Coordinated Proliferation and Differentiation of Human-Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Depend on Bone Morphogenetic Protein Signaling Regulation by GREMLIN 2

Bylund, Jeffery B.; Trinh, Linh T.; Awgulewitsch, Cassandra P.; Paik, David T.; Jetter, Christopher S.; Jha, Rajneesh; Zhang, Jianhua; Nolan, Kristof; Xu, Chunhui; Thompson, Thomas B.; Kamp, Timothy J.; Hatzopoulos, Antonis K.

doi:10.1089/scd.2016.0226

Cited by 19 publications

(19 citation statements)

References 52 publications

(74 reference statements)

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“…In addition, the overexpression of interleukin (IL)-33 could potentially result in the acceleration of platinum-induced apoptosis and prohibit the invasion of GC cells through the suppression of the JNK signaling pathway, as indicated by a previously conducted study [17]. Another study demonstrated that GEM2 could lead to the inhibition of canonical BMP signaling, which then accelerated the proliferation of cardiac progenitor cells through the indirect induction of differentiation via the JNK signaling pathway [18]. In the present study, we investigate the role and underlying mechanism of GREM2 in GC development with the objective of providing a new and effective therapeutic strategy for GC.…”

Section: Introductionmentioning

confidence: 98%

RETRACTED ARTICLE: GREM2 maintains stem cell-like phenotypes in gastric cancer cells by regulating the JNK signaling pathway

Lin

Wang

et al. 2019

Cell Cycle

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Gastric cancer (GC) is one of the major malignancies worldwide. This study was conducted to explore the mechanism by which GREM2 maintains biological properties of GC stem cells (GCSCs), and proved that GREM2 could potentially regulate the proliferation, apoptosis, invasion, migration and tumorigenic ability of GCSCs through the regulation of the JNK signaling pathway. In silico analysis was utilized to retrieve expression microarray related to GC, and differential analysis was conducted. The cell line with the highest GREM2 expression was overexpressed with GREM2 mimic, silencing GREM2 by siRNA, or treated with activator or inhibitor of the JNK signaling pathway. Subsequently, expression of GREM2, JNK signaling pathway-, apoptosis-or migration and invasion-associated factors were determined. Proliferation, migration, invasion, apoptosis of GCSCs in vitro and tumorigenic ability and lymph node metastasis of GCSCs in vivo were determined. Based on the in silico analysis of GSE49051, GREM2 was determined to be overexpressed in GC and its expression was the highest in the MKN-45 cell line, which was selected for the subsequent experiments. Silencing of GREM2 or inhibition of the JNK signaling pathway suppressed the proliferation, migration and invasion, while promoting apoptosis of GCSCs in vitro as well as inhibiting tumorigenesis and lymph node metastasis in vivo. In conclusion, the aforementioned findings suggest that the silencing of GREM2 suppresses the activation of the JNK signaling pathway, thereby inhibiting tumor progression. Therefore, GREM2-mediated JNK signaling pathway was expected to be a new therapeutic strategy for GC.

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Section: Introductionmentioning

confidence: 98%

RETRACTED ARTICLE: GREM2 maintains stem cell-like phenotypes in gastric cancer cells by regulating the JNK signaling pathway

Lin

Wang

et al. 2019

Cell Cycle

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“…Several studies have demonstrated that gremlin exerts its biological effects by activating TGF-β/ Smad, AKT, ERK and other signaling pathways [16,31]. Our previous studies demonstrated that gremlin could dose-dependently activate the Smad2/3 signaling pathway.…”

