Development of adeno-associated viral vectors targeting cardiac fibroblasts for efficient in vivo cardiac reprogramming.

Autor:	Nakano K; Department of Cardiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan., Sadahiro T; Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan., Fujita R; Department of Cardiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan; Division of Regenerative Medicine, Transborder Medical Research Center, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan., Isomi M; Department of Cardiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan., Abe Y; Department of Cardiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan., Yamada Y; Department of Cardiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan., Akiyama T; Department of Cardiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan; Department of Respiratory Medicine, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan., Honda S; Department of Cardiology, Institute of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba City, Ibaraki 305-8575, Japan., French BA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA., Mizukami H; Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, 3311-1, Yakushiji, Shimotsuke, Tochigi 329-0498, Japan., Ieda M; Department of Cardiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Electronic address: mieda@keio.jp.
Jazyk:	angličtina
Zdroj:	Stem cell reports [Stem Cell Reports] 2024 Aug 21. Date of Electronic Publication: 2024 Aug 21.
DOI:	10.1016/j.stemcr.2024.08.002
Abstrakt:	Overexpression of cardiac reprogramming factors, including GATA4, HAND2, TBX5, and MEF2C (GHT/M), can directly reprogram cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs). Adeno-associated virus (AAV) vectors are widely used clinically, and vectors targeting cardiomyocytes (CMs) have been extensively studied. However, safe and efficient AAV vectors targeting CFs for in vivo cardiac reprogramming remain elusive. Therefore, we screened multiple AAV capsids and promoters to develop efficient and safe CF-targeting AAV vectors for in vivo cardiac reprogramming. AAV-DJ capsids containing periostin promoter (AAV-DJ-Postn) strongly and specifically expressed transgenes in resident CFs in mice after myocardial infarction (MI). Lineage tracing revealed that AAV-DJ-Postn vectors expressing GHT/M reprogrammed CFs into iCMs, which was further increased 2-fold using activated MEF2C via the fusion of the powerful MYOD transactivation domain (M-TAD) with GHT (AAV-DJ-Postn-GHT/M-TAD). AAV-DJ-Postn-GHT/M-TAD injection improved cardiac function and reduced fibrosis after MI. Overall, we developed new AAV vectors that target CFs for cardiac reprogramming. Competing Interests: Declaration of interests M. Ieda holds a patent related to this work, U.S. Patent 9,517,250, entitled ‘‘Methods for Generating Cardiomyocytes,” issued on October 19, 2012. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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