{"entity": "journal", "iuid": "295b52b2b1af4904ae651d3f12de0590", "timestamp": "2026-07-18T21:28:58.720Z", "links": {"self": {"href": "https://publications.scilifelab.se/journal/Stem%20Cells.json"}, "display": {"href": "https://publications.scilifelab.se/journal/Stem%20Cells"}}, "title": "Stem Cells", "issn": "1549-4918", "issn-l": "1066-5099", "publications_count": 5, "publications": [{"entity": "publication", "iuid": "b77ba73fb7c241d09a2734a4ef5e2832", "links": {"self": {"href": "https://publications.scilifelab.se/publication/b77ba73fb7c241d09a2734a4ef5e2832.json"}, "display": {"href": "https://publications.scilifelab.se/publication/b77ba73fb7c241d09a2734a4ef5e2832"}}, "title": "Genome-wide CRISPR screen identifies ZIC2 as an essential gene that controls the cell fate of early mesodermal precursors to human heart progenitors.", "authors": [{"family": "Xu", "given": "Jiejia", "initials": "J", "orcid": "0000-0003-3885-3546", "researcher": {"href": "https://publications.scilifelab.se/researcher/144d8f8036b34c4f964c67255449c7a5.json"}}, {"family": "Zhou", "given": "Chikai", "initials": "C"}, {"family": "Foo", "given": "Kylie S", "initials": "KS"}, {"family": "Yang", "given": "Ran", "initials": "R"}, {"family": "Xiao", "given": "Yao", "initials": "Y"}, {"family": "Bylund", "given": "Kristine", "initials": "K"}, {"family": "Sahara", "given": "Makoto", "initials": "M"}, {"family": "Chien", "given": "Kenneth R", "initials": "KR"}], "type": "journal article", "published": "2020-06-00", "journal": {"title": "Stem Cells", "issn": "1549-4918", "volume": "38", "issue": "6", "pages": "741-755", "issn-l": "1066-5099"}, "abstract": "Cardiac progenitor formation is one of the earliest committed steps of human cardiogenesis and requires the cooperation of multiple gene sets governed by developmental signaling cascades. To determine the key regulators for cardiac progenitor formation, we have developed a two-stage genome-wide CRISPR-knockout screen. We mimicked the progenitor formation process by differentiating human pluripotent stem cells (hPSCs) into cardiomyocytes, monitored by two distinct stage markers of early cardiac mesodermal formation and commitment to a multipotent heart progenitor cell fate: MESP1 and ISL1, respectively. From the screen output, we compiled a list of 15 candidate genes. After validating seven of them, we identified ZIC2 as an essential gene for cardiac progenitor formation. ZIC2 is known as a master regulator of neurogenesis. hPSCs with ZIC2 mutated still express pluripotency markers. However, their ability to differentiate into cardiomyocytes was greatly attenuated. RNA-Seq profiling of the ZIC2-mutant cells revealed that the mutants switched their cell fate alternatively to the noncardiac cell lineage. Further, single cell RNA-seq analysis showed the ZIC2 mutants affected the apelin receptor-related signaling pathway during mesoderm formation. Our results provide a new link between ZIC2 and human cardiogenesis and document the potential power of a genome-wide unbiased CRISPR-knockout screen to identify the key steps in human mesoderm precursor cell- and heart progenitor cell-fate determination during in vitro hPSC cardiogenesis.", "doi": "10.1002/stem.3168", "pmid": "32129551", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Stockholm (Genomics Production)": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC7891398"}], "notes": [], "created": "2020-07-08T13:05:12.225Z", "modified": "2024-01-16T13:48:42.444Z"}, {"entity": "publication", "iuid": "8bbce7fb2cee400fba35ba3b383f90ab", "links": {"self": {"href": "https://publications.scilifelab.se/publication/8bbce7fb2cee400fba35ba3b383f90ab.json"}, "display": {"href": "https://publications.scilifelab.se/publication/8bbce7fb2cee400fba35ba3b383f90ab"}}, "title": "SMAD4 Is Essential for Human Cardiac Mesodermal Precursor Cell Formation.", "authors": [{"family": "Xu", "given": "Jiejia", "initials": "J"}, {"family": "Gruber", "given": "Peter J", "initials": "PJ"}, {"family": "Chien", "given": "Kenneth R", "initials": "KR"}], "type": "journal