Dataset Information

Impaired adhesion of induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) to isolated extracellular matrix from failing hearts.

ABSTRACT: We tested the hypothesis that induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) are less able to adhere to the extracellular matrix (ECM) derived from failing human hearts with dilated cardiomyopathy compared to nonfailing human heart ECM. We also hypothesized that morphological development, cell beating rates, and mRNA levels of Nkx2.5 and cardiac troponin T would be altered after culturing the iPSC-CPCs on the failing heart ECM under cardiomyocyte differentiation conditions. We used microscopy to distinguish between adhered and unadhered cells, and to determine morphological development and cell beating. We used qPCR to determine mRNA levels. iPSC-CPCs show a significantly reduced ability to adhere to the ECM of failing hearts and higher expression of Nkx2.5 mRNA. However, morphological development, cell beating rates, and cardiac troponin T levels were not significantly altered in the cells cultured on the failing heart ECM. Our study shows that the failing heart ECM from patients with dilated cardiomyopathy impairs initial iPSC-CPC adhesion and may have a modest effect on the ability of the cells to transdifferentiate into cardiomyocytes.

SUBMITTER: McKown EN

PROVIDER: S-EPMC6197956 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Impaired adhesion of induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) to isolated extracellular matrix from failing hearts.

McKown Elizabeth N EN DeAguero Joshua L JL Canan Benjamin D BD Kilic Ahmet A Zhu Yiliang Y Janssen Paul M L PML Delfín Dawn A DA

Heliyon 20181018 10

We tested the hypothesis that induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) are less able to adhere to the extracellular matrix (ECM) derived from failing human hearts with dilated cardiomyopathy compared to nonfailing human heart ECM. We also hypothesized that morphological development, cell beating rates, and mRNA levels of Nkx2.5 and cardiac troponin T would be altered after culturing the iPSC-CPCs on the failing heart ECM under cardiomyocyte differentiation condi ...[more]

PMID: 30364772

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Project description:Rationale: Cardiac extracellular matrix (ECM) comprises a dynamic molecular network providing structural support to heart tissue function. Understanding the impact of ECM remodeling on cardiac cells during heart failure (HF) is essential to prevent adverse ventricular remodeling and restore organ functionality in affected patients. Objectives: We aimed to (i) identify consistent modifications to cardiac ECM structure and mechanics that contribute to HF and (ii) determine the underlying molecular mechanisms. Methods and Results: We first performed decellularization of human and murine ECM (dECM) and then analyzed the pathological changes occurring in dECM during HF by atomic force (AFM), two-photon microscopy, high-resolution 3D image analysis and computational fluid dynamics (CFD) simulation. We then performed molecular and functional assays in patient-derived cardiac fibroblasts (CFs) based on YAP-TEAD mechanosensing activity and collagen contraction assays. The analysis of HF dECM resulting from ischemic (IHD) or dilated cardiomyopathy (DCM), as well as from mouse infarcted tissue, identified a common pattern of modifications in their 3D topography. As compared to healthy heart, HF ECM exhibited aligned, flat and compact fiber bundles, with reduced elasticity and organizational complexity. At the molecular level, RNA sequencing of HF CFs highlighted the overrepresentation of dysregulated genes involved in ECM organization, or being connected to TGFß1, Interleukin-1, TNF-alpha and BDNF signaling pathways. Functional tests performed on HF CFs pointed at mechanosensor YAP as a key player in ECM remodeling in the diseased heart via transcriptional activation of focal adhesion assembly. Finally, in vitro experiments clarified pathological cardiac ECM prevents cell homing, thus providing further hints to identify a possible window of action for cell therapy in cardiac diseases. Conclusions: Our multi-parametric approach has highlighted repercussions of ECM remodeling on cell homing, CF activation and focal adhesion protein expression via hyper-activated YAP signaling during HF. Key words: Decellularization, extracellular matrix, dilated cardiomyopathy, ischemic heart disease, YAP, dilated cardiomyopathy, mechanobiology.

Dataset Information

Impaired adhesion of induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) to isolated extracellular matrix from failing hearts.

Publications

Impaired adhesion of induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) to isolated extracellular matrix from failing hearts.

Similar Datasets

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