Comparison of the therapeutic effects of mesenchymal stem cells derived from human dental pulp (DP), adipose tissue (AD), placental amniotic membrane (PM), and umbilical cord (UC) on postmenopausal osteoporosis.

Background: Osteoporosis is a systemic bone disease characterized by bone loss and microstructural degeneration. Recent preclinical and clinical trials have further demonstrated that the transplantation of mesenchymal stem cells (MSCs) derived from human adipose tissue (AD), dental pulp (DP), placental amniotic membrane (AM), and umbilical cord (UC) tissues can serve as an effective form of cell therapy for osteoporosis. However, MSC-mediated osteoimmunology and the ability of these cells to regulate osteoclast-osteoblast differentiation varies markedly among different types of MSCs. Methods: In this study, we investigated whether transplanted allogeneic MSCs derived from AD, DP, AM, and UC tissues were able to prevent osteoporosis in an ovariectomy (OVX)-induced mouse model of osteoporosis. The homing and immunomodulatory ability of these cells as well as their effects on osteoblastogenesis and the maintenance of bone formation were compared for four types of MSCs to determine the ideal source of MSCs for the cell therapy-based treatment of OVX-induced osteoporosis. The bone formation and bone resorption ability of these four types of MSCs were analyzed using micro-computed tomography analyses and histological staining. In addition, cytokine array-based analyses of serological markers and bioluminescence imaging assays were employed to evaluate cell survival and homing efficiency. Immune regulation was determined by flow cytometer assay to reflect the mechanisms of osteoporosis treatment. Conclusion: These analyses demonstrated that MSCs isolated from different tissues have the capacity to treat osteoporosis when transplanted in vivo. Importantly, DP-MSCs infusion was able to maintain trabecular bone mass more efficiently with corresponding improvements in trabecular bone volume, mineral density, number, and separation. Among the tested MSC types, DP-MSCs were also found to exhibit greater immunoregulatory capabilities, regulating the Th17/Treg and M1/M2 ratios. These data thus suggest that DP-MSCs may represent an effective tool for the treatment of osteoporosis.

EPO regulates the differentiation and homing of bone marrow mesenchymal stem cells through Notch1/Jagged pathway to treat pulmonary hypertension.

Purpose: To investigate whether erythropoietin (EPO) can treat pulmonary arterial hypertension (PAH) in rats by regulating the differentiation and homing of bone marrow mesenchymal stem cells (BMSCs) through Notch1/Jagged signaling pathway. Materials & methods: BMSCs were isolated from the bone marrow of 6-week-old male SD rats by whole bone marrow method and identified. BMSCs were treated with 500 IU/mL EPO, and the proliferation, migration, invasion and differentiation ability, and the expression of MMP-2 and MMP-9 protein of BMSCs were detected in vitro. After the establishment of the pulmonary hypertension model in rats, BMSCs were intervened with different concentrations of EPO and injected into the rats through intravenous injection. The levels of TNF-α, IL-1ß and IL-6 in lung tissue, the expression of SRY CXCR4, CCR2, Notch1 and Jagged protein in lung tissue, and the levels of TGF-α, vascular endothelial factor (VEGF), IGF-1 and HGF in serum were detected. Immunofluorescence (IF) staining was used to detect the co-localization of CD34. Results: EPO promoted the proliferation, migration, and invasion of BMSCs by inhibiting Notch1/Jagged pathway in vitro, and induced BMSCs to differentiate into vascular smooth muscle cells and vascular endothelial cells. EPO inhibited Notch1/Jagged pathway in PAH rats, induced BMSCs homing and differentiation, increased the levels of TGF-α, VEGF, IGF-1 and HGF, and decreased the levels of TNF-α, IL-1ß and IL-6. Discussion & conclusion: EPO can inhibit the Notch1/Jagged pathway and promote the proliferation, migration, invasion, homing and differentiation of BMSCs to treat pulmonary hypertension in rats in vitro and in vivo.

Erythropoietin improves pulmonary hypertension by promoting the homing and differentiation of bone marrow mesenchymal stem cells in lung tissue.

