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Synovial-derived cells, found in the synovial membrane of human joints, were obtained by digestion of the synovial membrane and were subsequently expanded in vitro. The identity of synovial-derived cells has long been a topic of debate. The terms “type B synoviocytes,” “fibroblast-like synoviocytes (FLS),” “synovium-derived mesenchymal stem cells (MSCs),” and “synovial fibroblasts (SF)” appeared in different articles related to human synovial-derived cells in various disease models, yet they seemed to be describing the same cell type. However, to date, there is no clear standard to distinguish these terms; thus, the hypothesis that they represent the same cell type is currently inconclusive. Therefore, this review aims to clarify the similarities and differences between these terms and to diffuse the chaotic nomenclature of synovial-derived cells.

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The Notch signaling pathway regulates stem cell proliferation and differentiation in multiple tissues and organs, and is required for tissue maintenance. However, the role of Notch in regulation of olfactory epithelium (OE) progenitor/stem cells to maintain tissue function is still not clear. A recent study reported that leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is expressed in globose basal cells (GBCs) localized in OE. Through lineage tracing in vivo, we found that Lgr5 cells act as progenitor/stem cells in OE. The generation of daughter cells from Lgr5 progenitor/stem cells is delicately regulated by the Notch signaling pathway, which not only controls the proliferation of Lgr5 cells and their immediate progenies but also affects their subsequent terminal differentiation. In conditionally cultured OE organoids in vitro, inhibition of Notch signaling promotes neuronal differentiation. Besides, OE lesion through methimazole administration in mice induces generation of more Notch1 cells in the horizontal basal cell (HBC) layer, and organoids derived from lesioned OE possesses more proliferative Notch1 HBCs. In summary, we concluded that Notch signaling regulates Lgr5 GBCs by controlling cellular proliferation and differentiation as well as maintaining epithelial cell homeostasis in normal OE. Meanwhile, Notch1 also marks HBCs in lesioned OE and Notch1 HBCs are transiently present in OE after injury. This implies that Notch1 cells in OE may have dual roles, functioning as GBCs in early development of OE and HBCs in restoring the lesioned OE. Stem Cells 2018;36:1259-1272.

Lgr5, leucine-rich repeat-containing G-protein coupled receptor 5, is a biomarker for stem cells in multiple tissues. Lgr5 is also expressed in the brain, but the identities and properties of these Lgr5 cells are still elusive. Using an Lgr5-EGFP reporter mouse line, we found that, from early development to adulthood, Lgr5 is highly expressed in the olfactory bulb (OB), an area with ongoing neurogenesis. Immunostaining with stem cell, glial, and neuronal markers reveals that Lgr5 does not label stem cells in the OB but instead labels a heterogeneous population of neurons with preference in certain subtypes. Patch-clamp recordings in OB slices reveal that Lgr5-EGFP cells fire action potentials and display spontaneous excitatory postsynaptic events, indicating that these neurons are integrated into OB circuits. Interestingly, R-spondin 3, a potential ligand of Lgr5, is also expressed in the adult OB. Collectively, our data indicate that Lgr5-expressing cells in the OB are fully differentiated neurons and imply distinct roles of Lgr5 and its ligand in postmitotic cells. Lgr5 (leucine-rich repeat-containing G-protein coupled receptor 5) is a stem cell marker in many body organs. Here we report that Lgr5 is also highly expressed in the olfactory bulb (OB), the first relay station in the brain for processing odor information and one of the few neural structures that undergo continuous neurogenesis. Surprisingly, Lgr5 is not expressed in the OB stem cells, but instead in a few subtypes of terminally differentiated neurons, which are incorporated into the OB circuit. This study reveals that Lgr5 cells in the brain represent a nonstem cell lineage, implying distinct roles of Lgr5 in postmitotic neurons.

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The purpose of this study was to evaluate the effect of salmon calcitonin (sCT) on improving fibrosis‐related indicators in frozen shoulder synovial/capsular fibroblasts (SCFs) and detect the potential downstream pathway. Quantitative real‐time polymerase chain reaction and cell‐substrate adhesion assays were used to measure alterations in fibrosis‐related molecule expression and the cell adhesion ability of frozen shoulder SCFs after treatment with range concentrations of sCT. The presence of calcitonin receptors (CTRs) in shoulder joint synovial/capsular tissue samples was detected by immunohistochemistry (IHC). The downstream pathways of sCT in SCFs were further explored by utilizing three classical pathway inhibitors. With the addition of sCT to the culture medium of frozen shoulder SCFs, the messenger RNA (mRNA) expression of collagen type I (COL1A1), COL3A1, fibronectin 1, laminin 1, transforming growth factor‐β1 (TGF‐β1), and interleukin‐1α (IL‐1α) showed a descending trend as the sCT concentration increased. Treatment with sCT increased the expression of vascular endothelial growth factor and IL‐6 in a dose‐dependent manner. The enhanced adhesion ability of frozen shoulder SCFs gradually diminished with increasing concentrations of sCT. By using IHC, the CTR was detected extensively in the frozen shoulder joint synovium and capsule. Blocking the protein kinase C (PKC) pathway reversed the sCT‐mediated suppression of COL1A1 production. Blocking the PKC or protein kinase A (PKA) pathway eliminated the sCT‐induced inhibition of TGF‐β1 production. This study demonstrated that sCT effectively improved the mRNA expression of fibrosis‐related molecules and decreased the enhanced cell‐substrate adhesion ability of frozen shoulder SCFs. sCT might achieve these effects by interacting with the CTR that is expressed on the SCF surface and by activating the downstream PKC or PKA pathway.

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