Cardiac ultrastructure inspired matrix induces advanced metabolic and functional maturation of differentiated human cardiomyocytes

Afzal, Junaid; Liu, Yamin; Du, Wenqiang; Suhail, Yasir; Zong, Pengyu; Jin, Feng; Ajeti, Visar; Sayyad, Wasim A.; Nikolaus, Joerg; Yankova, Maya; Deymier, Alix C.; Yue, Lixia; Kshitiz, .

doi:10.1016/j.celrep.2022.111146

Cited by 15 publications

(14 citation statements)

References 112 publications

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“…Gene set enrichment analysis (GSEA) ( Subramanian et al, 2005 ) were performed on the genes that are downstream of Mrtf ( Gualdrini et al, 2016 ). Hierarchical clustering was performed using UPGMA method with Euclidian distance on z-scores as mentioned earlier ( Afzal et al, 2022 ). Briefly, a subset of genes was selected for clustering that were differentially expressed in either condition, and are known to be downstream of SRF-MRTF or SRF-TCF axis ( Gualdrini et al, 2016 ; Esnault et al, 2017 ).…”

Section: Methodsmentioning

confidence: 99%

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Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis

Afzal

Du²,

Novin³

et al. 2022

Front. Cell Dev. Biol.

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Multiple parallels exist between placentation and cancer dissemination at molecular, cellular, and anatomical levels, presenting placentation as a unique model to mechanistically understand the onset of cancer metastasis. In humans, interaction of placenta and the endometrium results eventually in deep invasion of placental extravillous trophoblasts (EVTs) into the maternal stroma, a process similar to stromal trespass by disseminating carcinoma cells. In anticipation of implantation, endometrial fibroblasts (ESFs) undergo a process called decidualization during the secretory phase of the menstrual cycle. Decidualization, among other substantial changes associated with ESF differentiation, also involves a component of fibroblast activation, and myofibroblast transformation. Here, using traction force microscopy, we show that increased cellular contractility in decidualized ESFs is reversed after interaction with EVTs. We also report here the large changes in energetic state of ESFs upon decidualization, showing increased oxidative phosphorylation, mitochondrial competency and ATP generation, as well as enhanced aerobic glycolysis, presenting mechanical contractility and energetic state as new functional hallmarks for decidualization. These energetic changes accompanying the marked increase in contractile force generation in decidualization were reduced in the presence of EVTs. We also show that increase in decidual contractility and mechanical resistance to invasion is achieved by SRF-MRTF transcriptional activation, achieved via increased phosphorylation of fibroblast-specific myosin light chain 9 (MYL9). EVT induced paracrine secretion of Heparin Binding Epidermal Growth Factor (HBEGF), a potent MAPK activator, which shifts the balance of SRF association away from MRTF based transcription, reducing decidual ESF contractility and mechanical resistance to placental invasion. Our results identify a new axis of intercellular communication in the placental bed modulating stromal force generation and resistance to invasion with concurrent downregulation of cellular energetics. These findings have important implications for implantation related disorders, as well as stromal control of cancer dissemination.

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Section: Methodsmentioning

confidence: 99%

“…Measurement of oxidative phosphorylation and glycolysis: XF analyzer from Agilent Technologies was used to monitor cellular energetics ( Reid et al, 2013 ; Afzal et al, 2017 ; Afzal et al, 2022 ). Cells were cultured in 96 wells XF plate and the assay was repeated three times to estimate the energetics of cells.…”

Section: Methodsmentioning

confidence: 99%

Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis

Afzal

Du²,

Novin³

et al. 2022

Front. Cell Dev. Biol.

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“…The most commonly adopted method to engineer the culture geometry is micropatterning of the substrates, which include polydimethylsiloxane (PDMS) ( Rao et al, 2013 ), polylactide-co-glycolide (PLGA) ( Khan et al, 2015 ), Matrigel ( Ribeiro et al, 2015 ), or polyacrylamide (PAA) hydrogel ( Strimaityte et al, 2022 ), using techniques such as electrospinning, photolithography, laser cutting, microcontact, even tissue-specific bio-3D printing ( Rao et al, 2013 ; Salick et al, 2014 ; Khan et al, 2015 ; Ribeiro et al, 2015 ; Rodriguez et al, 2019 ; Yu et al, 2019 ; Strimaityte et al, 2022 ). Recently, another group has developed a matrix mimicking various chemical and physical properties of native heart matrices, including a purposely designed substrate whose ultrastructure resembles the collagen network in natural human hearts ( Afzal et al, 2022 ). These micropatterned substrates generally possess microarchitectures similar to the morphology or organization of mammal (preferably human) adult CMs or decellularized myocardium, serving as scaffolds which guide the geometric growth of hSC-CMs.…”

Section: Mechanical Cuesmentioning

confidence: 99%

“…While studies have shown that culturing hSC-CMs on substrates with micropatterns that resemble the microstructure of adult CMs can improve maturation, traditional micropatterning methods are typically limited to two-dimensional (2D) substrates. Indeed, 2D systems have unique advantages, such as easy access to studying signaling pathways, metabolic features, and organelle behaviors, and to facilitating high-throughput drug screening ( Afzal et al, 2022 ). However, they cannot adequately represent the native three-dimensional (3D) environment in which human hearts develop.…”

Section: Mechanical Cuesmentioning

confidence: 99%

Engineering the maturation of stem cell-derived cardiomyocytes

Yang

Zhao

et al. 2023

Front. Bioeng. Biotechnol.

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The maturation of human stem cell-derived cardiomyocytes (hSC-CMs) has been a major challenge to further expand the scope of their application. Over the past years, several strategies have been proven to facilitate the structural and functional maturation of hSC-CMs, which include but are not limited to engineering the geometry or stiffness of substrates, providing favorable extracellular matrices, applying mechanical stretch, fluidic or electrical stimulation, co-culturing with niche cells, regulating biochemical cues such as hormones and transcription factors, engineering and redirecting metabolic patterns, developing 3D cardiac constructs such as cardiac organoid or engineered heart tissue, or culturing under in vivo implantation. In this review, we summarize these maturation strategies, especially the recent advancements, and discussed their advantages as well as the pressing problems that need to be addressed in future studies.

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“…These topographies have been shown to enhance CM maturation by promoting better cell alignment and attachment. 35,36 Cross-sectional scanning electron microscopy (SEM) images provided further insights into the effect of the P(NDI2OD-T2) coating on the interactions between the Matrigel and the substrate. Samples were prepared by coating the Matrigel on bare SEM stubs and P(NDI2OD-T2)-coated stubs with cryogenic treatment that preserves the protein structure before freeze-fracturing for imaging.…”

Section: ■ Introductionmentioning

confidence: 99%

Enhancing the Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes with an n-Type Organic Semiconductor Coating

Ramirez-Calderon,

Saleh,

Hidalgo Castillo

et al. 2024

ACS Appl. Mater. Interfaces

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Cardiac ultrastructure inspired matrix induces advanced metabolic and functional maturation of differentiated human cardiomyocytes

Cited by 15 publications

References 112 publications

Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis

Paracrine HB-EGF signaling reduce enhanced contractile and energetic state of activated decidual fibroblasts by rebalancing SRF-MRTF-TCF transcriptional axis

Engineering the maturation of stem cell-derived cardiomyocytes

Enhancing the Maturation of Human Pluripotent Stem Cell-Derived Cardiomyocytes with an n-Type Organic Semiconductor Coating

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