Chemical Enhancement of In Vitro and In Vivo Direct Cardiac Reprogramming

Mohamed, Tamer; Stone, Nicole R.; Berry, Emily C.; Radzinsky, Ethan; Huang, Yu; Pratt, Karishma; Ang, Yen‐Sin; Yu, Pengzhi; Wang, Haixia; Tang, Shibing; Magnitsky, Sergey; Ding, Sheng; Ivey, Kathryn N.; Srivastava, Deepak

doi:10.1161/circulationaha.116.024692

Cited by 202 publications

(237 citation statements)

References 40 publications

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“…At the same time, the success of our approach (a 1-wk delay in drug delivery following injury) reveals at a minimum a 1-wk window in which initiation of Porcn inhibitor delivery following myocardial infarction (MI) might be beneficial. Finally, we acknowledge that changes in the expression of Col6 may be only one proregenerative consequence of Porcn inhibition and that other molecular changes (38,39) may also be factors that influence heart function outcome.…”

Section: Discussionmentioning

confidence: 98%

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Moon

Zhou

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit, COL6A1, has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury.

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Section: Discussionmentioning

confidence: 98%

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Moon

Zhou

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Mouse transthoracic echocardiograms were performed as previously described (Mohamed et al, 2016). Briefly, mice were anesthetized with isoflurane, placed on a heating pad, and ventral fur shaved with clippers.…”

Section: Star Methodsmentioning

confidence: 99%

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

Newman

Covarrubias

Zhao³

et al. 2017

Cell Metabolism

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360

299

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Summary A ketogenic diet (KD) recapitulates certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether KD might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that an isoprotein KD, fed on alternate weeks to prevent obesity (Cyclic KD), reduces mid-life mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. Gene expression analysis identifies down-regulation of insulin, TOR, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, up-regulation of PPARα target genes is unique to KD, consistent across tissues, and preserved in old age. In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice.

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“…Another feature to consider is that humans have a longer developmental time than mice, potentially contributing to the species differences in cell reprogramming. Interestingly, despite the requirement of different factors for direct cardiac reprogramming between species, crucial endogenous signalling pathways such as the TGFβ1 and WNT signalling pathways contribute similarly to cardiac reprogramming in both mouse and human cells 120 .…”

Section: Direct Reprogramming For Heart Repairmentioning

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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Chemical Enhancement of In Vitro and In Vivo Direct Cardiac Reprogramming

Cited by 202 publications

References 40 publications

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice

Therapeutic approaches for cardiac regeneration and repair

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