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Molecules and Cells Jun 2024The coordinated movement of germ layer progenitor cells reaches its peak at the dorsal side, where the Bmp signaling gradient is low, and minimum at the ventral side,...
The coordinated movement of germ layer progenitor cells reaches its peak at the dorsal side, where the Bmp signaling gradient is low, and minimum at the ventral side, where the Bmp gradient is high. This dynamic cell movement is regulated by the interplay of various signaling pathways. The noncanonical Wnt signaling cascade serves as a pivotal regulator of convergence and extension cell movement, facilitated by the activation of small GTPases such as Rho, Rab, and Rac. However, the underlying cause of limited cell movement at the ventral side remains elusive. To explore the functional role of a key regulator in constraining gastrulation cell movement at the ventral side, we investigated the Bmp4-direct target gene, sizzled (szl), to assess its potential role in inhibiting noncanonical Wnt signaling. In our current study, we demonstrated that ectopic expression of szl led to gastrulation defects in a dose-dependent manner without altering cell fate specification. Overexpression of szl resulted in decreased elongation of Activin-treated animal cap and Keller explants. Furthermore, our immunoprecipitation assay unveiled the physical interaction of Szl with noncanonical Wnt ligand proteins (Wnt5 and Wnt11). Additionally, the activation of small GTPases involved in Wnt signaling mediation (RhoA and Rac1) was diminished upon szl overexpression. In summary, our findings suggest that Bmp4 signaling negatively modulates cell movement from the ventral side of the embryo by inducing szl expression during early Xenopus gastrulation.
Topics: Animals; Gastrulation; Cell Movement; Xenopus Proteins; Xenopus laevis; Bone Morphogenetic Protein 4; Wnt Proteins; Ligands; Wnt Signaling Pathway
PubMed: 38759887
DOI: 10.1016/j.mocell.2024.100068 -
Protein & Cell May 2024Tissue formation and organ homeostasis is achieved by precise coordination of proliferation and differentiation of stem cells and progenitors. While deregulation of...
Tissue formation and organ homeostasis is achieved by precise coordination of proliferation and differentiation of stem cells and progenitors. While deregulation of these processes can result in degenerative disease or cancer, their molecular interplays remain unclear. Here we show that the switch of human pluripotent stem cell (hPSC) self-renewal to differentiation is associated with the induction of distinct cyclin dependent kinase inhibitors (CDKIs). In hPSCs, Activin/Nodal/TGFβ signalling maintains CDKIs in a poised state via SMAD2/3-NANOG-OCT4-EZH2-SNON transcriptional complex. Upon gradual differentiation, CDKIs are induced by successive transcriptional complexes between SMAD2/3-SMYD2 and developmental regulators such as EOMES, thereby lengthening the G1 phase. This, in turn, induces SMAD2/3 transcriptional activity by blocking its linker phosphorylation. Such SMAD2/3-CDKI positive feedback loops drive the exit from pluripotency and stepwise cell fate specification that could be harnessed for producing cells for therapeutic applications. Our study uncovers fundamental mechanisms how cell fate specification is interconnected to cell cycle dynamics and provides insight to autonomous circuitries governing tissue self-formation.
PubMed: 38758030
DOI: 10.1093/procel/pwae031 -
American Journal of Hematology Jul 2024
Topics: beta-Thalassemia; Humans; Recombinant Fusion Proteins; Immunoglobulin Fc Fragments; Activin Receptors, Type II
PubMed: 38752378
DOI: 10.1002/ajh.27362 -
Pediatric Nephrology (Berlin, Germany) May 2024Activin A has been shown to enhance osteoclast activity and its inhibition results in bone growth. The potential role of activin A as a marker of chronic kidney...
BACKGROUND
Activin A has been shown to enhance osteoclast activity and its inhibition results in bone growth. The potential role of activin A as a marker of chronic kidney disease-mineral bone disease (CKD-MBD) and its relationship with other markers has not been studied in children with CKD.
