MicroRNA-302d promotes the proliferation of human pluripotent stem cell-derived cardiomyocytes by inhibiting LATS2 in the Hippo pathway

2019 ◽  
Vol 133 (13) ◽  
pp. 1387-1399 ◽  
Author(s):  
Fei Xu ◽  
Jingcheng Yang ◽  
Jun Shang ◽  
Feng Lan ◽  
Miaomiao Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Therapeutic Potential ◽  
Heart Function ◽  
Hippo Pathway ◽  
Sequencing Analysis ◽  
Human Pluripotent Stem Cell ◽  
Induced Changes ◽  
The Hippo Pathway

Abstract Recent evidence has shown that cardiomyocytes (CMs) can proliferate at a low level after myocardial infarction (MI), but it is insufficient to reestablish heart function. Several microRNAs (miRNAs) have been proven to sufficiently induce rodent CM proliferation. However, whether miRNAs identified in rodents can promote human CM proliferation is unknown due to the poorly conserved functions of miRNAs among species. In the present study, we demonstrate that i) expression of microRNA-302d (miR-302d) decreased significantly during CM differentiation from human pluripotent stem cells (hPSCs) from day 4 to day 18; ii) miR-302d efficiently promoted proliferation of hPSC-derived CMs; iii) miR-302d promoted CM proliferation by targeting LATS2 in the Hippo pathway; and iv) RNA-sequencing analysis revealed that overexpression of miR-302d induced changes in gene expression, which mainly converged on the cell cycle. Our study provides further evidence for the therapeutic potential of miR-302d.

scholarly journals The Hippo pathway controls myofibril assembly and muscle fiber growth by regulating sarcomeric gene expression

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Aynur Kaya-Çopur ◽  
Fabio Marchiano ◽  
Marco Y Hein ◽  
Daniel Alpern ◽  
Julie Russeil ◽  
...  
Keyword(s):  
Gene Expression ◽  
Muscle Fiber ◽  
Flight Muscle ◽  
Hippo Pathway ◽  
Muscle Fibers ◽  
Muscle Growth ◽  
Fiber Growth ◽  
Flight Muscles ◽  
Sarcomeric Gene ◽  
The Hippo Pathway

Skeletal muscles are composed of gigantic cells called muscle fibers, packed with force-producing myofibrils. During development the size of individual muscle fibers must dramatically enlarge to match with skeletal growth. How muscle growth is coordinated with growth of the contractile apparatus is not understood. Here, we use the large Drosophila flight muscles to mechanistically decipher how muscle fiber growth is controlled. We find that regulated activity of core members of the Hippo pathway is required to support flight muscle growth. Interestingly, we identify Dlg5 and Slmap as regulators of the STRIPAK phosphatase, which negatively regulates Hippo to enable post-mitotic muscle growth. Mechanistically, we show that the Hippo pathway controls timing and levels of sarcomeric gene expression during development and thus regulates the key components that physically mediate muscle growth. Since Dlg5, STRIPAK and the Hippo pathway are conserved a similar mechanism may contribute to muscle or cardiomyocyte growth in humans.

scholarly journals Activating Hippo Pathway via Rassf1 by Ursolic Acid Suppresses the Tumorigenesis of Gastric Cancer

2019 ◽  
Vol 20 (19) ◽  
pp. 4709 ◽  
Author(s):  
Seong-Hun Kim ◽  
Hua Jin ◽  
Ruo Yu Meng ◽  
Da-Yeah Kim ◽  
Yu Chuan Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Cancer Cells ◽  
Ursolic Acid ◽  
Hippo Pathway ◽  
Dependent Manner ◽  
Gastric Cancer Cells ◽  
Protein Levels ◽  
Tumor Tissues ◽  
The Hippo Pathway

The Hippo pathway is often dysregulated in many carcinomas, which results in various stages of tumor progression. Ursolic acid (UA), a natural compound that exists in many herbal plants, is known to obstruct cancer progression and exerts anti-carcinogenic effect on a number of human cancers. In this study, we aimed to examine the biological mechanisms of action of UA through the Hippo pathway in gastric cancer cells. MTT assay showed a decreased viability of gastric cancer cells after treatment with UA. Following treatment with UA, colony numbers and the sizes of gastric cancer cells were significantly diminished and apoptosis was observed in SNU484 and SNU638 cells. The invasion and migration rates of gastric cancer cells were suppressed by UA in a dose-dependent manner. To further determine the gene expression patterns that are related to the effects of UA, a microarray analysis was performed. Gene ontology analysis revealed that several genes, such as the Hippo pathway upstream target gene, ras association domain family (RASSF1), and its downstream target genes (MST1, MST2, and LATS1) were significantly upregulated by UA, while the expression of YAP1 gene, together with oncogenes (FOXM1, KRAS, and BATF), were significantly decreased. Similar to the gene expression profiling results, the protein levels of RASSF1, MST1, MST2, LATS1, and p-YAP were increased, whereas those of CTGF were decreased by UA in gastric cancer cells. The p-YAP expression induced in gastric cancer cells by UA was reversed with RASSF1 silencing. In addition, the protein levels in the Hippo pathway were increased in the UA-treated xenograft tumor tissues as compared with that in the control tumor tissues; thus, UA significantly inhibited the tumorigenesis of gastric cancer in vivo in xenograft animals. Collectively, UA diminishes the proliferation and metastasis of gastric cancer via the regulation of Hippo pathway through Rassf1, which suggests that UA can be used as a potential chemopreventive and therapeutic agent for gastric cancer.

