scholarly journals Bidirectional Wnt signaling between endoderm and mesoderm confer tracheal identity in mouse and human

2019 ◽  
Author(s):  
Keishi Kishimoto ◽  
Kana T. Furukawa ◽  
Agustin Luz Madrigal ◽  
Akira Yamaoka ◽  
Chisa Matsuoka ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Wnt Signaling ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Bmp Signaling ◽  
Lateral Plate ◽  
Tracheal Tissue ◽  
Canonical Wnt ◽  
Human And Mouse

AbstractThe periodic cartilage and smooth muscle structures in mammalian trachea are derived from tracheal mesoderm, and tracheal malformations result in serious respiratory defects in neonates. Here we show that canonical Wnt signaling in mesoderm is critical to confer trachea mesenchymal identity in human and mouse. Loss of β-catenin in fetal mouse mesoderm caused loss of Tbx4+ tracheal mesoderm and tracheal cartilage agenesis. The Tbx4 expression relied on endodermal Wnt activity and its downstream Wnt ligand but independent of known Nkx2.1-mediated respiratory development, suggesting that bidirectional Wnt signaling between endoderm and mesoderm promotes trachea development. Repopulating in vivo model, activating Wnt, Bmp signaling in mouse embryonic stem cell (ESC)-derived lateral plate mesoderm (LPM) generated tracheal mesoderm containing chondrocytes and smooth muscle cells. For human ESC-derived LPM, SHH activation was required along with Wnt to generate proper tracheal mesoderm. Together, these findings may contribute to developing applications for human tracheal tissue repair.

Abstract 1457: IGFBP-4-Mediated Wnt Inhibition is Required for Cardiac Myogenesis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Weidong Zhu ◽  
Ichiro Shiojima ◽  
Li Zhi ◽  
Hiroyuki Ikeda ◽  
Masashi Yoshida ◽  
...  
Keyword(s):  
Growth Factor ◽  
Wnt Signaling ◽  
Heart Diseases ◽  
Es Cells ◽  
Embryonic Stem ◽  
Cardiomyocyte Differentiation ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt

Insulin-like growth factor-binding proteins (IGFBPs) bind to and modulate the actions of insulin-like growth factors (IGFs). Although some of the effects of IGFBPs appear to be independent of IGFs, the precise mechanisms of IGF-independent actions of IGFBPs are largely unknown. In this study we demonstrate that IGFBP-4 is a novel cardiogenic growth factor. IGFBP-4 enhanced cardiomyocyte differentiation of P19CL6 embryonal carcinoma cells and embryonic stem (ES) cells in vitro. Conversely, siRNA-mediated knockdown of IGFBP-4 in P19CL6 cells or ES cells attenuated cardiomyocyte differentiation, and morpholino-mediated knockdown of IGFBP-4 in Xenopus embryos resulted in severe cardiac defects and complete absence of the heart in extreme cases. We also demonstrate that the cardiogenic effect of IGFBP-4 was independent of its IGF-binding activity but was mediated by the inhibitory effect on canonical Wnt signaling. IGFBP-4 physically interacted with a Wnt receptor Frizzled 8 (Frz8) and a Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6), and inhibited the binding of Wnt3A to Frz8 and LRP6. Moreover, the cardiogenic defects induced by IGFBP-4 knockdown both in vitro and in vivo was rescued by simultaneous inhibition of canonical Wnt signaling. Thus, IGFBP-4 is an inhibitor of the canonical Wnt signaling, and Wnt inhibition by IGFBP-4 is required for cardiogenesis. The present study provides a molecular link between IGF signaling and Wnt signaling, and suggests that IGFBP-4 may be a novel therapeutic target for heart diseases.

scholarly journals Neural crest stem cell maintenance by combinatorial Wnt and BMP signaling

2005 ◽  
Vol 169 (2) ◽  
pp. 309-320 ◽  
Author(s):  
Maurice Kléber ◽  
Hye-Youn Lee ◽  
Heiko Wurdak ◽  
Johanna Buchstaller ◽  
Martin M. Riccomagno ◽  
...  
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Neural Crest ◽  
Bmp Signaling ◽  
Neural Crest Stem Cells ◽  
Stem Cell Maintenance ◽  
Intrinsic Cues ◽  
Sensory Neurogenesis ◽  
Canonical Wnt