article", "published": "2018-10-30", "journal": {"volume": null, "issn": "1549-4918", "issue": null, "title": "Stem Cells", "issn-l": "1066-5099"}, "abstract": "Understanding stage-specific molecular mechanisms of human cardiomyocyte (CM) progenitor formation and subsequent differentiation are critical to identify pathways that might lead to congenital cardiovascular defects and malformations. In particular, gene mutations in the transforming growth factor (TGF)\u03b2 superfamily signaling pathways can cause human congenital heart defects, and murine loss of function studies of a central component in this pathway, Smad4, leads to early embryonic lethality. To define the role of SMAD4 at the earliest stages of human cardiogenesis, we generated SMAD4 mutant human embryonic stem cells (hESCs). Herein, we show that the loss of SMAD4 has no effect on hESC self-renewal, or neuroectoderm formation, but is essential for the formation of cardiac mesoderm, with a subsequent complete loss of CM formation during human ES cell cardiogenesis. Via transcriptional profiling, we show that SMAD4 mutant cell lines fail to generate cardiac mesodermal precursors, clarifying a role of NODAL/SMAD4 signaling in cardiac mesodermal precursor formation via enhancing the expression of primitive streak genes. Since SMAD4 relative pathways have been linked to congenital malformations, it will become of interest to determine whether these may due, in part, to defective cell fate decision during cardiac mesodermal precursor formation. Stem Cells 2018.", "doi": "10.1002/stem.2943", "pmid": "30376214", "labels": {"National Genomics Infrastructure": "Service", "NGI Stockholm (Genomics Applications)": "Service", "NGI Stockholm (Genomics Production)": "Service"}, "xrefs": [], "notes": [], "created": "2019-01-07T15:13:41.689Z", "modified": "2020-01-21T13:56:13.493Z"}, {"entity": "publication", "iuid": "150901597106460ca19322b5e9e8a83d", "links": {"self": {"href": "https://publications.scilifelab.se/publication/150901597106460ca19322b5e9e8a83d.json"}, "display": {"href": "https://publications.scilifelab.se/publication/150901597106460ca19322b5e9e8a83d"}}, "title": "Comprehensive Proteomic Analysis of Mesenchymal Stem Cell Exosomes Reveals Modulation of Angiogenesis via Nuclear Factor-KappaB Signaling.", "authors": [{"family": "Anderson", "given": "Johnathon D", "initials": "JD"}, {"family": "Johansson", "given": "Henrik J", "initials": "HJ"}, {"family": "Graham", "given": "Calvin S", "initials": "CS"}, {"family": "Vesterlund", "given": "Mattias", "initials": "M"}, {"family": "Pham", "given": "Missy T", "initials": "MT"}, {"family": "Bramlett", "given": "Charles S", "initials": "CS"}, {"family": "Montgomery", "given": "Elizabeth N", "initials": "EN"}, {"family": "Mellema", "given": "Matt S", "initials": "MS"}, {"family": "Bardini", "given": "Renee L", "initials": "RL"}, {"family": "Contreras", "given": "Zelenia", "initials": "Z"}, {"family": "Hoon", "given": "Madeline", "initials": "M"}, {"family": "Bauer", "given": "Gerhard", "initials": "G"}, {"family": "Fink", "given": "Kyle D", "initials": "KD"}, {"family": "Fury", "given": "Brian", "initials": "B"}, {"family": "Hendrix", "given": "Kyle J", "initials": "KJ"}, {"family": "Chedin", "given": "Frederic", "initials": "F"}, {"family": "El-Andaloussi", "given": "Samir", "initials": "S"}, {"family": "Hwang", "given": "Billie", "initials": "B"}, {"family": "Mulligan", "given": "Michael S", "initials": "MS"}, {"family": "Lehti\u00f6", "given": "Janne", "initials": "J", "orcid": "0000-0002-8100-9562", "researcher": {"href": "https://publications.scilifelab.se/researcher/8406a97bac744a59b1bc951978994581.json"}}, {"family": "Nolta", "given": "Jan A", "initials": "JA"}], "type": "journal article", "published": "2016-03-00", "journal": {"volume": "34", "issn": "1549-4918", "issue": "3", "pages": "601-613", "title": "Stem Cells", "issn-l": "1066-5099"}, "abstract": "Mesenchymal stem cells (MSC) are known to facilitate healing of ischemic tissue related diseases through proangiogenic secretory proteins. Recent studies further show that MSC derived exosomes