Section: The Roles Of Akt Erk and Smad2/3 Signaling Pathways In The mentioning

confidence: 91%

Gremlin is a potential target for posterior capsular opacification

Jing

Liu

et al. 2019

Cell Cycle

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Objective: The present study was conducted to determine the role of gremlin during the development of posterior capsular opacification (PCO) via in vitro and in vivo experiments. Methods: The activation, roles and relationships of the BMPs/Smad1/5, MAPK, FAK and AKT signaling pathways in human lens epithelial cells (HLECs) after gremlin induction were detected by western blotting and real-time PCR. Wound-healing, transwell, capsular bag models and rat PCO models assays were used to test the effects of gremlin on HLECs' migration, proliferation, EMT-specific protein α-smooth muscle actin(α-SMA)and development of PCO in rats. Results: Our data showed that knockdown of the gremlin inhibited the development of PCO and reduced expression of α-SMA in rats. While gremlin did not alter the migration of HLECs, it increased the expression of pERK and p-AKT. Knockout of Smad2 or Smad3 inhibited the expression of pERK and p-AKT proteins induced by gremlin. Gremlin also reduced BMP4induced expression of the p-Smad1/5 protein. Finally, knockout of Smad1/5 increased gremlininduced expression of α-SMA, fibronectin and type I collagen (COL-1) in HLECs. Conclusion: These results suggested that gremlin contributed to the development of PCO by promoting LEC proliferation, activation of TGF-β/Smad, ERK and AKT signaling and inhibition of BMPs/Smad1/5 signaling. Furthermore, inhibiting gremlin effectively impaired both PCO development in rats and EMT in the lens capsule. Thus, our data suggest that gremlin might be a potential target for PCO.

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“…Among them, Nkx2.5 and Gata4 were tightly associated with cardiogenic differentiation [38]. Gli2 [39], Grem2 [40], E2f7 [41], Nr2f2 [42] and Shox2 [43] are also related to stem cell biology. Interestingly, SETD4 KO significantly changed the transcript of these genes.…”

Section: Discussionmentioning

confidence: 99%

SET domain-containing protein 4: biological functions and role in genomic methylation profiles of bone marrow mesenchymal stem cells

Liao

Shao

et al. 2020

Preprint

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Background: Epigenetic modification is a crucial mechanism affecting the biological function of stem cells. SETD4 is a histone methyltransferase, and its biological role in bone marrow mesenchymal stem cells (BMSCs) is currently unknown. This work was aimed to reveal the SETD4 biological role as well as its impacts on the genomic methylation profiles in BMSCs. Methods: BMSCs were isolated form SETD4 knockout (KO) and wild type (WT) mice that established by CRISPR/Cas9 technology. The cell proliferation, migration, myogenic differentiation and angiogenesis were tested according to appropriate biology techniques. And the Reduced Representation Bisulfite Sequencing (RRBS) method was adopted to analyze the global genomic methylation profiles of BMSCs, following bioinformatics analysis of GO functions and KEGG signaling of differential methylated CpG sites and differential methylation regions (DMRs). Finally, validation experiments were conducted to examine the expression of histone lysine methyltransferase and some representative genes. Results: SETD4 KO significantly promoted BMSCs proliferation, which was characterized by enhanced cell viability and increased expression of PCNA, Cyclin A2, Cyclin E1, CDK2, CDK6, Bcl2 and decreased the expression of P16, P21 and Caspase3. SETD4 deficiency impaired BMSCs migration and myogenic differentiation potentials, and even the angiogenesis via paracrine of VEGF. Compared with WT control, the overall genomic methylation of BMSCs in the SETD4 KO group only was decreased by 0.47%. However, the changed genomic methylation covers a total of 96,331 differential methylated CpG sites and 8692 DMR, with part of them settled in promoter regions. GO and KEGG analysis revealed that differential CpG islands and DMRs in promotes impacted 270 GO functions and 34 KEGG signaling pathways, with some closely related to stem cell biology. SETD4 KO inhibited sets of monomethylases and dimethylases for histone lysine, along with significant changes in some factors including Nkx2.5, Gata4, Gli2, Grem2, E2f7, Map7, Nr2f2 and Shox2 that associated with stem cell biology. Conclusions: These results are the first to reveal that even though SETD4 changes the genome’s overall methylation to a limited extent in BMSCs, it still affects the numerous cellular functions and signaling pathways, implying SETD4-altered genomic methylation serves a crucial molecular role in BMSCs’ biological functions.

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Coordinated Proliferation and Differentiation of Human-Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Depend on Bone Morphogenetic Protein Signaling Regulation by GREMLIN 2

Cited by 19 publications

References 52 publications

RETRACTED ARTICLE: GREM2 maintains stem cell-like phenotypes in gastric cancer cells by regulating the JNK signaling pathway

RETRACTED ARTICLE: GREM2 maintains stem cell-like phenotypes in gastric cancer cells by regulating the JNK signaling pathway

Gremlin is a potential target for posterior capsular opacification

SET domain-containing protein 4: biological functions and role in genomic methylation profiles of bone marrow mesenchymal stem cells

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