Skin stem cells can regenerate epidermal appendages; however, hair follicles (HF) lost as a result of injury are barely regenerated. Here we show that macrophages in wounds activate HF stem cells, leading to telogen–anagen transition (TAT) around the wound and de novo HF regeneration, mostly through TNF signalling. Both TNF knockout and overexpression attenuate HF neogenesis in wounds, suggesting dose-dependent induction of HF neogenesis by TNF, which is consistent with TNF-induced AKT signalling in epidermal stem cells in vitro. TNF-induced β-catenin accumulation is dependent on AKT but not Wnt signalling. Inhibition of PI3K/AKT blocks depilation-induced HF TAT. Notably, Pten loss in Lgr5+ HF stem cells results in HF TAT independent of injury and promotes HF neogenesis after wounding. Thus, our results suggest that macrophage-TNF-induced AKT/β-catenin signalling in Lgr5+ HF stem cells has a crucial role in promoting HF cycling and neogenesis after wounding.
Mesenchymal stem cells (MSCs) are largely entrapped in the lungs after intravenous delivery. The underlying mechanisms have been poorly understood. Flow cytometry and Western blot analysis showed that the expression levels of many integrins such as b1, a5, and aVb3 in MSCs increased markedly upon cultured expansion in 2D monolayers, whose ligands fibronectin and vitronectin were detected on the surface of vascular endothelial cells in the lungs by immunostaining and flow cytometry. Blockade of integrin b1, integrin a5, or integrins aVb3 with functional blocking antibodies significantly decreased the amount of MSCs entrapped in the lungs following intravenous infusion as determined by real-time PCR and histological analysis; meanwhile, corresponding increases in the levels of circulating MSCs in the blood and MSCs homed to the ischemic myocardium and inflamed ear were found. Intriguingly, a short period of 3D spheroid culture of MSCs, which had been expanded for several passages in monolayers, substantially reduced the expression levels of many integrins and the number of MSCs entrapped in the lungs. Our results indicate that the excess expression and activation of integrins is a significant cause of lung entrapment of MSCs. STEM CELLS 2015;33:3315-3326 SIGNIFICANCE STATEMENTMesenchymal stem cells (MSCs) have shown profound therapeutic potential in tissue repair=regeneration, and intravenous infusion has been a popular translation route of the cells for its convenience and safety. However, recent studies indicate that MSCs are largely entrapped in lungs after intravenous delivery and die shortly. The underlying mechanisms have been poorly understood. In this study, we provide evidence to show that excess expression and activation of integrins in MSCs that are developed during conventional monolayer culture is a critical cause of MSC entrapment in the lungs. Our study suggests a novel approach to increase MSC homing and engraftment to sites of tissue injuries by reducing the ECM binding activity of surface integrins.
Low targeting efficiency limits the applications of nanoparticles in cancer therapy. The fact that mesenchymal stem cells (MSC) trapped in the lung after systemic infusion is a disadvantage for cell therapy purposes. Here, we utilized MSC as lung cancer-targeted drug delivery vehicles by loading nanoparticles (NP) with anti-cancer drug. MSC showed a higher drug intake capacity than fibroblasts. In addition, MSC showed predominant lung trapping in both rabbit and monkey. IR-780 dye, a fluorescent probe used to represent docetaxel (DTX) in NP, delivered via MSC accumulated in the lung. Both in vitro MSC/A549 cell experiments and in vivo MSC/lung cancer experiments validated the intercellular transportation of NP between MSC and cancer cells. In vivo assays showed that the MSC/NP/DTX drug delivery system exerted primary tumor inhibition efficiency similar to that of a NP/DTX drug system. Collectively, the MSC/NP drug delivery system is promising for lung-targeted drug delivery for the treatment of lung cancer and other lung-related diseases.
Abstract. MicroRNAs (miRNAs) are small non-coding RNAs, 8-23 nucleotides in length, which regulate gene expression at the post-transcriptional level. The present study was performed to analyze the association between microRNA-21 and cisplatin resistance in epithelial ovarian cancer (EOC) SKOV3 and SKOV3/DDP cells. In this experiment, the resistance of SKOV3 and SKOV3/DDP cells to cisplatin was evaluated using the MTT assay. Reverse transcription-quantitative polymerase chain reaction analysis was used to assess miRNA-21 levels and phosphatase and tensin homolog (PTEN) mRNA levels. Western blotting was used to assess PTEN protein levels. miRNA-21 mimics or inhibitors were transfected into SKOV3 and SKOV3/DDP cells. Prior to transfection, higher expression levels of miRNA-21 were observed in SKOV3/DDP cells compared with SKOV3 cells. Following transfection with miRNA-21 mimics, SKOV3 cells demonstrated increased sensitivity to cisplatin compared with negative control cells. Following transfection with the miRNA-21 inhibitor, SKOV3/DDP cells demonstrated decreased sensitivity to cisplatin compared with negative control cells. Furthermore, PTEN mRNA expression levels in SKOV3 cells transfected with miRNA-21 mimics was significantly lower compared with negative control cells. These results suggested that miRNA-21 may regulate cisplatin resistance by negatively targeting PTEN in EOC. IntroductionEpithelial ovarian cancer (EOC) is one of the most common malignant gynecologic tumors. Debulking surgery followed by a combination of platinum and taxane based chemotherapy are widely used treatments for EOC at present. Although overall survival rates have increased slightly over the past 25 years, 5-year survival remains <50% (1). The high mortality rate of ovarian cancer is due to late-stage diagnosis and resistance to platinum-based chemotherapy. However, the mechanisms underlying cisplatin resistance in EOC remain to be fully understood.MicroRNAs (miRNAs) are small non-coding RNAs of 8-23 nucleotides that post-transcriptionally regulate gene expression. Multiple previous reports have indicated that dysregulation of miRNA target genes promotes drug resistance, and inhibition of miRNAs may reverse drug resistance (2,3). miRNA-21 is overexpressed in multiple types of cancer, and promotes the initiation of cancer, progression and drug-resistance (4-9). miRNA-21 impacts tumorigenesis by negatively regulating several targets. Phosphatase and tensin homolog (PTEN) is a tumor suppressor molecule. Inactivating mutations and deletions of the PTEN gene have been observed in multiple types of cancer. Notably, bioinformatics tools have demonstrated that the 3'-untranslated region of the PTEN gene harbors a putative binding site for miRNA-21 (10). miRNA-21 expression has been revealed to be markedly increased in ovarian cancer compared with benign ovarian tumor tissues (11). miRNA-21 expression was also demonstrated to be increased in drug-resistant ovarian cancer compared with drug-sensitive ovarian cancer serum. In the present study,...
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