function as paracrine effectors of angiogenesis, however, the identity of which components of the exosome proteome responsible for this effect remains elusive. To address this we used high-resolution isoelectric focusing coupled liquid chromatography tandem mass spectrometry, an unbiased high throughput proteomics approach to comprehensively characterize the proteinaceous contents of MSCs and MSC derived exosomes. We probed the proteome of MSCs and MSC derived exosomes from cells cultured under expansion conditions and under ischemic tissue simulated conditions to elucidate key angiogenic paracrine effectors present and potentially differentially expressed in these conditions. In total, 6,342 proteins were identified in MSCs and 1,927 proteins in MSC derived exosomes, representing to our knowledge the first time these proteomes have been probed comprehensively. Multilayered analyses identified several putative paracrine effectors of angiogenesis present in MSC exosomes and increased in expression in MSCs exposed to ischemic tissue-simulated conditions; these include platelet derived growth factor, epidermal growth factor, fibroblast growth factor, and most notably nuclear factor-kappaB (NFkB) signaling pathway proteins. NFkB signaling was identified as a key mediator of MSC exosome induced angiogenesis in endothelial cells by functional in vitro validation using a specific inhibitor. Collectively, the results of our proteomic analysis show that MSC derived exosomes contain a robust profile of angiogenic paracrine effectors, which have potential for the treatment of ischemic tissue-related diseases.", "doi": "10.1002/stem.2298", "pmid": "26782178", "labels": {"Clinical Proteomics Mass spectrometry": "Collaborative", "Global Proteomics and Proteogenomics": "Collaborative"}, "xrefs": [{"db": "pmc", "key": "PMC5785927"}, {"db": "mid", "key": "NIHMS932042"}], "notes": [], "created": "2017-05-03T13:02:32.246Z", "modified": "2021-07-08T11:36:15.138Z"}, {"entity": "publication", "iuid": "1c66596de4844cd5aa64aef1025860e5", "links": {"self": {"href": "https://publications.scilifelab.se/publication/1c66596de4844cd5aa64aef1025860e5.json"}, "display": {"href": "https://publications.scilifelab.se/publication/1c66596de4844cd5aa64aef1025860e5"}}, "title": "Cytostatic Effect of Repeated Exposure to Simvastatin: A Mechanism for Chronic Myotoxicity Revealed by the Use of Mesodermal Progenitors Derived from Human Pluripotent Stem Cells.", "authors": [{"family": "Peric", "given": "Delphine", "initials": "D"}, {"family": "Barragan", "given": "Isabel", "initials": "I"}, {"family": "Giraud-Triboult", "given": "Karine", "initials": "K"}, {"family": "Egesipe", "given": "Anne-Laure", "initials": "AL"}, {"family": "Meyniel-Schicklin", "given": "Laur\u00e8ne", "initials": "L"}, {"family": "Cousin", "given": "Christelle", "initials": "C"}, {"family": "Lotteau", "given": "Vincent", "initials": "V"}, {"family": "Petit", "given": "Vincent", "initials": "V"}, {"family": "Touhami", "given": "Jawida", "initials": "J"}, {"family": "Battini", "given": "Jean-Luc", "initials": "JL"}, {"family": "Sitbon", "given": "Marc", "initials": "M"}, {"family": "Pinset", "given": "Christian", "initials": "C"}, {"family": "Ingelman-Sundberg", "given": "Magnus", "initials": "M"}, {"family": "Laustriat", "given": "Delphine", "initials": "D"}, {"family": "Peschanski", "given": "Marc", "initials": "M"}], "type": "journal article", "published": "2015-10-00", "journal": {"volume": "33", "issn": "1549-4918", "issue": "10", "pages": "2936-2948", "title": "Stem Cells", "issn-l": "1066-5099"}, "abstract": "Statin treatment of hypercholesterolemia can lead to chronic myotoxicity which is, in most cases, alleviated by drug withdrawal. Cellular and molecular mechanisms of this adverse effect have been elusive, in particular because of the lack of in vitro models suitable for long-term exposures. We have taken advantage of the properties of human pluripotent stem cell-derived mesodermal precursors, that can be maintained unaltered in vitro for a long period of time, to develop a model of repeated