title: MCSF orchestrates branching morphogenesis in developing submandibular gland tissue.
abstract: The importance of macrophages in tissue development and regeneration has been strongly emphasized. However, the specific roles of macrophage colony-stimulating factor (MCSF), the key regulator of macrophage differentiation, in glandular tissue development have been unexplored. Here, we disclose new macrophage-independent roles of MCSF in tissue development. We initially found that MCSF is markedly upregulated at embryonic day (E)13.5, at a stage preceding the colonization of macrophages (at E15.5), in mouse submandibular gland (SMG) tissue. Surprisingly, MCSF-induced branching morphogenesis was based on a direct effect on epithelial cells, as well as indirectly, by modulating the expression of major growth factors of SMG growth, FGF7 and FGF10, via the phosphoinositide 3-kinase (PI3K) pathway. Additionally, given the importance of neurons in SMG organogenesis, we found that MCSF-induced SMG growth was associated with regulation of neurturin expression and neuronal network development during early SMG development in anin vitroorganogenesis model as well asin vivoThese results indicate that MCSF plays pleiotropic roles and is an important regulator of early SMG morphogenesis.
authors.affiliation: Department of Biomaterials, Okayama University, 2-5-1 Shikata-Cho, Okayama 700-8558, Japan.
authors.forename: Gulsan Ara
authors.initials: GA
authors.lastname: Sathi
authors.affiliation: Department of Biomaterials, Okayama University, 2-5-1 Shikata-Cho, Okayama 700-8558, Japan.|Department of Oral Rehabilitation and Regenerative Medicine, Okayama University, 2-5-1 Shikata-Cho, Okayama 700-8558, Japan.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Farahat
authors.affiliation: Department of Biomaterials, Okayama University, 2-5-1 Shikata-Cho, Okayama 700-8558, Japan.
authors.forename: Emilio Satoshi
authors.initials: ES
authors.lastname: Hara
authors.affiliation: Center for the Development of Medical and Health Care Education, Okayama University, 2-5-1 Shikata-Cho, Okayama 700-8558, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taketa
authors.affiliation: Department of Oral Pathology and Medicine, Okayama University, 2-5-1 Shikata-Cho, Okayama 700-8558, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nagatsuka
authors.affiliation: Department of Oral Rehabilitation and Regenerative Medicine, Okayama University, 2-5-1 Shikata-Cho, Okayama 700-8558, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Kuboki
authors.affiliation: Department of Biomaterials, Okayama University, 2-5-1 Shikata-Cho, Okayama 700-8558, Japan tmatsu@md.okayama-u.ac.jp.
authors.forename: Takuya
authors.identifier: 0000-0002-9804-4786
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D004848:Epithelium / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008813:Mice, Inbred ICR; D009024:Morphogenesis / Q000187:drug effects*; D000071446:Neuronal Outgrowth / Q000187:drug effects; D051101:Neurturin / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013363:Submandibular Gland / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism
chemical_list: D051526:Fibroblast Growth Factor 10; D051101:Neurturin; C495056:Nrtn protein, mouse; D051523:Fibroblast Growth Factor 7; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases
keywords: 3D culture; Branching morphogenesis; Fibroblast growth factor; Macrophage colony-stimulating factor; Neurturin; Salivary gland