Prior antibiotic administration disrupts anti-PD-1 responses in advanced gastric cancer by altering the gut microbiome and systemic immune response.

Evidence on whether prior antibiotic (pATB) administration modulates outcomes of programmed cell death protein-1 (PD-1) inhibitors in advanced gastric cancer (AGC) is scarce. In this study, we find that pATB administration is consistently associated with poor progression-free survival (PFS) and overall survival (OS) in multiple cohorts consisting of patients with AGC treated with PD-1 inhibitors. In contrast, pATB does not affect outcomes among patients treated with irinotecan. Multivariable analysis of the overall patients treated with PD-1 inhibitors confirms that pATB administration independently predicts worse PFS and OS. Administration of pATBs is associated with diminished gut microbiome diversity, reduced abundance of Lactobacillus gasseri, and disproportional enrichment of circulating exhaustive CD8+ T cells, all of which are associated with worse outcomes. Considering the inferior treatment response and poor survival outcomes by pATB administration followed by PD-1 blockade, ATBs should be prescribed with caution in patients with AGC who are planning to receive PD-1 inhibitors.

Effect of Saengshik Supplementation on the Gut Microbial Composition of Healthy Korean Adults: A Single-Group Pilot Study.

Saengshik is a type of meal-replacement product or dietary supplement comprising an uncooked and dried plant-based food mixture with various health-promoting properties, such as antidiabetic, anti-dyslipidemic, antioxidant, and anticancer properties. Although these properties are considered attributable to the various bioactive components absorbed through the intestine and its remolding effect on intestinal microorganisms, the effect of Saengshik supplementation on gut microbiota profiles has not yet been studied. In this study, we investigated the effect of Saengshik administration on the composition of gut microbiota. This single-group design trial was conducted on 102 healthy men and women who received 40 g/day of Saengshik powder for 8 weeks, during which stool samples were collected at two fixed time points (baseline and the endpoint) for gut microbiota-profiling analysis. We observed a significant decrease in the α-diversity of gut microbiota after Saengshik consumption (P < 0.05), with significant changes identified in the composition of major microbial taxa, such as Bacteroidetes (P < 0.0001), Proteobacteria, Actinobacteria, and Verrucomicrobia (P < 0.0001). Notably, the gut microbial response was related to the inter-individual variability of habitual dietary intake and enterotype at baseline. To the best of our knowledge, this is the first study investigating the effects of Saengshik intake on changes in gut microbiota, with the results suggesting that individual habitual diet patterns and gut microbial shapes should be considered key aspects in Saengshik-mediated health-promotion effects.

Serum level of sex steroid hormone is associated with diversity and profiles of human gut microbiome.

Gut microbiota plays roles in host physiology including endocrine function. Although some data suggest a potential connection between biological sex differences and gut microbiota, the connection between sex steroid hormones and gut microbes remained unexplored. The current study investigates the relationship between gut microbes and serum levels of testosterone in men and estradiol in women. Fecal microbiota from a total of 57 men (n = 31) and women (n = 26) were assessed using 16s rRNA gene sequencing. Based on the levels of serum testosterone and estradiol in men and women, respectively, participants were stratified into three groups of Low, Medium, and High. Microbiome communities were analyzed as a function of the steroid hormone within sex. Men and women in the High group harbored more diverse gut microbial communities than others. In men, the abundance of Acinetobacter, Dorea, Ruminococcus, and Megamonas correlated significantly with testosterone levels. Women in the High group have more Bacteroidetes and less Firmicutes phyla than those in the Low group. Genera Slackia and Butyricimonas were significantly correlated with estradiol levels. These results demonstrate that sex steroid hormone levels are correlated with diversity and gut microbial composition, and provide fundamental information helpful for developing communication networks between human and microbial communities.

Single-Factor SOX2 Mediates Direct Neural Reprogramming of Human Mesenchymal Stem Cells via Transfection of In Vitro Transcribed mRNA.

