Wnt signaling plays an important role in embryogenesis and adult stem cell homeostasis. Its diminished activation is implicated in osteoporosis and degenerative neural diseases. However, systematic administration of Wnt-signaling agonists carries risk, as aberrantly activated Wnt/β-catenin signaling is linked to cancer. Therefore, technologies for local modulation and control of Wnt signaling targeted to specific sites of disease or degeneration have potential therapeutic value in the treatment of degenerative diseases. We reported a facile approach to locally activate the canonical Wnt signaling cascade using nanomagnetic actuation or ligand immobilized platforms. Using a human embryonic kidney (HEK293) Luc-TCF/LEF reporter cell line, we demonstrated that targeting the cell membrane Wnt receptor, Frizzled 2, with peptide-tagged magnetic nanoparticles (MNPs) triggered canonical Wnt signaling transduction when exposed to a high-gradient, time-varying magnetic field, and the induced TCF/LEF signal transduction was shown to be avidity-dependent. We also demonstrated that the peptide retained signaling activity after functionalization onto glass surfaces, providing a versatile platform for drug discovery or recreation of the cell niche. In conclusion, these results showed that peptide-mediated Wnt signaling kinetics depended not only on ligand concentration but also on the presentation method of the ligand, which may be further modulated by magnetic actuation. This has important implications when designing future therapeutic platforms involving Wnt mimetics.

Harsh local microenvironment, such as hypoxia and lack of instructive clues for transplanted stem cells, presents the serious obstacle for stem cell therapies’ efficacy. Therefore, continued efforts have been taken to improve stem cells’ viability and plasticity. Hepatocyte growth factor (HGF) has previously been reported to mitigate the complications of various human diseases in animal model studies and in some clinical trials. Besides, human stem cells from the root apical papilla (SCAP) are deemed a better resource of mesenchymal stem cells due to derived stem cells holding greater amplification ability in vitro compared with those from other dental resources. To move forward, evaluating effects and understanding underlying molecular mechanisms of HGF on SCAP for periodontal regeneration are needed. In this study, HGF was transgenically expressed in SCAP, and it was found that HGF enhanced osteo/dentinogenic differentiation capacity of SCAP compared with those of non-treated control in an ectopic mineralization model. Moreover, HGF reduced the apoptosis of SCAP under both normoxic and hypoxic conditions, whereas the combination of HGF and hypoxia exposure had inhibitory effects on cell proliferation during an 8-day in vitro culture period. Transcriptome analysis further revealed that suppressed cell cycle progression and activated BMP/TGFβ, Hedgehog, WNT, FGF, HOX, and other morphogen family members result upon HGF overexpression, which may render SCAP recapitulate part of neural crest stem cell characteristics. Moreover, strengthened stress response modulation such as unfolded protein response, macroautophagy, and anti-apoptotic molecules might explain the increased viability of SCAP. In all, our results imply that these potential mechanisms underlying HGF-promoting SCAP differentiation could be further elucidated and harnessed to improve periodontal tissue regeneration.

Background: The study aimed to determine latent patterns of geographical distribution of health-related air pollutants across the USA, and to evaluate real-world cumulative effects of these patterns on public health metrics. Methods: It was an ecological study using county-level data on the concentrations of 12 air pollutants (i.e., ozone, CO, NO2 and SO2, PM2.5 mass, and speciation, PM10 mass and speciation, HAPs, VOCs, NONOxNOy and lead) over 20 years, and the rigid measurements of population health including life expectancy at birth, age-specific mortality risks and cause-specific mortality rates (21 mutually exclusive disease groups). Latent class analysis (LCA) was used to identify the common clusters of life expectancy-associated air pollutants based on their concentration characteristics in the final studied counties (n=699). Multivariate linear regression analyses were then applied to assess the relationship between the LCA-derived clusters and health measurements with confounding adjustment. Results: PM2.5 mass, PM10 speciation, and NONOxNOy were associated with life expectancy and thus were included in LCA. Five clusters were identified: the ‘all low’ cluster (n=115, 16.5%), ‘all medium’ cluster (n=285, 40.8%), ‘high particulates’ cluster (n=152, 21.8%), ‘all high’ cluster (n=136, 19.5%) and ‘mixed profile’ cluster (n=11, 1.6%). Cluster with a more severe pollutant profile was associated with a decreasing life expectancy, an increasing mortality risk among the middle-aged and elderly populations (≥45 years), and an increasing mortality rate caused by chronic respiratory conditions, cardiovascular diseases, and neoplasms. Conclusions: Our study brings new perspectives of real-world geographical patterns of air pollution to explain health disparities across the USA.