scholarly journals Non-coding RNAs in Cardiac Regeneration

2021 ◽  
Vol 12 ◽  
Author(s):  
Ting Yuan ◽  
Jaya Krishnan
Keyword(s):  
Heart Failure ◽  
Cardiac Tissue ◽  
Cardiac Regeneration ◽  
Circular Rnas ◽  
Great Promise ◽  
Cardiomyocyte Proliferation ◽  
Non Coding Rnas ◽  
Key Aspects

The adult heart has a limited capacity to replace or regenerate damaged cardiac tissue following severe myocardial injury. Thus, therapies facilitating the induction of cardiac regeneration holds great promise for the treatment of end-stage heart failure, and for pathologies invoking severe cardiac dysfunction as a result of cardiomyocyte death. Recently, a number of studies have demonstrated that cardiac regeneration can be achieved through modulation and/or reprogramming of cardiomyocyte proliferation, differentiation, and survival signaling. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), are reported to play critical roles in regulating key aspects of cardiomyocyte physiologic and pathologic signaling, including the regulation of cardiac regeneration both in vitro and in vivo. In this review, we will explore and detail the current understanding of ncRNA function in cardiac regeneration, and highlight established and novel strategies for the treatment of heart failure through modulation of ncRNAs-driven cardiac regeneration.

scholarly journals Ephrin-B1 blocks adult cardiomyocyte proliferation and heart regeneration

2019 ◽  
Author(s):  
Marie Cauquil ◽  
Céline Mias ◽  
Céline Guilbeau-Frugier ◽  
Clément Karsenty ◽  
Marie-Hélène Seguelas ◽  
...  
Keyword(s):  
Resting State ◽  
Cardiac Tissue ◽  
Hippo Pathway ◽  
Cardiac Regeneration ◽  
Mouse Heart ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Postnatal Maturation

AbstractAimsDeciphering the innate mechanisms governing the blockade of proliferation in adult cardiomyocytes (CMs) is challenging for mammalian heart regeneration. Despite the exit of CMs from the cell cycle during the postnatal maturation period coincides with their morphological switch to a typical adult rod-shape, whether these two processes are connected is unknown. Here, we examined the role of ephrin-B1, a CM rod-shape stabilizer, in adult CM proliferation and cardiac regeneration.Methods and resultsTransgenic- or AAV9-based ephrin-B1 repression in adult mouse heart led to substantial proliferation of resident CMs and tissue regeneration to compensate for apex resection, myocardial infarction (MI) and senescence. Interestingly, in the resting state, CMs lacking ephrin-B1 did not constitutively proliferate, indicative of no major cardiac defects. However, they exhibited proliferation-competent signature, as indicated by higher mononucleated state and a dramatic decrease of miR-195 mitotic blocker, which can be mobilized under neuregulin-1 stimulation in vitro and in vivo. Mechanistically, the post-mitotic state of the adult CM relies on ephrin-B1 sequestering of inactive phospho-Yap1, the effector of the Hippo-pathway, at the lateral membrane. Hence, ephrin-B1 repression leads to phospho-Yap1 release in the cytosol but CM quiescence at resting state. Upon cardiac stresses (apectomy, MI, senescence), Yap1 could be activated and translocated to the nucleus to induce proliferation-gene expression and consequent CM proliferationConclusionsOur results identified ephrin-B1 as a new natural locker of adult CM proliferation and emphasize that targeting ephrin-B1 may prove a future promising approach in cardiac regenerative medicine for HF treatment.SignificanceThe mammalian adult heart is unable to regenerate due to the inability of cardiomyocytes (CMs) to proliferate and replace cardiac tissue lost. Exploiting CM-specific transgenic mice or AAV9-based gene therapy, this works identifies ephrin-B1, a specific rod-shape stabilizer of the adult CM, as a natural padlock of adult CM proliferation for compensatory adaptation to different cardiac stresses (apectomy, MI, senescence), thus emphasizing a new link between the adult CM morphology and their proliferation potential. Moreover, the study demonstrates proof-of-concept that targeting ephrin-B1 may be an innovative therapeutic approach for ischemic heart failure.