exposures to simvastatin during more than 2 weeks. This approach unveiled major differences, both in functional and molecular terms, in response to single versus repeated-dose exposures to simvastatin. The main functional effect of the in vitro simvastatin-induced long-term toxicity was a loss of proliferative capacity in the absence of concomitant cell death, revealing that cytostatic effect could be a major contributor to statin-induced myotoxicity. Comparative analysis of molecular modifications induced by simvastatin short-term versus prolonged exposures demonstrated powerful adaptive cell responses, as illustrated by the dramatic decrease in the number of differentially expressed genes, distinct biological pathway enrichments, and distinct patterns of nutrient transporters expressed at the cell surface. This study underlines the potential of derivatives of human pluripotent stem cells for developing new approaches in toxicology, in particular for chronic toxicity testing.", "doi": "10.1002/stem.2107", "pmid": "26184566", "labels": {"Bioinformatics and Expression Analysis (BEA)": null}, "xrefs": [], "notes": [], "created": "2017-05-02T12:58:16.743Z", "modified": "2017-05-30T13:16:55.221Z"}, {"entity": "publication", "iuid": "2891850ee95f4e8caad160da3a5b6147", "links": {"self": {"href": "https://publications.scilifelab.se/publication/2891850ee95f4e8caad160da3a5b6147.json"}, "display": {"href": "https://publications.scilifelab.se/publication/2891850ee95f4e8caad160da3a5b6147"}}, "title": "Somatic cells with a heavy mitochondrial DNA mutational load render induced pluripotent stem cells with distinct differentiation defects.", "authors": [{"family": "Wahlestedt", "given": "Martin", "initials": "M"}, {"family": "Ameur", "given": "Adam", "initials": "A", "orcid": "0000-0001-6085-6749", "researcher": {"href": "https://publications.scilifelab.se/researcher/e960811513664a78b2804a00ee70f7c3.json"}}, {"family": "Moraghebi", "given": "Roksana", "initials": "R"}, {"family": "Norddahl", "given": "Gudmundur L", "initials": "GL"}, {"family": "Sten", "given": "Gerd", "initials": "G"}, {"family": "Woods", "given": "Niels-Bjarne", "initials": "NB"}, {"family": "Bryder", "given": "David", "initials": "D"}], "type": "journal article", "published": "2014-05-00", "journal": {"volume": "32", "issn": "1549-4918", "issue": "5", "pages": "1173-1182", "title": "Stem Cells", "issn-l": "1066-5099"}, "abstract": "It has become increasingly clear that several age-associated pathologies associate with mutations in the mitochondrial genome. Experimental modeling of such events has revealed that acquisition of mitochondrial DNA (mtDNA) damage can impair respiratory function and, as a consequence, can lead to widespread decline in cellular function. This includes premature aging syndromes. By taking advantage of a mutator mouse model with an error-prone mtDNA polymerase, we here investigated the impact of an established mtDNA mutational load with regards to the generation, maintenance, and differentiation of induced pluripotent stem (iPS) cells. We demonstrate that somatic cells with a heavy mtDNA mutation burden were amenable for reprogramming into iPS cells. However, mutator iPS cells displayed delayed proliferation kinetics and harbored extensive differentiation defects. While mutator iPS cells had normal ATP levels and glycolytic activity, the induction of differentiation coincided with drastic decreases in ATP production and a hyperactive glycolysis. These data demonstrate the differential requirements of mitochondrial integrity for pluripotent stem cell self-renewal versus differentiation and highlight the relevance of assessing the mitochondrial genome when aiming to generate iPS cells with robust differentiation potential.", "doi": "10.1002/stem.1630", "pmid": "24446123", "labels": {"National Genomics Infrastructure": null, "NGI Uppsala (Uppsala Genome Center)": null}, "xrefs": [], "notes": [], "created": "2017-05-04T15:02:40.825Z", "modified": "2021-07-07T14:37:06.401Z"}], "created": "2017-05-09T09:12:29.565Z", "modified": "2020-11-27T13:14:05.184Z"}