Neural stem cells (NSCs) are a prominent cell source for understanding neural pathogenesis and for developing therapeutic applications to treat neurodegenerative disease because of their regenerative capacity and multipotency. Recently, a variety of cellular reprogramming technologies have been developed to facilitate in vitro generation of NSCs, called induced NSCs (iNSCs). However, the genetic safety aspects of established virus-based reprogramming methods have been considered, and non-integrating reprogramming methods have been developed. Reprogramming with in vitro transcribed (IVT) mRNA is one of the genetically safe reprogramming methods because exogenous mRNA temporally exists in the cell and is not integrated into the chromosome. Here, we successfully generated expandable iNSCs from human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) via transfection with IVT mRNA encoding SOX2 (SOX2 mRNA) with properly optimized conditions. We confirmed that generated human UCB-MSC-derived iNSCs (UM-iNSCs) possess characteristics of NSCs, including multipotency and self-renewal capacity. Additionally, we transfected human dermal fibroblasts (HDFs) with SOX2 mRNA. Compared with human embryonic stem cell-derived NSCs, HDFs transfected with SOX2 mRNA exhibited neural reprogramming with similar morphologies and NSC-enriched mRNA levels, but they showed limited proliferation ability. Our results demonstrated that human UCB-MSCs can be used for direct reprogramming into NSCs through transfection with IVT mRNA encoding a single factor, which provides an integration-free reprogramming tool for future therapeutic application.

Inhibition by miR-410 facilitates direct retinal pigment epithelium differentiation of umbilical cord blood-derived mesenchymal stem cells.

Retinal pigment epithelium (RPE) is a major component of the eye. This highly specialized cell type facilitates maintenance of the visual system. Because RPE loss induces an irreversible visual impairment, RPE generation techniques have recently been investigated as a potential therapeutic approach to RPE degeneration. A microRNA-based technique is a new strategy for producing RPE cells from adult stem cell sources. Previously, we identified that antisense microRNA-410 (anti-miR-410) induces RPE differentiation from amniotic epithelial stem cells. In this study, we investigated RPE differentiation from umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) via anti-miR-410 treatment. We identified miR-410 as a RPE-relevant microRNA in UCB-MSCs from among 21 putative human RPE-depleted microRNAs. Inhibition of miR-410 induces overexpression of immature and mature RPE-specific factors, including MITF, LRAT, RPE65, Bestrophin, and EMMPRIN. The RPE-induced cells were able to phagocytize microbeads. Results of our microRNA-based strategy demonstrated proof-of-principle for RPE differentiation in UCB-MSCs by using anti-miR-410 treatment without the use of additional factors or exogenous transduction.

Human adipose tissue-derived mesenchymal stem cells alleviate atopic dermatitis via regulation of B lymphocyte maturation.

Mesenchymal stem cell (MSC) has been applied for the therapy of allergic disorders due to its beneficial immunomodulatory abilities. However, the underlying mechanisms for therapeutic efficacy are reported to be diverse according to the source of cell isolation or the route of administration. We sought to investigate the safety and the efficacy of human adipose tissue-derived MSCs (hAT-MSCs) in mouse atopic dermatitis (AD) model and to determine the distribution of cells after intravenous administration. Murine AD model was established by multiple treatment of Dermatophagoides farinae. AD mice were intravenously infused with hAT-MSCs and monitored for clinical symptoms. The administration of hAT-MSCs reduced the gross and histological signatures of AD, as well as serum IgE level. hAT-MSCs were mostly detected in lung and heart of mice within 3 days after administration and were hardly detectable at 2 weeks. All of mice administered with hAT-MSCs survived until sacrifice and did not demonstrate any adverse events. Co-culture experiments revealed that hAT-MSCs significantly inhibited the proliferation and the maturation of B lymphocytes via cyclooxygenase (COX)-2 signaling. Moreover, mast cell (MC) degranulation was suppressed by hAT-MSC. In conclusion, the intravenous infusion of hAT-MSCs can alleviate AD through the regulation of B cell function.

Human umbilical cord blood-stem cells direct macrophage polarization and block inflammasome activation to alleviate rheumatoid arthritis.

