stable CAD (n = 5), acute CAD (n = 5) or healthy controls (n = 5). We performed a miRNA microarray screening throughout the differentiation, as well as compared iPSC-HLCs miRNA profiles of the patient groups to identify miRNAs involved in the development of CAD. MicroRNA profile changed during differentiation and started to resemble that of the primary human hepatocytes. In the microarray, 35 and 87 miRNAs were statistically significantly deregulated in the acute and stable CAD patients, respectively, compared to controls. Down-regulation of miR-149-5p, -92a-3p and -221-3p, and up-regulation of miR-122-5p was verified in the stable CAD patients when compared to other groups. The predicted targets of deregulated miRNAs were enriched in pathways connected to insulin signalling, inflammation and lipid metabolism. The iPSC-HLCs derived from stable CAD patients with extensive lesions had a distinct genetic miRNA profile possibly linked to metabolic dysfunction, potentially explaining the susceptibility to developing CAD. The iPSC-HLCs from acute CAD patients with only the acute rupture in otherwise healthy coronaries did not present a distinct miRNA profile, suggesting that hepatic miRNAs do not explain susceptibility to plaque rupture.
U2 - 10.1038/s41598-023-28981-7
DO - 10.1038/s41598-023-28981-7
M3 - Article
C2 - 36717592
AN - SCOPUS:85147121845
SN - 2045-2322
VL - 13
JO - Scientific Reports
JF - Scientific Reports
M1 - 1706
ER -
