共查询到20条相似文献,搜索用时 31 毫秒
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Haisong Liu Huan Yang Dicong Zhu Xin Sui Juan Li Zhen Liang Lei Xu Zeyu Chen Anzhi Yao Long Zhang Xi Zhang Xing Yi Meng Liu Shiqing Xu Wenjian Zhang Hua Lin Lan Xie Jinning Lou Yong Zhang Jianzhong Xi Hongkui Deng 《Cell research》2014,24(10):1181-1200
The applications of human pluripotent stem cell (hPSC)-derived cells in regenerative medicine has encountered a long-standing challenge: how can we efficiently obtain mature cell types from hPSCs? Attempts to address this problem are hindered by the complexity of controlling cell fate commitment and the lack of sufficient developmental knowledge for guiding hPSC differentiation. Here, we developed a systematic strategy to study hPSC differentiation by labeling sequential developmental genes to encompass the major developmental stages, using the directed differentiation of pancreatic β cells from hPSCs as a model. We therefore generated a large panel of pancreas-specific mono- and dual-reporter cell lines. With this unique platform, we visualized the kinetics of the entire differentiation process in real time for the first time by monitoring the expression dynamics of the reporter genes, identified desired cell populations at each differentiation stage and demonstrated the ability to isolate these cell populations for further characterization. We further revealed the expression profiles of isolated NGN3-eGFP+ cells by RNA sequencing and identified sushi domain-containing 2 (SUSD2) as a novel surface protein that enriches for pancreatic endocrine progenitors and early endocrine cells both in human embryonic stem cells (hESC)-derived pancreatic cells and in the developing human pancreas. Moreover, we captured a series of cell fate transition events in real time, identified multiple cell subpopulations and unveiled their distinct gene expression profiles, among heterogeneous progenitors for the first time using our dual reporter hESC lines. The exploration of this platform and our new findings will pave the way to obtain mature β cells in vitro. 相似文献
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Continuous taste bud cell renewal is essential to maintain taste function in adults; however, the molecular mechanisms that regulate taste cell turnover are unknown. Using inducible Cre-lox technology, we show that activation of β-catenin signaling in multipotent lingual epithelial progenitors outside of taste buds diverts daughter cells from a general epithelial to a taste bud fate. Moreover, while taste buds comprise 3 morphological types, β-catenin activation drives overproduction of primarily glial-like Type I taste cells in both anterior fungiform (FF) and posterior circumvallate (CV) taste buds, with a small increase in Type II receptor cells for sweet, bitter and umami, but does not alter Type III sour detector cells. Beta-catenin activation in post-mitotic taste bud precursors likewise regulates cell differentiation; forced activation of β-catenin in these Shh+ cells promotes Type I cell fate in both FF and CV taste buds, but likely does so non-cell autonomously. Our data are consistent with a model where β-catenin signaling levels within lingual epithelial progenitors dictate cell fate prior to or during entry of new cells into taste buds; high signaling induces Type I cells, intermediate levels drive Type II cell differentiation, while low levels may drive differentiation of Type III cells. 相似文献
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Rui Wei Jin Yang Wenfang Hou Guoqiang Liu Meijuan Gao Lin Zhang Haining Wang Genhong Mao Hongwei Gao Guian Chen Tianpei Hong 《PloS one》2013,8(8)
Human embryonic stem cells (hESCs) are pluripotent and capable of undergoing multilineage differentiation into highly specialized cells including pancreatic islet cells. Thus, they represent a novel alternative source for targeted therapies and regenerative medicine for diabetes. Significant progress has been made in differentiating hESCs toward pancreatic lineages. One approach is based on the similarities of pancreatic β cell and neuroepithelial development. Nestin-positive cells are selected as pancreatic β cell precursors and further differentiated to secrete insulin. The other approach is based on our knowledge of developmental biology in which the differentiation protocol sequentially reproduces the individual steps that are known in normal β cell ontogenesis during fetal pancreatic development. In the present study, the hESC cell line