Pulmonary arterial hypertension (PAH) is a chronic disease thatultimately progresses to right-sided heart failure and death. Erythropoietin (EPO) has been shown to have therapeutic potential in cardiovascular diseases, including PAH. In this study, we aimed to investigate the improvement effect of EPO pretreated bone marrow mesenchymal stem cells (BMSCs) on PAH. BMSCs were obtained from the bone marrow of male SD rats. Female rats were randomly divided into six groups, including control group, monocrotaline (MCT)-induced group, and four groups with different doses of EPO pretreated BMSCs. Lung tissue was taken for testing at 2 weeks of treatment. Our results showed EPO promoted homing and endothelial cell differentiation of BMSCs in the lung tissues of PAH rats. EPO and BMSCs treatment attenuated pulmonary arterial pressure, polycythemia, and pulmonary artery structural remodeling. Furthermore, BMSCs inhibited pulmonary vascular endothelial-to-mesenchymal transition (EndoMT) in PAH rats, which was further suppressed by EPO in a concentration-dependent manner. Meanwhile, EPO and BMSC treatment elevated pulmonary angiogenesis in PAH rats. BMSCs inhibited TNF-α, IL-1ß, IL-6, and MCP-1 in lung tissues of PAH rats, which was further decreased by EPO in a concentration-dependent manner. Thus, EPO improved pulmonary hypertension (PH) by promoting the homing and differentiation of BMSCs in lung tissue.

Liuwei Dihuang pills attenuate ovariectomy-induced bone loss by alleviating bone marrow mesenchymal stem cell (BMSC) senescence via the Yes-associated protein (YAP)-autophagy axis.

CONTEXT: Liuwei Dihuang pill (LWDH) has been used to treat postmenopausal osteoporosis (PMOP). OBJECTIVE: To explore the effects and mechanisms of action of LWDH in PMOP. MATERIALS AND METHODS: Forty-eight female Sprague-Dawley rats were divided into four groups: sham-operated (SHAM), ovariectomized (OVX), LWDH high dose (LWDH-H, 1.6 g/kg/d) and LWDH low dose (LWDH-L, 0.8 g/kg/d); the doses were administered after ovariectomy via gavage for eight weeks. After eight weeks, the bone microarchitecture was evaluated. The effect of LWDH on the differentiation of bone marrow mesenchymal stem cells (BMSCs) was assessed via osteogenesis- and lipogenesis-induced BMSC differentiation. The senescence-related biological indices were also detected using senescence staining, cell cycle analysis, quantitative real-time polymerase chain reaction and western blotting. Finally, the expression levels of autophagy-related proteins and Yes-associated protein (YAP) were evaluated. RESULTS: LWDH-L and LWDH-H significantly modified OVX-induced bone loss. LWDH promoted osteogenesis and inhibited adipogenesis in OVX-BMSCs. Additionally, LWDH decreased the positive ratio of senescence OVX-BMSCs and improved cell viability, cell cycle, and the mRNA and protein levels of p53 and p21. LWDH upregulated the expression of autophagy-related proteins, LC3, Beclin1 and YAP, in OVX-BMSCs and downregulated the expression of p62. DISCUSSION AND CONCLUSIONS: LWDH improves osteoporosis by delaying the BMSC senescence through the YAP-autophagy axis.

Endometriosis of the skeletal muscular system (ESMS): a systematic review.

