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Stem cell-derived exosomes are efficient and safe therapeutic tools for transferring endogenous biological cargo or functional biomolecules for regenerative medicine. The regulation of inflammation and angiogenesis plays a pivotal role in wound healing and tissue regeneration. The purpose of this study was to investigate the anti-inflammatory and pro-angiogenic roles of human adipose mesenchymal stem cell-derived exosomes, focusing on the underlying mechanisms. Exosomes inhibited LPS-induced inflammation by activating ROCK1 and PTEN expression. Moreover, microRNAs (miR-132 and miR-146a) released from exosomes upregulated the expression of pro-angiogenic genes and promoted proliferation activity and tube formation in human umbilical vein endothelial cells. Exosomal effects were verified using ROCK1/PTEN inhibitors for anti-inflammation and miR-132/miR-146a inhibitors for pro-angiogenesis. Our findings suggest that exosomes exert anti-inflammatory effects by targeting the ROCK1/PTEN pathway and exhibit pro-angiogenic effects via delivery of miR-132 and miR-146a. Taken together, these results suggest that exosomes may be promising therapeutic candidates for curing diseases involved in inflammation and angiogenesis.

Human adipose-derived stem cells (hADSCs) formed robust cell sheets by engineering the cells with soluble cell adhesive molecules (CAMs), which enabled unique approaches to harvest large area hADSC sheets. As a soluble CAM, fibronectin (FN) (100 pg/ml) enhanced the cell proliferation rate and control both cell-to-cell and cell-to-substrate interactions. Through this engineering of FN, a transferrable hADSC sheet was obtained as a free-stranding sheet (122.6 mm 2 ) by a photothermal method. During the harvesting of hADSC sheets by the photothermal method, a collagen layer in-between cells and conductive polymer film (CP) was dissociated, to protect cells from direct exposure to a near infrared (NIR) source. The hADSC sheets were applied to chronic wound of genetically diabetic db / db mice in vivo , to accelerate 30% faster wound closure with a high closure effect (ε wc ) than that of control groups. These results indicated that the engineering of CAM and collagens allow hADSC sheet harvesting, which could be extended to engineer various stem cell sheets for efficient therapies.

Accumulating evidence has shown that the paracrine factors derived from mesenchymal stem cells (MSCs) are capable of regulating the immune system via interaction with various immune cells. In this study, adipose-derived MSCs (AdMSCs) and human peripheral blood monocytes (PBMCs) were isolated and cultured to examine the effects of MSC-induced macrophages (iMΦ) on inflammation and immune modulation. Indirect coculture with MSCs increased the expression of arginase-1 and mannose receptor (CD206), markers of activated M2 macrophages, in the PBMCs demonstrating that MSC-secreted factors promoted M2-MΦ polarization. Additionally, iMΦ exhibited a similar higher inhibitory effect on the growth of activated T cells compared to that in the other groups (AdMSCs only, AdMSCs plus iMΦ), implying that iMΦ can play a sufficient functional role. Interestingly, the population of FoxP3 Treg cells significantly increased when cocultured with iMΦ, suggesting that iMΦ have an immunomodulatory effect on the Treg cells through the modulation of the FoxP3 expression. Notably, iMΦ expressed high levels of immunosuppressive and anti-inflammatory cytokines, namely IL-10 and TSG-6. Furthermore, we confirmed that the AdMSC-derived exosomes modulated macrophage polarization by upregulating the expression of M2 macrophage markers. Conclusively, our results suggest that iMΦ play a significant role in regulating the immunomodulatory- and inflammatory-mediated responses. Thus, iMΦ may be used as a novel stem cell-based cell-free therapy for the treatment of immune-mediated inflammatory disorders.

Mesenchymal stem cells (MSCs) are clinically useful due to their capacity for self-renewal, their immunomodulatory properties and tissue regenerative potential. These cells can be isolated from various tissues and exhibit different potential for clinical applications according to their origin, and thus comparative studies on MSCs from different tissues are essential. In this study, we investigated the immunophenotype, proliferative potential, multilineage differentiation and immunomodulatory capacity of MSCs derived from different tissue sources, namely bone marrow, adipose tissue, the placenta and umbilical cord blood. The gene expression profiles of stemness-related genes [octamer-binding transcription factor 4 (OCT4), sex determining region Y-box (SOX)2, MYC, Krüppel-like factor 4 (KLF4), NANOG, LIN28 and REX1] and lineage-related and differentiation stage-related genes [B4GALNT1 (GM2/GS2 synthase), inhibin, beta A (INHBA), distal-less homeobox 5 (DLX5), runt-related transcription factor 2 (RUNX2), proliferator-activated receptor gamma (PPARG), CCAAT/enhancer-binding protein alpha (C/EBPA), bone morphogenetic protein 7 (BMP7) and SOX9] were compared using RT-PCR. No significant differences in growth rate, colony-forming efficiency and immunophenotype were observed. Our results demonstrated that MSCs derived from bone marrow and adipose tissue shared not only in vitro trilineage differentiation potential, but also gene expression profiles. While there was considerable interdonor variation in DLX5 expression between MSCs derived from different tissues, its expression appears to be associated with the osteogenic potential of MSCs. Bone marrow-derived MSCs (BM-MSCs) significantly inhibited allogeneic T cell proliferation possibly via the high levels of the immunosuppressive cytokines, IL10 and TGFB1. Although MSCs derived from different tissues and fibroblasts share many characteristics, some of the marker genes, such as B4GALNT1 and DLX5 may be useful for the characterization of MSCs derived from different tissue sources. Collectively, our results suggest that, based on their tri-lineage differentiation potential and immunomodulatory effects, BM-MSCs and adipose tissue-derived MSCs (A-MSCs) represent the optimal stem cell source for tissue engineering and regenerative medicine.

Mesenchymal stem cells (MSCs) differentiate into multiple lineages and are a promising source of cells for clinical use. Previously, we found that the gene distal-less homeobox 5 (DLX5) is specifically expressed in MSCs with osteogenic potential. Understanding the mechanism of osteogenesis is necessary for successful bone regeneration using MSCs. The aim of this study was to examine the function of the DLX5 gene in MSCs during osteogenesis (bone development). We analyzed the possible association between DLX5 expression and osteogenesis-, chondrogenesis- and adipogenesis-related gene expression in different cells isolated from bone marrow and cord blood. Differentiation capacity was assessed by observing morphological changes, monitoring gene expression patterns, and staining with Von Kossa, safranin O, and Oil Red O. Suppression of DLX5 expression by means of a small interfering RNA (siRNA) downregulated osteogenic markers and reduced the signs of calcium mineralization. Tanshinone IIA is a known small molecule activator of bone morphogenetic protein (BMP) signaling. Here, we report that induction of DLX5 by tanshinone IIA in MSCs enhanced osteogenic differentiation. In addition, we showed that tanshinone IIA (as a mediator of BMP2 signaling) activates runt-related transcription factor 2 (RUNX2) in MSCs and initiates calcium mineralization during osteogenesis. Taken together, these findings indicate that, in MSCs, DLX5 is a master regulator of osteogenesis. Furthermore, tanshinone IIA may be valuable for stem cell-based therapies of certain bone diseases.

The positive effects of mesenchymal stem cells (MSCs) are primarily activated through molecular secretions known as paracrine activity, which regulates the function of various cell types including immune cells. Accumulating evidence shows that exosomes of soluble factors released from MSCs are potential alternative agents for stem cell-based therapy, although the exact underlying mechanism has not been elucidated. The purpose of this study was to evaluate the potential effects of exosomes produced by adipose-derived MSCs and to examine the changes in anti-inflammatory genes in concurrence with the polarization of M2 macrophages in cellular models ex vivo. Isolated exosomes were used to investigate the inflammatory modulation in pro-inflammatory cytokine-treated fibroblasts and THP-1 cells. The anti-inflammatory mRNA expression associated with M2 macrophages was significantly upregulated after exosome treatment in an interferon gamma and tumor necrosis factor alpha-treated inflammatory environment. Furthermore, melatonin-stimulated exosomes exerted superior anti-inflammatory modulation via exosomal miRNAs miR-34a, miR-124, and miR-135b, compared with exosomes. Our results indicate that melatonin-stimulated exosomes originating from adipose-derived MSCs are safe and efficient tools for regenerative medicine to treat inflammatory diseases.