Abstract 129: Embryonic Stem Cell Derived Exosomes Revive Endogenous Repair Mechanisms In Failing Heart

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Mohsin Khan ◽  
Suresh K Verma ◽  
Alexander R Mackie ◽  
Erin Vaughan ◽  
Srikanth Garikipati ◽  
...  
Keyword(s):  
Stem Cells ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Cardiac Regeneration ◽  
Great Promise ◽  
Target Cells ◽  
Free System ◽  
Teratoma Formation

Rationale: Embryonic stem cells (ESCs) hold great promise for cardiac regeneration but are susceptible to ethical concerns, lack of autologous donors and teratoma formation. Recently, it has been observed that beneficial effects of stem cells are mediated by exosomes secreted out under various physiological conditions. ESCs have the ability to produce exosomes however their effect in the context of the heart is unknown. Objective: Determine the effect of ESC derived exosomes for cardiac repair and modulation of CPCs functions in the heart following myocardial infarction. Methods and Results: Exosomes were isolated from murine ESCs (mES Ex) or embryonic fibroblasts (MEFs) by ultracentrifugation and verified by Flotillin-1 immunoblot analysis. Induction of pluripotent markers, survival and in vitro tube formation was enhanced in target cells receiving ESC exosomes indicating therapeutic potential of mES Ex. mES Ex administration resulted in enhanced neovascularization, cardiomyocyte survival and reduced fibrosis post infarction consistent with resurgence of cardiac proliferative response. Importantly, mES Ex mediated considerable enhancement of cardiac progenitor cell (CPC) survival, proliferation and cardiac commitment concurrent with increased c-kit+ CPCs in vivo 4 weeks after mES Ex transfer. miRNA Array analysis of ESC and MEF exosomes revealed significantly high expression of miR290-295 cluster in the ESC exosomes compared to MEF exosomes. The underlying beneficial effect of mES Ex was tied to delivery of ESC miR-294 to the heart and in particular CPCs thereby promoting CPC survival and proliferation as analyzed by FACS based cell death analysis and CyQuant assay respectively. Interestingly, enhanced G1/S transition was observed in CPCs treated with miR-294 in conjunction with significant reduction of G1 phase. Conclusion: In conclusion, mES Ex provide a novel cell free system for cardiac regeneration with the ability to modulate both cardiomyocyte and CPC based repair programs in the heart thereby avoiding the risk of teratoma formation associated with ESCs.

scholarly journals Soluble Alpha-Klotho Alleviates Cardiac Fibrosis without Altering Cardiomyocytes Renewal

2020 ◽  
Vol 21 (6) ◽  
pp. 2186
Author(s):  
Wei-Yu Chen
Keyword(s):  
Endothelial Cells ◽  
Cardiac Fibrosis ◽  
Fibroblast Growth Factor 23 ◽  
Cardiac Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Injured Myocardium ◽  
H9c2 Cardiomyocytes ◽  
Mapping Models

Heart disease is the leading cause of death worldwide. The major cause of heart failure is the death of the myocardium caused by myocardial infarction, detrimental cardiac remodeling, and cardiac fibrosis occurring after the injury. This study aimed at discovering the role of the anti-aging protein α-klotho (KL), which is the co-receptor of fibroblast growth factor-23 (FGF23), in cardiac regeneration, fibrosis, and repair. We found that the anti-apoptotic function of soluble KL in isoproterenol-treated H9c2 cardiomyocytes was independent of FGF23 in vitro. In vivo, isoproterenol-induced cardiac fibrosis and cardiomyocyte and endothelial cell apoptosis were reduced by KL treatment. Moreover, the number of Ki67-positive endothelial cells and microvessel density within the isoproterenol-injured myocardium were increased upon KL treatment. However, by using genetic fate-mapping models, no evident cardiomyocyte proliferation within the injured myocardium was detected with or without KL treatment. Collectively, the cardioprotective functions of KL could be predominantly attributed to its anti-apoptotic and pro-survival activities on endothelial cells and cardiomyocytes. KL could be a potential cardioprotective therapeutic agent with anti-apoptotic and pro-survival activities on cardiomyocytes and endothelial cells.

scholarly journals The TWIST1-centered competing endogenous RNA network promotes proliferation, invasion, and migration of lung adenocarcinoma

Oncogenesis ◽  
2019 ◽  
Vol 8 (11) ◽  
Author(s):  
Wenjie Xia ◽  
Qixing Mao ◽  
Bing Chen ◽  
Lin Wang ◽  
Weidong Ma ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Messenger Rnas ◽  
Competing Endogenous Rna ◽  
Invasion And Migration ◽  
Non Coding Rnas ◽  
And Migration

Abstract The proposed competing endogenous RNA (ceRNA) mechanism suggested that diverse RNA species, including protein-coding messenger RNAs and non-coding RNAs such as long non-coding RNAs, pseudogenes and circular RNAs could communicate with each other by competing for binding to shared microRNAs. The ceRNA network (ceRNET) is involved in tumor progression and has become a hot research topic in recent years. To date, more attention has been paid to the role of non-coding RNAs in ceRNA crosstalk. However, coding transcripts are more abundant and powerful than non-coding RNAs and make up the majority of miRNA targets. In this study, we constructed a mRNA-mRNA related ceRNET of lung adenocarcinoma (LUAD) and identified the highlighted TWIST1-centered ceRNET, which recruits SLC12A5 and ZFHX4 as its ceRNAs. We found that TWIST1/SLC12A5/ZFHX4 are all upregulated in LUAD and are associated with poorer prognosis. SLC12A5 and ZFHX4 facilitated proliferation, migration, and invasion in vivo and in vitro, and their effects were reversed by miR-194–3p and miR-514a-3p, respectively. We further verified that SLC12A5 and ZFHX4 affected the function of TWIST1 by acting as ceRNAs. In summary, we constructed a mRNA-mRNA related ceRNET for LUAD and highlighted the well-known oncogene TWIST1. Then we verified that SLC12A5 and ZFHX4 exert their oncogenic function by regulating TWIST1 expression through a ceRNA mechanism.

scholarly journals Non-Coding RNAs as Mediators of Epigenetic Changes in Malignancies

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3657
Author(s):  
Subhasree Kumar ◽  
Edward A. Gonzalez ◽  
Pranela Rameshwar ◽  
Jean-Pierre Etchegaray
Keyword(s):  
Cellular Proliferation ◽  
Circular Rnas ◽  
Cancer Type ◽  
Epigenetic Alterations ◽  
Gene Expressions ◽  
Aberrant Expression ◽  
In Vivo Experiments ◽  
Non Coding Rnas

Non-coding RNAs (ncRNAs) are untranslated RNA molecules that regulate gene expressions. NcRNAs include small nuclear RNAs (snRNAs), small nucleolar RNAs (snoRNAs), ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), circular RNAs (cRNAs) and piwi-interacting RNAs (piRNAs). This review focuses on two types of ncRNAs: microRNAs (miRNAs) or short interfering RNAs (siRNAs) and long non-coding RNAs (lncRNAs). We highlight the mechanisms by which miRNAs and lncRNAs impact the epigenome in the context of cancer. Both miRNAs and lncRNAs have the ability to interact with numerous epigenetic modifiers and transcription factors to influence gene expression. The aberrant expression of these ncRNAs is associated with the development and progression of tumors. The primary reason for their deregulated expression can be attributed to epigenetic alterations. Epigenetic alterations can cause the misregulation of ncRNAs. The experimental evidence indicated that most abnormally expressed ncRNAs impact cellular proliferation and apoptotic pathways, and such changes are cancer-dependent. In vitro and in vivo experiments show that, depending on the cancer type, either the upregulation or downregulation of ncRNAs can prevent the proliferation and progression of cancer. Therefore, a better understanding on how ncRNAs impact tumorigenesis could serve to develop new therapeutic treatments. Here, we review the involvement of ncRNAs in cancer epigenetics and highlight their use in clinical therapy.

scholarly journals Non-coding RNAs: emerging players in cardiomyocyte proliferation and cardiac regeneration

2020 ◽  
Vol 115 (5) ◽  
Author(s):  
Naisam Abbas ◽  
Filippo Perbellini ◽  
Thomas Thum
Keyword(s):  
Cell Cycle ◽  
Molecular Mechanisms ◽  
Contractile Function ◽  
Cardiac Regeneration ◽  
Therapeutic Interventions ◽  
Circular Rnas ◽  
Cardiomyocyte Proliferation ◽  
Protein Coding ◽  
Rna Molecules ◽  
Non Coding Rnas

Abstract Soon after birth, the regenerative capacity of the mammalian heart is lost, cardiomyocytes withdraw from the cell cycle and demonstrate a minimal proliferation rate. Despite improved treatment and reperfusion strategies, the uncompensated cardiomyocyte loss during injury and disease results in cardiac remodeling and subsequent heart failure. The promising field of regenerative medicine aims to restore both the structure and function of damaged tissue through modulation of cellular processes and regulatory mechanisms involved in cardiac cell cycle arrest to boost cardiomyocyte proliferation. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) are functional RNA molecules with no protein-coding function that have been reported to engage in cardiac regeneration and repair. In this review, we summarize the current understanding of both the biological functions and molecular mechanisms of ncRNAs involved in cardiomyocyte proliferation. Furthermore, we discuss their impact on the structure and contractile function of the heart in health and disease and their application for therapeutic interventions.

scholarly journals Repair Injured Heart by Regulating Cardiac Regenerative Signals

2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Wen-Feng Cai ◽  
Guan-Sheng Liu ◽  
Lei Wang ◽  
Christian Paul ◽  
Zhi-Li Wen ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Heart Diseases ◽  
Cardiac Regeneration ◽  
Heart Tissue ◽  
Cardiomyocyte Proliferation ◽  
Proliferation Capacity ◽  
End Stage

Cardiac regeneration is a homeostatic cardiogenic process by which the sections of malfunctioning adult cardiovascular tissues are repaired and renewed employing a combination of both cardiomyogenesis and angiogenesis. Unfortunately, while high-quality regeneration can be performed in amphibians and zebrafish hearts, mammalian hearts do not respond in kind. Indeed, a long-term loss of proliferative capacity in mammalian adult cardiomyocytes in combination with dysregulated induction of tissue fibrosis impairs mammalian endogenous heart regenerative capacity, leading to deleterious cardiac remodeling at the end stage of heart failure. Interestingly, several studies have demonstrated that cardiomyocyte proliferation capacity is retained in mammals very soon after birth, and cardiac regeneration potential is correspondingly preserved in some preadolescent vertebrates after myocardial infarction. There is therefore great interest in uncovering the molecular mechanisms that may allow heart regeneration during adult stages. This review will summarize recent findings on cardiac regenerative regulatory mechanisms, especially with respect to extracellular signals and intracellular pathways that may provide novel therapeutics for heart diseases. Particularly, bothin vitroandin vivoexperimental evidences will be presented to highlight the functional role of these signaling cascades in regulating cardiomyocyte proliferation, cardiomyocyte growth, and maturation, with special emphasis on their responses to heart tissue injury.

scholarly journals Myocardial matrix material supports a proliferative microenvironment for cardiomyocytes

2020 ◽  
Author(s):  
Raymond M. Wang ◽  
Paola Cattaneo ◽  
Nuno Camboa ◽  
Rebecca Braden ◽  
Colin Luo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Cardiac Tissue ◽  
Matrix Material ◽  
Cardiomyocyte Proliferation ◽  
Cycle Progression ◽  
Progression Marker ◽  
Repair Mechanisms

AbstractNovel therapeutics have sought to stimulate the endogenous repair mechanisms in the mammalian myocardium as the native regenerative potential of the adult cardiac tissue is limited. In particular, a myocardial matrix derived injectable hydrogel has shown efficacy and safety in various animal myocardial infarction (MI) including evidence of increased myocardium. In this study, investigation on the properties of this myocardial matrix material demonstrated its native capability as an effective reactive oxygen species (ROS) scavenger that can protect against oxidative stress and maintain cardiomyocyte proliferation in vitro. In vivo assessment of of myocardial matrix hydrogel treatment post-MI demonstrated increased thymidine analog uptake in cardiomyocytes compared to saline controls along with co-staining with cell cycle progression marker, phospho-histone H3. Overall, this study provides further evidence that properties of the myocardial matrix hydrogel promote an environment supportive of cardiomyocytes undergoing cell cycle progression.

