Biomaterial-induced conversion of quiescent cardiomyocytes into pacemaker cells in rats

Hu, Yufeng; Lee, An‐Sheng; Chang, Shih‐Lin; Lin, Shien‐Fong; Weng, Ching-Hui; Lo, Hsin-Yu; Chou, Pei-Chun; Tsai, Yung-Nan; Sung, Yen-Ling; Chen, Chien‐Chang; Yang, Ruey‐Bing; Lin, Yuh‐Charn; Kuo, Terry B.J.; Wu, Chung-Yu; Liu, Jindian; Chung, Tze-Wen; Chen, Shih‐Ann

doi:10.1038/s41551-021-00812-y

Cited by 19 publications

(22 citation statements)

References 64 publications

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“…Spontaneous local Ca2+ release events are a hallmark of automaticity in PCs. 23,24 Spontaneous local Ca2+ release events could be observed in Tbx18-PC cocultures. The inhibition of Aldoc by the Aldoc siRNAs decreased both spontaneous local Ca2+ release events and oscillating calcium transients (Figure S5).…”

Section: Fibroblasts Drive Glycolysis Adaptation Through Aldoc In Tbx...mentioning

confidence: 95%

“…10 Recently, induced PCs, generated by Tbx18 (T-box transcription factor 18) transduction or biomaterial, recapitulated not only electrical and morphological phenotypes, but also the metabolic properties of native SAN cardiomyocytes. [14][15][16] It is possible that Tbx18-induced PCs (Tbx18-PCs), considered a replacement for native PCs, might be used to establish engineered models to study unknown SAN biological processes, especially intercellular functional interactions within the microenvironment. 17 In this study, we used Tbx18-PCs and engineered tissue to explore how fibroblasts regulate the functional integrity of SANs.…”

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confidence: 99%

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Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes

Chou

Liu

Weng

et al. 2022

Circulation Research

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Background: The sinoatrial node (SAN) is characterized by the microenvironment of pacemaker cardiomyocytes (PCs) encased with fibroblasts. An altered microenvironment leads to rhythm failure. Operable cell or tissue models are either generally lacking or difficult to handle. The biological process behind the milieu of SANs to evoke pacemaker rhythm is unknown. We explored how fibroblasts interact with PCs and regulate metabolic reprogramming and rhythmic activity in the SAN. Methods: Tbx18 (T-box transcription factor 18)-induced PCs and fibroblasts were used for cocultures and engineered tissues, which were used as the in vitro models to explore how fibroblasts regulate the functional integrity of SANs. RNA-sequencing, metabolomics, and cellular and molecular techniques were applied to characterize the molecular signals underlying metabolic reprogramming and identify its critical regulators. These pathways were further validated in vivo in rodents and induced human pluripotent stem cell-derived cardiomyocytes. Results: We observed that rhythmicity in Tbx18-induced PCs was regulated by aerobic glycolysis. Fibroblasts critically activated metabolic reprogramming and aerobic glycolysis within PCs, and, therefore, regulated pacemaker activity in PCs. The metabolic reprogramming was attributed to the exclusive induction of Aldoc (aldolase c) within PCs after fibroblast-PC integration. Fibroblasts activated the integrin-dependent mitogen-activated protein kinase-E2F1 signal through cell-cell contact and turned on Aldoc expression in PCs. Interruption of fibroblast-PC interaction or Aldoc knockdown nullified electrical activity. Engineered Tbx18-PC tissue sheets were generated to recapitulate the microenvironment within SANs. Aldoc-driven rhythmic machinery could be replicated within tissue sheets. Similar machinery was faithfully validated in de novo PCs of adult mice and rats, and in human PCs derived from induced pluripotent stem cells. Conclusions: Fibroblasts drive Aldoc-mediated metabolic reprogramming and rhythmic regulation in SANs. This work details the cellular machinery behind the complex milieu of vertebrate SANs and opens a new direction for future therapy.

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Section: Fibroblasts Drive Glycolysis Adaptation Through Aldoc In Tbx...mentioning

confidence: 95%

mentioning

confidence: 99%

Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes

Chou

Liu

Weng

et al. 2022

Circulation Research

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“…95 Integrins (one of adhesion receptors) can mediate intracellular signals and mechanical interactions. 96 Secreted from marine mussels, the mussel adhesive protein (MAP) has a robust underwater adhesive property and biocompatibility. Solidified adhesive scaffolds with similar mechanical properties to those of organs were constructed via the oxidative cross-linking of catechol residues in bioengineered MAP, which integrates a synergistic strategy of spatially separating angiogenic growth factors with physical support equal to the surrounding tissue.…”

Section: Conductivitymentioning

confidence: 99%

Insight into Heart-Tailored Architectures of Hydrogel to Restore Cardiac Functions after Myocardial Infarction

et al. 2022

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With permanent heart muscle injury or death, myocardial infarction (MI) is complicated by inflammatory, proliferation and remodeling phases from both the early ischemic period and subsequent infarct expansion. Though in situ re-establishment of blood flow to the infarct zone and delays of the ventricular remodeling process are current treatment options of MI, they fail to address massive loss of viable cardiomyocytes while transplanting stem cells to regenerate heart is hindered by their poor retention in the infarct bed. Equipped with heart-specific mimicry and extracellular matrix (ECM)-like functionality on the network structure, hydrogels leveraging tissue-matching biomechanics and biocompatibility can mechanically constrain the infarct and act as localized transport of bioactive ingredients to refresh the dysfunctional heart under the constant cyclic stress. Given diverse characteristics of hydrogel including conductivity, anisotropy, adhesiveness, biodegradability, self-healing and mechanical properties driving local cardiac repair, we aim to investigate and conclude the dynamic balance between ordered architectures of hydrogels and the post-MI pathological milieu. Additionally, our review summarizes advantages of heart-tailored architectures of hydrogels in cardiac repair following MI. Finally, we propose challenges and prospects in clinical translation of hydrogels to draw theoretical guidance on cardiac repair and regeneration after MI.

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“…L929 cells were purchased from Lonza Corp. (Lonza Group Ltd., Switzerland). The detailed procedures for proliferation and evaluating cytotoxicity of L929 cells for this study are described elsewhere [3,25,26]. According to the guidelines of International Standard Organization (ISO) 10993-5 for evaluating the cytotoxicity of cells for the SF and SF/NAC NPs, the viability of L929 cells was measured using an MTT assay (CGD1, Sigma, USA) after they were incubated with different concentrations of the NPs (e.g., 0~6000 µg/mL) for 24 h [7,26].…”

Section: Cytotoxicity Of Sf and Sf/nac Npsmentioning

confidence: 99%

“…Sericin-free SF has a low immune-inflammatory response and excellent biological response [2], so it is a suitable biomaterial for engineering various tissues, such as cardiac patches, hydrogels and scaffolds, refs. [3][4][5] and drug delivery in varying forms (e.g., NPs or hydrogels) or with multifunctional properties such as photothermal responses [6][7][8]. The SF polymer also contains several hydrophilic and hydrophobic segments, and the crystallinity of the polymer is easily modulated, so it is a suitable biomaterial for drug delivery vehicles [9,10].…”

Section: Introductionmentioning

confidence: 99%

Antioxidative NAC-Loaded Silk Nanoparticles with Opening Mucosal Tight Junctions for Nasal Drug Delivery: An In Vitro and In Vivo Study

Chung

Siah

et al. 2022

Pharmaceutics

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Using nasal routes to deliver drugs to the brain using multifunctional nanoparticles (NPs) to bypass the blood–brain barrier (BBB) might enhance the delivery efficacy. Anti-oxidative N-Acetyl-L-cysteine (NAC)-loaded silk fibroin (SF/NAC) NPs are produced, characterized and studied as a potential delivery vehicle for NAC delivered to the brain via nasal for both in vitro and in vivo studies. The NPs are not cytotoxic to RPMI 2650 cells, mucosal model cells, at a concentration of 6000 μg/mL. The anti-oxidative activities of SF/NAC NPs are demonstrated by high H2O2 scavenge capacities of the NPs and shown by mitochondrial superoxide (MitoSOX) immunostaining of human mesenchymal stem cells. Tight junctions in RPMI 2650 cells are opened after 30 min of incubation with SF/NAC NPs, which are demonstrated by measuring the decrease in trans-epithelial electrical resistance (TEER) values and discreteness in ZO-1 stains. The cellular uptake of SF/NAC NPs by RPMI 2650 cells is significantly greater than that for SF NPs and increased with increasing incubation time. In an in vivo imaging study (IVIS) using rats shows that the amount of NAC that is delivered to the brain by SF/NAC NPs increased by 1.40–2.60 times and NAC is retained longer in the nasal cavity than NAC solutions in a 2-h study.

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Biomaterial-induced conversion of quiescent cardiomyocytes into pacemaker cells in rats

Cited by 19 publications

References 64 publications

Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes

Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes

Insight into Heart-Tailored Architectures of Hydrogel to Restore Cardiac Functions after Myocardial Infarction

Antioxidative NAC-Loaded Silk Nanoparticles with Opening Mucosal Tight Junctions for Nasal Drug Delivery: An In Vitro and In Vivo Study

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