Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors

被引：36

作者：

Poch, Christine M. ^{[1
]}

Foo, Kylie S. ^{[2
,3
]}

De Angelis, Maria Teresa ^{[1
,4
]}

Jennbacken, Karin ^{[5
]}

Santamaria, Gianluca ^{[1
,4
]}

Baehr, Andrea ^{[1
]}

Wang, Qing-Dong ^{[5
]}

Reiter, Franziska ^{[1
]}

Hornaschewitz, Nadja ^{[1
]}

Zawada, Dorota ^{[1
,4
]}

Bozoglu, Tarik ^{[1
]}

My, Ilaria ^{[1
]}

Meier, Anna ^{[1
,4
]}

Dorn, Tatjana ^{[1
,4
]}

Hege, Simon ^{[1
]}

Lehtinen, Miia L. ^{[3
]}

Tsoi, Yat Long ^{[2
]}

Hovdal, Daniel ^{[5
]}

Hyllner, Johan ^{[5
,6
]}

Schwarz, Sascha ^{[7
]}

Sudhop, Stefanie ^{[7
]}

Jurisch, Victoria ^{[1
]}

Sini, Marcella ^{[8
]}

Fellows, Mick D. ^{[8
]}

Cummings, Matthew ^{[9
]}

Clarke, Jonathan ^{[10
]}

Baptista, Ricardo ^{[10
]}

Eroglu, Elif ^{[2
]}

Wolf, Eckhard ^{[11
,12
]}

Klymiuk, Nikolai ^{[1
,13
]}

Lu, Kun ^{[14
]}

Tomasi, Roland ^{[14
]}

Dendorfer, Andreas ^{[13
,14
]}

Gaspari, Marco ^{[15
]}

Parrotta, Elvira ^{[15
]}

Cuda, Giovanni ^{[15
]}

Krane, Markus ^{[13
,16
]}

Sinnecker, Daniel ^{[1
,13
]}

Hoppmann, Petra ^{[1
]}

Kupatt, Christian ^{[1
,13
]}

Fritsche-Danielson, Regina ^{[5
]}

Moretti, Alessandra ^{[1
,4
,13
]}

Chien, Kenneth R. ^{[2
,3
]}

Laugwitz, Karl-Ludwig ^{[1
,13
]}

机构：

[1] Tech Univ Munich, Med Dept I, Klinikum Rechts Isar, Cardiol,Angiol,Pneumol, Munich, Germany

[2] Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden

[3] Karolinska Inst, Dept Med, Huddinge, Sweden

[4] Tech Univ Munich, Inst Regenerat Med Cardiol, Munich, Germany

[5] AstraZeneca, Res & Early Dev, Cardiovasc Renal & Metab CVRM, BioPharmaceut R&D, Gothenburg, Sweden

[6] Linkoping Univ, IFM, Div Biotechnol, Linkoping, Sweden

[7] Munich Univ Appl Sci, Ctr Appl Tissue Engn & Regenerat Med CANTER, Munich, Germany

[8] AstraZeneca, BioPharmaceut R&D, Clin Pharmacol & Safety Sci, Cambridge, England

[9] Western Michigan Sch Med, Kalamazoo, MI USA

[10] Procella Therapeut, Stockholm, Sweden

[11] Ludwig Maximilians Univ Munchen, Chair Mol Anim Breeding & Biotechnol, Gene Ctr, Munich, Germany

[12] Ludwig Maximilians Univ Munchen, Dept Vet Sci, Munich, Germany

[13] DZHK German Ctr Cardiovasc Res, Munich Heart Alliance, Munich, Germany

[14] Ludwig Maximilians Univ Munchen, Univ Hosp, Walter Brendel Ctr Expt Med, Munich, Germany

[15] Univ Magna Grecia, Dept Expt & Clin Med, Catanzaro, Italy

[16] Tech Univ Munich, Dept Cardiovasc Surg, INSURE, German Heart Ctr Munich, Munich, Germany

来源：

NATURE CELL BIOLOGY | 2022年 / 24卷 / 05期

基金：

瑞典研究理事会; 欧洲研究理事会;

关键词：

HUMAN HEART; CELLS; CARDIOMYOCYTES; RECONSTRUCTION; THERAPIES; DYNAMICS; FIBROSIS;

D O I：

10.1038/s41556-022-00899-8

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host-graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury. In this study, the authors report that pluripotent stem cell-derived ventricular progenitors target loss of myocardium and fibrotic scarring to promote heart regeneration, thus offering new potential therapeutic strategies for heart injury.

引用

页码：659 / +

页数：35

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