METHODS
A cross sectional study was conducted among 40 children aged 2 to 18 years with CKD (Stage 2 to 5; 10 in each stage) and 40 matched controls. Activin A, cathepsin K, FGF-23, PTH, serum calcium, phosphorous and alkaline phosphatase in both groups were measured and compared. The correlation of activin A and markers of CKD-MBD was studied. A p value of < 0.05 was considered significant.
RESULTS
The mean age of children with CKD was 9.30 ± 3.64 years. Mean levels of activin A in cases were 485.55 pg/ml compared to 76.19 pg/ml in controls (p < 0.001). FGF-23 levels in cases were 133.18 pg/ml while in controls it was 6.93 pg/ml (p < 0.001). Mean levels of cathepsin K were also significantly higher in cases as compared to controls. There was a progressive increase in activin A and cathepsin K levels with increasing stage of CKD. Activin A had a significant positive correlation with serum creatinine (r = 0.51; p < 0.001).
CONCLUSIONS
Activin A levels progressively rise with advancing CKD stage. These findings suggest that activin A can be a potential early marker of CKD-MBD in children.
PubMed: 38744714
DOI: 10.1007/s00467-024-06400-x -
International Journal of Biological... Jun 2024Colorectal cancer (CRC) is a major worldwide health issue, with high rates of both occurrence and mortality. Dysregulation of the transforming growth factor-beta...
Colorectal cancer (CRC) is a major worldwide health issue, with high rates of both occurrence and mortality. Dysregulation of the transforming growth factor-beta (TGF-β) signaling pathway is recognized as a pivotal factor in CRC pathogenesis. Notably, the INHBA gene and long non-coding RNAs (lncRNAs) have emerged as key contributors to CRC progression. The aim of this research is to explore the immunological roles of INHBA and PELATON in CRC through a combination of computational predictions and experimental validations, with the goal of enhancing diagnostic and therapeutic strategies. In this study, we utilized bioinformatics analyses, which involved examining differential gene expression (DEG) in the TCGA-COAD dataset and exploring the INHBA gene in relation to the TGF-β pathway. Additionally, we analyzed mutations of INHBA, evaluated the microenvironment and tumor purity, investigated the INHBA's connection to immune checkpoint inhibitors, and measured its potential as an immunotherapy target using the TIDE score. Utilizing bioinformatics analyses of the TCGA-COAD dataset beside experimental methodologies such as RT-qPCR, our investigation revealed significant upregulation of INHBA in CRC. As results, our analysis of the protein-protein interaction network associated with INHBA showed 10 interacting proteins that play a role in CRC-associated processes. We observed a notable prevalence of mutations within INHBA and explored its correlation with the response to immune checkpoint inhibitors. Our study highlights INHBA as a promising target for immunotherapy in CRC. Moreover, our study identified PELATON as a closely correlated lncRNA with INHBA, with experimental validation confirming their concurrent upregulation in CRC tissues. Thus, these findings highlight the importance of INHBA and PELATON in driving CRC progression, suggesting their potential utility as diagnostic and prognostic biomarkers. By integrating computational predictions with experimental validations, this research enhances our understanding of CRC pathogenesis and uncovers prospects for personalized therapeutic interventions.
Topics: Colorectal Neoplasms; Humans; Computational Biology; Gene Expression Regulation, Neoplastic; Transforming Growth Factor beta; Protein Interaction Maps; Signal Transduction; Inhibin-beta Subunits; RNA, Long Noncoding; Tumor Microenvironment; Mutation; Biomarkers, Tumor
PubMed: 38735606
DOI: 10.1016/j.ijbiomac.2024.132239 -
Cells May 2024During the secretory phase of the menstrual cycle, endometrial fibroblast cells begin to change into large epithelial-like cells called decidual cells in a process...