BACKGROUND: Extrapelvic endometriosis occurring at skeletal muscle and joint sites is not rare and is prone to delayed diagnosis and inappropriate treatment. Herein, endometriosis of the skeletal muscular system (ESMS) is systematically reviewed to facilitate early diagnosis and treatment. METHODS: Literature on ESMS published before March 2022 was retrieved from the Ovid Medline and Web of Science databases, and the major clinical data were extracted for descriptive analysis. RESULTS: A total of 62 studies (78 ESMS cases) met these requirements. The ESMS included the abdominal muscles (50.7%), pelvic floor muscles (11.6%), lower limb muscles (11.6%), hip muscles (8.7%), lumbar muscles (7.2%), joints (5.8%), upper limb muscles (2.9%), and shoulder-neck muscles (1.4%). The age was 34.0 ± 7.2 years (range 17-49 years). Approximately 63.8% of patients had at least one previous pelvic surgery, and 76.8% of local symptoms were related to the menstrual cycle. The course of disease was 29.6 ± 25.4 months (range 0.5-96 months). Only 30.3% of the patients sought initial medical advice from gynecologists, while 69.7% sought initial medical advice from a nongynecological physician. Twenty-seven patients underwent fine-needle aspiration (FNA) under ultrasound or CT monitoring, and only 44.4% (12/27) were confirmed to have endometriosis by FNA tissue pathology. Approximately 47.4% (37/78) of the patients had a normal pelvic cavity appearance. Surgical resection was performed in 92.3% (72/78) of the patients, of whom 88.9% (64/72) underwent complete resection of the lesion (negative surgical margin) and 20.8% (15/72) received postoperative hormone therapy. At 16.7 months of follow-up, 83.3%, 13.8%, 2.9%, and four patients had complete response, partial response, recurrence, and permanent function impairment, respectively. CONCLUSION: Endometriosis can occur at almost any site in the musculoskeletal system. For women of reproductive age with catamenial pain or a mass in the musculoskeletal system, endometriosis should be suspected. Fine-needle aspiration can easily lead to missed diagnoses. Surgical resection for negative margins is the main treatment, and permanent impairment of function may occur in a few patients due to delayed diagnosis. Vascular lymphatic metastasis is the most likely mechanism of pathogenesis.

Bavachin inhibits IL-4 expression by downregulating STAT6 phosphorylation and GATA-3 expression and ameliorates asthma inflammation in an animal model.

IL-4 plays a key role in many human diseases, including allergic asthma, autoimmunity, allergies, and cancer. Therefore, the investigation of small compounds that regulate IL-4 secretion is of great interest for fighting these diseases. Natural flavonoids are useful compounds reported to have therapeutic effects in diseases involving IL-4. This study aimed to investigate small compounds that inhibit the effect of IL-4 with the lowest cell toxicity. We found that Bavachin had the greatest ability to downregulate IL-4 in the spleen of T cells from 4get IL-4-GFP mice. To identify the underlying molecular mechanisms, we found that Bavachin could decrease the IL-4 levels by downregulating the level of Gata-3 expression and STAT6 phosphorylation. These findings reveal the potential use of Bavachin as a tool for selectively controlling diseases involving IL-4 and, more generally, STAT6-dependent responses.

Why Are Viruses Spiked?

Many viruses, such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV), have a structure consisting of spikes protruding from an underlying spherical surface. Research in biological and colloidal sciences has revealed secrets of why spikes exist on virus surfaces. Specifically, the spikes favor virus attachment on surfaces via receptor-specific interactions (RSIs), mediate the membrane fusion, and determine or change viral tropism. The spikes also facilitate viruses to approach surfaces before attachment and subsequently escape back to the environment if RSIs do not occur (i.e., easy come and easy go). Therefore, virus spikes create the paradox of having a large capacity for binding with cells (high infectivity) and meanwhile great mobility in the environment. Such structure-function relationships have important implications for the fabrication of virus-like particles and analogous colloids (e.g., hedgehog- and raspberry-like particles) for applications such as the development of antiviral vaccines and drug delivery.

Long non-coding RNAs: Emerging regulators for chemo/immunotherapy resistance in cancer stem cells.

Cancer stem cells (CSCs) are a small subpopulation of tumor cells critical for tumor development. Their unique abilities, such as self-renewal, have resulted in tumor resistance to various cancer treatments, including traditional chemotherapy and latest immunotherapy. CSCs-targeting therapy is a promising treatment to overcome the therapeutic resistances to different tumors. However, despite their significance, the regulatory mechanism generating therapy-resistant CSCs is still obscure. Long non-coding RNAs (lncRNAs) are key regulators in various biological processes, including cell proliferation, apoptosis, migration, and invasion. Recent studies have revealed that lncRNAs play an important role in the therapeutic resistance of CSCs. Here we summarize the latest studies on the regulatory role of lncRNAs in sustaining the stemness of CSCs, and discuss the associated mechanisms behind these behavior changes in CSCs-related chemo- and immune-resistance. Future research implications are also discussed, shedding light on the potential CSCs-targeted strategies to break through the resistance of current therapies.

