Regenerative therapy of the salivary gland (SG) is a promising therapeutic approach for irreversible hyposalivation in patients with head and neck cancer treated by radiotherapy. However, little is known about the molecular regulators of stem/progenitor cell activity and regenerative processes in the SG. Wnt/β-catenin signaling regulates the function of many adult stem cell populations, but its role in SG development and regeneration is unknown. Using BAT-gal Wnt reporter transgenic mice, we demonstrate that in the submandibular glands (SMGs) of newborn mice Wnt/β-catenin signaling is active in a few cells at the basal layer of intercalated ducts, the putative location of salivary gland stem/progenitor cells (SGPCs). Wnt activity decreases as mice age, but is markedly enhanced in SG ducts during regeneration of adult SMG after ligation of the main secretory duct. The Hedgehog (Hh) pathway is also activated after duct ligation. Inhibition of epithelial β-catenin signaling in young Keratin5-rtTA/tetO-Dkk1 mice impairs the postnatal development of SMG, particularly affecting maturation of granular convoluted tubules. Conversely, forced activation of epithelial β-catenin signaling in adult Keratin5-rtTA/tetO-Cre/Ctnnb1((Ex3)fl) mice promotes proliferation of ductal cells, expansion of the SGPC compartment, and ectopic activation of Hh signaling. Taken together, these results indicate that Wnt/β-catenin signaling regulates the activity of SGPCs during postnatal development and regeneration upstream of the Hh pathway, and suggest the potential of modulating Wnt/β-catenin and/or Hh pathways for functional restoration of SGs after irradiation.

Jiang et al. generated Dpy30 conditional knockout mice to determine what role Dpy30 and its associated H3K4 methylation may play in the fate determination of tissue-specific stem cells such as HSCs.

Bone marrow mesenchymal stem cells (BM-MSCs) have multiple therapeutic potentials for regenerative, antiinflammatory, and immunomodulatory purposes and also show promise as vehicles for gene therapy of various metastatic cancers based on their tumor-tropic capacity. However, BM-MSCs are also a source of carcinoma-associated fibroblasts (CAFs) and may promote growth and metastasis of cancer.

microRNAs could be mechanosensitive and emerge as critical posttranscriptional regulators in the bone-remodeling process. During orthodontic tooth movement (OTM), the application of mechanical force induces alveolar bone remodeling, but whether microRNAs respond to orthodontic force and contribute to OTM is unknown. microRNA-21 (miR-21) has been previously reported in vitro to mediate stretch-induced osteogenic differentiation of periodontal ligament stem cells and support osteoclast differentiation. In this study, the authors show that miR-21 responded to orthodontic force in periodontal tissue in a dose- and time-dependent manner and regulated the osteogenesis of human periodontal ligament stem cells following OTM. Using mmu-miR-21-deficient (miR-21) mice, the authors discovered that mmu-miR-21 deficiency inhibited OTM and prevented force-induced maxillary bone loss. The authors found that miR-21 mice showed a normal skeletal phenotype in development and a similar alveolar bone formation rate to wild-type mice postnatally. During OTM, mmu-miR-21 regulated force-induced alveolar osteoblastogenesis in the tensile side, while no effects were detected in the compressive side. However, miR-21 mice showed inhibited alveolar osteoclastogenesis when compared with wild-type mice. During OTM, mmu-miR-21 deficiency blocked alveolar bone resorption in both the compressive and tensile sides. To dissect the mechanism by which miR-21 regulates alveolar bone remodeling, the authors screened the reported functional targets of miR-21 and found that periodontal expression of programmed cell death 4 ( Pdcd4) was inhibited following OTM. Furthermore, mmu-miR-21 deficiency removed the suppression of Pdcd4 at both the mRNA and protein levels in the periodontium, resulting in upregulation of the downstream effector C-fos. Further analysis of OTM under lipopolysaccharide-induced periodontal inflammation showed that mmu-miR-21 mediated lipopolysaccharide (LPS)-accelerated OTM and that mmu-miR-21 deficiency blocked lipopolysaccharide-induced maxillary bone loss. In summary, these findings reveal a previously unrecognized mechanism that a microRNA can modulate OTM and alveolar bone remodeling under both normal and inflammatory microenvironments in vivo.

This study suggests that several risk factors for breast cancer were associated with breast density in Chinese women. Information on the determinants of mammographic density may provide valuable insights into breast cancer aetiology.