Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy

Tsuru, Hirofumi; Yoshihara, Chika; Suginobe, Hidehiro; Matsumoto, Mizuki; Ishii, Yoichiro; Narita, Jun; Ishii, Ryo; Wang, Renjie; Ueyama, Atsuko; Ueda, Kazutoshi; Hirose, Masaki; Hashimoto, Kazuhisa; Nagano, Hiroki; Tanaka, Ryosuke; Okajima, Takaharu; Ozono, Keiichi; Ishida, Hidekazu

doi:https://doi.org/10.1161/JAHA.123.029676

Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy

Tsuru, Hirofumi; Yoshihara, Chika; Suginobe, Hidehiro et al.

Journal of the American Heart Association, 2023, 12(13), e029676

Number of Access:2,028（2025-08-16 00:38 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/92522

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Title	Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy
Creator	CreatorName Tsuru, Hirofumi
	CreatorName Yoshihara, Chika
	CreatorName Suginobe, Hidehiro
	CreatorName Matsumoto, Mizuki
	CreatorName Ishii, Yoichiro
	NRID 1000070467562 1000070467562 researchmap permalink J-narita J-narita Scopus Author ID 36993204400 36993204400 CreatorName Narita, Jun
	NRID 1000090794008 1000090794008 researchmap permalink iryo-0918 iryo-0918 Scopus Author ID 56017974100 56017974100 CreatorName Ishii, Ryo
	CreatorName Wang, Renjie
	CreatorName Ueyama, Atsuko
	CreatorName Ueda, Kazutoshi
	NRID 1000010973662 1000010973662 researchmap permalink masahirose masahirose Scopus Author ID 57908743200 57908743200 CreatorName Hirose, Masaki
	CreatorName Hashimoto, Kazuhisa
	CreatorName Nagano, Hiroki
	CreatorName Tanaka, Ryosuke
	CreatorName Okajima, Takaharu
	NRID 1000020270770 1000020270770 researchmap permalink read0092357 read0092357 Scopus Author ID 55545335700 55545335700 CreatorName Ozono, Keiichi
	NRID 1000050467552 1000050467552 researchmap permalink researcher_cardio researcher_cardio Scopus Author ID 36863872000 36863872000 CreatorName Ishida, Hidekazu
Subject	cardiac fibroblast
	cardiomyocyte
	dilated cardiomyopathy
	pediatric
	RNA-seq
Description	Tsuru H., Yoshihara C., Suginobe H., et al. Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy. Journal of the American Heart Association 12, e029676 (2023); https://doi.org/10.1161/JAHA.123.029676.
Abstract	BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure in children. Despite intensive genetic analyses, pathogenic gene variants have not been identified in most patients with DCM, which suggests that cardiomyocytes are not solely responsible for DCM. Cardiac fibroblasts (CFs) are the most abundant cell type in the heart. They have several roles in maintaining cardiac function; however, the pathological role of CFs in DCM remains unknown. METHODS AND RESULTS: Four primary cultured CF cell lines were established from pediatric patients with DCM and compared with 3 CF lines from healthy controls. There were no significant differences in cellular proliferation, adhesion, migration, ap-optosis, or myofibroblast activation between DCM CFs compared with healthy CFs. Atomic force microscopy revealed that cellular stiffness, fluidity, and viscosity were not significantly changed in DCM CFs. However, when DCM CFs were cocultured with healthy cardiomyocytes, they deteriorated the contractile and diastolic functions of cardiomyocytes. RNA sequencing revealed markedly different comprehensive gene expression profiles in DCM CFs compared with healthy CFs. Several hu-moral factors and the extracellular matrix were significantly upregulated or downregulated in DCM CFs. The pathway analysis revealed that extracellular matrix receptor interactions, focal adhesion signaling, Hippo signaling, and transforming growth factor-β signaling pathways were significantly affected in DCM CFs. In contrast, single-cell RNA sequencing revealed that there was no specific subpopulation in the DCM CFs that contributed to the alterations in gene expression. CONCLUSIONS: Although cellular physiological behavior was not altered in DCM CFs, they deteriorated the contractile and diastolic functions of healthy cardiomyocytes through humoral factors and direct cell–cell contact.
Publisher	American Heart Association Inc.
