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Spatiotemporal signaling underlies progressive vascular rarefaction in myocardial infarction
Enhancing vascularization to improve cardiac disease outcomes is a therapeutic approach with limited success. Here, the authors show that cardiac repair is governed by spatiotemporally regulated programs and underline the signaling mechanisms driving vascular deterioration.
- Lin Wei Tung
- , Elena Groppa
- & Fabio Rossi
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Article
| Open Access
Cardiomyocyte proliferation is suppressed by ARID1A-mediated YAP inhibition during cardiac maturation
Cardiac regeneration is hindered by the limited division of cardiomyocytes. Here, the authors show that Arid1a drives maturation and limits proliferation through interaction with Yap. Suppression of Arid1a enhances proliferation after injury.
- Cornelis J. Boogerd
- , Ilaria Perini
- & Eva van Rooij
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| Open Access
Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI
Modulating pro-inflammatory immune cell kinetics after myocardial infarction is a critical step to prevent heart dysfunction. In this study, the authors show that Ezh2 pharmacological inhibition, acting as an epigenetic checkpoint in monocytes and macrophages, prevents myocardial infarction-induced cardiac dysfunction.
- Julie Rondeaux
- , Déborah Groussard
- & Sylvain Fraineau
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| Open Access
Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells
Transdifferentiation has been proposed as an approach for regenerative medicine, but the mechanisms that safeguard cell identity are not well established. Here they identify transcription factors that oppose transdifferentiation and show that knockdown of these genes improves recovery after myocardial infarction.
- Maria A. Missinato
- , Sean Murphy
- & Alexandre R. Colas
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| Open Access
Activation of a transient progenitor state in the epicardium is required for zebrafish heart regeneration
The epicardium supports heart regeneration, though precisely how is unclear. Here the authors define an activated epicardial progenitor population as the source of essential cell types and paracrine factors for successful heart regeneration in zebrafish.
- Yu Xia
- , Sierra Duca
- & Jingli Cao
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| Open Access
Kynurenine promotes neonatal heart regeneration by stimulating cardiomyocyte proliferation and cardiac angiogenesis
Failed cardiac regeneration to repair adult acute myocardial ischemia is the leading cause of heart failure. Here, the authors show that IDO1-derived kynurenine metabolism promotes cardiomyocyte proliferation and cardiac angiogenesis via cytoplasmic aryl hydrocarbon receptor (AhR) and nucleic AhR translocation signalling.
- Donghong Zhang
- , Jinfeng Ning
- & Ming-Hui Zou
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Article
| Open Access
Cell proliferation fate mapping reveals regional cardiomyocyte cell-cycle activity in subendocardial muscle of left ventricle
The adult mammalian heart exhibits stubbornly low levels of cardiomyocyte proliferation, leading to high morbidity after injury or heart attack. Here the authors develop an approach for tracking cardiomyocyte cell cycling and show that the majority are located adjacent to the endocardium.
- Xiuxiu Liu
- , Wenjuan Pu
- & Bin Zhou
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| Open Access
Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance
Following injury, cells in regenerative tissues can regrow, but how they adapt to injury conditions to regenerate the tissue is unclear. Here the authors identify a stress-responsive and cardioprotective factor Nrf1 that is critical for neonatal heart regeneration.
- Miao Cui
- , Ayhan Atmanli
- & Eric N. Olson
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Article
| Open Access
Human iPS-derived pre-epicardial cells direct cardiomyocyte aggregation expansion and organization in vitro
The authors form pre-epicardial cells (PECs) from hiPSC-derived lateral plate mesoderm on treating with BMP4, RA and VEGF, and co-culture these PECs with cardiomyocytes, inducing cardiomyocyte aggregation, proliferation and network formation with more mature structures and improved beating/contractility.
- Jun Jie Tan
- , Jacques P. Guyette
- & Harald C. Ott
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| Open Access
A microRNA program regulates the balance between cardiomyocyte hyperplasia and hypertrophy and stimulates cardiac regeneration
Myocardial regeneration and proliferation of heart muscle cells is limited to a short period after birth early postnatal life, after which heart muscle cells can only grow in size and not in number. Here, the authors identified that the expression level of an endogenous microRNA cluster in heart muscle promotes the passage of the proliferative state to adult heart growth, and modulating the expression of this cluster can stimulate heart regeneration after myocardial infarction.
