Circulating SSEA-1+ stem cell-mediated tissue repair in allergic airway inflammation.

Structural changes known as airway remodeling characterize chronic/severe asthma and contribute to lung dysfunction. We previously reported that neonatal SSEA-1+ pulmonary stem/progenitor cells (PSCs) ameliorated airway inflammation in asthmatic mice. However, the molecular mechanisms by which endogenous SSEA-1+ PSC of adult mice afford beneficial effects in alveolar homeostasis and lung repair after allergen challenge remain incompletely understood. To analyze the expression profile and clarify the biological significance of endogenous adult lung SSEA-1+ cells in asthmatic mice. Lung SSEA-1+ cells and circulating SSEA-1+ cells in peripheral blood were determined by confocal microscopy and cytometric analysis. GFP chimeric mice were used to trace cell lineage in vivo. The roles of circulating SSEA-1+ cells were verified in ovalbumin-induced and house dust mite-induced allergic asthmatic models. In asthmatic mice, endogenous lung SSEA-1+ cells almost disappeared; however, a unique population of circulating SSEA-1+ cells was enriched after the challenge phase. In asthmatic mice, adoptive transfer of circulating SSEA-1+ cells had a specific homing preference for the lung in response to inhaled antigen through upregulating CXCR7-CXCL11 chemokine axis. Circulating SSEA-1+ cells can transdifferentiate in the alveolar space and ameliorate lung inflammation and structural damage through inhibiting the infiltration of inflammatory cells into peribronchovascular and goblet cell hyperplasia areas, reducing the thickened smooth muscle layers and PAS-positive mucus-containing goblet cells. Reinforcing bone marrow-derived circulating SSEA-1+ cells from peripheral blood into lung tissue which create a rescue mechanism in maintaining alveolar homeostasis and tissue repair to mediate lung protection for emergency responses after allergen challenge in asthmatic conditions.

Neonatal lung-derived SSEA-1+ cells exhibited distinct stem/progenitor characteristics and organoid developmental potential.

Stem/progenitor cells, because of their self-renewal and multiple cell type differentiation abilities, have good potential in regenerative medicine. We previously reported a lung epithelial cell population that expressed the stem cell marker SSEA-1 was abundant in neonatal but scarce in adult mice. In the current study, neonatal and adult mouse-derived pulmonary SSEA-1+ cells were isolated for further characterization. The results showed that neonatal-derived pulmonary SSEA-1+ cells highly expressed lung development-associated genes and had enhanced organoid generation ability compared with the adult cells. Neonatal pulmonary SSEA-1+ cells generated airway-like and alveolar-like organoids, suggesting multilineage cell differentiation ability. Organoid generation of neonatal but not adult pulmonary SSEA-1+ cells was enhanced by fibroblast growth factor 7 (FGF 7). Furthermore, neonatal pulmonary SSEA-1+ cells colonized and developed in decellularized and injured lungs. These results suggest the potential of lung-derived neonatal-stage SSEA-1+ cells with enhanced stem/progenitor activity and shed light on future lung engineering applications.

Intestinal Dysbiosis Featuring Abundance of Ruminococcus gnavus Associates With Allergic Diseases in Infants.

