The Notch1 signaling pathway directly modulates the human RANKL-induced osteoclastogenesis

Notch signaling is an evolutionary conserved pathway with a key role in tissue homeostasis, differentiation and proliferation. It was reported that Notch1 receptor negatively regulates mouse osteoclast development and formation by inhibiting the expression of macrophage colony-stimulating factor in...

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Bibliographic Details
Published in:	Scientific reports Vol. 13; no. 1; p. 21199
Main Authors:	Padovano, Costanzo, Bianco, Salvatore Daniele, Sansico, Francesca, De Santis, Elisabetta, Tamiro, Francesco, Colucci, Mattia, Totti, Beatrice, Di Iasio, Serena, Bruno, Gaja, Panelli, Patrizio, Miscio, Giuseppe, Mazza, Tommaso, Giambra, Vincenzo
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 01-12-2023 Nature Publishing Group Nature Portfolio
Subjects:	631/136/818 631/1647/514/2254 631/80/86 Antibodies CD14 antigen Cell Differentiation Cell interactions Cell surface Cells Colony-stimulating factor Cytokines Evolutionary conservation Gene expression Homeostasis Humanities and Social Sciences Humans Immunomodulation Interleukin 7 Interleukin 7 receptors Leukocytes Leukocytes, Mononuclear Ligands Lymphocytes Macrophage colony-stimulating factor Mesenchyme multidisciplinary Notch1 protein Osteoclastogenesis Osteoclasts Osteoclasts - metabolism Osteogenesis Osteoprogenitor cells Peripheral blood mononuclear cells Phosphatase Proteins Quorum sensing RANK Ligand - metabolism RANK Ligand - pharmacology Science Science (multidisciplinary) Signal Transduction Surface markers TRANCE protein Wnt protein
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Summary:	Notch signaling is an evolutionary conserved pathway with a key role in tissue homeostasis, differentiation and proliferation. It was reported that Notch1 receptor negatively regulates mouse osteoclast development and formation by inhibiting the expression of macrophage colony-stimulating factor in mesenchymal cells. Nonetheless, the involvement of Notch1 pathway in the generation of human osteoclasts is still controversial. Here, we report that the constitutive activation of Notch1 signaling induced a differentiation block in human mononuclear CD14 + cells directly isolated from peripheral blood mononuclear cells (PBMCs) upon in vitro stimulation to osteoclasts. Additionally, using a combined approach of single-cell RNA sequencing (scRNA-Seq) simultaneously with a panel of 31 oligo-conjugated antibodies against cell surface markers (AbSeq assay) as well as unsupervised learning methods, we detected four different cell stages of human RANKL-induced osteoclastogenesis after 5 days in which Notch1 signaling enforces the cell expansion of specific subsets. These cell populations were characterized by distinct gene expression and immunophenotypic profiles and active Notch1, JAK/STAT and WNT signaling pathways. Furthermore, cell–cell communication analyses revealed extrinsic modulators of osteoclast progenitors including the IL7/IL7R and WNT5a/RYK axes. Interestingly, we also report that Interleukin-7 receptor (IL7R) was a downstream effector of Notch1 pathway and that Notch1 and IL7R interplay promoted cell expansion of human RANKL-induced osteoclast progenitors. Taken together, these findings underline a novel cell pattern of human osteoclastogenesis, outlining the key role of Notch1 and IL-7R signaling pathways.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-023-48615-2