Engineered Cardiac Tissues as a Platform for CRISPR‐Based Mitogen Discovery DOI
Sophia DeLuca, Nicholas Strash, Yifan Chen

et al.

Advanced Healthcare Materials, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

Improved understanding of cardiomyocyte (CM) cell cycle regulation may allow researchers to stimulate pro-regenerative effects in injured hearts or promote maturation human stem cell-derived CMs. Gene therapies, particular, hold promise induce controlled proliferation endogenous transplanted CMs via transient activation mitogenic processes. Methods identify and characterize candidate cardiac mitogens vitro can accelerate translational efforts contribute the complex regulatory landscape CM postnatal maturation. In this study, A CRISPR knockout-based screening strategy using neonatal rat ventricular myocyte (NRVM) monolayers is established, followed by mitogen validation mature 3-D engineered tissues (ECTs). This screen identified knockout purine metabolism enzyme adenosine deaminase (ADA-KO) as an effective pro-mitogenic stimulus. RNA-sequencing ECTs further reveals increased pentose phosphate pathway (PPP) activity primary driver ADA-KO-induced cycling. Inhibition pathway's rate limiting enzyme, glucose-6-phosphate dehydrogenase (G6PD), prevented ADA-KO induced cycling, while increasing PPP G6PD overexpression Together, study demonstrates development application a genetic/tissue engineering platform for discovery new affecting regenerative states cardiomyocytes.

Language: Английский

The flexible chain: regulation of structure and activity of ETC complexes defines rate of ATP synthesis and sites of superoxide generation DOI

Zhanna V. Bochkova,

А. А. Байжуманов,

A. I. Yusipovich

et al.

Biophysical Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 25, 2025

Language: Английский

Citations

1
Biomimetic peroxisome targets myocardial injury and promotes heart repair and regeneration DOI Creative Commons
Ning Zhang,

Menghan Gao,

Xiaolong Hu

et al.

Biomaterials, Journal Year: 2025, Volume and Issue: 319, P. 123214 - 123214

Published: Feb. 25, 2025

Language: Английский

Citations

1
Cardiac Regeneration in Adult Zebrafish: A Review of Signaling and Metabolic Coordination DOI
Arkadeep Mitra, Subhadeep Mandal,

Kalyan Banerjee

et al.

Current Cardiology Reports, Journal Year: 2025, Volume and Issue: 27(1)

Published: Jan. 10, 2025

Language: Английский

Citations

0
Targeting miRNA‐1a and miRNA‐15b: A Novel Combinatorial Strategy to Drive Adult Cardiac Regeneration DOI Creative Commons
Ting Yuan,

Meiqian Wu,

Chaonan Zhu

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Despite its promise, cardiac regenerative therapy remains clinically elusive due to the difficulty of spatio-temporal control proliferative induction, and need coordinately reprogram multiple regulatory pathways overcome strict post-mitotic state human adult cardiomyocytes. To address this unmet therapeutic need, a combinatorial miRNA interference screen is performed specifically targeting cardiac-predominant miRNAs regulating key aspects cardiomyocyte mitotic induction cell-cycle completion in neonatal rat In doing so miRNA-1a miRNA-15b (LNA-1a/15b) identified as drivers proliferation. Due miRNA-1a/15b function on processes modulating mitosis, inhibition augmented daughter cell formation, improved contractility 3D organoids, mouse model ST-segment elevation myocardial infarction. cardiac-restricted pattern expression, strategy provides feasible means for specific with minimal risk neoplasm formation off-target toxicity. The approach further highlights an underutilized simultaneous co-regulation disease through miRNAs.

Language: Английский

Citations

0
Activation of Mitochondria in Mesenchymal Stem Cells by Mitochondrial Delivery of Coenzyme Q<sub>10</sub> DOI Open Access
Yuji Maruo,

Masahiro Shiraishi,

Mitsue Hibino

et al.

Biological and Pharmaceutical Bulletin, Journal Year: 2024, Volume and Issue: 47(8), P. 1415 - 1421

Published: Aug. 5, 2024

The efficacy of mesenchymal stem cell (MSC) transplantation has been reported for various diseases. We previously developed a drug delivery system targeting mitochondria (MITO-Porter) by using microfluidic device to encapsulate Coenzyme Q10 (CoQ10) on large scale. current study aimed confirm if treatment with CoQ10 encapsulated MITO-Porter enhanced mitochondrial functions in MSCs, the potential improve MSC therapy. used highly purified human bone marrow-derived described as rapidly expanding clones (RECs), and attempted control increase amount system. treated these RECs MITO-Porter, evaluated its cellular uptake, co-localization mitochondria, changes respiratory capacity, toxicity. There was no significant change capacity following previous MITO-Porter; however, significantly increased CoQ10-rich MITO-Porter. Utilization enabled be controlled, successfully activated MSCs. thus provides promising tool

Language: Английский

Citations

3
Transition from fetal to postnatal state in the heart: Crosstalk between metabolism and regeneration DOI Creative Commons
Tai Sada, Wataru Kimura

Development Growth & Differentiation, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 27, 2024

Abstract Cardiovascular disease is the leading cause of mortality worldwide. Myocardial injury resulting from ischemia can be fatal because limited regenerative capacity adult myocardium. Mammalian cardiomyocytes rapidly lose their proliferative capacities, with only a small fraction myocardium remaining proliferative, which insufficient to support post‐injury recovery. Recent investigations have revealed that this decline in myocardial closely linked perinatal metabolic shifts. Predominantly glycolytic fetal metabolism transitions towards mitochondrial fatty acid oxidation postnatally, not enables efficient production ATP but also causes dramatic reduction cardiomyocyte capacity. Extensive research has elucidated mechanisms behind shift, as well methods modulate these pathways. Some been successfully applied enhance reprogramming and regeneration. This review discusses recently acquired insights into interplay between proliferation, emphasizing postnatal transitions.

