Harnessing stem cell and lineage reprogramming technology to treat cardiac fibrosis

Figures

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  Fig. 1. Challenges in treating cardiac fibrosis and potential solutions with stem cell technology. The red boxes above delineate some of the primary challenges encountered in the development of antifibrotic drugs, as discussed in this review. The subsequent blue box elucidates the applications of stem cell technology, wherein abundant cardiac cells derived from human pluripotent stem cells can be cultured into diverse structures to meet specific demands. Moreover, both the transplantation of products derived from human pluripotent stem cells and the in vivo reprogramming of cardiac fibroblasts into cardiomyocytes demonstrate promising potential for cardiac fibrosis therapy, as depicted by the adjacent brown and green boxes. TGF-β, transforming growth factor-β; Wnt/β-catenin, Wnt family/β-catenin; NF-κB, nuclear factor kappa B subunit; CF, cardiac fibroblasts; CM, cardiomyocytes; hPSC, human pluripotent stem cell; EC, endothelial cells

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  Fig. 2. Major signaling pathways involved in cardiac fibrosis. Mechanosensitive pathways play a pivotal role in activating fibroblasts during various cardiac pathological conditions. Integrins, mechanosensitive ion channels, and activation of G-protein coupled receptors all initiate signaling pathways, including FAK, MAPK, and PI-3 K, which mediate the response of fibroblasts to mechanical stress. Secreted signals from diverse cell types have profound effects on phenotypic changes. In response to injury, the heart releases a wide range of cellular factors that trigger and exacerbate the phenotype in a paracrine manner. These secreted factors are implicated in various outcomes such as fibrosis, myofibroblast activation, collagen synthesis, calcification, hypertrophy, and inflammation. TGF-β: transforming growth factor-β; AT1R, type 1 angiotensin II receptor; ERK; extracellular-signal-regulated kinase; FAK, focal adhesion kinase; IL-11RA, IL-11 receptor subunit-α; MAPK, mitogen-activated protein kinase; MR, mineralocorticoid receptor; PI3K, phosphoinositide 3-kinase; TAK1; TGF-beta activated kinase 1, TGFβ-activated kinase 1; TGFβR1, TGFβ receptor type 1. PAK, p21-Activated kinases; NF-κB,…

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  Fig. 3. Development of stem cell-based cardiac fibrosis models. The advancement of stem cell technology has facilitated the establishment of models for cardiac fibrosis in the past two decades (Drakhlis et al. 2021; Song et al. 2021; Silva et al. 2021; Richards et al. 2020; Bao et al. 2017; Iyer et al. 2015; Witty et al. 2014; Lancaster and Knoblich 2014; Thavandiran et al. 2013; Nunes et al. 2013; Kensah et al. 2013; Tulloch et al. 2011; Schaaf et al. 2011; Yu et al. 2007; Takahashi et al. 2007; Takahashi and Yamanaka 2006). Due to the self-renewal and pluripotency characteristics of induced pluripotent stem cells, it has become possible to produce target cardiac cells on a large scale in vitro. Building upon this progress, the creation of three-dimensional structures that closely resemble an authentic heart has now become a reality. Oct3/4: organic cation/carnitine transporter 3/4; Sox2: SRY-box transcription factor 2; c-Myc: transcriptional regulator Myc-like; Klf4:KLF transcription factor 4; NANOG: Nanog homeobox; LIN28: Protein lin-28; CFs: cardiac fibroblasts; hPSCs: human pluripotent stem cells; hEHT: human engineered heart tissue; hPSC-ECs: human pluripotent stem cell derived…

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  Fig. 4. Cell reprogramming technique for cardiac fibrosis therapy. Cardiac fibroblasts could be directly reprogrammed to cardiomyocyte-like cells through microRNAs, transcription factors and small molecules in vivo to achieve in situ cardiac tissue repair. The microRNAs and transcription factors switch the cell fate through limiting the original lineage specific genes expression or promoting the target lineage specific genes expression, and the small molecules function by promoting the chromatin opening at lineage specific loci. Cardiac fibroblasts could also be indirectly reprogrammed to cardiac progenitor cells through small molecules in vitro, which can be used for transplantation or differentiate into various cardiac cell types in a large scale for cell transplantation, disease modeling, and biobanking of patient-specific samples. CFs, cardiac fibroblasts; miRNAs, microRNAs; iCMs, induced cardiomyocyte-like cells; ciCPCs, chemically induced cardiovascular progenitor cells; ECs, endothelia cells; CMs, cardiomyocytes; SMCs, smooth muscle cells