During the secretory phase of the menstrual cycle, endometrial fibroblast cells begin to change into large epithelial-like cells called decidual cells in a process called decidualization. This differentiation continues more broadly in the endometrium and forms the decidual tissue during early pregnancy. The cells undergoing decidualization as well as the resulting decidual cells, support successful implantation and placentation during early pregnancy. This study was carried out to identify new potentially important long non-coding RNA (lncRNA) genes that may play a role in human endometrial stromal fibroblast cells (hESF) undergoing decidualization in vitro, and several were found. The expression of nine was further characterized. One of these, , showed a dramatic increase in the expression of hESF cells undergoing decidualization. When expression was targeted, the ability of the cells to undergo decidualization as determined by the expression of decidualization marker protein-coding genes was significantly altered. The most affected markers of decidualization whose expression was significantly reduced were , , and . Therefore, may be a major upstream regulator of the WNT-FOXO1 pathway and activin-SMAD3 pathways previously shown as critical for hESF decidualization. Finally, we explored possible regulators of expression during human ESF decidualization. Expression was regulated by cAMP and progesterone. Our results suggest that plays a role in hESF decidualization and identifies several other lncRNA genes that may also play a role.
Topics: Humans; Female; RNA, Long Noncoding; Fibroblasts; Decidua; Endometrium; Stromal Cells; Forkhead Box Protein O1; Pregnancy; Adult; Cell Differentiation
PubMed: 38727314
DOI: 10.3390/cells13090778 -
Cells Apr 2024Natural killer (NK) cells can migrate quickly to the tumor site to exert cytotoxic effects on tumors, and some chemokines, including CXCL8, CXCL10 or and CXCL12, can...
Natural killer (NK) cells can migrate quickly to the tumor site to exert cytotoxic effects on tumors, and some chemokines, including CXCL8, CXCL10 or and CXCL12, can regulate the migration of NK cells. Activin A, a member of the transforming growth factor β (TGF-β) superfamily, is highly expressed in tumor tissues and involved in tumor development and immune cell activation. In this study, we focus on the effects of activin A on NK cell migration. In vitro, activin A induced NK cell migration and invasion, promoted cell polarization and inhibited cell adhesion. Moreover, activin A increased Ca, p-SMAD3 and p-AKT levels in NK cells. An AKT inhibitor and Ca chelator partially blocked activin A-induced NK cell migration. In vivo, exogenous activin A increased tumor-infiltrating NK cells in NS-1 cell solid tumors and inhibited tumor growth, and blocking endogenous activin A with anti-activin A antibody reduced tumor-infiltrating NK cells in 4T-1 cell solid tumors. These results suggest that activin A induces NK cell migration through AKT signaling and calcium signaling and may enhance the antitumor effect of NK cells by increasing tumor-infiltrating NK cells.
Topics: Animals; Mice; Activins; Calcium Signaling; Cell Line, Tumor; Cell Movement; Killer Cells, Natural; Mice, Inbred C57BL; Proto-Oncogene Proteins c-akt
PubMed: 38727264
DOI: 10.3390/cells13090728 -
Journal of Periodontal & Implant Science Apr 2024A combination of activin and bone morphogenetic protein-2 (BMP-2), termed AB204, has been shown to improve osteogenic potential with fewer side effects than BMP-2 alone....
PURPOSE
A combination of activin and bone morphogenetic protein-2 (BMP-2), termed AB204, has been shown to improve osteogenic potential with fewer side effects than BMP-2 alone. This study was performed to evaluate the effect of AB204 on periodontal tissue regeneration in a dog buccal dehiscence model.
METHODS
Buccal dehiscence defects were created on the maxillary premolars (P1, P2, and P3) of 6 mongrel dogs. After 5 weeks, the dogs were randomly assigned to 1 of 3 groups: the control, collagen matrix (CM), and CM/AB204 groups. Grafting procedures were then performed. The dogs were sacrificed 8 weeks after the grafting procedure, and volumetric and histological analyses were conducted.