Language: Английский

Citations

2
Effects and mechanisms of the myocardial microenvironment on cardiomyocyte proliferation and regeneration DOI Creative Commons

Kexiao Zheng,

Yanglin Hao,

Chenkun Xia

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2024, Volume and Issue: 12

Published: July 10, 2024

The adult mammalian cardiomyocyte has a limited capacity for self-renewal, which leads to the irreversible heart dysfunction and poses significant threat myocardial infarction patients. In past decades, research efforts have been predominantly concentrated on proliferation regeneration. However, is complex organ that comprises not only cardiomyocytes but also numerous noncardiomyocyte cells, all playing integral roles in maintaining cardiac function. addition, are exposed dynamically changing physical environment includes oxygen saturation mechanical forces. Recently, growing number of studies microenvironment regeneration ongoing. this review, we provide an overview recent advances microenvironment, plays important role

Language: Английский

Citations

1
Advancing Human iPSC-Derived Cardiomyocyte Hypoxia Resistance for Cardiac Regenerative Therapies through a Systematic Assessment of In Vitro Conditioning DOI Open Access
Caroline A. Snyder, Kiera D. Dwyer, Kareen L. K. Coulombe

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9627 - 9627

Published: Sept. 5, 2024

Acute myocardial infarction (MI) is a sudden, severe cardiac ischemic event that results in the death of up to one billion cardiomyocytes (CMs) and subsequent decrease function. Engineered tissues (ECTs) are promising approach deliver necessary mass CMs remuscularize heart. However, hypoxic environment heart post-MI presents critical challenge for CM engraftment. Here, we present high-throughput, systematic study targeting several physiological features human induced pluripotent stem cell-derived (hiPSC-CMs), including metabolism, Wnt signaling, substrate, heat shock, apoptosis, mitochondrial stabilization, assess their efficacy promoting ischemia resistance hiPSC-CMs. The 2D experiments identify hypoxia preconditioning (HPC) metabolic conditioning as having significant influence on hiPSC-CM function normoxia hypoxia. Within 3D engineered (ECTs), with maturation media (MM), featuring high fatty acid calcium concentration, 1.5-fold increase active stress generation compared RPMI/B27 control ECTs normoxic conditions. Yet, this functional improvement lost after treatment. Interestingly, HPC can partially rescue MM-treated Our iterative provides strong foundation assessing leveraging vitro culture conditions enhance resistance, thus successful clinical translation, hiPSC-CMs regenerative therapies.

Language: Английский

Citations

1
Combinatorial miRNA1a/15b interference drives adult cardiac regeneration DOI Creative Commons
Ting Yuan, Meiqian Wu, Chaonan Zhu

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: April 21, 2024

Abstract BACKGROUND Despite its promise, cardiac regenerative therapy remains clinically elusive due to the difficulty of spatio-temporal control proliferative induction, and need coordinately reprogram multiple regulatory pathways overcome strict post-mitotic state human adult cardiomyocytes. The present study was designed identify a novel combinatorial miRNA address this unmet therapeutic need. METHODS We performed interference screen specifically targeting cardiac-predominant miRNAs regulating key aspects cardiomyocyte mitotic induction cell-cycle completion, including sarcomerogenesis, metabolic pathways. Cardiomyocyte proliferation function were assessed in biopsies, tissue mimetics mouse disease models. RESULTS identified miR-1a miR-15b (LNA-1a/15b) as drivers proliferation. Due miR-1a/15b on processes modulating mitosis, inhibition augmented completion daughter cell formation, improved contractility vitro 2D 3D ischemic models, model ST-segment elevation myocardial infarction (STEMI). cardiac-restricted pattern expression, strategy provides feasible for specific with minimal risk neoplasm formation off-target toxicity. CONCLUSIONS Combinatorial drives re-entry cardiomyocytes improves response infarction. Our data LNA-based anti-miR-1a/15b attenuate heart failure highlights an underutilized simultaneous co-regulation through interference.

Language: Английский

Citations

0
Engineered Cardiac Tissues as a Platform for CRISPR‐Based Mitogen Discovery DOI
Sophia DeLuca, Nicholas Strash, Yifan Chen

et al.

Advanced Healthcare Materials, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 7, 2024

Improved understanding of cardiomyocyte (CM) cell cycle regulation may allow researchers to stimulate pro-regenerative effects in injured hearts or promote maturation human stem cell-derived CMs. Gene therapies, particular, hold promise induce controlled proliferation endogenous transplanted CMs via transient activation mitogenic processes. Methods identify and characterize candidate cardiac mitogens vitro can accelerate translational efforts contribute the complex regulatory landscape CM postnatal maturation. In this study, A CRISPR knockout-based screening strategy using neonatal rat ventricular myocyte (NRVM) monolayers is established, followed by mitogen validation mature 3-D engineered tissues (ECTs). This screen identified knockout purine metabolism enzyme adenosine deaminase (ADA-KO) as an effective pro-mitogenic stimulus. RNA-sequencing ECTs further reveals increased pentose phosphate pathway (PPP) activity primary driver ADA-KO-induced cycling. Inhibition pathway's rate limiting enzyme, glucose-6-phosphate dehydrogenase (G6PD), prevented ADA-KO induced cycling, while increasing PPP G6PD overexpression Together, study demonstrates development application a genetic/tissue engineering platform for discovery new affecting regenerative states cardiomyocytes.

Language: Английский

Citations

0