Abstract
BackgroundThis study aimed to investigate the tolerogenic mechanisms induced by semimature dendritic cells (smDCs) and regulatory dendritic cells (regDCs) after transplantation of hepatocytes differentiated from mouse embryonic stem cells (ESCs) and to confirm the low immunogenicity of hepatocytes differentiated from ESCs.MethodsGreen fluorescent protein-labeled ESCs collected from 129 mice were cultured to differentiate into hepatocytes. smDCs and regDCs were cultured in vitro. The hepatocytes were cultured after being extracted from the livers of 129 mice. After injecting smDCs or regDCs 3 days in advance, these differentiated hepatocytes and normal hepatocytes were transplanted into the livers of BALB/c mice separately. Subsequently, the histopathological features and cytokines in transplant tissues as well as the Foxp3 expression in peripheral blood CD4+ T cells of the recipients were examined.ResultsThe morphological phenotypes of smDCs and regDCs were similar. They both expressed medium levels of MHC-II, CD40, CD80, and CD86, high levels of TGF-β and IL-10, and low levels of IL-2. The survival of differentiated hepatocytes was prolonged and inflammatory infiltration in transplant tissues was reduced in both the smDC and regDC groups. Foxp3 expression in peripheral blood CD4+ T cells of the smDC group increased to 5.38% and that of the regDC group also rose to 3.87%. Moreover, the inflammatory infiltration in the tissues receiving transplanted hepatocytes was more obvious.ConclusionssmDCs and regDCs were similar tolerogenic dendritic cells. They both could alleviate the immune injury by inducing CD4+CD25+Foxp3+ regulatory T cells through the medium expression of MHC-II, CD40, CD80, and CD86 and the appropriate secretion of cytokines. Hepatocytes differentiated from ESCs displayed low immunogenicity.
Highlights
This study aimed to investigate the tolerogenic mechanisms induced by semimature dendritic cells and regulatory dendritic cells after transplantation of hepatocytes differentiated from mouse embryonic stem cells (ESCs) and to confirm the low immunogenicity of hepatocytes differentiated from Embryonic stem cell (ESC)
This study aimed to identify the links between Semimature dendritic cell (smDC) and Regulatory dendritic cell (regDC) in inducing tolerance after transplanting hepatocytes differentiated from mouse ESCs
These growth factors were added to the medium at the following times: as early stage factors, acidic fibroblast growth factor (aFGF) was added to embryoid bodies (EB) on days 7–11, and transforming growth factor (TGF) and AFP were added on days 7–19; as middle stage factors, hepatocyte growth factor (HGF) was added on days 11–19; and as late stage factors, oncostatin M (OSM), DEX, insulin, transferrin, and selenious acid were added on days 15–19
Summary
This study aimed to investigate the tolerogenic mechanisms induced by semimature dendritic cells (smDCs) and regulatory dendritic cells (regDCs) after transplantation of hepatocytes differentiated from mouse embryonic stem cells (ESCs) and to confirm the low immunogenicity of hepatocytes differentiated from ESCs. It has been confirmed that smDCs can induce immune tolerance after mouse skin transplantation and can significantly alleviate immune injury after transplanting hepatocytes differentiated from mouse ESCs [6, 7]. As a type of tolerogenic dendritic cells, regulatory dendritic cells (regDCs) play important roles in inducing immune tolerance after stem cell transplantation [8] It remains unclear whether smDCs are similar to regDCs in terms of cell morphology, immunological phenotype, and their mechanisms of alleviating immune injury after transplanting hepatocytes differentiated from mouse ESCs. This study aimed to identify the links between smDCs and regDCs in inducing tolerance after transplanting hepatocytes differentiated from mouse ESCs. The findings of this study are beneficial to promote the clinical applications of stem cell transplantation and to provide some insights for transplantation tolerance
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