Canonical Wnt signaling instructively promotes sensory neurogenesis in early neural crest stem cells (eNCSCs) (Lee, H.Y., M. Kléber, L. Hari, V. Brault, U. Suter, M.M. Taketo, R. Kemler, and L. Sommer. 2004. Science. 303:1020–1023). However, during normal development Wnt signaling induces a sensory fate only in a subpopulation of eNCSCs while other cells maintain their stem cell features, despite the presence of Wnt activity. Hence, factors counteracting Wnt signaling must exist. Here, we show that bone morphogenic protein (BMP) signaling antagonizes the sensory fate-inducing activity of Wnt/β-catenin. Intriguingly, Wnt and BMP act synergistically to suppress differentiation and to maintain NCSC marker expression and multipotency. Similar to NCSCs in vivo, NCSCs maintained in culture alter their responsiveness to instructive growth factors with time. Thus, stem cell development is regulated by combinatorial growth factor activities that interact with changing cell-intrinsic cues.

scholarly journals Sclerostin Small Molecule Inhibitors Promote Osteogenesis by Activating Canonical Wnt and BMP Pathways

2021 ◽  
Author(s):  
Sreedhara Sangadala ◽  
Chi Heon Kim ◽  
Lorenzo M Fernandes ◽  
Pooja Makkara ◽  
Scott D Boden ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Bone Graft ◽  
Spinal Fusion ◽  
De Novo ◽  
Spine Fusion ◽  
Bmp Signaling ◽  
Canonical Wnt Signaling ◽  
Posterolateral Spine Fusion ◽  
Canonical Wnt

Background: The healing environment within the posterolateral lumbar spine is one of the most clinically challenging bone healing environments in all of orthopaedics due to a lack of a contained space and the need to form de novo bone in a nonbony environment. Our group has previously published data that suggests that sclerostin in expressed locally at high levels throughout the process of a spinal fusion mass maturing. Methods: We computationally identified multiple FDA approved drugs, as well as a novel drug, for their ability to disrupt the interaction between sclerostin and its receptor, LRP5/6. The drugs were tested in several in vitro biochemical assays using murine MC3T3 and MSCs, assessing their ability to (1) enhance canonical Wnt signaling, (2) promote the accumulation of the active (non-phosphorylated) form of B-catenin, and (3) enhance the intensity and signaling duration of BMP signaling. These drugs were then tested subcutaneously in rats as standalone osteoinductive agents on plain collagen sponges. Finally, the top drug candidates (called VA1 and C07) were tested in a rabbit posterolateral spine fusion model for their ability to achieve a successful fusion. Results: We show that by controlling GSK3b phosphorylation, these SMIs simultaneously enhance canonical Wnt signaling and potentiate canonical BMP signaling intensity and duration. We also demonstrate that the SMIs produce dose-dependent ectopic mineralization in vivo in rats as well as significantly increase posterolateral spine fusion rates in rabbits in vivo, both as standalone osteogenic drugs and in combination with autologous iliac crest bone graft. Conclusions: Few if any osteogenic small molecules have been described that possess the osteoinductive potency of BMP itself - that is, the ability to form de novo ectopic bone as a standalone agent, particularly in stringent in vivo environments. Herein, we describe two such SMIs that have this unique ability and thus may have potential application as novel cost-effective biologic bone graft substitutes for achieving consistent spinal fusion or even or critical-sized fracture defects.

BMP4 and WNT signaling interact to promote mouse tracheal mesenchyme morphogenesis

2021 ◽  
Author(s):  
Natalia Bottasso Arias ◽  
Lauren Leesman ◽  
Kaulini Burra ◽  
John Snowball ◽  
Ronak M Shah ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Wnt Signaling ◽  
Rna Sequencing ◽  
Muscle Development ◽  
Target Genes ◽  
Bmp Signaling ◽  
Embryonic Mouse ◽  
Tracheal Cartilage ◽  
Cartilage Formation

Tracheobronchomalacia and Complete Tracheal Rings are congenital malformations of the trachea associated with morbidity and mortality for which the etiology remains poorly understood. Epithelial expression of Wls (a cargo receptor mediating Wnt ligand secretion) by tracheal cells is essential for patterning the embryonic mouse trachea's cartilage and muscle. RNA sequencing indicated that Wls differentially modulated the expression of BMP signaling molecules. We tested whether BMP signaling, induced by epithelial Wnt ligands, mediates cartilage formation. Deletion of Bmp4 from respiratory tract mesenchyme impaired tracheal cartilage formation that was replaced by ectopic smooth muscle, recapitulating the phenotype observed after epithelial deletion of Wls in the embryonic trachea. Ectopic muscle was caused in part by anomalous differentiation and proliferation of smooth muscle progenitors rather than tracheal cartilage progenitors. Mesenchymal deletion of Bmp4 impaired expression of Wnt/β-catenin target genes, including targets of WNTsignaling: Notum, and Axin2. In vitro, rBMP4 rescued the expression of Notum in Bmp4 deficient tracheal mesenchymal cells and induced Notum promoter activity via SMAD1/5. RNA sequencing of Bmp4 deficient tracheas identified genes essential for chondrogenesis and muscle development co-regulated by BMP and WNT signaling. During tracheal morphogenesis, WNT signaling induces Bmp4 in mesenchymal progenitors to promote cartilage differentiation and restrict trachealis muscle. In turn, Bmp4 differentially regulates the expression of Wnt/β-catenin targets to attenuate mesenchymal WNT signaling and to further support chondrogenesis.

scholarly journals Dickkopf Wnt signaling pathway inhibitor 1 regulates the differentiation of mouse embryonic stem cells in vitro and in vivo

2015 ◽  
Vol 13 (1) ◽  
pp. 720-730 ◽  
Author(s):  
LIPING OU ◽  
LIAOQIONG FANG ◽  
HEJING TANG ◽  
HAI QIAO ◽  
XIAOMEI ZHANG ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Wnt Signaling ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cells

scholarly journals TCam-2 Cells Deficient for SOX2 and FOXA2 Are Blocked in Differentiation and Maintain a Seminoma-Like Cell Fate In Vivo

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 728 ◽  
Author(s):  
Daniel Nettersheim ◽  
Saskia Vadder ◽  
Sina Jostes ◽  
Alena Heimsoeth ◽  
Hubert Schorle
Keyword(s):  
Cell Fate ◽  
Primordial Germ Cells ◽  
Germ Cell Tumors ◽  
Embryonic Stem ◽  
Bmp Signaling ◽  
Stem Cell Population ◽  
Testicular Germ Cell ◽  
Key Factor ◽  
Pioneer Factor

Testicular germ cell tumors (GCTs) are very common in young men and can be stratified into seminomas and non-seminomas. While seminomas share a similar gene expression and epigenetic profile with primordial germ cells, the stem cell population of the non-seminomas, the embryonal carcinoma (EC), resembles malignant embryonic stem cells. Thus, ECs are able to differentiate into cells of all three germ layers (teratomas) and even extra-embryonic-tissue-like cells (yolk-sac tumor, choriocarcinoma). In the last years, we demonstrated that the cellular microenvironment considerably influences the plasticity of seminomas (TCam-2 cells). Upon a microenvironment-triggered inhibition of the BMP signaling pathway in vivo (murine flank or brain), seminomatous TCam-2 cells reprogram to an EC-like cell fate. We identified SOX2 as a key factor activated upon BMP inhibition mediating the reprogramming process by regulating pluripotency, reprogramming and epigenetic factors. Indeed, CRISPR/Cas9 SOX2-deleted TCam-2 cells were able to maintain a seminoma-cell fate in vivo for about six weeks, but after six weeks in vivo still small sub-populations initiated differentiation. Closer analyses of these differentiated clusters suggested that the pioneer factor FOXA2 might be the driving force behind this induction of differentiation, since many FOXA2 interacting genes and differentiation factors like AFP, EOMES, CDX1, ALB, HAND1, DKK, DLK1, MSX1 and PITX2 were upregulated. In this study, we generated TCam-2 cells double-deficient for SOX2 and FOXA2 using the CRISPR/Cas9 technique and xenografted those cells into the flank of nude mice. Upon loss of SOX2 and FOXA2, TCam-2 maintained a seminoma cell fate for at least twelve weeks, demonstrating that both factors are key players in the reprogramming to an EC-like cell fate. Therefore, our study adds an important piece to the puzzle of GCT development and plasticity, providing interesting insights in what can be expected in a patient, when GCT cells are confronted with different microenvironments.

scholarly journals Mouse embryo geometry drives formation of robust signaling gradients through receptor localization

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Zhechun Zhang ◽  
Steven Zwick ◽  
Ethan Loew ◽  
Joshua S. Grimley ◽  
Sharad Ramanathan
Keyword(s):  
Cell Fate ◽  
Mouse Embryo ◽  
Basolateral Membrane ◽  
Embryonic Stem ◽  
Bmp Signaling ◽  
Receptor Localization ◽  
Bmp Receptors ◽  
Early Mouse

Abstract Morphogen signals are essential for cell fate specification during embryogenesis. Some receptors that sense these morphogens are known to localize to only the apical or basolateral membrane of polarized cell lines in vitro. How such localization affects morphogen sensing and patterning in the developing embryo remains unknown. Here, we show that the formation of a robust BMP signaling gradient in the early mouse embryo depends on the restricted, basolateral localization of BMP receptors. The mis-localization of receptors to the apical membrane results in ectopic BMP signaling in the mouse epiblast in vivo. With evidence from mathematical modeling, human embryonic stem cells in vitro, and mouse embryos in vivo, we find that the geometric compartmentalization of BMP receptors and ligands creates a signaling gradient that is buffered against fluctuations. Our results demonstrate the importance of receptor localization and embryo geometry in shaping morphogen signaling during embryogenesis.

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