학술논문
Abstract 14391: Transient Cell Cycle Induction in Cardiomyocytes is a Promising Approach to Treat Ischemia Induced Heart Failure
Document Type
Academic Journal
Author
Abouleisa, Riham; Ou, Qinghui; Tang, Xian-liang; Solanki, Mitesh; Guo, Yiru; McNally, Lindsey; Lorkiewicz, Pawel; Choudhary, Krishna; Thomas, Reuben; Juhardeen, Hamzah Ruxshan; Siddique, Aisha; Ifthikar, Zainab; Salama, Abou Bakr; Huang, Yu; Ivey, Kathryn N; Hill, Bradford; Srivastava, Deepak; Bolli, Roberto; Mohamed, Tamer
Source
Circulation. Nov 17, 2020 142(Suppl_3 Suppl 3):A14391-A14391
Subject
Language
English
ISSN
0009-7322
Abstract
Rationale: The regenerative capacity of the heart to repair itself after myocardial infarction (MI)is limited. Our previous study showed that ectopic introduction of Cdk1/CyclinB1 andCdk4/CyclinD1 complexes (4F) promotes cardiomyocyte proliferation in vitro and in vivo andimproves cardiac function after MI. However, its clinical application is limited due to the concernsfor tumorigenic potential in other organs.Objectives: To first, identify on a single cell transcriptomic basis the necessary reprogrammingsteps that cardiomyocytes need to undertake to progress through the proliferation processfollowing 4F overexpression, and then, to determine the pre-clinical efficacy of transient andcardiomyocyte specific expression of 4F in improving cardiac function after MI in small and largeanimals.Methods and Results: Temporal bulk and single cell RNAseq of mature hiPS-CMs treated with4F or LacZ control for 24, 48, or 72 h revealed full cell cycle reprogramming in 15% of thecardiomyocyte population which was associated with sarcomere disassembly and metabolicreprogramming. Transient overexpression of 4F specifically in cardiomyocytes was achievedusing non-integrating lentivirus (NIL) driven by TNNT2 (TNNT2-4F-NIL). One week after inductionof ischemia-reperfusion injury in rats or pigs, TNNT2-4F-NIL or control virus was injectedintramyocardially. Compared with controls, rats or pigs treated with TNNT2-4F-NIL showed a 20-30% significant improvement in ejection fraction and scar size four weeks after treatment, asassessed by echocardiography and histological analysis. Quantification of cardiomyocyteproliferation in pigs using a novel cytokinesis reporter showed that ~10% of the cardiomyocyteswithin the injection site were labelled as daughter cells following injection with TNNT2-4F-NILcompared with ~0.5% background labelling in control groups.Conclusions: We provide the first understanding of the process of forced cardiomyocyteproliferation and advanced the clinical applicability of this approach through minimization ofoncogenic potential of the cell cycle factors using a novel transient and cardiomyocyte-specificviral construct.