In dit proefschrift begin ik met een algemene inleiding in Hoofdstuk 1 om kort de relevantie van EC-gedrag in vasculaire morfogenese en in angiogenese te presenteren. Bovendien bespreek ik hoe de... Show moreIn dit proefschrift begin ik met een algemene inleiding in Hoofdstuk 1 om kort de relevantie van EC-gedrag in vasculaire morfogenese en in angiogenese te presenteren. Bovendien bespreek ik hoe de EC-functie ingewikkeld wordt gereguleerd door positieve en negatieve factoren, en hoe hun functie kan worden gemanipuleerd voor therapeutische winst bij kanker en hart- en vaatziekten. In Hoofdstuk 2 bespreken we in detail de rol van de TGF-β-signaleringsroute in EndMT en bespreken we de bijdrage van dit proces aan de ontwikkeling van ziekten, evenals de mogelijke toepassingen ervan in weefselmanipulatie. In Hoofdstuk 3 onthullen we gedetailleerde werkprotocollen om TGF-β-geïnduceerde EndMT te onderzoeken en hoe de betrokkenheid van EndMT-effectoren te beoordelen met behulp van CRISPR/Cas9-genediting. In Hoofdstuk 4 hebben we de functie van EndMT transcriptiefactoren onderzocht en hun werkingsmechanisme opgehelderd. We ontdekten dat de EndMT-transcriptiefactoren (TF's) SNAIL en SLUG cruciaal zijn voor EndMT in endotheelcellen van muizen en dat de ID-eiwitten hun functie in EndMT compenseren. In Hoofdstuk 5 geven we een technisch overzicht van embryonale zebravis-xenotransplantaattesten om TGF-β-familiesignalering in de progressie van borstkanker bij de mens te onderzoeken, waaronder intravasatie/extravasatie van tumorcellen en tumorangiogenese. In Hoofdstuk 6 identificeren en onderzoeken we twee nieuwe BMP type I receptor macrocyclische kinaseremmers met therapeutisch potentieel om angiogenese in normale en tumorvatvorming bij zebravissen te normaliseren. In Hoofdstuk 7 vat ik alle studies in het proefschrift samen en geef ik enkele toekomstperspectieven met betrekking tot onze resultaten. Show less
Addante, A.; Roncero, C.; Lazcanoiturburu, N.; Mendez, R.; Almale, L.; Garcia-Alvaro, M.; ... ; Sanchez, A. 2020
During chronic liver disease, hepatic progenitor cells (HPC, oval cells in rodents) become activated, proliferate, and differentiate into cholangiocytes and/or hepatocytes contributing to the final... Show moreDuring chronic liver disease, hepatic progenitor cells (HPC, oval cells in rodents) become activated, proliferate, and differentiate into cholangiocytes and/or hepatocytes contributing to the final outcome of the regenerative process in a context-dependent fashion. Here, we analyze the crosstalk between the hepatocyte growth factor (HGF)/c-Met signaling axis, key for liver regeneration, and bone morphogenetic protein (BMP)9, a BMP family ligand that has emerged as a critical regulator of liver pathology. Our results show that HGF/c-Met signaling blocks BMP9-mediated apoptotic cell death, while it potentiates small mothers against decapentaplegic (SMAD)1 signaling triggered by BMP9 in oval cells. Interestingly, HGF-induced overactivation of SMAD1, -5, -8 requires the upregulation of TGF-beta type receptor activin receptor-like kinase (ALK)1, and both ALK1 and SMAD1 are required for the counteracting effect of HGF on BMP9 apoptotic activity. On the other hand, we also prove that BMP9 triggers the activation of p38MAPK in oval cells, which drives BMP9-apoptotic cell death. Therefore, our data support a model in which BMP9 and HGF/c-Met signaling axes establish a signaling crosstalk via ALK1 that modulates the balance between the two pathways with opposing activities, SMAD1 (pro-survival) and p38 mitogen-activated protein kinases (p38MAPK; pro-apoptotic), which determines oval cell fate. These data help delineate the complex signaling network established during chronic liver injury and its impact on the oval cell regenerative response. Show less
Endoglin, a type-III accessory receptor for the Transforming Growth Factor (TGF)-beta superfamily pathway, is known for its crucial role during angiogenesis. Extensive work has shown the important... Show moreEndoglin, a type-III accessory receptor for the Transforming Growth Factor (TGF)-beta superfamily pathway, is known for its crucial role during angiogenesis. Extensive work has shown the important roles that endoglin plays in balancing the TGF-beta signaling pathway, thereby regulating endothelial cell proliferation and migration. However, recent work indicates a far more widespread role for endoglin beyond the endothelial cells. In this review, we will provide a summary of recent publications on endoglin expression on epithelial (cancer) cells, cancer-associated fibroblasts, and mesenchymal stem cells. Additionally, we will discuss the role of endoglin in innate and adaptive immunity. Finally, we will discuss the results of clinical trials using the endoglin targeting antibody (TRC105), focusing on the effects observed beyond the endothelium. In conclusion, although endoglin was initially identified as an endothelial marker, additional roles for endoglin on other cell types have been shown, although the number of studies is still limited, with sometimes conflicting data. Future studies will further establish the roles of endoglin beyond the endothelium. Show less
Lawera, A.; Tong, Z.; Thorikay, M.; Redgrave, R.E.; Cai, J.; Dinther, M. van; ... ; Li, W. 2019
