Biphasic Regulation of Mesenchymal Genes Controls Fate Switches During Hematopoietic Differentiation of Human Pluripotent Stem Cells

Wang, Hongtao; Wang, Mengge; Wen, Yao; Xu, Changlu; Chen, Xiaoyuan; Wu, Dan; Su, Pei; Zhou, Wen; Cheng, Tao; Shi, Lihong; Zhou, Jiaxi

doi:10.1002/advs.202001019

Cited by 10 publications

(9 citation statements)

References 52 publications

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“…1G), suggesting that a biphasic regulation of the cell cycle plays an important role in EHT. A previous report of the biphasic regulation of mesenchymal genes during EHT ( 27 ) was also confirmed in our study at the single-cell level. We demonstrated that the expression of mesenchymal genes was up-regulated before EHT and attenuated during EHT (Fig.…”

Section: Discussionsupporting

confidence: 91%

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Single-cell transcriptome of early hematopoiesis guides arterial endothelial-enhanced functional T cell generation from human PSCs

Shen

Zhang

et al. 2021

Sci. Adv.

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Hematopoietic differentiation of human pluripotent stem cells (hPSCs) requires orchestration of dynamic cell and gene regulatory networks but often generates blood cells that lack natural function. Here, we performed extensive single-cell transcriptomic analyses to map fate choices and gene expression patterns during hematopoietic differentiation of hPSCs and showed that oxidative metabolism was dysregulated during in vitro directed differentiation. Applying hypoxic conditions at the stage of endothelial-to-hematopoietic transition in vitro effectively promoted the development of arterial specification programs that governed the generation of hematopoietic progenitor cells (HPCs) with functional T cell potential. Following engineered expression of the anti-CD19 chimeric antigen receptor, the T cells generated from arterial endothelium-primed HPCs inhibited tumor growth both in vitro and in vivo. Collectively, our study provides benchmark datasets as a resource to further understand the origins of human hematopoiesis and represents an advance in guiding in vitro generation of functional T cells for clinical applications.

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Section: Discussionsupporting

confidence: 91%

“…1, F to H, and fig. S1F) ( 27 ). Last, the genes in cluster 4 were activated at the later stage of differentiation with predominant involved in EC-HC development (e.g., ESM1 and SPN ) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcriptome of early hematopoiesis guides arterial endothelial-enhanced functional T cell generation from human PSCs

Shen

Zhang

et al. 2021

Sci. Adv.

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“…Additionally, emerging evidence suggests that the plasticity of the epithelial–mesenchymal transition (EMT) phenotype of tumor cells had an important clinical significance for the progress of cancer and chemotherapy resistance. 40 , 41 In this study, we also observed genes negatively correlation with CYFIP2 were enriched on hallmark of EMT and angiogenesis. Taking together, we hypothesized that CYFIP2 might play a regulatory role in metabolic reprogramming and the EMT pathway in ccRCC.…”

Section: Discussionsupporting

confidence: 66%

The Downregulation of Prognosis- and Immune Infiltration-Related Gene CYFIP2 Serves as a Novel Target in ccRCC

Tong

Meng

et al. 2021

IJGM

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Background: Increasing evidence indicated that the aberrant expression of the cytoplasmic FMR1-interacting protein (CYFIP) family might possess critical role and potential functions in cancer. But the role of CYFIP2 in clear cell renal cell carcinoma (ccRCC) is still uncharacteristic. Methods: We investigated the Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database for the expression profile, clinicopathological variables, clinical prognosis information, and promoter methylation levels of CYFIPs in ccRCC. The aberrant CYFIP2 protein expression was validated by the Human Protein Atlas (HPA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). Quantitative real-time polymerase chain reaction (qRT-PCR) was used to uncover CYFIP2 mRNA levels in 28 pairs of ccRCC cancer tissues. Kaplan-Meier analysis, univariate and multivariate Cox proportional hazard regression were performed to assess CYFIPs' prognosis value. Gene set enrichment analysis (GSEA) was used to determined hallmark functions, gene ontology of CYFIP2. TIMER database was utilized to assess the correlation with immune infiltration in ccRCC. Results: Results showed CYFIP2 was downregulated in ccRCC, relative to paired normal tissues in TCGA-KIRC database and 28 pairs of clinical samples (P < 0.0001). Similarly, a decreased CYFIP2 protein expression was confirmed by ccRCC tissues. The results showed CYFIP2 was negatively regulated by promoter DNA methylation. Survival analysis results showed CYFIP2 could be an independent biomarker for ccRCC and its reduction predicted a poor overall survival (OS) and disease-free survival (DFS). GSEA showed CYFIP2 was involved in metabolic pathways and epithelial-mesenchymal transition (EMT). Immune infiltration analysis revealed that a list of immune markers was significantly correlated with CYFIP2 expression especially with CD4+ cells and CD8+ cells in ccRCC. Conclusion:These results show that CYFIP2 was downregulated in ccRCC patients and predicted an unfavorable prognosis. CYFIP2 might be a potential novel prognostic molecule, and related to immune infiltration, the metabolism, as well as EMT process in ccRCC. CYFIP2 could act as tumor suppressor gene in ccRCC and positive modulation of CYFIP2 might lead to development of a novel strategy for ccRCC treatment.

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“…The differentiation of hESCs to hematopoietic cells occurs in a sequential manner (Wang et al , 2018a; Wang et al , 2018b; Wang et al , 2020). This process involves exit from a pluripotent state and generation of lateral plate mesoderm cells (APLNR + ) at day 2.…”

Section: Resultsmentioning

confidence: 99%

A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells

Wang

et al. 2020

EMBO Reports

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Alternative splicing (AS) leads to transcriptome diversity in eukaryotic cells and is one of the key regulators driving cellular differentiation. Although AS is of crucial importance for normal hematopoiesis and hematopoietic malignancies, its role in early hematopoietic development is still largely unknown. Here, by using high-throughput transcriptomic analyses, we show that pervasive and dynamic AS takes place during hematopoietic development of human pluripotent stem cells (hPSCs). We identify a splicing factor switch that occurs during the differentiation of mesodermal cells to endothelial progenitor cells (EPCs). Perturbation of this switch selectively impairs the emergence of EPCs and hemogenic endothelial progenitor cells (HEPs). Mechanistically, an EPCinduced alternative spliced isoform of NUMB dictates EPC specification by controlling NOTCH signaling. Furthermore, we demonstrate that the splicing factor SRSF2 regulates splicing of the EPCinduced NUMB isoform, and the SRSF2-NUMB-NOTCH splicing axis regulates EPC generation. The identification of this splicing factor switch provides a new molecular mechanism to control cell fate and lineage specification.

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Biphasic Regulation of Mesenchymal Genes Controls Fate Switches During Hematopoietic Differentiation of Human Pluripotent Stem Cells

Cited by 10 publications

References 52 publications

Single-cell transcriptome of early hematopoiesis guides arterial endothelial-enhanced functional T cell generation from human PSCs

Single-cell transcriptome of early hematopoiesis guides arterial endothelial-enhanced functional T cell generation from human PSCs

The Downregulation of Prognosis- and Immune Infiltration-Related Gene CYFIP2 Serves as a Novel Target in ccRCC

A splicing factor switch controls hematopoietic lineage specification of pluripotent stem cells

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