- Andrea Raso
- , Ellen Dirkx
- & Leon J. De Windt
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| Open Access
Generation of mature compact ventricular cardiomyocytes from human pluripotent stem cells
Cardiomyocytes of heart ventricles consist of subpopulations of trabecular and compact subtypes. Here the authors describe the generation of structurally, metabolically and functionally mature compact ventricular cardiomyocytes as well as mature atrial cardiomyocytes from human pluripotent stem cells.
- Shunsuke Funakoshi
- , Ian Fernandes
- & Gordon Keller
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Article
| Open Access
Enhancing myocardial repair with CardioClusters
Despite recent progress to advance cardiac cell-based therapy for patients, heart failure mortality rivals most cancers. Here, the authors describe an approach to control and pattern 3 distinct human cardiac cell populations to promote superior repair and regeneration after myocardial infarction.
- Megan M. Monsanto
- , Bingyan J. Wang
- & Mark A. Sussman
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| Open Access
Macrophages directly contribute collagen to scar formation during zebrafish heart regeneration and mouse heart repair
Macrophages mediate the fibrotic response after a heart attack by extracellular matrix turnover and cardiac fibroblasts activation. Here the authors identify an evolutionarily-conserved function of macrophages that contributes directly to the forming post-injury scar through cell-autonomous deposition of collagen.
- Filipa C. Simões
- , Thomas J. Cahill
- & Paul R. Riley
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| Open Access
Functional cardiac fibroblasts derived from human pluripotent stem cells via second heart field progenitors
Cardiac fibroblasts (CFs) play critical roles in heart development, homeostasis, and disease. Here the authors efficiently differentiate human pluripotent stem cells through second heart field progenitors to CFs that exhibit features and functional properties similar to native CFs.
- Jianhua Zhang
- , Ran Tao
- & Timothy J. Kamp
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| Open Access
Therapeutic role of miR-19a/19b in cardiac regeneration and protection from myocardial infarction
The miR-17-92 cluster has been shown to regulate cardiomyocyte proliferation in vitro and in genetic mutation and overexpression models. Here the authors show that the cluster member miR-19a/19b regulates cardiomyocyte proliferation in vivo, and that delivery of miR-19a/19b to the heart leads to both short-term and long-term protective responses to myocardial infarction.
- Feng Gao
- , Masaharu Kataoka
- & Da-Zhi Wang
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| Open Access
Patterned human microvascular grafts enable rapid vascularization and increase perfusion in infarcted rat hearts
Heart grafts need good vascularization to survive. Here, the authors engineer perfusable constructs of human embryonic stem cell-derived endothelial cells seeded in collagen matrix in patterned microchannels that form anastomosed vessels in vitro and have increased coronary vascular perfusion on transplantation in rats.
- Meredith A. Redd
- , Nicole Zeinstra
- & Ying Zheng
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| Open Access
A conserved HH-Gli1-Mycn network regulates heart regeneration from newt to human
Due to the limited proliferation capacity of adult mammalian cardiomyocytes, the human heart has negligible regenerative capacity after injury. Here the authors show that a Hedgehog-Gli1-Mycn signaling cascade regulates cardiomyocyte proliferation and cardiac regeneration from amphibians to mammals.
- Bhairab N. Singh
- , Naoko Koyano-Nakagawa
- & Daniel J. Garry
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| Open Access
Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction
Regulatory T cells (Tregs) expand during pregnancy to promote tolerance towards the fetus. Here the authors show that Tregs induce proliferation of fetal and maternal cardiomyocytes during pregnancy and enhance myocardial repair via proliferation-promoting paracrine actions.
- Serena Zacchigna
- , Valentina Martinelli
- & Mauro Giacca
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Article
| Open Access
Exercise induces new cardiomyocyte generation in the adult mammalian heart
The adult mammalian heart has a limited cardiomyogenic capacity. Here the authors show that intensive exercise leads to a 4.6-fold increase in murine cardiomyocyte proliferation requiring the expression of miR-222, and that exercise induces an extended cardiomyogenic response in the murine heart after infarction.
