Regulatory aspects of small molecule drugs for heart regeneration

Rodgers, Kathleen E.; Papinska, Anna; Mordwinkin, Nicholas M.

doi:10.1016/j.addr.2015.06.013

Cited by 7 publications

(8 citation statements)

References 103 publications

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“…A central pursuit for researchers pursuing cardiac regeneration is the induction and control of proliferation in differentiated cardiomyocytes, particularly adult cardiomyocytes, which otherwise exhibit very low levels of proliferation 6 . Since the neonatal mouse heart has been shown to transiently retain regenerative potential 7 , strategies to reactivate proliferation in damaged adult heart have attracted interest for therapeutic application 8 9 . The mechanisms driving post-natal cardiomyocyte cell cycle arrest in mammals are still poorly understood and so there is great potential in identifying factors that effectively modulate cardiomyocyte proliferation and stimulate cardiomyocytes to re-enter the cell cycle and divide.…”

mentioning

confidence: 99%

Induction of Human iPSC-Derived Cardiomyocyte Proliferation Revealed by Combinatorial Screening in High Density Microbioreactor Arrays

Titmarsh

Glass

Mills

et al. 2016

Sci Rep

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Inducing cardiomyocyte proliferation in post-mitotic adult heart tissue is attracting significant attention as a therapeutic strategy to regenerate the heart after injury. Model animal screens have identified several candidate signalling pathways, however, it remains unclear as to what extent these pathways can be exploited, either individually or in combination, in the human system. The advent of human cardiac cells from directed differentiation of human pluripotent stem cells (hPSCs) now provides the ability to interrogate human cardiac biology in vitro, but it remains difficult with existing culture formats to simply and rapidly elucidate signalling pathway penetrance and interplay. To facilitate high-throughput combinatorial screening of candidate biologicals or factors driving relevant molecular pathways, we developed a high-density microbioreactor array (HDMA) – a microfluidic cell culture array containing 8100 culture chambers. We used HDMAs to combinatorially screen Wnt, Hedgehog, IGF and FGF pathway agonists. The Wnt activator CHIR99021 was identified as the most potent molecular inducer of human cardiomyocyte proliferation, inducing cell cycle activity marked by Ki67, and an increase in cardiomyocyte numbers compared to controls. The combination of human cardiomyocytes with the HDMA provides a versatile and rapid tool for stratifying combinations of factors for heart regeneration.

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mentioning

confidence: 99%

Induction of Human iPSC-Derived Cardiomyocyte Proliferation Revealed by Combinatorial Screening in High Density Microbioreactor Arrays

Titmarsh

Glass

Mills

et al. 2016

Sci Rep

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“…[ 2 ] Following MI, the damaged myocardium eventually undergoes a remodeling process with cardiomyocyte depletion, tissue fibrosis, cardiac dilatation, and dysfunction, culminating in heart failure. [ 3 ] Currently, several therapeutic strategies have been exploited to repair and regenerate the damaged cardiac tissues caused by MI, including pharmaceutic approaches, [ 4 ] injectable hydrogels, [ 5 ] cardiac patches, [ 6 ] cell transplantation, [ 7 ] and cell reprogramming. [ 8 ] Among them, injectable hydrogels have shown great potential to treat MI by providing mechanical support and tissue integration to increase myocardial thickness and prevent ventricular remodeling through a minimally invasive and cost‐effective manner.…”

Section: Introductionmentioning

confidence: 99%

“…Pharmacological treatments are commonly used in clinic to slow down or reverse detrimental cardiac remodeling in MI patients, [ 17 ] with specific effects such as proangiogenesis, [ 18 ] anti‐fibrosis, [ 18,19 ] anti‐inflammatory, [ 20 ] anti‐cardiomyocyte death, [ 4b ] antiarrhythmic, [ 21 ] and anti‐thrombosis. [ 22 ] The cyclic adenosine monophosphate (cAMP) is an essential second messenger and mediates many critical intracellular signaling under physiological and pathophysiological conditions.…”

Section: Introductionmentioning

confidence: 99%

Injectable Drug‐Releasing Microporous Annealed Particle Scaffolds for Treating Myocardial Infarction

