Abstract
Lumen formation of salivary glands has been investigated using in vivo or ex vivo rudiment culture models. In this study, we used a three-dimensional (3D) salivary gland organoid culture system and demonstrated that lumen formation could be recapitulated in mouse SMG organoids. In our organoid culture system, lumen formation was induced by vasoactive intestinal peptide and accelerated by treatment with RA. Furthermore, lumen formation was observed in branching duct-like structure when cultured in combination of fibroblast growth factors (FGF) in the presence of retinoic acid (RA). We suggest RA signaling-mediated regulation of VIPR1 and KRT7 as the underlying mechanism for lumen formation, rather than apoptosis in the organoid culture system. Collectively, our results support a fundamental role for RA in lumen formation and demonstrate the feasibility of 3D organoid culture as a tool for studying salivary gland morphogenesis.
Highlights
Murine salivary glands, submandibular glands (SMGs), have been widely used as a model for studying salivary gland development and common processes in branching morphogenesis and tubulogenesis (Steinberg et al, 2005; Nitta et al, 2009; Hsu and Yamada, 2010; Knox et al, 2010; Nedvetsky et al, 2014)
We investigated whether the cell constitution and organoid characteristics recapitulate the process of lumen formation during morphogenesis
In order to examine the effect of retinoic acid (RA) and vasoactive intestinal protein (VIP) on lumen formation of SMG organoids, the SMG organoids were cultured with different doses of RA and treated with 200 nM VIP on day 4
Summary
Submandibular glands (SMGs), have been widely used as a model for studying salivary gland development and common processes in branching morphogenesis and tubulogenesis (Steinberg et al, 2005; Nitta et al, 2009; Hsu and Yamada, 2010; Knox et al, 2010; Nedvetsky et al, 2014). Retinoids are a group of nutritional compounds that include retinol, retinal, and retinoic acid (RA). RA has several roles in organ morphogenesis, embryonic development, immune system, and growth of various cell types (Tanumihardjo, 2011). RA-mediated signaling activates its nuclear receptors, including the retinoic acid receptor (RAR) family and retinoid X receptor (RXR) family transcription factors. RAR or RXR isoforms have redundant roles, enabling them to compensate
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