Source Title	Journal of the American Heart Association
Volume (Issue)	12(13)
Page	e029676
Date of Issued	2023-07-04
Language	English
Handle URL	https://hdl.handle.net/11094/92522
eISSN	20479980
Relation	PMID 37345811
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1161/JAHA.123.029676
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Journal of the American Heart Association. 2023, 12(13), p. e029676
DC.title	Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy
DC.creator	Tsuru, Hirofumi
	Yoshihara, Chika
	Suginobe, Hidehiro
	Matsumoto, Mizuki
	Ishii, Yoichiro
	Narita, Jun
	Ishii, Ryo
	Wang, Renjie
	Ueyama, Atsuko
	Ueda, Kazutoshi
	Hirose, Masaki
	Hashimoto, Kazuhisa
	Nagano, Hiroki
	Tanaka, Ryosuke
	Okajima, Takaharu
	Ozono, Keiichi
	Ishida, Hidekazu
DC.publisher	American Heart Association Inc.
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2023-07-04
DC.identifier	https://doi.org/10.1161/JAHA.123.029676
DC.subject	cardiac fibroblast
	cardiomyocyte
	dilated cardiomyopathy
	pediatric
	RNA-seq
DC.description	Tsuru H., Yoshihara C., Suginobe H., et al. Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy. Journal of the American Heart Association 12, e029676 (2023); https://doi.org/10.1161/JAHA.123.029676.
DCTERMS.abstract	BACKGROUND: Dilated cardiomyopathy (DCM) is a major cause of heart failure in children. Despite intensive genetic analyses, pathogenic gene variants have not been identified in most patients with DCM, which suggests that cardiomyocytes are not solely responsible for DCM. Cardiac fibroblasts (CFs) are the most abundant cell type in the heart. They have several roles in maintaining cardiac function; however, the pathological role of CFs in DCM remains unknown. METHODS AND RESULTS: Four primary cultured CF cell lines were established from pediatric patients with DCM and compared with 3 CF lines from healthy controls. There were no significant differences in cellular proliferation, adhesion, migration, ap-optosis, or myofibroblast activation between DCM CFs compared with healthy CFs. Atomic force microscopy revealed that cellular stiffness, fluidity, and viscosity were not significantly changed in DCM CFs. However, when DCM CFs were cocultured with healthy cardiomyocytes, they deteriorated the contractile and diastolic functions of cardiomyocytes. RNA sequencing revealed markedly different comprehensive gene expression profiles in DCM CFs compared with healthy CFs. Several hu-moral factors and the extracellular matrix were significantly upregulated or downregulated in DCM CFs. The pathway analysis revealed that extracellular matrix receptor interactions, focal adhesion signaling, Hippo signaling, and transforming growth factor-β signaling pathways were significantly affected in DCM CFs. In contrast, single-cell RNA sequencing revealed that there was no specific subpopulation in the DCM CFs that contributed to the alterations in gene expression. CONCLUSIONS: Although cellular physiological behavior was not altered in DCM CFs, they deteriorated the contractile and diastolic functions of healthy cardiomyocytes through humoral factors and direct cell–cell contact.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	92522
citation_title	Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy
citation_author	Tsuru, Hirofumi
	Yoshihara, Chika
	Suginobe, Hidehiro
	Matsumoto, Mizuki
	Ishii, Yoichiro
	Narita, Jun
	Ishii, Ryo
	Wang, Renjie
	Ueyama, Atsuko
	Ueda, Kazutoshi
	Hirose, Masaki
	Hashimoto, Kazuhisa
	Nagano, Hiroki
	Tanaka, Ryosuke
	Okajima, Takaharu
	Ozono, Keiichi
	Ishida, Hidekazu
citation_publisher	American Heart Association Inc.
citation_language	English
citation_date	2023-07-04
citation_journal_title	Journal of the American Heart Association
citation_volume	12
citation_issue	13
citation_firstpage	e029676
citation_doi	https://doi.org/10.1161/JAHA.123.029676
citation_pmid	37345811
citation_public_url	https://hdl.handle.net/11094/92522

Pathogenic Roles of Cardiac Fibroblasts in Pediatric Dilated Cardiomyopathy

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