Biology subjects

Mitsiadis, T.

Publications and source records attributed to Mitsiadis, T..

4 recordsLinked to original sources

bioRxiv2024

The Notch1/Delta-like-4 axis is crucial for the initiation and progression of oral squamous cell carcinoma

The Notch signaling pathway is frequently altered in Oral Squamous Cell Carcinoma (OSCC), the most common malignant neoplasm of the oral mucosa. In this study, we aimed to elucidate the functional role of this pathway in OSCC initiation and progression. Using transgenic animal models, advanced imaging, and next-generation-sequencing techniques, we analyzed Notch-dependent changes driving OSCC. We found specific expression patterns of Notch1 and Delta-like-4 confined to the malignant tissue, while Jagged1 was downregulated in OSCC. This mutually exclusive expression of Delta-like-4 and Jagged1 occurs at the early hyperplastic stage and persists until more advanced stages of the tumor. Transcriptomic analyses confirmed the dysregulation of the Notch pathway circuitry associated with a genetic signature for undifferentiation in OSCC. Furthermore, pharmacological Notch inhibition significantly impaired cancer cell motility. Taken together, these results reveal the pivotal importance of the Notch1/Delta-like-4 signaling axis as a central oncogenic driver in OSCC.

cancer biology↗

bioRxiv2023

Single-cell transcriptomics analysis reveals extracellular matrix remodelling in carious human dental pulp

The carious lesion is a bacteria caused destruction of tooth mineralized matrices marked by concurrent tissue reparative and immune responses in the dental pulp. While major molecular players in tooth pulp decay have been uncovered, a detailed map of the molecular and cellular landscape of the diseased pulp is still missing. Here we used single-cell RNA sequencing analysis, to generate a comprehensive single-cell atlas of the carious human dental pulp tissue. Our data demonstrated modifications in various cell clusters of the carious pulp, such as immune cells, mesenchymal stem cells (MSC) and fibroblasts, when compared to the healthy dental pulp. These changes include upregulation of genes encoding extracellular matrix (ECM) components and the enrichment of the fibroblast cluster with myofibroblasts. Assessment of the Fibronectin fibres mechanical strain showed a significant tension reduction in the carious human pulp, compared to the healthy one. Collectively, the present data demonstrate molecular, cellular and biomechanical alterations in the carious pulp tissue, indicative of extensive ECM remodelling and reminiscent of fibrosis observed in other organs.

cell biology↗

bioRxiv2022

Notch signaling pathway in tooth shape variations

Evolutionary changes in vertebrates are linked to genetic alterations that often affect tooth-crown shape, which is a criterion of speciation events. The Notch pathway is highly conserved between species and controls morphogenetic processes in most developing organs, including teeth. Epithelial loss of the Notch-ligand Jagged1 in developing mouse molars affects the location, size and interconnections of their cusps that lead to minor tooth-crown shape modifications convergent to those observed along Muridae evolution. These alterations are due to the modulation of numerous genes, where Notch signaling is a hub for essential morphogenetic networks. A three-dimensional metamorphosis approach allowed tooth morphology prediction in individuals carrying Jagged1 mutations. These results shed new light on Notch/Jagged1-mediated signaling as one of the crucial components for dental variations in evolution. Significance statementDental microevolution changes in vertebrates are regulated by the Notch signaling pathway.

developmental biology↗

bioRxiv2022

Nogo-A regulates the fate of human dental pulp stem cells towards osteogenic, adipogenic, and neurogenic differentiation

Human teeth are highly innervated organs that contain a variety of mesenchymal stem cell populations that could be used for cell-based regenerative therapies. Specific molecules are often used in these treatments to favorably modulate stem cells function and fate. Nogo-A, a key regulator of neuronal growth and differentiation, is already used in clinical tissue regeneration trials. While the functions of Nogo-A in neuronal tissues are extensively explored, its role in teeth still remains unknown. In this work, we first immunohistochemically analyzed the distribution of Nogo-A protein in the dental pulp of human teeth. Nogo-A is localized in a variety of cellular and structural components of the dental pulp, including odontoblasts, fibroblasts, neurons and vessels. We also cross-examined Nogo expression in the various pulp cell clusters in a single cell RNA sequencing dataset of human dental pulp, which showed high levels of expression in all cell clusters, including that of stem cells. We then assessed the role of Nogo-A on the fate of human dental pulp stem cells and their differentiation capacity in vitro. Using immunostaining, Alizarin Red S and Oil Red O staining we showed that Nogo-A delayed the differentiation of cultured dental pulp stem cells towards the osteogenic, adipogenic and neurogenic lineages, while addition of the blocking anti-Nogo-A antibody had opposite effects. These results were further confirmed by qRT-PCR, which demonstrated overexpression of genes involved in osteogenic (RUNX2, ALP, SP7/OSX), adipogenic (PPAR-{gamma}2, LPL) and neurogenic (DCX, TUBB3, NEFL) differentiation in presence of the anti-Nogo-A antibody. Conversely, the osteogenic and adipogenic genes were downregulated by Nogo-A. Taken together, our results show that the functions of Nogo-A are not restricted to neuronal cells, but are extended to other cell populations, including dental pulp stem cells. We show that Nogo-A regulates their fates towards osteogenic, adipogenic and neurogenic differentiation, thus indicating its potential use in the clinics.

cell biology↗