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Chen P.-M.,Institute of Cellular and System Medicine | Liu K.-J.,National Health Research Institute | Liu K.-J.,Taipei Medical University | Hsu P.-J.,Institute of Cellular and System Medicine | And 5 more authors.
Journal of Leukocyte Biology | Year: 2014

Monocytes are a population of leukocytes that terminally differentiate into macrophages and DCs. Whereas these differentiated progeny have inflammatory and resident-which are more immunomodulatory-phenotypes, less has been reported on the plasticity of monocytes themselves. We found that MSCs, a population of somatic stem cells, can rapidly induce human and murine monocytes through secretion of HGF to acquire an immunomodulatory phenotype to suppress T cell effector function. MSCs are multilineage postnatal progenitor cells with strong immunomodulatory effects toward T lymphocytes, NK lymphocytes, and DCs, but less is known regarding their interactions with monocytes. We found that CD14+ human monocytes express c-Met, the receptor for HGF, and both depletion of HGF-treated CD14+ monocytes and knockdown of HGF secretion in MSCs abrogate the suppression of anti-CD3/28-activated T cell proliferation. HGF-treated monocytes remain undifferentiated and can alter activated T cell cytokine expression from a Th1 toward Th2 profile. Moreover, monocytes cocultured with MSCs or treated with HGF alone can produce high levels of IL-10, a potent immunomodulatory cytokine. Injection of HGF to WT mice also results in an increase in IL-10+-expressing monocytes from the spleen, a known reservoir for circulating monocytes. Mechanistically, HGFs modulate IL-10 production in monocytes through the ERK1/2 pathway. Our data demonstrate further the pleomorphic nature of MSC immunomodulation, as well as highlight the important role of immunomodulatory monocytes in altering T cell effector function. © Society for Leukocyte Biology. Source


Wu K.-J.,National Health Research Institute | Yu S.-J.,National Health Research Institute | Chiang C.-W.,Institute of Biomedical Engineering and Nanomedicine | Cho K.-H.,National Yang Ming University | And 4 more authors.
Cell Transplantation | Year: 2015

After the onset of stroke, a series of progressive and degenerative reactions, including inflammation, is activated, which leads to cell death. We recently reported that human placenta-derived multipotent stem cells (hPDMCs) process potent anti-inflammatory effects. In this study, we examined the protective effect of hPDMC transplants in a rodent model of stroke. Adult male Sprague–Dawley rats were anesthetized. hPDMCs labeled with a vital dye of fluorescing microparticles, DiI, or vehicle were transplanted into three cortical areas adjacent to the right middle cerebral artery (MCA). Five minutes after grafting, the right MCA was transiently occluded for 60 min. Stroke animals receiving hPDMCs showed a significant behavioral improvement and reduction in lesion volume examined by T2-weighted images 4 days poststroke. Brain tissues were collected 1 day later. Human-specific marker HuNu immunoreactivity and DiI fluorescence were found at the hPDMC graft sites, suggesting the survival of hPDMCs in host brain. Grafting of hPDMCs suppressed IBA1 immunoreactivity and deramification of IBA1+ cells in the perilesioned area, suggesting activation of microglia was attenuated by the transplants. Taken together, our data indicate that hPDMC transplantation reduced cortical lesions and behavioral deficits in adult stroke rats, and these cells could serve as a unique anti-inflammatory reservoir for the treatment of ischemic brain injury. © 2015 Cognizant Comm. Corp. Source


Fang W.-T.,National Health Research Institute | Fan C.-C.,Mackay Memorial Hospital | Fan C.-C.,Yuanpei University | Li S.-M.,National Health Research Institute | And 24 more authors.
International Journal of Cancer | Year: 2014

SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently, SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. Here, we show that BMP4 is a downstream target of SOX2 in lung SQC. We found that SOX2-silencing-mediated inhibition of cell growth was accompanied by upregulation of BMP4 mRNA and its protein expression. Meta-analysis with 293 samples and qRT-PCR validation with 73 clinical samples revealed an inversely correlated relationship between levels of SOX2 and BMP4 mRNA, and significantly lower mRNA levels in tumor than in adjacent normal tissues. This was corroborated by immunohistochemistry analysis of 35 lung SQC samples showing lower BMP4 protein expression in tumor tissues. Cell-based experiments including siRNA transfection, growth assay and flow cytometry assay, further combined with a xenograft tumor model in mice, revealed that reactivation of BMP4 signaling could partially account for growth inhibition and cell cycle arrest in lung SQC cells upon silencing SOX2. Finally, chromatin immunoprecipitation analysis and luciferase reporter assay revealed that SOX2 could negatively regulate BMP4 promoter activity, possibly through binding to the promoter located in the first intron region of BMP4. Collectively, our findings suggest that BMP4 could act as a tumor suppressor and its downregulation by elevated SOX2 resulting in enhanced growth of lung SQC cells. © 2014 UICC. Source


Hsu Y.-C.,Institute of Cellular and System Medicine | Chen S.-L.,Institute of Cellular and System Medicine | Wang Y.-J.,National Health Research Institute | Chen Y.-H.,National Health Research Institute | And 9 more authors.
Stem Cells Translational Medicine | Year: 2014

Recent advances in somatic cell reprogramming have highlighted the plasticity of the somatic epigenome, particularly through demonstrations of direct lineage reprogramming of adult mouse and human fibroblasts to induced pluripotent stem cells (iPSCs) and induced neurons (iNs) under defined conditions. However, human cells appear to be less plastic and have a higher epigenetic hurdle for reprogramming to both iPSCs and iNs. Here, we show that SH2B adaptor protein 1β (SH2B1) can enhance neurite outgrowth of iNs reprogrammed from human fibroblasts as early as day 14, when combined with miR124 and transcription factors BRN2 and MYT1L (IBM) under defined conditions. These SH2B1-enhanced iNs (S-IBM) showed canonical neuronal morphology, and expressed multiple neuronal markers, such as TuJ1, NeuN, and synapsin, and functional proteins for neurotransmitter release, such as GABA, vGluT2, and tyrosine hydroxylase. Importantly, SH2B1 accelerated mature process of functional neurons and exhibited action potentials as early as day 14; without SH2B1, the IBM iNs do not exhibit action potentials until day 21. Our data demonstrate that SH2B1 can enhance neurite outgrowth and accelerate the maturation of human iNs under defined conditions. This approach will facilitate the application of iNs in regenerative medicine and in vitro disease modeling. © AlphaMed Press 2014. Source


Ni H.-C.,National Chung Hsing University | Lin Z.-Y.,National Chung Hsing University | Hsu S.-H.,National Taiwan University | Hsu S.-H.,Institute of Cellular and System Medicine | Chiu I.-M.,Institute of Cellular and System Medicine
Acta Biomaterialia | Year: 2010

Surface modification is a conventional approach in biomaterials development, but most of the modification processes are intricate and time inefficient. In this study, a convenient open air plasma treatment was employed to modify the surface of poly(D,L-lactide) (PLA). Chitosan and fibroblast growth factor 1 (FGF1) were sequentially grafted with the assistance of open air plasma treatment onto the PLA nerve conduits with designed micropores and surface microgrooves. Grafting of these components was verified by electron spectroscopy for chemical analysis. The modified nerve conduits showed enhanced ability in the repair of 10-mm sciatic nerve transection defects in rats. The sequential air plasma treatment can be a convenient way to introduce biocompatible (e.g., chitosan) and bioactive components (e.g., growth factors) onto the surface of biomaterials. © 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. Source

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