Differentiating human pluripotent stem cells into vascular smooth muscle cells in three dimensional thermoreversible hydrogels

2019 ◽  
Vol 7 (1) ◽  
pp. 347-361 ◽  
Author(s):  
Haishuang Lin ◽  
Qian Du ◽  
Qiang Li ◽  
Ou Wang ◽  
Zhanqi Wang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Three Dimensional ◽  
Muscle Cells ◽  
Human Pluripotent Stem Cell ◽  
Scalable Production

3D thermoreversible PNIPAAm-PEG hydrogels are used for scalable production of human pluripotent stem cell-derived vascular smooth muscle cells.

scholarly journals Modeling endodermal organ development and diseases using human pluripotent stem cell-derived organoids

2020 ◽  
Vol 12 (8) ◽  
pp. 580-592
Author(s):  
Fong Cheng Pan ◽  
Todd Evans ◽  
Shuibing Chen
Keyword(s):  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Disease Modeling ◽  
State Of The Art ◽  
Directed Differentiation ◽  
Organ Development ◽  
Human Pluripotent Stem Cell ◽  
Human Organ ◽  
Current State

Abstract Recent advances in development of protocols for directed differentiation from human pluripotent stem cells (hPSCs) to defined lineages, in combination with 3D organoid technology, have facilitated the generation of various endoderm-derived organoids for in vitro modeling of human gastrointestinal development and associated diseases. In this review, we discuss current state-of-the-art strategies for generating hPSC-derived endodermal organoids including stomach, liver, pancreatic, small intestine, and colonic organoids. We also review the advantages of using this system to model various human diseases and evaluate the shortcomings of this technology. Finally, we emphasize how other technologies, such as genome editing and bioengineering, can be incorporated into the 3D hPSC-organoid models to generate even more robust and powerful platforms for understanding human organ development and disease modeling.

scholarly journals Expansion Culture of Human Pluripotent Stem Cells and Production of Cardiomyocytes

2019 ◽  
Vol 6 (2) ◽  
pp. 48 ◽  
Author(s):  
Minh Nguyen Tuyet Le ◽  
Kouichi Hasegawa
Keyword(s):  
Heart Failure ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Clinical Applications ◽  
Cardiac Differentiation ◽  
Cardiomyocyte Differentiation ◽  
Human Pluripotent Stem Cell ◽  
Future Prospects ◽  
Culture Methods ◽  
Dynamic Culture

Transplantation of human pluripotent stem cell (hPSCs)-derived cardiomyocytes for the treatment of heart failure is a promising therapy. In order to implement this therapy requiring numerous cardiomyocytes, substantial production of hPSCs followed by cardiac differentiation seems practical. Conventional methods of culturing hPSCs involve using a 2D culture monolayer that hinders the expansion of hPSCs, thereby limiting their productivity. Advanced culture of hPSCs in 3D aggregates in the suspension overcomes the limitations of 2D culture and attracts immense attention. Although the hPSC production needs to be suitable for subsequent cardiac differentiation, many studies have independently focused on either expansion of hPSCs or cardiac differentiation protocols. In this review, we summarize the recent approaches to expand hPSCs in combination with cardiomyocyte differentiation. A comparison of various suspension culture methods and future prospects for dynamic culture of hPSCs are discussed in this study. Understanding hPSC characteristics in different models of dynamic culture helps to produce numerous cells that are useful for further clinical applications.

scholarly journals Expression of miRNAs from the Imprinted DLK1/DIO3 Locus Signals the Osteogenic Potential of Human Pluripotent Stem Cells

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1523 ◽  
Author(s):  
Laetitia Barrault ◽  
Jacqueline Gide ◽  
Tingting Qing ◽  
Lea Lesueur ◽  
Jorg Tost ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Osteogenic Differentiation ◽  
Cell Lines ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Human Pluripotent Stem Cells ◽  
Osteogenic Potential ◽  
Human Pluripotent Stem Cell ◽  
Stem Cell Lines

Substantial variations in differentiation properties have been reported among human pluripotent cell lines (hPSC), which could affect their utility and clinical safety. We characterized the variable osteogenic capacity observed between different human pluripotent stem cell lines. By focusing on the miRNA expression profile, we demonstrated that the osteogenic differentiation propensity of human pluripotent stem cell lines could be associated with the methylation status and the expression of miRNAs from the imprinted DLK1/DIO3 locus. More specifically, quantitative analysis of the expression of six different miRNAs of that locus prospectively identified human embryonic stem cells and human-induced pluripotent stem cells with differential osteogenic differentiation capacities. At the molecular and functional levels, we showed that these miRNAs modulated the expression of the activin receptor type 2B and the downstream signal transduction, which impacted osteogenesis. In conclusion, miRNAs of the imprinted DLK1/DIO3 locus appear to have both a predictive value and a functional impact in determining the osteogenic fate of human pluripotent stem cells.