BACKGROUND & AIMS: Dysbiosis of the intestinal microbiota has been associated with development of allergies in infants. However, it is not clear what microbes might contribute to this process. We investigated what microbe(s) might be involved in analyses of infant twins and mice. METHODS: We studied fecal specimens prospectively in a twin cohort (n = 30) and age-matched singletons (n = 14) born at National Taiwan University Children's Hospital, Taipei, Taiwan, from April 2011 to March 2013. Clinical parameters (gestational age, birth body weight, mode of delivery and feeding, immunizations, and medical events) were recorded. Fecal samples were collected beginning immediately after birth and for 1 year; the children were followed until 3 years of age and allergic symptoms (repetitive and continuous for at least 6 months) were noted. A skin prick test was used to ascertain atopy. Bacterial communities in fecal samples were profiled by 16S ribosomal RNA-based polymerase chain reaction-temporal temperature gradient gel electrophoresis and next-generation sequencing. BALB/c mice without and with ovalbumin sensitization/challenge were infected with candidate bacteria by oral gauge intragastric intubation. Fecal, serum, lung, and colon tissue samples were collected from mice and analyzed for mechanisms of allergy development. RESULTS: During the investigation period, 20 children (45.5%) developed allergic diseases, including respiratory (allergic rhinitis and asthma) and skin (atopic dermatitis and eczema) allergies. Lachnospiraceae were detected at significantly higher frequency in allergic infants than nonallergic infants (P < .004); the high fecal count of Lachnospiraceae in allergic subjects appeared at 2 months of age and persisted until 12 months of age. The enrichment of Lachnospiraceae in allergic infants was attributed to the overgrowth of Ruminococcus gnavus, which tended to have a low frequency in nonallergic subjects (P = .0004). Increased R gnavus was observed before the onset of allergic manifestations, and was associated with respiratory allergies (P < .002) or respiratory allergies coexistent with atopic eczema (P < .001). In mice, endogenous R gnavus grew rapidly after sensitization and challenge with ovalbumin. Mice gavaged with purified R gnavus developed airway hyper-responsiveness and had histologic evidence of airway inflammation (asthma). Expansion of R gnavus in mice stimulated secretion of cytokines (interleukin [IL] 25, IL33, and thymic stromal lymphopoietin) by colon tissues, which activated type 2 innate lymphoid cells and dendritic cells to promote differentiation of T-helper 2 cells and production of their cytokines (IL4, IL5, and IL13). This led to infiltration of the colon and lung parenchyma by eosinophils and mast cells. CONCLUSIONS: In a study of a twin cohort (some infants with, some without allergies), we associated development of allergies, particularly respiratory allergies, with increased fecal abundance of R gnavus. Mice fed R gnavus developed airway inflammation, characterized by expansion of T-helper 2 cells in the colon and lung, and infiltration of colon and lung parenchyma by eosinophils and mast cells.

Targeting tumor-infiltrating Ly6G+ myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma.

Sorafenib, a multikinase inhibitor with antiangiogenic activity, is an approved therapy for hepatocellular carcinoma (HCC). It is unclear whether the proinflammatory and immunosuppressive mechanisms may limit the therapeutic efficacy of sorafenib in HCC. We used a syngeneic mouse liver cancer cell line to establish orthotopic liver or subcutaneous tumors to study how proinflammatory and immunosuppressive mechanisms impact on the efficacy of sorafenib. We found sorafenib exhibited a potent therapeutic effect in subcutaneous tumors, but a less potent effect in orthotopic liver tumors. The protein levels of interleukin-6 (IL-6) and vascular endothelial growth factor A (VEGF-A) were persistently elevated in orthotopic liver tumors, but not in subcutaneous tumors, treated with sorafenib. Likewise, the tumor-infiltrating Ly6G+ myeloid-derived suppressor cells (MDSCs) and immune suppressors were increased in orthotopic liver tumors, not in subcutaneous tumors, treated with sorafenib. The tumor-infiltrating Ly6G+ MDSCs of sorafenib-treated orthotopic liver tumors significantly induced IL-10 and TGF-ß expressing CD4+ T cells, and downregulated the cytotoxic activity of CD8+ T cells. IL-6, but not VEGF-A, protected Ly6G+ MDSCs from sorafenib-induced cell death in vitro. The combination of anti-Ly6G antibody or anti-IL-6 antibody with sorafenib significantly reduced the cell proportion of Ly6G+ MDSCs in orthotopic liver tumors, enhanced the T cells proliferation and improved the therapeutic effect of sorafenib synergistically. Modulating tumor microenvironment through targeting tumor-infiltrating Ly6G+ MDSCs represents a potential strategy to improve the anti-HCC efficacy of sorafenib.