Removal of hexavalent chromium from aqueous solution by fabricating novel heteroaggregates of montmorillonite microparticles with nanoscale zero-valent iron.

This study fabricated novel heteroaggregates of montmorillonite (Mt) microparticles with nanoscale zero-valent iron (nZVI) (Mt-nZVI) and examined the removal of Cr(VI) by the Mt-nZVI through batch experiments. Spherical nZVI particles were synthesized by the liquid phase reduction method, which were then attached on the flat Mt surfaces in monolayer. The fabricated Mt-nZVI had similar removal efficiency for Cr(VI) compared to the monodispersed nZVI particles, but was much greater than that of nZVI aggregates. The removal efficiency of Mt-nZVI increased with decreasing its dosage and increasing initial Cr(VI) concentration, whereas had insignificant change with solution pH. The removal of Cr(VI) by Mt-nZVI was well described by the pseudo second-order kinetics and the Langmuir equilibrium model. The removal was spontaneous and exothermic, which was mainly due to chemsorption rather than intra-particle diffusion according to calculation of change in free energy and enthalpy and Weber-Morris model simulations. X-ray diffraction and X-ray photoelectron spectroscopy analysis revealed that the adsorption was likely due to reduction of Cr(VI) to Cr(III) by Fe(0) and co-precipitation in the form of oxide-hydroxide of Fe(III) and Cr(III). The fabricated Mt-nZVI showed the promise for in-situ soil remediation due to both high removal efficiency and great mobility in porous media.

CD47: the next checkpoint target for cancer immunotherapy.

Cancer immunotherapy using checkpoint blockade has brought about a paradigm shift in the treatment of advanced-stage cancers. Unfortunately, not all patients benefit from these therapies, paving the way for other immune checkpoints to be targeted. CD47, a 'marker-of-self' protein that is overexpressed broadly across tumor types, is emerging as a novel potent macrophage immune checkpoint for cancer immunotherapy. Recently, CD47 blockade by Hu5F9-G4 has shown promise combined with Rituximab in non-Hodgkin's lymphoma. Here we review the complex structure and various physiological functions of CD47 and their implications in cancer biology. Further, this review considers future directions and challenges in advancing this promising target platform to widespread therapeutic use.

Mobility of Cellulose Nanocrystals in Porous Media: Effects of Ionic Strength, Iron Oxides, and Soil Colloids.

Understanding the dispersivity and migration of cellulose nanocrystals (CNCs) in porous media is important for exploring their potential for soil and water remediation. In this study, a series of saturated column experiments were conducted to investigate the coupled effects of ionic strength, iron oxides (hematite), and soil colloids on the transport of CNCs through quartz sand and natural soils (red earth and brown earth). Results showed that CNCs had high mobility in oxide-free sand and that iron oxide coating reduced the mobility of CNCs. An analysis of Derjaguin-Landau-Verwey-Overbeek interactions indicated that CNCs exhibited a deep primary minimum, nonexistent maximum repulsion and secondary minimum on hematite-coated sand, favorable for the attachment of CNCs. The maximum effluent percentage of CNCs was 96% in natural soils at 5 mM, but this value decreased to 4% at 50 mM. Soil colloids facilitated the transport of CNCs in brown earth with larger effect at higher ionic strength. The ionic strength effect was larger in natural soils than sand and in red earth than brown earth. The study showed that CNCs can travel 0.2 m to 72 m in porous media, depending on soil properties, solution chemistry, and soil colloids.

An adaptive Kalman filtering algorithm based on back-propagation (BP) neural network applied for simultaneously detection of exhaled CO and N2O.

A compact high-resolution spectroscopic sensor using a thermoelectrically (TE) cooled continuous-wave (CW) room temperature (RT) quantum cascade laser (QCL) was demonstrated for simultaneous measurements of exhaled carbon monoxide (CO) and nitrous oxide (N2O). The sampling pressure was optimized to improve the sensitivity, the optimal pressure was determined to be 150 mbar based on an optical density analysis of simulated and measured absorption spectra. An adaptive Kalman filtering algorithm based on back-propagation (BP) neural network was developed and proposed for real-time exhaled breath analysis in order to perform fast and high precision on-line measurements. The detection limits (1σ) of 1.14 ppb and 1.12 ppb were experimentally achieved for CO and N2O detection, respectively. Typical concentrations of exhaled CO and N2O from smokers and non-smokers were analyzed. The experimental results indicated that the state-of-the-art CW-QCL based sensor has a great potential for non-invasive, on-line identification and quantification of biomarkers in human breath.

A novel method for the preparation of solvent-free, microwave-assisted and nitrogen-doped carbon dots as fluorescent probes for chromium(vi) detection and bioimaging.

Chromium(vi) [Cr(vi)] has been shown to be toxic to organisms due to its mutagenicity and carcinogenicity. Therefore, the exploitation of probes with low toxicity and high sensitivity for Cr(vi) detection is needed. In this study, a one-step, solvent-free, and microwave-assisted method was developed for the preparation of nitrogen-doped carbon dots (N-CDs). The reaction could be finished in just three minutes, and the yield of the dots could reach 58.5%; the as-prepared N-CDs exhibited excellent water solubility, emitted bright cyan fluorescence with a high quantum yield of 38.88%, and possessed excitation- and concentration-dependent characteristics. The N-CDs could be effectively applied to Cr(vi) detection with a linear range of 1-100 µM, and the detection limit could be as low as 0.12 µM. The quenching mechanism was responsible for the inner filter effect, and the quenched fluorescence could be recovered with a linear range of 5-100 µM by the addition of ascorbic acid. We showed that the fluorescent probes could even be employed for the detection of Cr(vi) in river water and for bio-imaging because of their nearly zero cytotoxicity; this showed the potential application of these probes in ion detection and cellular bioimaging. Herein, we have provided an effective strategy to rapidly obtain high-quality N-CDs using a solid-phase microwave method, and the as-prepared N-CDs exhibit various potential applications in environmental and biological fields.

Histone demethylase JMJD6 regulates cellular migration and proliferation in adipose-derived mesenchymal stem cells.

BACKGROUND: Adipose-derived mesenchymal stem cells (ADSCs) have been extensively explored as a promising therapeutic agent due to their differentiation, proliferation and migration abilities. The epigenetic mechanisms that regulate the fate of mesenchymal stem cells (MSCs) have been described in detail. However, the epigenetic modulation of ADSCs proliferation and migration is poorly understood. METHODS: The present study examined histone demethylases roles and expression by RT-PCR, as well as through siRNA screening and ChIP-qPCR assay. Cellular proliferation and migration assays were employed in shRNA-mediated JMJD6 knockdown and control ADSCs. PDE1C inhibition studies were conducted to confirm its role in JMJD6-mediated epigenetic regulation of ADSCs. RESULTS: The data demonstrate that the histone demethylase JMJD6 plays a critical role in regulating the proliferation and migration of ADSCs by removing H4R3me2a at the promoter regions of PDEC1 and suppressing PDEC1 expression. Importantly, the depletion of JMJD6 in ADSCs significantly increased cellular proliferation and motility, which was associated with increases in PDE1C expression and decreases in the levels of both cAMP and cGMP. The increase in proliferation and migration was reversed by treatment with a PDE1C inhibitor, suggesting that JMJD6 attenuates the proliferation and migration of ADSCs as an epigenetic regulator and PDE1C partially contributes to the JMJD6-mediated regulation. CONCLUSIONS: Taken together, our results indicate for the first time that JMJD6 plays an important role in the regulation of ADSCs proliferation and migration through the modulation of PDE1C expression.

Role of solution chemistry in the retention and release of graphene oxide nanomaterials in uncoated and iron oxide-coated sand.

Understanding the fate and transport including remobilization of graphene oxide nanomaterials (GONMs) in the subsurface would enable us to expedite their benign use and evaluate their environmental impacts and health risks. In this study, the retention and release of GONMs were investigated in water-saturated columns packed with uncoated sand (Un-S) or iron oxide-coated sand (FeS) at environmentally relevant solution chemistries (1-100mM KCl and 0.1-10mM CaCl2 at pH7 and 11). Our results showed that increasing ionic strength (IS) inhibited GONMs' transport, and the impact of K+ was less than Ca2+. The positively charged iron oxide coating on sand surfaces immobilized the negatively charged GONMs (pH7) in the primary minimum, yielding hyperexponential retention profiles particularly in Ca2+. A stepwise decrease in pore-water IS caused detachment of previously retained GONMs. The mass of GONMs released during each detachment step correlated positively with the difference in secondary minimum depth (ΔΦmin2) at each IS, indicating that the released GONMs were retained in the secondary minimum. While most retained GONMs were re-entrained upon lowering pore-water IS in Un-S, decreasing IS only released limited GONMs in FeS, which were captured in the primary minimum. Introducing 1mM NaOH (pH11) released most retained GONMs in FeS; and average hydrodynamic diameters of the detached GONMs upon injecting NaOH were significantly smaller than those of GONMs in the influent and retentate, suggesting that NaOH induced GONMs disaggregation. Our findings advance current knowledge to better predict NMs' fate and transport under various solution chemistries such as during rainfall events or in the mixing zones between sea water and fresh water where transient IS changes drastically.

Effective removal of nemacide fosthiazate from an aqueous solution using zero-valent iron.

In this study, the removal of fosthiazate in an aqueous solution using zero valent iron (ZVI) and the related removal reaction mechanism were investigated. The results indicate that the dissipation of fosthiazate adheres to a pseudo-first order reaction law. The apparent rate constant of fosthiazate removal could be improved by increasing the ZVI dosage, control temperature and initial pH. The observed pseudo-first-order degradation rate constants (Kobs) of fosthiazate removal using ZVI were varied in the different electrolyte solutions, and were determined as follows: Kobs (MgSO4) < Kobs (KCl) < Kobs (Control)

Human Umbilical Cord Mesenchymal Stem Cells Inhibit the Function of Allogeneic Activated Vγ9Vδ2 T Lymphocytes In Vitro.

BACKGROUND: Human umbilical cord mesenchymal stem cells (UC-MSCs) can regulate the function of immune cells. However, whether and how UC-MSCs can modulate the function of Vγ9Vδ2 T cells has not been fully understood. METHODS: The PBMCs or Vγ9Vδ2 T cells were activated and expanded with pamidronate (PAM) and interleukin-2 (IL-2) with or without the presence UC-MSCs. The effects of UC-MSCs on the proliferation, cytokine expression, and cytotoxicity of Vγ9Vδ2 T cells were determined by flow cytometry. The effects of UC-MSCs on Fas-L, TRAIL-expressing Vγ9Vδ2 T cells, and Vγ9Vδ2 T cell apoptosis were determined by flow cytometry. RESULTS: UC-MSCs inhibited Vγ9Vδ2 T cell proliferation in a dose-dependent but cell-contact independent manner. Coculture with UC-MSCs reduced the frequency of IFNγ+ but increased granzyme B+ Vγ9Vδ2 T cells. UC-MSCs inhibited the cytotoxicity of Vγ9Vδ2 T cells against influenza virus H1N1 infected A549 cells and also reduced the frequency of Fas-L+, TRAIL+ Vγ9Vδ2 T cells but failed to modulate the apoptosis of Vγ9Vδ2 T cells. CONCLUSIONS: These results indicated that UC-MSCs efficiently suppressed the proliferation and cytotoxicity of Vγ9Vδ2 T cells and modulated their cytokine production. Fas-L and TRAIL were involved in the regulation. Cell contact and apoptosis of Vγ9Vδ2 T cells were not necessary for the inhibition.

Conditioned medium from umbilical cord mesenchymal stem cells induces migration and angiogenesis.