Fang

Koh

Fang

et al. 2020

Adv Funct Materials

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Intramyocardial injection of hydrogels offers great potential for treating myocardial infarction (MI) in a minimally invasive manner. However, traditional bulk hydrogels generally lack microporous structures to support rapid tissue ingrowth and biochemical signals to prevent fibrotic remodeling toward heart failure. To address such challenges, a novel drugreleasing microporous annealed particle (drugMAP) system is developed by encapsulating hydrophobic drug-loaded nanoparticles into microgel building blocks via microfluidic manufacturing. By modulating nanoparticle hydrophilicity and pregel solution viscosity, drugMAP building blocks are generated with consistent and homogeneous encapsulation of nanoparticles. In addition, the complementary effects of forskolin (F) and Repsox (R) on the functional modulations of cardiomyocytes, fibroblasts, and endothelial cells in vitro are demonstrated. After that, both hydrophobic drugs (F and R) are loaded into drugMAP to generate FR/drugMAP for MI therapy in a rat model. The intramyocardial injection of MAP gel improves left ventricular functions, which are further enhanced by FR/drugMAP treatment with increased angiogenesis and reduced fibrosis and inflammatory response. This drugMAP platform represents a new generation of microgel particles for MI therapy and will have broad applications in regenerative medicine and disease therapy.

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“…Moreover, the population of cardiac stem cells is not adequate to regenerate entire cardiac tissue after a major injury. 2 Therefore, it is essential to find a strategy to improve the regeneration of cardiac tissue. The use of stem cells has emerged over the last decade as a leading path in regenerative medicine.…”

Section: Introductionmentioning

confidence: 99%

Computational and in vitro validation of cardiogenic induction of quercetin on adipose‐derived mesenchymal stromal cells through the inhibition of Wnt and non‐Smad‐dependent TGF‐β pathways

Azadian

Hosseini

Dizjikan

et al. 2021

J of Cellular Biochemistry

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Exploiting human mesenchymal stem cells (hMSCs) was proposed as a promising therapeutic approach for cardiovascular disease due to their capacity to differentiate into cardiac cells. Though modulation of the intracellular signaling pathways dominantly WNT/β catenin and transforming growth factor-β (TGF-β) have been reported to promote differentiation of hMSCs into cardiomyocytes in the prevailing literature, a safe and reproducible system for their clinical application has not yet turned into reality. In the present study, the molecular docking-based strategy was first applied for evaluating the potency of some natural phenolic compounds in the modulation of Wnt and TGF-β signaling pathways using a vital class of crystallographic protein structures of WNT signaling regulators such as Frizzled, Disheveled, GSK3-β, β-catenin, LRP 5/6 extracellular domain, Tankyrase and their variety of active pockets. Then, the impacts of plant-derived chemical compounds on the regulation of the relevant signals for the differentiation of hMSCs into the definitive mesoderm lineage and cardiac progenitors were assessed in vitro. Data obtained revealed the synergistic activity of Wnt and TGF-β superfamily to direct cardiac differentiation in human cardiogenesis by comparing cardiac gene expression in the presence and absence of the TGF-β inhibitors. We found that the inhibitory effect of canonical Wnt/βcatenin is sufficient to cause proper cardiomyocyte differentiation, but the TGF-β pathway plays a vital role in enhancing the expression of the cardiomyocytespecific marker (cTnT). It was found that quercetin, a p38MAPK inhibitor with the high energy dock to the active pocket of Wnt receptors, promotes cardiac differentiation via the inhibition of both Wnt and non-Smad TGF-β pathways.Altogether, data presented here can contribute to the development of a feasible and efficient cardiac differentiation protocol as an "off-the-shelf" therapeutic source using novel natural agents for cardiac repair or regeneration.

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Regulatory aspects of small molecule drugs for heart regeneration

Cited by 7 publications

References 103 publications

Induction of Human iPSC-Derived Cardiomyocyte Proliferation Revealed by Combinatorial Screening in High Density Microbioreactor Arrays

Induction of Human iPSC-Derived Cardiomyocyte Proliferation Revealed by Combinatorial Screening in High Density Microbioreactor Arrays

Injectable Drug‐Releasing Microporous Annealed Particle Scaffolds for Treating Myocardial Infarction

Computational and in vitro validation of cardiogenic induction of quercetin on adipose‐derived mesenchymal stromal cells through the inhibition of Wnt and non‐Smad‐dependent TGF‐β pathways

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