摘要: Growing number studies show that lncRNA is an important regulatory factor and plays an irreplaceable role in innate immunity. However, most studies on lncRNA have focused on mammals and it is unknown in lower vertebrates. In this study, we identify a new lncRNA, named MIR144HG, which can have a negative role in antibacterial immunity of Miichthys miiuy caused by Vibrio anguillarum and V. harveyi. MyD88, TAK1 and p65 are very important pathway genes in antibacterial innate immune responses, whether in mammals or lower vertebrates. Here, we found that miR-144-3p could target MyD88, TAK1 and p65, inhibit host antibacterial response and promote bacterial escape. Further studies found that miR-144-3p can be derived by MIR144HG, and finally enhance the inhibitory effect of miR-144-3p on host antibacterial immunity. Moreover, V. anguillarum and V. harveyi are the two most susceptible Gram-negative pathogens in aquaculture, and the economic losses caused by these two bacteria are immeasurable every year. Our results not only elucidate the mechanism of the lncRNAmiRNA-mRNA axis in antibacterial immune responses, but also provide new insights for understanding the impact of lncRNA on host immunity and bacteria escape.

摘要: A broad spectrum of lethal kidney diseases involves the irreversible destruction of the tubular structures, leading to renal function loss. Following injury, a spectrum of tissue-resident epithelial stem/progenitor cells are known to be activated and then differentiate into mature renal cells to replace the damaged renal epithelium. Here, however, we reported an alternative way that tissue-resident cells could be activated to secrete multiple factors to promote organ repair. At single-cell resolution, we showed that the resident SOX9+ renal epithelial cells (RECs) could expand in the acutely injured kidney of both mouse and human. Compared to other cells, the SOX9+ RECs overexpressed much more secretion related genes, whose functions were linked to kidney repair pathways. We also obtained long-term, feeder-free cultured SOX9+ RECs from human urine and analysed their secretory profile at both transcriptional and proteomic levels. Engraftment of cultured human SOX9+ RECs or injection of its conditional medium facilitated the regeneration of renal tubular and glomerular epithelium, probably through stimulating endogenous REC self-activation and mediating crosstalk with other renal cells. We also identified S100A9 as one of the key factors in the SOX9+ REC secretome. Altogether, the abilities to extensively propagate SOX9+ RECs in culture whilst concomitantly maintaining their intrinsic secretory capacity suggest their future application in cell-free therapies and regeneration medicine.

摘要: Regeneration is the regrowth of damaged tissues or organs, a vital process in response to damages from primitive organisms to higher mammals. Planarian possesses active whole-body regenerative capability owing to its vast reservoir of adult stem cells, neoblasts, providing an ideal model to delineate the underlying mechanisms for regeneration. RNA N-6-methyladenosine (m(6)A) modification participates in many biological processes, including stem cell self-renewal and differentiation, in particular the regeneration of haematopoietic stem cells and axons. However, how m(6)A controls regeneration at the whole-organism level remains largely unknown. Here, we demonstrate that the depletion of m(6)A methyltransferase regulatory subunit wtap abolishes planarian regeneration, potentially through regulating genes related to cell-cell communication and cell cycle. Single-cell RNA-seq (scRNA-seq) analysis unveils that the wtap knockdown induces a unique type of neural progenitor-like cells (NP-like cells), characterized by specific expression of the cell-cell communication ligand grn. Intriguingly, the depletion of m(6)A-modified transcripts grn, cdk9 or cdk7 partially rescues the defective regeneration of planarian caused by wtap knockdown. Overall, our study reveals an indispensable role of m(6)A modification in regulating whole-organism regeneration.

摘要: Porphyromonas gingivalis (P. gingivalis) is a key pathogen of chronic periodontitis. Aryl hydrocarbon receptor (AhR) is essential in immune homeostasis via modulation of pro-inflammatory cytokines production and indoleamine 2,3-dioxygenase (IDO). In this study, it is demonstrated that P. gingivalis may regulate AhR signalling in periodontitis, which provides a potential target for further immune regulation studies in periodontitis. Experimental periodontitis was induced in C57BL/6 mice by silk ligature and P. gingivalis oral inoculation. The alveolar bone resorption was examined using Micro-CT. Histological structures were observed and related cytokines involved in AhR signalling pathway were analysed. RAW264.7 cells were pretreated with AhR agonist (FICZ) and antagonist (CH223191) and infected with P. gingivalis subsequently. The levels of IDO, AhR and other related cytokines were measured. To demonstrate IDO activity, the concentrations of tryptophan (Trp) and kynurenine (Kyn) were assessed by HPLC. Histological analysis of periodontitis mice showed distinct alveolar bone resorption and inflammatory cell infiltration. The level of AhR and its downstream target factors were significantly decreased in inflamed gingival tissue. Furthermore, RAW 264.7 cells incubated by P. gingivalis exhibited increased pro-inflammatory cytokines production and decreased AhR, CYP1A1, CYP1B1, and IDO expression. Decreased IDO activity was observed as decreased Kyn/Trp ratio in the supernatant. Moreover, FICZ decreased the pro-inflammatory cytokines levels in P. gingivalis infected cells. It is concluded that P. gingivalis may promote inflammatory responses via inhibiting the AhR signalling pathway in periodontitis.

摘要: Objective Osteochondroma is a common benign skeletal disorder for which different molecular and histological features of long bones have been reported. We investigated cell-of-origin and molecular mechanisms of a rare condylar osteochondroma (CO). Methods Human fibrocartilage stem cells (hFCSCs) isolated from CO and normal condyle tissue were used for RNA sequencing, real-time PCR, Western Blotting, immunohistology, flowcytometry, as well as for chondrogenic differentiation, proliferation, and apoptosis detection assays. Results HFCSCs were fewer in number with weaker proliferative capacity and higher apoptosis ratio in the CO group. During the chondrogenic inducing process, hFCSCs from CO were prone to form more mature and hypertrophic cartilage. The result of RNA sequencing of hFCSCs from CO and normal condyle revealed a correlation between the PI3K/AKT signalling pathway and CO. Activated PI3K/AKT signalling might lead to functional changes in hFCSCs by enhancing cell apoptosis in the developmental process of CO. Increased expression of BCL2-like protein 11 (BIM) in CO tissue also supports this conclusion. Furthermore, the activation of the PI3K/AKT pathway in TMJ of mice induced histological disorder and increased apoptosis in condylar cartilage. Conclusion We conclude that the activation of PI3K/AKT signalling in hFCSCs of CO suggests a new hypothesis for the cell-of-origin of human CO and another possible target to treat it.