Mesenchymal stem cell (MSC)-derived exosomes have emerged as an attractive cell-free tool in tissue engineering and regenerative medicine. The current study aimed to examine the anti-inflammatory, pro-angiogenic, and wound-repair effects of both exosomes and selenium-stimulated exosomes, and check whether the latter had superior wound healing capacity over others. The cellular and molecular network of exosomes, as a paracrine signal, was extensively studied by performing miRNA arrays to explore the key mediators of exosomes in wound healing. Selenium is known to play a critical role in enhancing the proliferation, multi-potency, and anti-inflammatory effects of MSCs. Selenium-stimulated exosomes showed significant effects in inhibiting inflammation and improving pro-angiogenesis in human umbilical vein endothelial cells. Cell growth and the migration of human dermal fibroblasts and wound regeneration were more enhanced in the selenium-stimulated exosome group than in the selenium and exosome groups, thereby further promoting the wound healing in vivo. Taken together, selenium was found to augment the therapeutic effects of adipose MSC-derived exosomes in tissue regeneration. We concluded that selenium may be considered a vital agent for wound healing in stem cell-based cell-free therapies.

Mesenchymal stem cells (MSCs) are capable of differentiating into other cell types and exhibit immunomodulatory effects. MSCs are affected by several intrinsic and extrinsic signaling modulators, including growth factors, cytokines, extracellular matrix and hormones. Melatonin, produced by the pineal gland, is a hormone that regulates sleep cycles. Recent studies have shown that melatonin improves the therapeutic effects of stem cells. The present study aimed to investigate whether melatonin enhances the biological activities of human adipose-derived MSCs. The results demonstrated that treatment with melatonin promoted cell proliferation by inducing SRY-box transcription factor 2 gene expression and preventing replicative senescence. In addition, melatonin exerted anti-adipogenic effects on MSCs. PCR analysis revealed that the expression of the CCAAT enhancer binding protein a gene, a key transcription factor in adipogenesis, was decreased following melatonin treatment, resulting in reduced adipogenic differentiation in an in vitro assay. The present study also examined the effect of melatonin on the immunomodulatory response using a co-culture system of human peripheral blood mononuclear cells and MSCs. Activated T cells were strongly inhibited following melatonin exposure compared with those in the control group. Finally, the favorable effects of melatonin on MSCs were confirmed using luzindole, a selective melatonin receptor antagonist. The proliferation-promoting, anti-inflammatory effects of melatonin suggested that melatonin-treated MSCs may be used for effective cell therapy.

Accumulating evidence has revealed that both high sensitivity C-reactive protein (hsCRP) and homocysteine (HCY) are associated with increased risk of metabolic syndrome (MetS) and cardiovascular disease. However, it is unclear whether the coexistence of these conditions accelerates the risk of metabolic syndrome (MetS). We hypothesized that the combination of high sensitivity C-reactive protein (hsCRP) and homocysteine (HCY) levels could exacerbate the development of MetS in a large prospective cohort study. We selected data from 3,170 individuals (1,614 men and 1,556 women) who participated in the Korean Genome and Epidemiology Study. Participants with high hsCRP and HCY levels were categorized into quartiles. MetS was defined based on the criteria of the modified National Cholesterol Education Program, Adult Treatment Panel III. The prevalence of MetS was higher in participants with concurrent high hsCRP and HCY compared to those with low hsCRP and HCY levels. The incidence of MetS at the 6-year follow-up was the highest in participants with concomitant high hsCRP and HCY levels, regardless of obesity. Even after adjusting for potential confounding factors including body mass index in a multivariate logistic regression model, subjects with elevated hsCRP and HCY levels had a 2.50-fold increased risk of developing MetS at the six-year follow-up compared to those who did not have high hsCRP and HCY level. MetS is more prevalent in the concurrent presence of elevated hsCRP and HCY levels. The combination of the two conditions may contribute to an increased risk of MetS, but these factors may not be synergistic.

Mesenchymal stem cells (MSCs) are a promising tool for studying intractable diseases. Unfortunately, MSCs can easily undergo cellular senescence during in vitro expansion by losing stemness. The aim of this study was to improve the stemness and differentiation of MSCs by using glabridin, a natural flavonoid. Assessments of cell viability, cell proliferation, β-galactosidase activity, differentiation, and gene expression by reverse transcription PCR were subsequently performed in the absence or presence of glabridin. Glabridin enhanced the self-renewal capacity of MSCs, as indicated by the upregulation of the OCT4 gene. In addition, it resulted in an increase in the osteogenic differentiation potential by inducing the expression of osteogenesis-related genes such as DLX5 and RUNX2. We confirmed that glabridin improved the osteogenesis of MSCs with a significant elevation in the expression of OSTEOCALCIN and OSTEOPONTIN genes. Taken together, these results suggest that glabridin enhances osteogenic differentiation of MSCs with induction of the OCT4 gene; thus, glabridin could be useful for stem cell-based therapies.