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1.
JCI Insight ; 4(22)2019 11 14.
Article in English | MEDLINE | ID: mdl-31723055

ABSTRACT

The adult mammalian heart regenerates poorly after injury and, as a result, ischemic heart diseases are among the leading causes of death worldwide. The recovery of the injured heart is dependent on orchestrated repair processes including inflammation, fibrosis, cardiomyocyte survival, proliferation, and contraction properties that could be modulated in patients. In this work we designed an automated high-throughput screening system for small molecules that induce cardiomyocyte proliferation in vitro and identified the small molecule Chicago Sky Blue 6B (CSB). Following induced myocardial infarction, CSB treatment reduced scar size and improved heart function of adult mice. Mechanistically, we show that although initially identified using in vitro screening for cardiomyocyte proliferation, in the adult mouse CSB promotes heart repair through (i) inhibition of CaMKII signaling, which improves cardiomyocyte contractility; and (ii) inhibition of neutrophil and macrophage activation, which attenuates the acute inflammatory response, thereby contributing to reduced scarring. In summary, we identified CSB as a potential therapeutic agent that enhances cardiac repair and function by suppressing postinjury detrimental processes, with no evidence for cardiomyocyte renewal.


Subject(s)
Heart/drug effects , Myocardial Infarction/metabolism , Myocytes, Cardiac , Trypan Blue/pharmacology , Animals , Cell Proliferation/drug effects , Cells, Cultured , Cicatrix/metabolism , Female , Mice , Mice, Inbred ICR , Myocardium/metabolism , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism
2.
Nature ; 547(7662): 179-184, 2017 07 13.
Article in English | MEDLINE | ID: mdl-28581497

ABSTRACT

The adult mammalian heart is non-regenerative owing to the post-mitotic nature of cardiomyocytes. The neonatal mouse heart can regenerate, but only during the first week of life. Here we show that changes in the composition of the extracellular matrix during this week can affect cardiomyocyte growth and differentiation in mice. We identify agrin, a component of neonatal extracellular matrix, as required for the full regenerative capacity of neonatal mouse hearts. In vitro, recombinant agrin promotes the division of cardiomyocytes that are derived from mouse and human induced pluripotent stem cells through a mechanism that involves the disassembly of the dystrophin-glycoprotein complex, and Yap- and ERK-mediated signalling. In vivo, a single administration of agrin promotes cardiac regeneration in adult mice after myocardial infarction, although the degree of cardiomyocyte proliferation observed in this model suggests that there are additional therapeutic mechanisms. Together, our results uncover a new inducer of mammalian heart regeneration and highlight fundamental roles of the extracellular matrix in cardiac repair.


Subject(s)
Agrin/metabolism , Extracellular Matrix Proteins/metabolism , Heart/physiology , Regeneration , Adaptor Proteins, Signal Transducing/metabolism , Animals , Animals, Newborn , Cell Cycle Proteins , Cell Proliferation , Dystroglycans/metabolism , Female , Mice , Myocardial Infarction/metabolism , Myocardial Infarction/pathology , Myocardium/cytology , Myocardium/metabolism , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , Phosphoproteins/metabolism , YAP-Signaling Proteins
3.
Oncotarget ; 7(16): 21168-80, 2016 Apr 19.
Article in English | MEDLINE | ID: mdl-26934560

ABSTRACT

Mouse Mammary Tumor Virus (MMTV) causes mammary carcinoma or lymphoma in mice. An increasing body of evidence in recent years supports its involvement also in human sporadic breast cancer. It is thus of importance to develop new strategies to impair the development, growth and metastasis of MMTV-associated cancers. The signal peptide of the envelope precursor protein of this virus: MMTV-p14 (p14) is an excellent target for such strategies, due to unique characteristics distinct from its regular endoplasmic reticulum targeting function. These include cell surface expression in: murine cancer cells that harbor the virus, human breast cancer (MCF-7) cells that ectopically express p14, as well as cultured human cells derived from an invasive ductal breast carcinoma positive for MMTV sequences. These findings support its use in signal peptide-based immune targeting. Indeed, priming and boosting mice with p14 elicits a specific anti-signal peptide immune response sufficient for protective vaccination against MMTV-associated tumors. Furthermore, passive immunization using a combination of anti-p14 monoclonal antibodies or the transfer of T-cells from immunized mice (Adoptive Cell Transfer) is also therapeutically effective. With reports demonstrating involvement of MMTV in human breast cancer, we propose the immune-mediated targeting of p14 as a strategy for prevention, treatment and diagnosis of MMTV-associated cancers.


