Periodontitis impairs the osteogenic differentiation of human periodontal mesenchymal stem cells (hPDLSCs), but the underlying molecular mechanisms are still poorly understood. Long noncoding RNAs (lncRNAs) have been demonstrated to have significant roles under both physiologic and pathological conditions. In this study, we performed comprehensive lncRNA profiling by lncRNA microarray analysis and identified a novel lncRNA, osteogenesis impairment-related lncRNA of PDLSCs from periodontitis patients (lncRNA-POIR), the expression of which was significantly decreased in PDLSCs from periodontitis patients (pPDLSCs) and was upregulated by osteogenic induction. To study the functions of lncRNA-POIR, we prepared cells with overexpression and knockdown of lncRNA-POIR and found that lncRNA-POIR positively regulated osteogenic differentiation of hPDLSCs and pPDLSCs both in vitro and in vivo. Using quantitative real-time PCRs (qPCRs) and luciferase reporter assays, we demonstrated that lncRNA-POIR may act as a competing endogenous RNA (ceRNA) for miR-182, leading to derepression of its target gene, FoxO1. In this process, lncRNA-POIR and miR-182 suppress each other and form a network to regulate FoxO1. FoxO1 increased bone formation of pPDLSCs by competing with TCF-4 for β-catenin and inhibiting the canonical Wnt pathway. Finally, inflammation increases miR-182 expression through the nuclear factor-κB pathway, and the miR-182 overexpression in the inflammatory microenvironment resulted in an imbalance in the lncRNA-POIR-miR-182 regulatory network. In conclusion, our results provide novel evidence that this lncRNA-miRNA (microRNA) regulatory network has a significant role in osteogenic differentiation of pPDLSCs and that it has potential as a therapeutic target in mesenchymal stem cells during inflammation.

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The application of periodontal ligament stem cells (PDLSCs) may be effective for periodontal regenerative therapy. As tissue regenerative potential may be negatively regulated by aging, whether aging and its microenvironment modify human PDLSCs remains a question. In this study, we compared the proliferation and differentiation capacity of PDLSCs obtained from young and aged donors. Then, we exposed aged PDLSCs to young periodontal ligament cell-conditioned medium (PLC-CM), and young PDLSCs were exposed to aged PLC-CM. Morphological appearance, colony-forming assay, cell cycle analysis, osteogenic and adipogenic induction media, gene expression of cementoblast phenotype, and in vivo differentiation capacities of PDLSCs were evaluated. PDLSCs obtained from aged donors exhibited decreased proliferation and differentiation capacity when compared with those from young donors. Young PLC-CM enhanced the proliferation and differentiation capacity of PDLSCs from aged donors. Aged PDLSCs induced by young PLC-CM showed enhanced tissue-regenerative capacity to produce cementum/periodontal ligament-like structures, whereas young PDLSCs induced by aged PLC-CM transplants mainly formed connective tissues. To our knowledge, this is the first study to mimic the developmental microenvironment of PDLSCs in vitro, and our data suggest that age influences the proliferation and differentiation potential of human PDLSCs, and that the activity of human PDLSCs can be modulated by the extrinsic microenvironment.

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AimsTo evaluate the safety profile and efficacy of bone marrow mononuclear cells (BMMNC) transplantation for ST-segment elevation myocardial infarction (STEMI) by assessing patients and their left ventricular function at up to 4 years follow-up.Methods and resultsEighty-six patients with STEMI who had successfully undergone percutaneous coronary intervention (PCI) were randomized to receive intracoronary injection of BMMNC (n = 41) or saline (n = 45). Left ventricular ejection fraction, as evaluated by UCG, was markedly improved at 6 months (0.484 ± 0.5 vs. 0.457 ± 0.6, P = 0.001), 1 year (0.482 ± 0.7 vs. 0.446 ± 0.6, P < 0.001), and 4 years (0.505 ± 0.8 vs. 0.464 ± 0.8, P < 0.001) after BMMNC transplant when compared with control group. However, the current cell therapy did not improve the myocardial viability of the infarcted area as assessed by single-photon emission computed tomography analysis at 4 years post-transplant (0.263 ± 0.007 in BMMNC group vs. 0.281 ± 0.008 in control group, P = 0.10). During the follow-up period, one control group case (2.2%) of in-stent restenosis was confirmed by coronary angiography and underwent repeat PCI. Also during follow-up, one death (2.2%) occurred in the control group, and one patient (2.4%) in the BMMNC group had transient acute heart failure.ConclusionThis study indicates that intracoronary delivery of autologous BMMNC is safe and feasible for STEMI patients who have undergone PCI, and can lead to long-term improvement in myocardial function.