Umbilical cord mesenchymal stem cells (UC-MSCs) have been suggested as a candidate for various clinical applications, however, major limitations include the lack of organ-specific accumulation and low survival rates of transplanted cells. In the present study, it was hypothesized that the paracrine effects of UC­MSCs may enhance stem cell-based tissue repair and regeneration by promoting the specific homing of stem/progenitor cells and the overall ability to drive them to the damaged area. UC-MSCs-derived conditioned medium (UC-CM) was analyzed using liquid chip and ELISA techniques. In vitro tube formation assays of human umbilical vein endothelial cells (HUVECs) and UC-MSCs were then performed to assess the angiogenic properties of UC-CM. Subsequently, UC-MSCs, HUVECs and fibroblasts were labeled with PKH26 for an in vivo cell migration assay. The expression levels of C-X-C chemokine receptor 4 (CXCR4), C-C chemokine receptor 2 (CCR2) and c-met were determined in the UC-MSCs, HUVECs and fibroblasts using reverse transcription-quantitative polymerase chain reaction and flow cytometry. UC-CM was incubated with or without antibodies, and the contribution of stromal cell-derived factor 1 (SDF-1), monocyte chemotactic protein 1 (MCP-1) and hepatocyte growth factor (HGF) on the migration of cells was investigated in vitro. The results demonstrated that UC-MSCs secreted different cytokines and chemokines, including increased quantities of SDF-1, MCP-1 and HGF, in addition to the angiogenic factors, vascular cell adhesion protein-1, interleukin-8, insulin-like growth factor-1 and vascular endothelial growth factor. The total lengths of the tubes were significantly increased in the UC-MSCs and HUVECs incubated in UC-CM compared with those incubated in Dulbecco's modified Eagle's medium. In vivo cell migration assays demonstrated that UC-CM was a chemotactic stimulus for the UC-MSCs and HUVECs. In vitro Matrigel migration and scratch healing assays demonstrated that UC-CM increased the migration of CXCR4-positive or/and CCR2-positive cells in a dose-dependent manner. In addition, different molecules were screened under antibody-based blocking migration conditions. The data revealed that the SDF-1/CXCR4 and MCP-1/CCR2 axes were involved in the chemoattractive activity of UC-CM and suggested that the effective paracrine factor of UC-CM is a large complex rather than a single factor. The results of the present study supported the hypothesis that UC-MSCs release soluble factors, which may extend the therapeutic applicability of stem cells.

Negligible immunogenicity of induced pluripotent stem cells derived from human skin fibroblasts.

Human induced pluripotent stem cells (hiPSCs) have potential applications in cell replacement therapy and regenerative medicine. However, limited information is available regarding the immunologic features of iPSCs. In this study, expression of MHC and T cell co-stimulatory molecules in hiPSCs, and the effects on activation, proliferation and cytokine production in allogeneic human peripheral blood mononuclear cells were examined. We found that no-integrate hiPSCs had no MHC-II and T cell co-stimulatory molecules expressions but had moderate level of MHC-I and HLA-G expressions. In contrast to human skin fibroblasts (HSFs) which significantly induced allogeneic T cell activation and proliferation, hiPSCs failed to induce allogeneic CD45+ lymphocyte and CD8+ T cell activation and proliferation but could induce a low level of allogeneic CD4+ T cell proliferation. Unlike HSFs which induced allogeneic lymphocytes to produce high levels of IFN-γ, TNF-α and IL-17, hiPSCs only induced allogeneic lymphocytes to produce IL-2 and IL-10, and promote IL-10-secreting regulatory T cell (Treg) generation. Our study suggests that the integration-free hiPSCs had low or negligible immunogenicity, which may result from their induction of IL-10-secreting Treg.

Impaired NK cell antiviral cytokine response against influenza virus in small-for-gestational-age neonates.

The neonates, particularly small-for-gestational-age (SGA) ones, are susceptible to various microbial infections. Natural killer (NK) cells are critical components of host innate immunity system and the main source of the inflammatory cytokines, which provide critical protection during the early phase of viral infections before the development of an appropriate adaptive immune response. However, little is known about the antiviral effects of NK cells in neonates especially the SGA population. Herein, a prospective descriptive study was performed to determine the differences of NK cell immunity among adults, appropriate-for gestational-age (AGA) and SGA neonates. Adults have much higher NK cell number in peripheral blood than that in cord blood from neonates. In response to influenza virus stimulation, neonatal NK cells, especially SGA baby cells, expressed significantly lower antiviral cytokines including perforin, interferon (IFN)-γ and tumor-necrosis factor (TNF)-α responses than adult NK cells. In addition, the antiviral cytokine responses of NK cells were positively correlated with neonatal birth weight. Our data suggested that the depressed antiviral activity and less frequency of NK cells are likely to be responsible for the high susceptibility to microbial infection in neonates, at least in part. Improving the function of innate immunity may provide a new way to defend virus infection.