- Ana Vujic
- , Carolin Lerchenmüller
- & Anthony Rosenzweig
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Analysis of cardiomyocyte clonal expansion during mouse heart development and injury
During cardiac tissue formation it is unclear whether newly generated myocytes originate from cardiac progenitor cells or from pre-existing cardiomyocytes. Here, the authors use a stochastic four-colour reporter system (Rainbow) to identify the source of new cardiomyocytes during mouse development.
- Konstantina-Ioanna Sereti
- , Ngoc B. Nguyen
- & Reza Ardehali
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| Open Access
Loss of microRNA-128 promotes cardiomyocyte proliferation and heart regeneration
During early postnatal development in mammals, cardiomyocytes exit the cell cycle, losing their regenerative capacity. Here the authors show that, following myocardial infarction, loss of microRNA-128 promotes cardiomyocyte proliferation and cardiac regeneration in adult mice partly via enhancing the expression of the chromatin modifier SUZ12.
- Wei Huang
- , Yuliang Feng
- & Yigang Wang
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| Open Access
Tbx5a lineage tracing shows cardiomyocyte plasticity during zebrafish heart regeneration
It is not clear if it is the embryonic origin or anatomical location of cardiomyocytes that restrict their contribution to zebrafish heart regeneration. Here, the authors show a plasticity of embryonic precursors following tbx5a fate mapping and that trabecular cardiomyocytes help to rebuild the cortical myocardium.
- Héctor Sánchez-Iranzo
- , María Galardi-Castilla
- & Nadia Mercader
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| Open Access
RETRACTED ARTICLE: REST regulates the cell cycle for cardiac development and regeneration
The mechanisms regulating cardiomyocyte proliferation during development and cardiac regeneration are incompletely understood. The authors show that the transcription factor REST regulates cardiomyocyte proliferation by binding and repressing the cell cycle inhibitor p21.
- Donghong Zhang
- , Yidong Wang
- & Bin Zhou
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| Open Access
Opposite effects of Activin type 2 receptor ligands on cardiomyocyte proliferation during development and repair
Zebrafish can regenerate damaged myocardial tissue but it is unclear how this is regulated. Here, the authors show that two TGF-β family members, Mstnb and Inhbaa, have opposite effects in regeneration, with mstnb overexpression or inhbaa loss-of-function causing cardiac scarring after injury.
- Deepika Dogra
- , Suchit Ahuja
- & Sven Reischauer
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| Open Access
Single cardiomyocyte nuclear transcriptomes reveal a lincRNA-regulated de-differentiation and cell cycle stress-response in vivo
Adult mammalian cardiomyocytes are predominantly binucleated and unable to divide. Using single nuclear RNA-sequencing of cardiomyocytes from mouse and human failing and non-failing adult hearts, See et al. show that some cardiomyocytes respond to stress by dedifferentiation and cell cycle re-entry regulated by lncRNAs.
- Kelvin See
- , Wilson L. W. Tan
- & Roger S. Foo
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| Open Access
Therapeutic microparticles functionalized with biomimetic cardiac stem cell membranes and secretome
Stem cells exert their beneficial effects through secretion of regenerative factors. Here, the authors take the membranes and secreted factors from cardiac stem cells and generate a synthetic cell-mimicking microparticle, which, on injection in a mouse model of myocardial infarction, improves cardiac function.
- Junnan Tang
- , Deliang Shen
- & Ke Cheng
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Article
| Open Access
CD163 interacts with TWEAK to regulate tissue regeneration after ischaemic injury
CD163 is a glycoprotein receptor expressed on the surface of macrophages. Here, the authors demonstrate that a soluble form of CD163 can act as a decoy receptor for the pro inflammatory cytokine TWEAK, thereby revealing a new mechanism for the regulation of tissue repair after ischaemic injury.
- Hirokuni Akahori
- , Vinit Karmali
- & Aloke V. Finn
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| Open Access
PDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium
Adult cardiac progenitor/stem cells (CPSCs) possess valuable potential for heart repair that is limited by the elusiveness of these cells. Here Noseda et al. refine the definition of murine CPSCs producing stem cell antigen 1 (Sca1), mapping the cardiogenic signature and clonogenicity to the subgroup of Sca1+cells expressing PDGFRα.
- Michela Noseda
- , Mutsuo Harada
- & Michael D. Schneider
N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration