Hypoxia-induced epigenetic silencing of polo-like kinase 2 promotes fibrosis in atrial fibrillation

Kuenzel, S; Sekeres, Karolina; Kaemmerer, Susanne; Kolanowski, Tomasz; Meyer-Roxlau, Stefanie; Piorkowski, Christopher; Tugtekin, Sems Malte; Rose–John, Stefan; Yin, Xiaoke; Mayr, Manuel; Kuhlmann, Jan Dominik; Wimberger, Pauline; Gruetzmann, Konrad; Herzog, Natalie; Kuepper, Jan-Heiner; Guan, Kaomei; Wagner, Michael; Ravens, Ursula; Weber, Silvio; El‐Armouche, Ali

doi:10.1101/445098

Cited by 2 publications

(3 citation statements)

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“…Epigenetic regulation of proliferationrelevant genes was shown to affect functional properties of isolated cells [27,28]. The finding of, for example, aberrant methylation patterns in fibroblasts from AF patients compared to control samples reinforces this assumption [21] and stresses the value of adequate cell lines matching the scientific question. Fibroblast migration to areas of myocardial tissue damage is important for wound healing and fibrosis development in the heart [29,30].…”

Section: Resultsmentioning

confidence: 72%

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Modeling atrial fibrosis in vitro—Generation and characterization of a novel human atrial fibroblast cell line

et al. 2020

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Atrial fibrillation (AF) is regularly accompanied by cardiac fibrosis and concomitant heart failure. Due to the heterogeneous nature and complexity of fibrosis, the knowledge about the underlying mechanisms is limited, which prevents effective pharmacotherapy. A deeper understanding of cardiac fibroblasts is essential to meet this need. We previously described phenotypic and functional differences between atrial fibroblasts from patients in sinus rhythm and with AF. Herein, we established and characterized a novel human atrial fibroblast line, which displays typical fibroblast morphology and function comparable to primary cells but with improved proliferation capacity and low spontaneous myofibroblast differentiation. These traits make our model suitable for the study of fibrosis mechanisms and for drug screening aimed at developing effective antifibrotic pharmacotherapy. Cardiovascular diseases (CVD) such as heart failure and arrhythmia represent the leading cause of death worldwide [1,2]. A well-recognized concomitant of CVD is cardiac fibrosis [1], which is the structural manifestation of an imbalance in extracellular matrix (ECM) homeostasis. With nearly 45% of all deaths in the Western world attributable to fibroproliferative disease, the clinical relevance of fibrotic remodeling is enormous [3,4]. This is particularly true in the case of atrial fibrosis, associated with a detrimental clinical outcome of highly abundant supraventricular arrhythmias like atrial fibrillation (AF) [5]. However, due to

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Section: Resultsmentioning

confidence: 72%

“…The protein concentration was determined using a bicinchoninic acid kit. Subsequently, a standard WB protocol was performed [21].…”

Section: Sds/page Western Blotting and Immunodetectionmentioning

confidence: 99%

Modeling atrial fibrosis in vitro—Generation and characterization of a novel human atrial fibroblast cell line

et al. 2020

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“…Its expression is downregulated under hypoxia. 41 We detected a significant reduction in PLK2 expression in the peptide group ( Figure 3(d) and ( e )). In addition, placental growth factor (PGF) is known to be involved in angiogenesis 42 and is released under hypoxic conditions.…”

Section: Resultsmentioning

confidence: 74%

Extracellular matrix-derived peptide stimulates the generation of endocrine progenitors and islet organoids from iPSCs

Heaton

Liu

et al. 2023

J Tissue Eng

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Induced pluripotent stem cells (iPSCs) have enormous potential in producing human tissues endlessly. We previously reported that type V collagen (COL5), a pancreatic extracellular matrix protein, promotes islet development and maturation from iPSCs. In this study, we identified a bioactive peptide domain of COL5, WWASKS, through bioinformatic analysis of decellularized pancreatic ECM (dpECM)-derived collagens. RNA-sequencing suggests that WWASKS induces the formation of pancreatic endocrine progenitors while suppressing the development of other types of organs. The expressions of hypoxic genes were significantly downregulated in the endocrine progenitors formed under peptide stimulation. Furthermore, we unveiled an enhancement of iPSC-derived islets’ (i-islets) glucose sensitivity under peptide stimulation. These i-islets secrete insulin in a glucose responsive manner. They were comprised of α, β, δ, and γ cells and were assembled into a tissue architecture similar to that of human islets. Mechanistically, the peptide is able to activate the canonical Wnt signaling pathway, permitting the translocation of β-catenin from the cytoplasm to the nucleus for pancreatic progenitor development. Collectively, for the first time, we demonstrated that an ECM-derived peptide dictates iPSC fate toward the generation of endocrine progenitors and subsequent islet organoids.

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Hypoxia-induced epigenetic silencing of polo-like kinase 2 promotes fibrosis in atrial fibrillation

Cited by 2 publications

References 55 publications

Modeling atrial fibrosis in vitro—Generation and characterization of a novel human atrial fibroblast cell line

Modeling atrial fibrosis in vitro—Generation and characterization of a novel human atrial fibroblast cell line

Extracellular matrix-derived peptide stimulates the generation of endocrine progenitors and islet organoids from iPSCs

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