Multicellular Transcriptional Analysis of Mammalian Heart Regeneration

Quaife-Ryan, Gregory A.; Sim, Choon Boon; Ziemann, Mark; Kaspi, Antony; Rafehi, Haloom; Ramialison, Mirana; El‐Osta, Assam; Hudson, James E.; Porrello, Enzo R.

doi:10.1161/circulationaha.117.028252

Cited by 225 publications

(212 citation statements)

References 48 publications

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“…A study analysing the transcriptome and the chromatin landscape in neonatal and adult mouse hearts also revealed that noncardiomyocytes activate a distinct injury-induced transcriptional programme in response to MI 171 . Another report demonstrated an apparent difference in the immune response after MI between newborn mice at day 1 and at week 2 (REF 172 ).…”

Section: Future Perspectivesmentioning

confidence: 99%

Therapeutic approaches for cardiac regeneration and repair

2018

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Ischaemic heart disease is a leading cause of death worldwide. Injury to the heart is followed by loss of the damaged cardiomyocytes, which are replaced with fibrotic scar tissue. Depletion of cardiomyocytes results in decreased cardiac contraction, which leads to pathological cardiac dilatation, additional cardiomyocyte loss, and mechanical dysfunction, culminating in heart failure. This sequential reaction is defined as cardiac remodelling. Many therapies have focused on preventing the progressive process of cardiac remodelling to heart failure. However, after patients have developed end-stage heart failure, intervention is limited to heart transplantation. One of the main reasons for the dramatic injurious effect of cardiomyocyte loss is that the adult human heart has minimal regenerative capacity. In the past 2 decades, several strategies to repair the injured heart and improve heart function have been pursued, including cellular and noncellular therapies. In this Review, we discuss current therapeutic approaches for cardiac repair and regeneration, describing outcomes, limitations, and future prospects of preclinical and clinical trials of heart regeneration. Substantial progress has been made towards understanding the cellular and molecular mechanisms regulating heart regeneration, offering the potential to control cardiac remodelling and redirect the adult heart to a regenerative state.

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Section: Future Perspectivesmentioning

confidence: 99%

Therapeutic approaches for cardiac regeneration and repair

2018

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“…In search of regenerative therapies, a number of studies have utilized transcriptomics to identify mechanisms regulating cardiac regeneration (for recent examples, see [25][26][27] ). However, proteomic and metabolomic changes have not been thoroughly investigated.…”

Section: Introductionmentioning

confidence: 99%

Molecular atlas of postnatal mouse heart development

Talman

Teppo

Pöhö

et al. 2018

Preprint

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Rationale: Mammals lose the ability to regenerate their hearts within one week after birth. During this regenerative window, cardiac energy metabolism shifts from glycolysis to fatty acid oxidation, and recent evidence suggests that metabolism may participate in controlling cardiomyocyte cell cycle. However, the molecular mechanisms mediating the loss of postnatal cardiac regeneration are not fully understood.Objective: This study aims at providing an integrated resource of mRNA, protein and metabolite changes in the neonatal heart to identify metabolism-related mechanisms associated with the postnatal loss of regenerative capacity. Methods and Results: Mouse ventricular tissue samples taken on postnatal days 1, 4, 9 and 23 (P01, P04, P09 and P23, respectively) were analyzed with RNA sequencing (RNAseq) and global proteomics and metabolomics. Differential expression was observed for 8547 mRNAs and for 1199 of the 2285 quantified proteins. Furthermore, 151 metabolites with significant changes were identified. Gene ontology analysis, KEGG pathway analysis and fuzzy c-means clustering were used to identify biological processes and metabolic pathways either up-or downregulated on all three levels. Among these were branched chain amino acid degradation (upregulated at P23) and production of free saturated and monounsaturated medium-to long-chain fatty acids (upregulated at P04 and P09; downregulated at P23). Moreover, the HMG-CoA synthase (HMGCS)-mediated mevalonate pathway and ketogenesis were transiently activated. Pharmacological inhibition of HMGCS in primary neonatal rat ventricular cardiomyocytes reduced the percentage of BrdU+ cardiomyocytes, providing evidence that the mevalonate and ketogenesis routes may participate in regulating cardiomyocyte cell cycle. Conclusions: This is the first systems-level resource combining data from genome-wide transcriptomics with global quantitative proteomics and untargeted metabolomics analyses of the mouse heart throughout the early postnatal period. This integrated multi-level data of molecular changes associated with the loss of cardiac regeneration may open up new possibilities for the development of regenerative therapies.

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“…The cardiac injury response in young swine after the postnatal period includes inflammation and scarring. Young pigs after cardiac injury produce an immune response to initiate cardiac healing and subsequent ECM remodeling, as has been observed in older large and small mammals (30,37,51,54). With transient ischemic injury in P30 pigs, we observed localized ECM upregulation with increased inflammation and thickening of the epicardial collagen matrix at the site of injury.…”

Section: Discussionmentioning

confidence: 87%

Scar Formation and Decreased Cardiac Function Following Ischemia/Reperfusion Injury in 1-Month-Old Swine

Agnew

Velayutham

Ortiz

et al. 2019

Preprint

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Studies in mice show a brief neonatal period of cardiac regeneration with minimal scar formation. Less is known about reparative mechanisms in large mammals. A transient cardiac injury approach (ischemia/reperfusion, IR) was used in weaned postnatal day (P)30 pigs, to assess regenerative repair in young large mammals. Female and male P30 pigs were subjected to cardiac ischemia (1 hour) by occlusion of the left anterior descending artery followed by reperfusion, or to sham operation. Following IR, myocardial damage occurred, with cardiac ejection fraction significantly decreased 2 hours post-ischemia. No improvement or worsening of cardiac function to the 4 week study end-point was observed. Histology demonstrated cardiomyocyte (CM) cell cycling at 2-months-of-age in multinucleated CMs in both sham-operated and IR pigs. Regional scar formation and inflammation in the epicardial region proximal to injury were observed 4 weeks post-IR. Sex differences were found, suggestive of females creating a greater fibrotic response with worse cardiac function, highlighting the importance of representing both sexes in cardiac injury studies. Together, our results describe an effective novel cardiac injury model in P30 swine, at a time when CMs are still cycling. Pigs subjected to IR show myocardial damage with a prolonged decrease in cardiac function, formation of a small, regional scar with increased inflammation. These data demonstrate that P30 pigs do not regenerate myocardium, even in the presence of CM mitotic activity, but form a scar after transient IR injury.NEW & NOTEWORTHYHere, we report for the first time ischemia/reperfusion (IR) cardiac injury in 1-month-old (P30) pigs. This model of IR injury highlights lack of cardiac regeneration, even in the presence of cardiomyocyte (CM) cell cycling in young swine. An effective injury approach is described for use in large mammals to investigate cardiac function, CM cell cycling, extracellular matrix (ECM) remodeling, and gene expression changes, while highlighting the importance of studying both sexes.

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Multicellular Transcriptional Analysis of Mammalian Heart Regeneration

Abstract: Supplemental Digital Content is available in the text.

Cited by 225 publications

References 48 publications

Therapeutic approaches for cardiac regeneration and repair

Therapeutic approaches for cardiac regeneration and repair

Molecular atlas of postnatal mouse heart development

Scar Formation and Decreased Cardiac Function Following Ischemia/Reperfusion Injury in 1-Month-Old Swine

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