Distinct fibroblast progenitor subpopulation expedites regenerative mucosal healing by immunomodulation.

Injuries that heal by fibrosis can compromise organ function and increase patient morbidity. The oral mucosal barrier has a high regenerative capacity with minimal scarring, but the cellular mechanisms remain elusive. Here, we identify distinct postnatal paired-related homeobox-1+ (Prx1+) cells as a critical fibroblast subpopulation that expedites mucosal healing by facilitating early immune response. Using transplantation and genetic ablation model in mice, we show that oral mucosa enriched with Prx1+ cells heals faster than those that lack Prx1+ cells. Lineage tracing and scRNA-seq reveal that Prx1+ fibroblasts exhibit progenitor signatures in physiologic and injured conditions. Mechanistically, Prx1+ progenitors accelerate wound healing by differentiating into immunomodulatory SCA1+ fibroblasts, which prime macrophage recruitment through CCL2 as a key part of pro-wound healing response. Furthermore, human Prx1+ fibroblasts share similar gene and spatial profiles compared to their murine counterpart. Thus, our data suggest that Prx1+ fibroblasts may provide a valuable source in regenerative procedures for the treatment of corneal wounds and enteropathic fibrosis.

NF-κB perturbation reveals unique immunomodulatory functions in Prx1+ fibroblasts that promote development of atopic dermatitis.

Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor κB (NF-κB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1)+ fibroblast subpopulation. Disruption of Ikkb-NF-κB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or eotaxin-1) characterized by eosinophil infiltration and a subsequent TH2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb-NF-κB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and TH2 inflammation in a mouse model. Together, the murine model and human AD specimens point to dysregulated Prx1+ fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD and suggest that targeting CCL11 may be a way to treat AD-like skin lesions.

Impact of Periodonto-pathogenic Microbiota and Sociodemographic Variables on Periodontal Status during Pregnancy and Postpartum Period.

PURPOSE: This study examines the difference in the oral microbiome during pregnancy and the postpartum period of a Chinese population, with the focus on P. gingivalis, P. intermedia and P. nigrescens and their shift during pregnancy, in order to understand the host-microbe relationship in maintaining homeostasis during pregnancy. MATERIALS AND METHODS: This cross-sectional study was carried out in a total of 117 women who underwent prenatal or regular examinations at four public hospitals, including 84 pregnant and 33 postpartum women. Women in the postpartum group were examined within 0.5-1 year after delivery, while the pregnant group was divided into early pregnancy (0-13 weeks), middle pregnancy (14-27 weeks), and late pregnancy (28-39 weeks) according to gestational age. Sociodemographic parameters were self-reported by recruited women. The study required evaluations of probing depth (PD), bleeding index (BI), clinical attachment loss (CAL), and plaque index (PlI). Unstimulated whole saliva samples were collected for the detection of P. gingivalis, P. intermedia, and P. nigrescens. Bacterial populations were evaluated using 16S rRNA-based polymerase chain reaction. RESULTS: P. nigrescens exhibited higher prevalence in the pregnant group compared to the postpartum group (45.67% vs 12.10%, p < 0.01). P. nigrescens was more frequently detected in late than in early pregnancy (57.7% vs 48.3%, p < 0.05) and middle pregnancy (57.7% vs 31.0%, p < 0.01). Initially high prevalence of P. gingivalis in early pregnancy wanes in middle and late pregnancy (69.0%, 44.8%, 38.5%). However, the prevalence of P. gingivalis in the postpartum group (81.8%) exceeds all of the pregnant groups (p < 0.01). The change in the prevalence of P. intermedia among different groups was not statistically significant. The percentages of bleeding on probing (BOP%) sites and PD ≥4 mm sites in the postpartum group were statistically significantly higher when compared with each of the pregnant groups (p < 0.01). During pregnancy, women experienced elevated PlI, BI, PD, and BOP% (p < 0.05). The proportions of subjects in the pregnant group who agreed with the statements 'Gingival bleeding is normal', 'Can't brush teeth within 1st month postpartum', 'It's unnecessary to see a dentist if not uncomfortable' were 39.3%, 28.6%, and 35.7%, respectively. CONCLUSIONS: P. nigrescens is more related than P. gingivalis to pregnancy status. The periodontal status of Chinese women progressively deteriorates during pregnancy and persists into the postpartum period, which may result from lack of dental care knowledge.

Diabetes-Induced NF-κB Dysregulation in Skeletal Stem Cells Prevents Resolution of Inflammation.

Type 1 diabetes (T1D) imposes a significant health burden by negatively affecting tissue regeneration during wound healing. The adverse effect of diabetes is attributed to high levels of inflammation, but the cellular mechanisms responsible remain elusive. In this study, we show that intrinsic skeletal stem cells (SSCs), a subset of mesenchymal stem cells, are essential for resolution of inflammation to occur during osseous healing by using genetic approaches to selectively ablate SSCs. T1D caused aberrant nuclear factor-κB (NF-κB) activation in SSCs and substantially enhanced inflammation in vivo. Constitutive or tamoxifen-induced inhibition of NF-κB in SSCs rescued the impact of diabetes on inflammation, SSC expansion, and tissue formation. In contrast, NF-κB inhibition in chondrocytes failed to reverse the effect of T1D. Mechanistically, diabetes caused defective proresolving macrophage (M2) polarization by reducing TGF-ß1 expression by SSCs, which was recovered by NF-κB inhibition or exogenous TGF-ß1 treatment. These data identify an underlying mechanism for altered healing in T1D and demonstrate that diabetes induces NF-κB hyperactivation in SSCs to disrupt their ability to modulate M2 polarization and resolve inflammation.