Transcription factor TRIM33 controls liver progenitor cell towards hepatocyte differentiation through synergizing with phosphorylated Smad2/3 in liver cirrhosis
Tao LinShan WangChen ShaoXiaodong YuanFranziska WandrerHeike BantelMP EbertHuiguo DingSteven DooleyHL Weng
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In liver diseases with severe parenchymal loss, e.g. acute-on-chronic liver failure (ACLF), liver progenitor cells (LPC) are the main cell source to replenish lost hepatocytes through cell reprogramming. The molecular mechanisms underlying LPC towards hepatocytes differentiation in ACLF largely remain unknown to date. Activation of LPC is morphologically demonstrated as ductular reaction (DR). The similarity between DR and ductal plate (DP) of embryonic liver implies that LPC/DR differentiation towards hepatocytes might exploit similar mechanisms stem cells adopted in embryonic development. Tripartite motif protein (TRIM) 33 is a crucial transcription factor for differentiation of embryonic stem cells through the formation of transcription factor complexes with phosphorylated Smad2 and Smad3, the downstream substrates of activated TGF-β signaling. This transcription factor complex replaces heterochromatin protein 1, a main inhibitor of master regulators of cell differentiation, and thus opens binding sites at promoters for the additional transcription factor complexes, such as Smad4-pSmad2/3-FoxH1. The binding of the latter complexes leads to expression of master regulators of differentiation, e.g. goosecoid (GSC). The current study investigated the role of TRIM33 in LPC differentiation towards hepatocytes in ACLF.Objective:To research the optimal culture condition of chicken embryonic stem cells,compare the effect of different feeders on cultured chicken embryonic stem cells in vitro.Methods:The second generation chicken embryonic fibroblast(CEF) and duck embryonic fibroblast(DEF) were used to make feeders after treated with mitomycin C.The state of chicken embryonic stem cells were observed and the number of cell clones was counted on the culture system with those two feeder layers or feeder layer free.Results:The results showed that chicken embryonic stem cells growth well both on the CEF and DEF feeder,and the number of cell clones was no distinct difference between CEF and DEF(P0.05).Conclusion:The results indicated that both of CEF and DEF can be used as feeders to culture chicken embryonic stem cells.
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Developmental Biology
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Despite significant use in basic research, embryonic stem cells have just begun to be used in the drug discovery process. Barriers to the adoption of embryonic stem cells in drug discovery include the difficulty in growing cells and inconsistent differentiation to the desired cellular phenotype. Embryonic stem cell cultures require consistent and frequent handling to maintain the cells in a pluripotent state. In addition, the preferred hanging drop method of embryoid body (EB) differentiation is not amenable to high-throughput methods, and suspension cultures of EBs show a high degree of variability. Murine embryonic stem cells passaged on an automated platform maintained ≥ 90% viability and pluripotency. We also developed a method of EB formation using 384-well microplates that form a single EB per well, with excellent uniformity across EBs. This format facilitated high-throughput differentiation and enabled screens to optimize directed differentiation into a desired cell type. Using this approach, we identified conditions that enhanced cardiomyocyte differentiation sevenfold. This optimized differentiation method showed excellent consistency for such a complex biological process. This automated approach to embryonic stem cell handling and differentiation can provide the high and consistent yields of differentiated cell types required for basic research, compound screens, and toxicity studies.
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The discovery of circulating endothelial progenitor cells (EPCs) opened up a new era of EPC-based therapies for cardiovascular diseases. While researchers are enthusiastic about applying EPCs to clinical therapy, progress has been substantially limited due to the lack of a thorough characterization and understanding of early and late outgrowth EPCs (also called endothelial colony-forming cell, ECFCs) biology. As a means of facilitating the understanding of how late EPCs can most effectively be applied to clinical therapeutics, this article reviews the recent progress covering 5 important issues: (1) The best passages of ex vivo-cultivated EPCs for cell therapy; (2) inflammatory activation of late EPCs: a real world consideration; (3) late EPC is not an endothelial cell: an issue of cell contamination; (4) ways to improve EPC function and differentiation; and (5) how to separate and delete smooth muscle progenitor cells (SPCs).Cardiovascular disease; Cell therapy; Endothelial progenitor cell; Smooth muscle progenitor cell.
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Human embryonic stem cell (hESC) growth is dependent on various factors released by feeder cells. Some of them have already been elucidated, although much research is still needed to understand the biology of stem cell maintenance in culture. Traditionally, primary mouse embryonic fibroblasts (PMEFs) have been used as feeder layers, and both murine and human fibroblast cell lines have been shown to support pluripotency and self-renewal of hESC. Here we report the derivation of three new mouse embryonic fibroblast cell lines, MEFLU-M, MEFLU-T, and MEFLU-TB, with different properties regarding growth and support for undifferentiated hESCs. MEFLU-TB is able to support continuous growth of the newly derived Man-1, as well as H1, HUES-1, HUES-7, HUES-8, and HUES-9 human embryonic stem cell lines. After more than 50 passages and doublings, MEFLU-TB feeders compare to early passage primary mouse embryonic fibroblasts in their ability to support undifferentiated hESC growth. Our results contradict a previous paradigm that PMEFs tend to lose their capacity to support proliferation of hESCs with increasing passages, and show that the MEFLU-TB mouse embryonic fibroblast cell line and its conditioned medium have the potential to support the maintenance of hESC lines. Also, our results clearly show that spontaneous immortalization of primary fibroblasts can be achieved in culture without any chemical addition or genetic modification.
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Atherosclerosis and its associated complications are the primary cause of death in humans.Aging is the main risk factor for atherosclerosis,compared with any other risk factor.After the age of 60 years,age dominates all other risk factors in the risk prediction.But the specific mechanism that contributes to the aging risk remains unknown.For the past few years,the studies on correlations of stem or progenitor cells with disease made great progress.The correla tions of vascular progenitor cells with vascular disease are also paid more and more attention.In 1997,Asahara reported,for the first time,the isolation of putative endothelial progenitor cells(EPC) in the circulating blood.These cells were able to differentiate into mature endothelial cells in vitro and to incorporate into sites of active angiogenesis.This discovery led to a new era of vascular biology and a novel understanding of atherosclerosis and thromboembolic complications.A novel concept for atherosclerosis risk implicates a lack of endothelial progenitor cell(EPC)-dependent arterial repair in the development of atherosclerosis that is secondary to exhaustion of repair-competent EPC.And smooth muscle progenitor cell is one of the sources of smooth muscle cell derived foam cell.This article focuses on the effects of progenitor cells on atherosclerosis,especially on the correlations of endothelial progenitor cell,smooth muscle progenitor cell with atherosclerosis,and the differentiation of vascular progenitor cells.
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Regenerative Medicine
Directed differentiation
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Circulating CFU-GM, BFU-E and CFU-MIX were assayed in 21 infants aged between 1 day and 44 weeks. Compared to 15 adults, progenitor cells of all types were increased until 10 weeks following birth and approached the respective ranges of adults thereafter. The mean increases of progenitor cells in infants aged between 1 day and 10 weeks were 26-fold for CFU-GM, 7-fold for BFU-E and 5-fold for CFU-MIX. Our results demonstrate that not only committed progenitor cells (CFU-GM, BFU-E), but also early progenitor cells with the capacity for self-renewal (CFU-MIX), are increased in early infancy. These data further support the hypothesis that high levels of blood progenitor cells in very early stages of life reflect the colonization process of developing bone marrow by circulating progenitor cells and demonstrate the terminal phase of this process during the first 10 weeks after birth.
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