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Prospective isolation of ISL1+ cardiac progenitors from human ESCs for myocardial infarction therapy

ABSTRACT: The LIM-homeodomain transcription factor ISL1 marks multipotent cardiac progenitors that give rise to cardiac muscle, endothelium, and smooth muscle cells. ISL1+ progenitors can be derived from human pluripotent stem cells, but the inability to efficiently isolate pure populations has limited their characterization. Using a genetic selection strategy, we were able to highly enrich ISL1+ cells derived from human embryonic stem cells. Comparative quantitative proteomic analysis of enriched ISL1+ cells identified ALCAM (CD166) as a surface marker that enabled the isolation of ISL1+ progenitor cells. ALCAM+/ISL1+ progenitors are multipotent and differentiate into cardiomyocytes, endothelial cells, and smooth muscle cells. Transplantation of ALCAM+ progenitors enhances tissue recovery, restores cardiac function and improves angiogenesis through activation of AKT-MAPK signaling in a rat model of myocardial infarction, based on cardiac MRI and histology. Our study establishes a new efficient method for scalable purification of human ISL1+ cardiac precursor cells for therapeutic applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109339 | GEO | 2018/01/19

REPOSITORIES: GEO

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A Regulatory Pathway Involving Notch1/β-Catenin/Isl1 Determines Cardiac Progenitor Cell Fate

Project description:The regulation of multipotent cardiac progenitor cell (CPC) expansion and subsequent differentiation into cardiomyocytes, smooth muscle, or endothelial cells is a fundamental aspect of basic cardiovascular biology and cardiac regenerative medicine. However, the mechanisms governing these decisions remain unclear. Here, we show that Wnt/β-Catenin signaling, which promotes expansion of CPCs, is negatively regulated by Notch1-mediated control of phosphorylated β-Catenin accumulation within CPCs, and that Notch1 activity in CPCs is required for their differentiation. Notch1 positively, and β-Catenin negatively, regulated expression of the cardiac transcription factors, Isl1, Myocd and Smyd1. Surprisingly, disruption of Isl1, normally expressed transiently in CPCs prior to their differentiation, resulted in expansion of CPCs in vivo and in an embryonic stem (ES) cell system. Furthermore, Isl1 was required for CPC differentiation into cardiomyocyte and smooth muscle cells, but not endothelial cells. These findings reveal a regulatory network controlling CPC expansion and cell fate that involve unanticipated functions of β-Catenin, Notch1 and Isl1 that may be leveraged for regenerative approaches involving CPCs. YFP+ cells marking precardiac mesoderm (Isl1-cre domain) were FACS-sorted (w/wo stabilized Beta-catenin). Their total RNA was amplified with the WT-Ovation Pico RNA Amplification System, fragmented and labeled with the FL-Ovation cDNA Biotin Module V2 (Nugen). The hybridization, staining and scanning of the Affymetrix GeneChips were performed in the Gladstone Genomics Core Lab. Raw data generated from at least three independent experiments were further analyzed by the group of Dr. Ru-Fang Yeh at the Center for Informatics and Molecular Biostatistics, UCSF.

2009-05-13 | E-GEOD-15232 | biostudies-arrayexpress

A Regulatory Pathway Involving Notch1/β-Catenin/Isl1 Determines Cardiac Progenitor Cell Fate

2009-05-13 | GSE15232 | GEO

Single cell RNA-sequencing (scRNA-seq) of ISL1 knockout (KO) or knockdown and NKX2.5 KO compared to WT in cardiac progenitors (CPs); scRNA-seq of ISL1 KO compared to WT in motor neuron progenitors (MNPs)

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2023-10-17 | GSE223339 | GEO

ISL1 and JMJD3 synergistically control cardiac differentiation of embryonic stem cells (RNA-Seq)