Laminin-511 and recombinant vitronectin supplementation enables human pluripotent stem cell culture and differentiation on conventional tissue culture polystyrene surfaces in xeno-free conditions

2021 ◽  
Author(s):  
Ya-Chu Liu ◽  
Lee-Kiat Ban ◽  
Henry Hsin-Chung Lee ◽  
Hsin-Ting Lee ◽  
Yu-Tang Chang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Culture ◽  
Extracellular Matrix ◽  
Tissue Culture ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Culture Conditions ◽  
Human Pluripotent Stem Cell ◽  
Tissue Culture Polystyrene ◽  
Ecm Proteins

Human pluripotent stem cells (hPSCs) are typically cultivated on extracellular matrix (ECM) protein-coated dishes in xeno-free culture conditions. We supplemented mixed ECM proteins (laminin-511 and recombinant vitronectin, rVT) in culture...

scholarly journals Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors

Cancers ◽  
2018 ◽  
Vol 10 (3) ◽  
pp. 81 ◽  
Author(s):  
◽  
Keyword(s):  
Transcription Factors ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Therapeutic Potential ◽  
Hippo Pathway ◽  
Large Body ◽  
Hippo Signaling ◽  
Wide Range ◽  
The Hippo Pathway

The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo.

Convergence of human pluripotent stem cell, organoid, and genome editing technologies

2021 ◽  
pp. 153537022098580
Author(s):  
Lin Wang ◽  
Zhaohui Ye ◽  
Yoon-Young Jang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Genome Editing ◽  
Pluripotent Stem Cells ◽  
Pluripotent Stem Cell ◽  
Three Dimensional ◽  
Experimental Models ◽  
Human Pluripotent Stem Cell ◽  
Research Areas ◽  
Technological Advances

The last decade has seen many exciting technological breakthroughs that greatly expanded the toolboxes for biological and biomedical research, yet few have had more impact than induced pluripotent stem cells and modern-day genome editing. These technologies are providing unprecedented opportunities to improve physiological relevance of experimental models, further our understanding of developmental processes, and develop novel therapies. One of the research areas that benefit greatly from these technological advances is the three-dimensional human organoid culture systems that resemble human tissues morphologically and physiologically. Here we summarize the development of human pluripotent stem cells and their differentiation through organoid formation. We further discuss how genetic modifications, genome editing in particular, were applied to answer basic biological and biomedical questions using organoid cultures of both somatic and pluripotent stem cell origins. Finally, we discuss the potential challenges of applying human pluripotent stem cell and organoid technologies for safety and efficiency evaluation of emerging genome editing tools.

scholarly journals Distinct transcriptional programs of SOX2 in different types of small cell lung cancers

2019 ◽  
Author(s):  
Yuki Tenjin ◽  
Kumi Matsuura ◽  
Shinji Kudoh ◽  
Shingo Usuki ◽  
Tatsuya Yamada ◽  
...  
Keyword(s):  
Clinical Utility ◽  
Therapeutic Potential ◽  
Hippo Pathway ◽  
Biological Marker ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Different Types ◽  
Signaling Axis ◽  
The Hippo Pathway

AbstractSOX2 is an oncogene in human small cell lung cancer (SCLC), an aggressive neuroendocrine (NE) tumor. However, the roles of SOX2 in SCLC remain unclear, and strategies to selectively target SOX2 in SCLC cells have not yet been established. We herein demonstrated that SOX2 is involved in NE differentiation and tumorigenesis in cooperation with ASCL1, a lineage-specific transcriptional factor, in the classical subtype of SCLC cell lines. ASCL1 recruits SOX2, which promotes INSM1 expression. Precursor SCLC lesions were established in Trp53 (-/-); CCSPrtTA; tetOCre; floxedRb1; floxedHes1 mice, and the NE neoplasms induced were positive for Ascl1, Sox2, and Insm1. In contrast to the ASCL1-SOX2 signaling axis to control the SCLC phenotype in classical subtype SCLC, SOX2 targeted distinct genes, such as those related to the Hippo pathway, in ASCL1-negative, variant subtype SCLC. The present results support the importance of the ASCL1-SOX2 axis as a main subtype of SCLC, and suggest the therapeutic potential of targeting the ASCL1-SOX2 signaling axis and the clinical utility of SOX2 as a biological marker in the classical subtype of SCLC.

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