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Cheng H.-Y.,Center for Vascularized Composite Allotransplantation | Hung S.-H.,Chang Gung University | Chu P.-J.,Chang Gung University
Cellular and Molecular Neurobiology | Year: 2015

Responses of primary hippocampal and cortical neurons derived from male and female rats to cellular stressors were studied. It is demonstrated that 17β-estradiol (E2), a potent neuroprotectant, protected the female neurons but had no effects on the male neurons from CoCl2- and glutamate-induced toxicity. Agonists of the estrogen receptor (ER) subtypes ERα and ERβ, DPN and PPT, respectively, had similar effects to E2. By contrast, effects of E2 were abolished by the ER antagonist ICI-182780, further corroborating the neuroprotective role of ERs. In male neurons, CoCl2 predominately activated the apoptosis-inducing factor (AIF)-dependent pathway and AIF translocation from the cytosol to the nucleus. In comparison, CoCl2 activated the caspase pathway and cytochrome c release in female neurons. The inhibitors of these pathways, namely DiQ for AIF and zVAD for caspase, specifically rescued CoCl2-induced cell death in male and female neurons, respectively. When zVAD and ICI-182780, and E2 were applied in combination, it was demonstrated E2 acted on the caspase pathway leading to female-specific neuroprotection. Furthermore, the PI3 kinase (PI3K) inhibitor blocked the rescue effects of DiQ and zVAD on the male and female neurons, respectively, suggesting that PI3K is a common upstream regulator for both pathways. The present study suggested that both sex-specific and nonspecific mechanisms played a role in neuronal responses to stressors and protective reagents. © 2015 Springer Science+Business Media New York

Cheng H.-Y.,Center for Vascularized Composite Allotransplantation
Translational Research in Biomedicine | Year: 2016

Although vascularized composite allotransplantation (VCA) of the face and extremities has been successfully performed with satisfactory aesthetic and functional outcomes, potentially serious side effects derived from long-term immunosuppression impede broader application of VCA. Induction of donor-specific tolerance to eliminate the requirement of immunosuppression has thus become an ultimate goal that is actively pursued in the field of transplantation. Among the various strategies, great potential has been shown with cellular therapeutics in many animal studies. This chapter summarizes recent progress in the efforts to induce donor-specific tolerance across the full major histocompatibility barrier by strategies based on defined populations of cells, including dendritic cells, mesenchymal stem cells, and regulatory T cells, as well as more recent studies to utilize combinatorial cell-based therapy. Current data and potential influences of cell source (donor versus recipient) are also discussed. © 2016 S. Karger AG, Basel.

Wang A.Y.L.,Center for Vascularized Composite Allotransplantation
Translational Research in Biomedicine | Year: 2016

Differentiated somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) via transduction of transcription factors or small molecule compounds. Similar to embryonic stem cells, iPSCs have the capacity to differentiate into any type of cell in the body. Because they can be generated from the patient's own somatic cells through various reprogramming techniques, iPSCs have great potential in disease modeling, drug screening, regenerative medicine, and cell therapy. Vascularized composite allotransplantation (VCA) differs from organ transplantation involving a specific type of cell. A composite graft contains several kinds of cells such as skin, muscle, bone, and nerve. Ensuring the success of VCA poses more challenges compared with organ transplantation. In this chapter, we summarize recent studies that show the application of iPSCs in wound healing, nerve regeneration, and tolerance induction. © 2016 S. Karger AG, Basel.

Wu L.W.,Johns Hopkins University | Wu L.W.,Huazhong University of Science and Technology | Wang Y.-L.,Johns Hopkins University | Wang Y.-L.,Center for Vascularized Composite Allotransplantation | And 8 more authors.
Transplant Immunology | Year: 2014

Purpose: Age negatively impacts the biologic features of mesenchymal stem cells (MSCs), including decreased expansion kinetics and differentiation potential. Clinically, donor-age may be within a wide spectrum; therefore, investigation of the role of donor's age on immunoregulatory potential is of critical importance to translate stem cell therapies from bench to bedside. Methods: Adipose and bone marrow derived MSCs (ASCs and BMSCs) were isolated in parallel from Lewis and Brown Norway rats of young (less than 4-week old) and senior groups (older than 15-month). The presentation of cells and time required for growth to 90% confluence was recorded. FACS sorting based on the expression of CD90 and CD29 double positive and CD45 CD11 double negative quantified the proportions of MSCs. After expansion, ASCs and BMSCs from different age groups were co-cultured in mixed lymphocyte reaction (MLR; Lewis vs. Brown Norway) assays. The suppression of CD3+CD4+ and CD3+CD8+ T cell populations by different sources of MSCs were compared. Results: The kinetics of cell growth was slower in old animals (17.3±2days) compared with young animals (8.8±3days), and cell morphology was irregular and enlarged in the senior groups. The yield of MSCs by FACS sorting was significantly higher in young groups compared to senior groups (p<0.02). With regard to immunoregulatory potential, senior ASCs failed to induce any CD3+CD4+ T cell suppression (p>0.05). In addition, young BMSCs-induced suppression was more prominent than seniors (p<0.05). Conclusions: Donor age should be taken into consideration when using recipient MSC of either bone marrow or adipose origin in clinical applications. © 2014 Elsevier B.V.

Zhang L.-W.,Chang Gung University | Wen C.-J.,Chang Gung University | Wen C.-J.,Center for Vascularized Composite Allotransplantation | Al-Suwayeh S.A.,King Saud University | And 2 more authors.
Journal of Nanoparticle Research | Year: 2012

We aimed to develop liposomes for loading both cisplatin and quantum dots (QDs) for both drug delivery and bioimaging. The resultant quantum-dot-liposomes (QDLs) with cisplatin were characterized using dynamic light scattering, transmission electron microscopy (TEM), encapsulation efficiencies, and fluorescence intensity. QDLs composed of CdSe or CdSe/ZnS QDs represented a size of about 100 nm. The QDLs were prepared at a high QD loading efficiency of nearly 100 %. Most QDs were located within the liposomal bilayers as evidenced by TEM. Slow and sustained cisplatin release from QDLs was achieved. The cellular uptake of QDLs demonstrated effective internalization and significant fluorescence in melanoma cells. The signal derived from QDLs could be observed by different wavelength settings. The cisplatin-containing QDLs revealed higher cytotoxic activity compared to an equal dose of free cisplatin. CdSe/ZnS QDLs were intravenously administered to mice, and the biodistribution was observed with an in vivo imaging system. Significant fluorescence signal and cisplatin accumulation were detected in the brain and skin, as verified by ex vivo imaging and drug distribution. Liposomal inclusion could reduce the reticuloendothelial system uptake of QDs and cisplatin. QDLs evaluated in this study represent a new potential method for theranostic purposes. © 2012 Springer Science+Business Media B.V.

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