Subject(s)
Antibodies, Monoclonal/pharmacology , Breast Neoplasms/prevention & control , Carcinoma, Ductal, Breast/prevention & control , Immunization/methods , Mammary Tumor Virus, Mouse/pathogenicity , Viral Envelope Proteins/antagonists & inhibitors , Animals , Apoptosis , Breast Neoplasms/immunology , Breast Neoplasms/virology , Carcinoma, Ductal, Breast/immunology , Carcinoma, Ductal, Breast/virology , Cell Proliferation , Female , Humans , MCF-7 Cells , Mice , Mice, Inbred BALB C , Tumor Cells, Cultured , Viral Envelope Proteins/immunology
4.
Elife ; 42015 Aug 12.
Article in English | MEDLINE | ID: mdl-26267307

ABSTRACT

Cardiomyocyte (CM) maturation in mammals is accompanied by a sharp decline in their proliferative and regenerative potential shortly after birth. In this study, we explored the role of the mechanical properties of the underlying matrix in the regulation of CM maturation. We show that rat and mouse neonatal CMs cultured on rigid surfaces exhibited increased myofibrillar organization, spread morphology, and reduced cell cycle activity. In contrast, compliant elastic matrices induced features of CM dedifferentiation, including a disorganized sarcomere network, rounding, and conspicuous cell-cycle re-entry. The rigid matrix facilitated nuclear division (karyokinesis) leading to binucleation, while compliant matrices promoted CM mitotic rounding and cell division (cytokinesis), associated with loss of differentiation markers. Moreover, the compliant matrix potentiated clonal expansion of CMs that involves multiple cell divisions. Thus, the compliant microenvironment facilitates CM dedifferentiation and proliferation via its effect on the organization of the myoskeleton. Our findings may be exploited to design new cardiac regenerative approaches.


Subject(s)
Cell Dedifferentiation , Cell Proliferation , Chemical Phenomena , Extracellular Matrix , Myocytes, Cardiac/physiology , Animals , Animals, Newborn , Cells, Cultured , Mice , Microscopy, Fluorescence , Models, Biological , Rats, Wistar
5.
Nat Cell Biol ; 17(5): 627-38, 2015 May.
Article in English | MEDLINE | ID: mdl-25848746

ABSTRACT

The murine neonatal heart can regenerate after injury through cardiomyocyte (CM) proliferation, although this capacity markedly diminishes after the first week of life. Neuregulin-1 (NRG1) administration has been proposed as a strategy to promote cardiac regeneration. Here, using loss- and gain-of-function genetic tools, we explore the role of the NRG1 co-receptor ERBB2 in cardiac regeneration. NRG1-induced CM proliferation diminished one week after birth owing to a reduction in ERBB2 expression. CM-specific Erbb2 knockout revealed that ERBB2 is required for CM proliferation at embryonic/neonatal stages. Induction of a constitutively active ERBB2 (caERBB2) in neonatal, juvenile and adult CMs resulted in cardiomegaly, characterized by extensive CM hypertrophy, dedifferentiation and proliferation, differentially mediated by ERK, AKT and GSK3ß/ß-catenin signalling pathways. Transient induction of caERBB2 following myocardial infarction triggered CM dedifferentiation and proliferation followed by redifferentiation and regeneration. Thus, ERBB2 is both necessary for CM proliferation and sufficient to reactivate postnatal CM proliferative and regenerative potentials.


Subject(s)
Cell Dedifferentiation , Cell Proliferation , Myocardial Infarction/metabolism , Myocytes, Cardiac/metabolism , Receptor, ErbB-2/metabolism , Regeneration , Signal Transduction , Age Factors , Animals , Animals, Newborn , Cell Dedifferentiation/drug effects , Cell Proliferation/drug effects , Cells, Cultured , Disease Models, Animal , Dose-Response Relationship, Drug , Extracellular Signal-Regulated MAP Kinases/metabolism , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Magnetic Resonance Imaging , Mice, Knockout , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/pathology , Neuregulin-1/metabolism , Neuregulin-1/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Receptor, ErbB-2/agonists , Receptor, ErbB-2/deficiency , Receptor, ErbB-2/genetics , Regeneration/drug effects , Signal Transduction/drug effects , Time Factors , Time-Lapse Imaging , beta Catenin/metabolism
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