RESULTS
The thickness of the buccal gingiva in the CM/AB204 group was greater than those in the other groups at 2 weeks (<0.05). The ridge width in the AB204/CM group exceeded the width in the other groups at 4 and 8 weeks; however, the difference was not statistically significant. Histological analysis revealed that the CM/AB204 group demonstrated the formation of new bone surrounded by newly formed periodontal ligament and cementum (=0.035).
CONCLUSIONS
The combined application of CM and AB204 shows promise in facilitating the regeneration of periodontal attachment, including the formation of new bone, cementum, and periodontal ligament.
PubMed: 38725427
DOI: 10.5051/jpis.2303600180 -
Journal of Periodontal & Implant Science Feb 2024Collagen has long been recognized as an excellent carrier for growth factors, and membrane-type collagen has been widely applied in dentistry for guided bone...
PURPOSE
Collagen has long been recognized as an excellent carrier for growth factors, and membrane-type collagen has been widely applied in dentistry for guided bone regeneration. This study was conducted to examine the effects of an activin A/BMP2 chimera (AB204) combined with a collagen membrane (CM) on bone repair in a rat calvarial defect model.
METHODS
A unilateral calvarial defect measuring 5.0 mm was surgically created in 32 Sprague-Dawley rats. The rats were then randomly assigned to 1 of 4 groups, each consisting of 8 animals: control (untreated), CM (treated with a CM only), CM/bone morphogenetic protein 2 (BMP2) (treated with a CM and 1.0 μg of BMP2), and CM/AB204 (treated with a CM and 1.0 μg of AB204). Bone regeneration was evaluated using micro-computed tomography (CT) and histological analysis at 2 and 4 weeks following surgery.
RESULTS
Micro-CT analysis revealed that bone formation in the CM/BMP2 and CM/AB204 groups was superior to that observed in the control and CM groups at both 2 and 4 weeks postoperatively. BMP2 induced greater bone regeneration than AB204 at 2 weeks; however, AB204 resulted in a greater bone volume at 4 weeks, achieving the highest values recorded. No significant differences were found between the CM/BMP2 and CM/AB204 groups at either time point (>0.05). On histological examination, new bone formation was evident in both CM/BMP2 and CM/AB204 groups.
CONCLUSIONS
Within the limitations of this study, the findings indicate that AB204 may enhance osteogenic potential when used in combination with CM for bone regeneration.
PubMed: 38725424
DOI: 10.5051/jpis.2303820191 -
Inflammation and Regeneration May 2024Cancer tissues contain a wide variety of immune cells that play critical roles in suppressing or promoting tumor progression. Macrophages are one of the most predominant... (Review)
Review
BACKGROUND
Cancer tissues contain a wide variety of immune cells that play critical roles in suppressing or promoting tumor progression. Macrophages are one of the most predominant populations in the tumor microenvironment and are composed of two classes: infiltrating macrophages from the bone marrow and tissue-resident macrophages (TRMs). This review aimed to outline the function of TRMs in the tumor microenvironment, focusing on lung cancer.
REVIEW
Although the functions of infiltrating macrophages and tumor-associated macrophages have been intensively analyzed, a comprehensive understanding of TRM function in cancer is relatively insufficient because it differs depending on the tissue and organ. Alveolar macrophages (AMs), one of the most important TRMs in the lungs, are replenished in situ, independent of hematopoietic stem cells in the bone marrow, and are abundant in lung cancer tissue. Recently, we reported that AMs support cancer cell proliferation and contribute to unfavorable outcomes.
CONCLUSION
In this review, we introduce the functions of AMs in lung cancer and their underlying molecular mechanisms. A thorough understanding of the functions of AMs in lung cancer will lead to improved treatment outcomes.
PubMed: 38720352
DOI: 10.1186/s41232-024-00335-4