P5388N-cadherin promotes cardiac regeneration by stabilizing beta-catenin

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y S Tseng ◽  
M Y You ◽  
Y C Hsu ◽  
K C Yang
Keyword(s):  
Cell Cycle ◽  
Proliferative Activity ◽  
Cardiac Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Regenerative Capacity ◽  
Cell Cycle Genes ◽  
Multiple Cell

Abstract Background Although the adult mammalian heart fails to regenerate after injury, it is known that newborn mice within a week have full cardiac regenerative capacity. The molecular determinants underlying the disparate regenerative capacity between neonatal and adult mice, however, remain incompletely understood. Exploiting RNA sequencing in isolated cardiomyocytes from neonatal and adult mouse heart, we identified Cdh2, which encodes the adherence junction protein N-cadherin, as a potential novel mediator of cardiac regeneration. Cdh2 expression levels were much higher in neonatal, compared with adult, cardiomyocytes and showed a strong positive correlation with that of multiple cell cycle genes. N-cadherin has been reported to be essential for embryonic cardiac development; its role in cardiac regeneration, however, remains unknown. Purpose To determine the role of Cdh2 (N-cadherin) in cardiac regeneration and to investigate the underlying molecular mechanisms. Methods Apical resection in postnatal day 1 mice was used as a cardiac regenerative model. The in vitro gain/loss-of function studies of Cdh2/N-cadherin was performed in postnatal day 1 neonatal mouse cardiomyocytes (P1CM) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM). N-cadherin inhibitor exherin was used to study the effects of N-cadherin in vivo. Results Comparing to sham-operated control, Cdh2 was significantly upregulated in mouse cardiac apex and border zone following apical resection, which was accompanied with increased cardiomyocyte proliferation activity. In vitro, knocking down Cdh2 or inhibition of N-cadherin activity with exherin in P1CM significantly reduced the proliferative activity of cardiomyocytes, whereas overexpression of Cdh2 markedly increased the proliferation of P1CM. In addition, forced expression of Cdh2 resulted in significant upregulation of multiple cell cycle genes, including Ccnd1 (Cyclin D1) and Pcna (proliferating cell nuclear antigen), in P1CM. In vivo inhibition of N-cadherin in P1 neonatal mice with exherin following apical resection impaired cardiac regeneration and increased scar formation (Figure). Knocking down CDH2 in human iPSC-CMs significantly reduced the proliferative activity and the expression levels of cell cycle gene CCND1 in iPSC-CMs. Mechanistically, we demonstrated that the pro-mitotic effects of N-cadherin in cardiomyocytes were mediated, at least partially, by stabilizing β-catenin, a pro-mitotic transcription factor, through direct interaction with its cytoplasmic domain and/or inactivation of GSK3β, a critical component of β-catenin destruction complex. N-Cad blocker impairs heart regeneration Conclusion Our study uncovered a previously unrecognized role of Cdh2 (N-cadherin) in cardiomyocyte proliferation and cardiac regeneration. Enhancing cardiac expression or activity of N-cadherin, therefore, could be a potential novel therapeutic approach to promote cardiac regeneration and restore cardiac function in adult heart following injury.

scholarly journals The Mechanistic Roles of ncRNAs in Promoting and Supporting Chemoresistance of Colorectal Cancer

2021 ◽  
Vol 7 (2) ◽  
pp. 24
Author(s):  
Isaac Micallef ◽  
Byron Baron
Keyword(s):  
Colorectal Cancer ◽  
Epithelial Mesenchymal Transition ◽  
Circular Rnas ◽  
Gastrointestinal Malignancies ◽  
Mesenchymal Transition ◽  
Non Coding Rna ◽  
Non Coding Rnas ◽  
Made In

Colorectal Cancer (CRC) is one of the most common gastrointestinal malignancies which has quite a high mortality rate. Despite the advances made in CRC treatment, effective therapy is still quite challenging, particularly due to resistance arising throughout the treatment regimen. Several studies have been carried out to identify CRC chemoresistance mechanisms, with research showing different signalling pathways, certain ATP binding cassette (ABC) transporters and epithelial mesenchymal transition (EMT), among others to be responsible for the failure of CRC chemotherapies. In the last decade, it has become increasingly evident that certain non-coding RNA (ncRNA) families are involved in chemoresistance. Research investigations have demonstrated that dysregulation of microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) contribute towards promoting resistance in CRC via different mechanisms. Considering the currently available data on this phenomenon, a better understanding of how these ncRNAs participate in chemoresistance can lead to suitable solutions to overcome this problem in CRC. This review will first focus on discussing the different mechanisms of CRC resistance identified so far. The focus will then shift onto the roles of miRNAs, lncRNAs and circRNAs in promoting 5-fluorouracil (5-FU), oxaliplatin (OXA), cisplatin and doxorubicin (DOX) resistance in CRC, specifically using ncRNAs which have been recently identified and validated under in vivo or in vitro conditions.

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