Abstract:A chemically defined protocol requiring no animal-derived components allows for the easier derivation and enduring expansion of epicardial cells from human pluripotent stem cells.
“…While human iPSCs are known to have only partial XaXa (Barakat et al., 2015, Kim et al., 2014), we identified two loci (chrXp11 and chrXp22) encoding genes whose expression levels are associated with two distinct cardiac differentiation trajectories (CMs versus EPDCs). The higher expression of chrXp11 genes in CM-fated iPSCs may at least in part be due to fact that ELK1 and PORCN are both encoded in this interval, as the protein product of PORCN (Porcupine) is inhibited by IWP-2 during CM differentiation (Mo et al., 2013) but not during EPDC differentiation (Bao et al., 2016, Iyer et al., 2015, Witty et al., 2014) (some EPDC protocols inhibit Porcupine but then reactivate the WNT pathway at a later time point [Guadix et al., 2017, Paik and Wu, 2017, Zhao et al., 2017]). Furthermore, we found that ELK1 targets are overexpressed in CM-fated iPSCs, which is consistent with previous studies showing that knockdown of ELK1 in immortalized human bronchial epithelial cells, small airway epithelial cells, and luminal breast cancer cell line (MCF-7) is associated with increased EMT (Desai et al., 2017, Tatler et al., 2016).…”
SummaryDespite the importance of understanding how variability across induced pluripotent stem cell (iPSC) lines due to non-genetic factors (clone and passage) influences their differentiation outcome, large-scale studies capable of addressing this question have not yet been conducted. Here, we differentiated 191 iPSC lines to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). We observed cellular heterogeneity across the iPSC-CVPC samples due to varying fractions of two cell types: cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Comparing the transcriptomes of CM-fated and EPDC-fated iPSCs, we discovered that 91 signature genes and X chromosome dosage differences are associated with these two distinct cardiac developmental trajectories. In an independent set of 39 iPSCs differentiated into CMs, we confirmed that sex and transcriptional differences affect cardiac-fate outcome. Our study provides novel insights into how iPSC transcriptional and X chromosome gene dosage differences influence their response to differentiation stimuli and, hence, cardiac cell fate.
“…While human iPSCs are known to have only partial XaXa (Barakat et al., 2015, Kim et al., 2014), we identified two loci (chrXp11 and chrXp22) encoding genes whose expression levels are associated with two distinct cardiac differentiation trajectories (CMs versus EPDCs). The higher expression of chrXp11 genes in CM-fated iPSCs may at least in part be due to fact that ELK1 and PORCN are both encoded in this interval, as the protein product of PORCN (Porcupine) is inhibited by IWP-2 during CM differentiation (Mo et al., 2013) but not during EPDC differentiation (Bao et al., 2016, Iyer et al., 2015, Witty et al., 2014) (some EPDC protocols inhibit Porcupine but then reactivate the WNT pathway at a later time point [Guadix et al., 2017, Paik and Wu, 2017, Zhao et al., 2017]). Furthermore, we found that ELK1 targets are overexpressed in CM-fated iPSCs, which is consistent with previous studies showing that knockdown of ELK1 in immortalized human bronchial epithelial cells, small airway epithelial cells, and luminal breast cancer cell line (MCF-7) is associated with increased EMT (Desai et al., 2017, Tatler et al., 2016).…”
SummaryDespite the importance of understanding how variability across induced pluripotent stem cell (iPSC) lines due to non-genetic factors (clone and passage) influences their differentiation outcome, large-scale studies capable of addressing this question have not yet been conducted. Here, we differentiated 191 iPSC lines to generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). We observed cellular heterogeneity across the iPSC-CVPC samples due to varying fractions of two cell types: cardiomyocytes (CMs) and epicardium-derived cells (EPDCs). Comparing the transcriptomes of CM-fated and EPDC-fated iPSCs, we discovered that 91 signature genes and X chromosome dosage differences are associated with these two distinct cardiac developmental trajectories. In an independent set of 39 iPSCs differentiated into CMs, we confirmed that sex and transcriptional differences affect cardiac-fate outcome. Our study provides novel insights into how iPSC transcriptional and X chromosome gene dosage differences influence their response to differentiation stimuli and, hence, cardiac cell fate.
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