Rheumatoid arthritis (RA) is a long-lasting intractable autoimmune disorder, which has become a substantial public health problem. Despite widespread use of biologic drugs, there have been uncertainties in efficacy and long-term safety. Mesenchymal stem cells (MSCs) have been suggested as a promising alternative for the treatment of RA because of their immunomodulatory properties. However, the precise mechanisms of MSCs on RA-related immune cells are not fully elucidated. The aim of this study was to investigate the therapeutic potential of human umbilical cord blood-derived MSCs (hUCB-MSCs) as a new therapeutic strategy for patients with RA and to explore the mechanisms underlying hUCB-MSC-mediated immunomodulation. Mice with collagen-induced arthritis (CIA) were administered with hUCB-MSCs after the onset of disease, and therapeutic efficacy was assessed. Systemic delivery of hUCB-MSCs significantly ameliorated the severity of CIA to a similar extent observed in the etanercept-treated group. hUCB-MSCs exerted this therapeutic effect by regulating macrophage function. To verify the regulatory effects of hUCB-MSCs on macrophages, macrophages were co-cultured with hUCB-MSCs. The tumor necrosis factor (TNF)-α-mediated activation of cyclooxygenase-2 and TNF-stimulated gene/protein 6 in hUCB-MSCs polarized naive macrophages toward an M2 phenotype. In addition, hUCB-MSCs down-regulated the activation of nucleotide-binding domain and leucine-rich repeat pyrin 3 inflammasome via a paracrine loop of interleukin-1ß signaling. These immune-balancing effects of hUCB-MSCs were reproducible in co-culture experiments using peripheral blood mononuclear cells from patients with active RA. hUCB-MSCs can simultaneously regulate multiple cytokine pathways in response to pro-inflammatory cytokines elevated in RA microenvironment, suggesting that treatment with hUCB-MSCs could be an attractive candidate for patients with treatment-refractory RA.

BMI1 inhibits senescence and enhances the immunomodulatory properties of human mesenchymal stem cells via the direct suppression of MKP-1/DUSP1.

For the application of mesenchymal stem cells (MSCs) as clinical therapeutics, the regulation of cellular aging is important to protect hMSCs from an age-associated decline in their function. In this study, we evaluated the effects of hypoxia on cellular senescence and the immunomodulatory abilities of hUCB-MSCs. Hypoxic-cultured hUCB-MSCs showed enhanced proliferation and had increased immunosuppressive effects on mitogen-induced mononuclear cell proliferation. We found that BMI1, a member of the polycomb repressive complex protein group, showed increased expression in hypoxic-cultured hUCB-MSCs, and the further knock-down of BMI1 in hypoxic cells induced decreased proliferative and immunomodulatory abilities in hUCB-MSCs, along with COX-2/PGE2 down-regulation. Furthermore, the expression of phosphorylated p38 MAP kinase increased in response to the over-expression of BMI1 in normoxic conditions, suggesting that BMI1 regulates the immunomodulatory properties of hUCB-MSCs via p38 MAP kinase-mediated COX-2 expression. More importantly, we identified BMI1 as a direct repressor of MAP kinase phosphatase-1 (MKP-1)/DUSP1, which suppresses p38 MAP kinase activity. In conclusion, our results demonstrate that BMI1 plays a key role in the regulation of the immunomodulatory properties of hUCB-MSCs, and we suggest that these findings might provide a strategy to enhance the functionality of hUCB-MSCs for use in therapeutic applications.

STB-HO, a novel mica fine particle, inhibits the teratoma-forming ability of human embryonic stem cells after in vivo transplantation.

Although pluripotent stem cell (PSC) therapy has advantages for clinical applications because of the self-renewal and multi-lineage differentiation abilities of PSCs, it also has disadvantages in terms of the potential for PSCs to undergo malignant transformation or unexpected differentiation. The prevention of teratoma formation is the largest hurdle of all. Despite intensive studies that have investigated ways to block teratomas, such methods have yet to be further developed for clinical use. Here, a new approach has focused on exerting anti-tumorigenic effects using a novel mica fine particle (MFP) designated STB-HO. Treatment with STB-HO regulated pluripotency- and apoptosis-related genes in differentiating human embryonic stem (hES) cells, while there is no effects in undifferentiated hES cells. In particular, STB-HO blocked the anti-apoptotic gene BIRC5 and activated p53, p21 and the pro-apoptotic proteins Bim, Puma and p-Bad during early spontaneous differentiation. Moreover, STB-HO-pretreated differentiating hES cells did not give rise to teratomas following in vivo stem cell transplantation. Our in vitro and in vivo results suggest a method for teratoma prevention in the context of PSC-derived cell transplantation. This novel MFP could break through the limitations of PSC therapy.