Therapeutic approaches for cardiac regeneration and repair

Hashimoto, Hisayuki; Olson, Eric N.; Bassel‐Duby, Rhonda

doi:10.1038/s41569-018-0036-6

Cited by 313 publications

(281 citation statements)

References 217 publications

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“…Our results, together with previous reports, show that cardiac injury after the postnatal period of P0-P3 leads to inflammation and scarring, not CM renewal in young pigs, despite presence of cell cycling CMs. Loss of cardiac regenerative capacity has been linked to oxidative stress at birth, ECM maturation, and 30 infiltration of macrophages in addition to CM cell cycle exit (11,19,34,51,54). Further understanding the factors which inhibit regeneration in the developing pig will add to the current limited knowledge on mechanistic regulation of cardiac repair following injury in young large mammals.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Because the regenerative effects of activating Yap in organs such as the retina and heart have been characterized extensively 5,14,15,17 , we investigated whether TRULI treatment is effective in eliciting cellular proliferation in these contexts.…”

Section: Effects Of Truli On Cardiomyocytes and Müller Gliamentioning

confidence: 99%

“…Regeneration occurs either by activation and amplification of resident stem cells, as in the epithelia of the skin and intestine, or through cellular de-differentiation and proliferation, as in the liver. In other instances, such as central nervous and cardiac-muscle tissues, cells exhibit little or no potential for regeneration after injury 1,4,5 .…”

Section: Introductionmentioning

confidence: 99%

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

Kastan

Gnedeva

Alisch

et al. 2020

Preprint

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Hippo signaling is an evolutionarily conserved pathway that restricts organ growth during development and suppresses regeneration in mature organs 1-3 . Using a high-throughput phenotypic screen, we have identified a potent, non-toxic, and reversible inhibitor of Hippo signaling. An ATP-competitive inhibitor of Lats kinases, the compound causes Yapdependent proliferation of murine supporting cells in the inner ear, murine cardiomyocytes, and human Müller glia in retinal organoids. RNA sequencing indicates that the substance fosters both the G1-S and G2-M checkpoint transitions and yields supporting cells capable of transdifferentiation. Upon withdrawal of the compound, a subset of supporting cells move their nuclei into the hair-cell layer and express genes characteristic of hair cells. Viral transfection of Atoh1 induces the expression of hair cellspecific proteins in progeny. The compound promotes the initial stages of the proliferative regeneration of hair cells, a process thought to be permanently suppressed in the adult mammalian inner ear. This project was made possible by the dedicated personnel of two service facilities. At Rockefeller University's High-Throughput Screening Resource Center directed by Fraser Glickman, Carolina Adura Alcaino helped design assays for enzyme activity. assisted with assay design and Rui Liang performed chemical syntheses. Declaration of InterestsKG, NK, TA, AAP, and AJH are parties to an application for patent protection of derivatives of the Lats inhibitor presented here.

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“…The adult mammalian heart exhibits a very slow rate of cardiomyocyte renewal, clearly insufficient for a robust regenerative response 10,11 . Improving the proliferative ability of endogenous adult cardiomyocytes represents an emerging strategy to repair the heart tissue and to boost cardiac function in heart failure patients [2][3][4][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid Receptor ablation promotes cardiac regeneration by hampering cardiomyocyte terminal differentiation

Pianca

Pontis

Chirivì

et al. 2020

Preprint

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In mammals, glucocorticoid levels rise dramatically shortly before birth and prepare the foetus for post-natal life by promoting the maturation of the lungs and other organs.However, their impact on cardiac postnatal growth and regenerative plasticity is unknown.Here, we demonstrate that exposure to endogenous glucocorticoids facilitates cell cycle exit and reduces the proliferation of neonatal cardiomyocytes. This cytostatic activity is shared by several synthetic glucocorticoid receptor (GR) agonists routinely used in clinical settings. We also observed that GR levels increase in cardiomyocytes during early post-natal development. Importantly, in vivo cardiomyocyte-specific GR ablation delayed the transition from hyperplastic (increase in cell number) to hypertrophic (increase in cell size) growth. Further, GR ablation partially impaired cardiomyocyte maturation, reducing myofibrils-mitochondria organization along with the expression of genes involved in fatty acid metabolism, mitochondrial respiration and energy transfer from mitochondria to the cytosol. Finally, we show increased cardiomyocyte proliferation in GR ablated juvenile and adult cardiomyocytes in response to myocardial infarction in vivo, thus promoting cardiac tissue regeneration.We suggest that GR antagonization could serve as a strategy for heart regeneration based on endogenous cardiomyocyte renewal.3

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Therapeutic approaches for cardiac regeneration and repair

Cited by 313 publications

References 217 publications

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

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

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

Glucocorticoid Receptor ablation promotes cardiac regeneration by hampering cardiomyocyte terminal differentiation

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