CXCL4/PF4 is a predictive biomarker of cardiac differentiation potential of human induced pluripotent stem cells

Ohashi, Fumiya; Miyagawa, Shigeru; Yasuda, Satoshi; Miura, Takumi; Kuroda, Takuya; Itoh, Masayoshi; Kawaji, Hideya; Ito, Emiko; Yoshida, Shohei; Saito, Atsuhiro; Sameshima, Tadashi; Kawai, Jun; Sawa, Yoshiki; Sato, Yoji

doi:10.1038/s41598-019-40915-w

Cited by 13 publications

(11 citation statements)

References 66 publications

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“…Further, our enrichment analysis showed downregulation of a number of genes, viz. Pf4, Gdf6, Sall1, Apln, Kctd11, and Twist2 have functions associated with the differentiation of cardiomyocytes, endothelial cells and striated muscles (66,69,(73)(74)(75)(76). In addition to differentiation, the regulation of proliferation in cardiomyocytes is important for heart development and its normal functions.…”

Section: Discussionmentioning

confidence: 99%

Pregestational diabetes alters cardiac structure and function of neonatal rats through developmental plasticity

Alam

Uppulapu

Tiwari

et al. 2022

Front. Cardiovasc. Med.

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Pregestational diabetes (PGDM) leads to developmental impairment, especially cardiac dysfunction, in their offspring. The hyperglycemic microenvironment inside the uterus alters the cardiac plasticity characterized by electrical and structural remodeling of the heart. The altered expression of several transcription factors due to hyperglycemia during fetal development might be responsible for molecular defects and phenotypic changes in the heart. The molecular mechanism of the developmental defects in the heart due to PGDM remains unclear. To understand the molecular defects in the 2-days old neonatal rats, streptozotocin-induced diabetic female rats were bred with healthy male rats. We collected 2-day-old hearts from the neonates and identified the molecular basis for phenotypic changes. Neonates from diabetic mothers showed altered electrocardiography and echocardiography parameters. Transcriptomic profiling of the RNA-seq data revealed that several altered genes were associated with heart development, myocardial fibrosis, cardiac conduction, and cell proliferation. Histopathology data showed the presence of focal cardiac fibrosis and increased cell proliferation in neonates from diabetic mothers. Thus, our results provide a comprehensive map of the cellular events and molecular pathways perturbed in the neonatal heart during PGDM. All of the molecular and structural changes lead to developmental plasticity in neonatal rat hearts and develop cardiac anomalies in their early life.

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Section: Discussionmentioning

confidence: 99%

Pregestational diabetes alters cardiac structure and function of neonatal rats through developmental plasticity

Alam

Uppulapu

Tiwari

et al. 2022

Front. Cardiovasc. Med.

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“…Zhang et al [ 46 ] reported a generation of 80 to 95% cTnT + cells in 2D for an embryonic stem cell line (HuES6) and three different hiPSC lines (FS3.2, PF6.2, and SPF5.2). The differences in yield might be due to the unknown—and possible later—timepoint of flow cytometry analyses by these authors, or the different stem cell lines used, which are known to frequently affect general hiPSC differentiation outcomes [ 67 , 68 ]. For example, Zhang et al [ 46 ] observed beating generally after 6 days, while iPS11 cells started beating after 7–8 days in culture ( Figure 4 ), a dissimilarity that could be attributed to line or handling differences.…”

Section: Resultsmentioning

confidence: 99%

The Human Induced Pluripotent Stem Cell Test as an Alternative Method for Embryotoxicity Testing

Galanjuk

Zühr

Dönmez

et al. 2022

IJMS

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The evaluation of substances for their potency to induce embryotoxicity is controlled by safety regulations. Test guidelines for reproductive and developmental toxicity rely mainly on animal studies, which make up the majority of animal usage in regulatory toxicology. Therefore, there is an urgent need for alternative in vitro methods to follow the 3R principles. To improve human safety, cell models based on human cells are of great interest to overcome species differences. Here, human induced pluripotent stem cells (hiPSCs) are an ideal cell source as they largely recapitulate embryonic stem cells without bearing ethical concerns and they are able to differentiate into most cell types of the human body. Here, we set up and characterized a fetal bovine serum (FBS)-free hiPSC-based in vitro test method, called the human induced pluripotent stem cell test (hiPS Test), to evaluate the embryotoxic potential of substances. After 10 days in culture, hiPSCs develop into beating cardiomyocytes. As terminal endpoint evaluations, cell viability, qPCR analyses as well as beating frequency and area of beating cardiomyocytes by video analyses are measured. The embryotoxic positive and non-embryotoxic negative controls, 5-Fluorouracil (5-FU) and Penicillin G (PenG), respectively, were correctly assessed in the hiPS Test. More compounds need to be screened in the future for defining the assay’s applicability domain, which will inform us of the suitability of the hiPS Test for detecting adverse effects of substances on embryonic development.

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“…This protein is chemotactic for numerous other cell type and also functions as an inhibitor of hematopoiesis, angiogenesis and T-cell function. It is involved in regulating the differentiation of hematopoietic stem cells/progenitor cells, maintaining the survival and self-renewal of hematopoietic stem cells, and regulating the cardiac differentiation potential of induced pluripotent stem cells ( 32 , 33 ). Previous studies have shown that PF4 is an endocrine factor, and its overexpression in tumors is associated with decreased OS of patients ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of six hub genes and analysis of their correlation with drug sensitivity in acute myeloid leukemia through bioinformatics

Cai¹,

Liang²,

Cai³

et al. 2021

Transl Cancer Res TCR

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Background: Acute myeloid leukemia (AML) is a common hematopoietic malignancy and have unsatisfactory prognosis. Our study aimed to identify hub genes in AML and explore potential biomarkers through integrated bioinformatics.Methods: Microarray datasets were analyzed to screen the differentially expressed genes (DEGs).Functional enrichment analysis was performed, and protein-protein interaction (PPI) network was generated by the STRING (11.0) database and Cytoscape (3.7.2) software. Hub genes were screened and verified through GEPIA2 and GEO microarray database. Sensitivity of AML cell lines with high expression of hub genes to the small-molecule drugs were identified using GSCA Lite.Results: A total of 456 DEGs were identified and top 100 genes were screened out, of which six genes (FLT3, PF4, CD163, MRC1, CSF2RB, PPBP) were upregulated in AML and individually had a worse prognosis by the overall survival (OS) analysis. AML cell lines with FLT3-overexpression and CSF2RB-overexpression were sensitive to most small-molecule drugs, while, AML cells with CD163-overexpression were only sensitive to a few drugs. However, sensitivity to Erlotinib was correlated with high expression of PF4 and PPBP.

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CXCL4/PF4 is a predictive biomarker of cardiac differentiation potential of human induced pluripotent stem cells

Cited by 13 publications

References 66 publications

Pregestational diabetes alters cardiac structure and function of neonatal rats through developmental plasticity

Pregestational diabetes alters cardiac structure and function of neonatal rats through developmental plasticity

The Human Induced Pluripotent Stem Cell Test as an Alternative Method for Embryotoxicity Testing

Identification of six hub genes and analysis of their correlation with drug sensitivity in acute myeloid leukemia through bioinformatics

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