The local microenvironment limits the regenerative potential of the mouse neonatal heart

Notari, Mario; Ventura-Rubio, Antoni; Bedford-Guaus, Sylvia J.; Jorba, Ignasi; Mulero, Lola; Navajas, Daniel; Martí, Mercè; Raya, Ángel

doi:10.1126/sciadv.aao5553

Cited by 151 publications

(154 citation statements)

References 45 publications

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“…Furthermore, direct fluorescence visualization of FUCCI readouts allowed monitoring of cCIC cell cycle progression in host myocardium. From the outset when cCIC delivery occurs at the optimal P3 time point (Figure A), the reparative capacity of the postnatal heart that is present at P1‐P2 has largely been lost coinciding with cardiomyocyte exodus from cell cycle and increases in local ECM stiffness . Comparable phenotypic traits with cCIC previously found in the fetal context include expression of Vim (Figure J) but lack cardiac lineage markers (Figure B,C).…”

Section: Discussionmentioning

confidence: 82%

Adaptation within embryonic and neonatal heart environment reveals alternative fates for adult c-kit+ cardiac interstitial cells

Wang

Álvarez

Muliono

et al. 2019

Stem Cells Translational Medicine

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Cardiac interstitial cells (CICs) perform essential roles in myocardial biology through preservation of homeostasis as well as response to injury or stress. Studies of murine CIC biology reveal remarkable plasticity in terms of transcriptional reprogramming and ploidy state with important implications for function. Despite over a decade of characterization and in vivo utilization of adult c-Kit + CIC (cCIC), adaptability and functional responses upon delivery to adult mammalian hearts remain poorly understood. Limitations of characterizing cCIC biology following in vitro expansion and adoptive transfer into the adult heart were circumvented by delivery of the donated cells into early cardiogenic environments of embryonic, fetal, and early postnatal developing hearts. These three developmental stages were permissive for retention and persistence, enabling phenotypic evaluation of in vitro expanded cCICs after delivery as well as tissue response following introduction to the host environment. Embryonic blastocyst environment prompted cCIC integration into trophectoderm as well as persistence in amniochorionic membrane. Delivery to fetal myocardium yielded cCIC perivascular localization with fibroblast-like phenotype, similar to cCICs introduced to postnatal P3 heart with persistent cell cycle activity for up to 4 weeks. Fibroblast-like phenotype of exogenously transferred cCICs in fetal and postnatal cardiogenic environments is consistent with inability to contribute directly toward cardiogenesis and lack of functional integration with host myocardium. In contrast, cCICs incorporation into extraembryonic membranes is consistent with fate of polyploid cells in blastocysts. These findings provide insight into cCIC biology, their inherent predisposition toward fibroblast fates in cardiogenic environments, and remarkable participation in extraembryonic tissue formation.

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Section: Discussionmentioning

confidence: 82%

Adaptation within embryonic and neonatal heart environment reveals alternative fates for adult c-kit+ cardiac interstitial cells

Wang

Álvarez

Muliono

et al. 2019

Stem Cells Translational Medicine

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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: 86%

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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“…This suggests that changes in ECM composition result in organ-wide effects at the biomechanical level. Interestingly, recent data from our laboratories have identified a low ECM stiffness as a permissive factor regulating the heart regeneration ability of neonatal mice (59). The exact mechanism(s) by which ECM stiffness regulates heart regeneration competence in adult zebrafish and/or neonatal mice require further investigation.…”

Section: Discussionmentioning

confidence: 99%

Proteomics analysis of extracellular matrix remodeling during zebrafish heart regeneration

Garcia-Puig

Mosquera

Jiménez‐Delgado

et al. 2019

Preprint

Self Cite

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Adult zebrafish, in contrast to mammals, are able to regenerate their hearts in response to injury or experimental amputation. Our understanding of the cellular and molecular bases that underlie this process, although fragmentary, has increased significantly over the last years. However, the role of the extracellular matrix (ECM) during zebrafish heart regeneration has been comparatively rarely explored. Here, we set out to characterize the ECM protein composition in adult zebrafish hearts, and whether it changed during the regenerative response. For this purpose, we first established a decellularization protocol of adult zebrafish ventricles that significantly enriched the yield of ECM proteins. We then performed proteomic analyses of decellularized control hearts and at different times of regeneration. Our results show a dynamic change in ECM protein composition, most evident at the earliest (7 days post-amputation) time-point analyzed. Regeneration associated with sharp increases in specific ECM proteins, and with an overall decrease in collagens and cytoskeletal proteins. We finally tested by atomic force microscopy that the changes in ECM composition translated to decreased ECM stiffness. Our cumulative results identify changes in the protein composition and mechanical properties of the zebrafish heart ECM during regeneration.

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The local microenvironment limits the regenerative potential of the mouse neonatal heart

Abstract: Decreasing ECM stiffness rescues the regeneration ability of the neonatal mouse heart.

Cited by 151 publications

References 45 publications

Adaptation within embryonic and neonatal heart environment reveals alternative fates for adult c-kit+ cardiac interstitial cells

Adaptation within embryonic and neonatal heart environment reveals alternative fates for adult c-kit+ cardiac interstitial cells

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

Proteomics analysis of extracellular matrix remodeling during zebrafish heart regeneration

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