Project description:ISL1 is expressed in cardiac progenitor cells and plays critical roles in cardiac lineage differentiation and heart development. Cardiac progenitor cells hold great potential for clinical and translational applications. However the mechanisms underlying ISL1 function in cardiac progenitor cells have not been fully elucidated. Here we uncover a hierarchical role of ISL1 in cardiac progenitor cells, showing that ISL1 directly regulates hundreds of potential downstream targets that are implicated in cardiac differentiation, through an epigenetic mechanism. Specifically, ISL1 promotes the demethylation of tri-methylation of histone H3K27 (H3K27me3) at the enhancers of key downstream target genes, including Myocd and Mef2c, which are core cardiac transcription factors. ISL1 physically interacts with JMJD3, a H3K27me3 demethylase, and conditional depletion of JMJD3 leads to impaired cardiac progenitor cell differentiation, phenocopying that of ISL1 depletion. Interestingly, ISL1 is not only responsible for the recruitment of JMJD3 to specific target loci during cardiac progenitor differentiation, but also modulates its demethylase activity. In conclusion, ISL1 and JMJD3 partners to alter the cardiac epigenome, instructing gene expression changes that drive cardiac differentiation.

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ISL1 and JMJD3 synergistically control cardiac differentiation of embryonic stem cells (ChIP-Seq)

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scRNA-seq of E15.5 epicardium and epicardium-derived cells

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Endothelin-1 supports clonal derivation and expansion of cardiovascular progenitors derived from human embryonic stem cells

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2015-12-15 | E-GEOD-75985 | biostudies-arrayexpress

Endothelin-1 supports clonal derivation and expansion of cardiovascular progenitors derived from human embryonic stem cells

2015-12-15 | GSE75985 | GEO

The multi-lineage transcription factor ISL1 controls cardiomyocyte cell fate through interaction with NKX2.5

Project description:Congenital heart disease (CHD) is a leading cause of infant mortality in the US and is commonly thought to arise from perturbations of transcription factors (TFs) during cardiac development. ISLET1 (ISL1) is one such TF, although it also directs differentiation of other cell types, including motor neuron progenitors (MNPs) and pancreatic islet cells. Although cellular specificity of ISL1 function is likely achieved through combinatorial interactions, its essential cardiac interacting partners are unknown. By assaying ISL1 genomic occupancy in human iPSC-derived cardiac progenitors (CPs) or MNPs and leveraging the deep learning approach BPNet, we identified cell-type-specific motifs of other TFs that predicted ISL1 occupancy in each lineage, with the NKX2.5 motif being most closely associated to ISL1 in CPs. We demonstrated ISL1 forms a protein complex with NKX2.5 in CPs, and the two regulated similar gene networks. NKX2.5 co-occupied more than half of ISL1-bound loci, and ISL1 was dependent on NKX2.5 for CP-specific localization. Furthermore, overexpression of NKX2.5 in MNPs led to ISL1 redistribution to CP-specific loci. These results reveal how ISL1 can guide differential lineage choices through a combinatorial code that dictates genomic occupancy and transcription.

2023-10-17 | PXD031059 | panorama

Pioneering function of Isl1 in the epigenetic control of cardiomyocyte cell fate [Isl1_E8_75_RNA_seq]

Project description:Generation of widely differing and specialized cell types from a single totipotent zygote involves large-scale transcriptional changes and chromatin reorganization. Pioneer transcription factors play key roles in programming the epigenome and facilitating recruitment of additional regulatory factors during successive cell lineage specification and differentiation steps. Here we show that Isl1 acts as a pioneer factor driving cardiomyocyte lineage commitment by shaping the chromatin landscape of cardiac progenitor cells. Using an Isl1 hypomorphic mouse line which shows congenital heart defects, genome-wide profiling of Isl1 binding together with RNA- and ATAC-sequencing of cardiac progenitor cells and their derivatives, we uncover a regulatory network downstream of Isl1 that orchestrates cardiogenesis. Mechanistically, we show that Isl1 binds to compacted chromatin and woks in concert with the Brg1-Baf60c-based SWI/SNF complex to promote permissive cardiac lineage-specific alterations in the chromatin landscape not only of genes with critical functions in cardiac progenitor cells, but also of cardiomyocyte structural genes that are highly expressed when Isl1 itself is no longer present. Thus, the Isl1/Brg1-Baf60c complex plays a crucial role in orchestrating proper cardiogenesis and in establishing epigenetic memory of cardiomyocyte fate commitment.

2019-05-02 | GSE126406 | GEO

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