2019
DOI: 10.1161/circresaha.119.315491
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Generation of Quiescent Cardiac Fibroblasts From Human Induced Pluripotent Stem Cells for In Vitro Modeling of Cardiac Fibrosis

Abstract: Rationale: Activated fibroblasts are the major cell type that secretes excessive extracellular matrix in response to injury, contributing to pathological fibrosis and leading to organ failure. Effective anti-fibrotic therapeutic solutions, however, are not available due to the poorly defined characteristics and unavailability of tissue-specific fibroblasts. Recent advances in single-cell RNA-sequencing fill such gaps of knowledge by enabling delineation of the developmental trajectorie… Show more

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Cited by 127 publications
(119 citation statements)
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“…Because cardiac fibroblasts are responsible for most of the fibrillar collagen production in the heart and are widely distributed in the left and right ventricles, which have different embryological origins and physiological characteristics (32,33), we next determined whether there was a ventricle-specific expression pattern for Slit3. Although the ventricles possessed widely varying levels of Slit3 transcripts among animals, we found that Slit3 transcript levels were strongly correlated in the right ventricle and left ventricle in the same individual (R 2 = 0.98, Figure 3D), indicating a tightly regulated balance of Slit3 ventricular expression, which is also consistent with the common embryological origin of fibroblasts in both ventricles (34)(35)(36). Because SLIT3 deficiency reduces the myocardial fibrillar collagen content, which plays crucial mechanical roles in the ventricle, we then investigated its effect on LV toughness, i.e., the amount of energy absorbed before irreversibly fracturing/tearing.…”
Section: Resultssupporting
confidence: 73%
“…Because cardiac fibroblasts are responsible for most of the fibrillar collagen production in the heart and are widely distributed in the left and right ventricles, which have different embryological origins and physiological characteristics (32,33), we next determined whether there was a ventricle-specific expression pattern for Slit3. Although the ventricles possessed widely varying levels of Slit3 transcripts among animals, we found that Slit3 transcript levels were strongly correlated in the right ventricle and left ventricle in the same individual (R 2 = 0.98, Figure 3D), indicating a tightly regulated balance of Slit3 ventricular expression, which is also consistent with the common embryological origin of fibroblasts in both ventricles (34)(35)(36). Because SLIT3 deficiency reduces the myocardial fibrillar collagen content, which plays crucial mechanical roles in the ventricle, we then investigated its effect on LV toughness, i.e., the amount of energy absorbed before irreversibly fracturing/tearing.…”
Section: Resultssupporting
confidence: 73%
“…Finally, it would be ideal to derive all organoid cell fractions from the identical parental hiPSC line for the triculture approach. There exist established protocols to derive hiPSCs into endothelial cells and cardiac fibroblast [47,48]. We suggest that the recapitulation of cardiomyopathic properties in such organoids could be even more pronounced, especially in diseases where the pathophysiology does not solely stem from cardiomyocytes pathology but also from nonmyocyte components.…”
Section: Discussionmentioning
confidence: 98%
“…CFs, have been increasingly recognised as major players in cardiac development and homeostasis, having a similarly significant effect upon the capacity to build cardiac tissues in the lab. Recently, two independent groups have reported the generation of hPSC-derived CFs, giving also proof of their capacity to affect hPSC-CM function (Zhang H. et al, 2019;Zhang J. et al, 2019). Epicardial cells have similarly been derived, (Witty et al, 2014) demonstrating their ability to increase the therapeutic capacity of hPSC-CMs in vivo (Bargehr et al, 2019).…”
Section: Cellsmentioning
confidence: 99%