Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most important causes of peptic ulcer disease in high-income countries. Proton pump inhibitors are the current standard treatment; however, safety and long-term adverse effects of using these drugs are attracting more and more concerns in recent years. Using a porcine model of NSAID-related gastric ulcer, we herein show that adipose-derived mesenchymal stem cells (ADMSCs) delivered by endoscopic submucosal injection promoted ulcer healing with less inflammatory infiltration and enhanced reepithelization and neovascularization at day 7 and day 21 when compared with the controls (saline injection). However, only few engrafted ADMSCs showed myofibroblast and epithelial cell phenotype in vivo, suggesting the ulcer healing process might be much less dependent on the stem cell transdifferentiation. Further experiment with submucosal injection of MSC-derived secretome revealed a therapeutic efficacy comparable to that of stem cell transplantation. Profiling analysis showed up-regulation of genes associated with inflammation, granulation formation, and extracellular matrix remodeling at day 7 after injection of MSC-derived secretome. In addition, the extracellular signal–regulated kinase/mitogen-activated protein kinase and the phosphoinositide-3-kinase/protein kinase B pathways were activated after injection of ADMSCs or MSC-derived secretome. Both signaling pathways were involved in mediating the major events critical to gastric ulcer healing, including cell survival, migration, and angiogenesis. Our data suggest that endoscopic submucosal injection of ADMSCs serves as a promising approach to promote healing of NSAID-related peptic ulcer, and the paracrine effectors released from stem cells play a crucial role in this process.

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Background Gene expression profiling has been used to classify molecular subtypes in colorectal cancer (CRC). Given that tumour transcriptome signals not only derive from cancer cells but also from tumour microenvironment. Recent studies have shown that noncancerous components might affect the classification of CRC subtypes. We hypothesised that using stroma-specific gene signature would be more effective to identify CRC subtypes with clinical relevance. Methods To this end, we analysed gene expression profiles from 1821 CRCs. We firstly constructed a signature where genes were both stroma-specifically expressed and associated with drug response. Further, we identified CRC stroma-specific subtypes (CRSS) using K-means clustering based on the signature and verified the classification in two datasets. We also used the nearest template prediction algorithm to predict drug response. Results The CRSS subtypes were associated with distinct clinicopathological, molecular and phenotypic characteristics and specific enrichments of gene signatures and signalling pathways (table 1): (i) CRSS-A: non-serrated adenomas, colon crypt top derived, glycolytic, epithelial, KRAS-mutant, sensitive to Cetuximab, enriched with NK cells; (ii) CRSS-B: non-serrated adenomas, colon crypt base derived, DNA replication activity, epithelial, BRAF wild-type, TP53 mutant, chromosomal stability, distal CRC, sensitive to Cetuximab; (iii) CRSS-C: serrated adenomas, colon crypt top derived, interleukin-6 pathway activity, epithelial, microsatellite instability (MSI), BRAF mutant, hypermutation, chromosomal instability, CpG island methylator phenotype, proximal CRC, sensitive to Gefitinib, good prognosis, enriched with cytotoxic lymphocytes and monocytic lineage; (iv) CRSS-D: non-serrated adenomas, colon crypt top derived, interleukin-2 pathway activity, epithelialmesenchymal transition (EMT), chromosomal stability, sensitive to FOLFIRI and FOLFOX chemotherapy regimens; (v) CRSS-E: serrated adenomas, colon crypt base derived, EMT, immune pathways activation, poor prognosis, sensitive to FOLFIRI and FOLFOX, enriched with endothelial cells and fibroblasts; (vi) CRSS-F: serrated adenomas, colon crypt base derived, EMT, IGF1 pathway activity, poor prognosis, sensitive to FOLFIRI and FOLFOX, enriched with endothelial cells, fibroblasts and monocytic lineage. ConclusionsWe classified CRC into six molecular subtypes (CRSS). The identification of CRSS subtypes is critical, as it provides possibilities to identify robust prognostic models and provide more precise therapeutic options for each CRC subtype.