PKU1.1 was induced to differentiate into insulin-producing cells (IPCs) using both protocols. The differentiation process was dynamically investigated and the similarities and differences between both strategies were explored. Our results show that IPCs can be successfully induced with both differentiation strategies. The resulting IPCs from both protocols shared many similar features with pancreatic islet cells, but not mature, functional β cells. However, these differently-derived IPC cell types displayed specific morphologies and different expression levels of pancreatic islet development-related markers. These data not only broaden our outlook on hESC differentiation into IPCs, but also extend the full potential of these processes for regenerative medicine in diabetes. 相似文献
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Following thymic output, αβ+CD4+ T cells become activated in the periphery when they encounter peptide–major histocompatibility complex. A combination of cytokine and co-stimulatory signals instructs the differentiation of T cells into various lineages and subsequent expansion and contraction during an appropriate and protective immune response. Our understanding of the events leading to T-cell lineage commitment has been dominated by a single fate model describing the commitment of T cells to one of several helper (TH), follicular helper (TFH) or regulatory (TREG) phenotypes. Although a single lineage-committed and dedicated T cell may best execute a single function, the view of a single fate for T cells has recently been challenged. A relatively new paradigm in αβ+CD4+ T-cell biology indicates that T cells are much more flexible than previously appreciated, with the ability to change between helper phenotypes, between helper and follicular helper, or, most extremely, between helper and regulatory functions. In this review, we comprehensively summarize the recent literature identifying when TH or TREG cell plasticity occurs, provide potential mechanisms of plasticity and ask if T-cell plasticity is beneficial or detrimental to immunity. 相似文献
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Hong-Xia Wang Jinwook Shin Shang Wang Balachandra Gorentla Xingguang Lin Jimin Gao Yu-Rong Qiu Xiao-Ping Zhong 《PLoS biology》2016,14(2)
Thymus is crucial for generation of a diverse repertoire of T cells essential for adaptive immunity. Although thymic epithelial cells (TECs) are crucial for thymopoiesis and T cell generation, how TEC development and function are controlled is poorly understood. We report here that mTOR complex 1 (mTORC1) in TECs plays critical roles in thymopoiesis and thymus function. Acute deletion of mTORC1 in adult mice caused severe thymic involution. TEC-specific deficiency of mTORC1 (mTORC1KO) impaired TEC maturation and function such as decreased expression of thymotropic chemokines, decreased medullary TEC to cortical TEC ratios, and altered thymic architecture, leading to severe thymic atrophy, reduced recruitment of early thymic progenitors, and impaired development of virtually all T-cell lineages. Strikingly, temporal control of IL-17-producing γδT (γδT17) cell differentiation and TCRVγ/δ recombination in fetal thymus is lost in mTORC1KO thymus, leading to elevated γδT17 differentiation and rearranging of fetal specific TCRVγ/δ in adulthood. Thus, mTORC1 is central for TEC development/function and establishment of thymic environment for proper T cell development, and modulating mTORC1 activity can be a strategy for preventing thymic involution/atrophy. 相似文献
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Shuyuan Chen Masyuki Shimoda Jiaxi Chen Shinichi Matsumodo Paul A Grayburn 《Cell cycle (Georgetown, Tex.)》2012,11(4):695-705
The molecular mechanism of β-cell regeneration remains poorly understood. Cyclin D2/CDK4 expresses in normal β cells and maintains adult β-cell growth. We hypothesized that gene therapy with cyclin D2/CDK4/GLP-1 plasmids targeted to the pancreas of STZ-treated rats by ultrasound-targeted microbubble destruction (UTMD) would force cell cycle re-entry of residual G0-phase islet cells into G1/S phase to regenerate β cells. A single UTMD treatment induced β-cell regeneration with reversal of diabetes for 6 mo without evidence of toxicity. We observed that this β-cell regeneration was not mediated by self-replication of pre-existing β cells. Instead, cyclin D2/CDK4/GLP-1 initiated robust proliferation of adult pancreatic progenitor cells that exist within islets and terminally differentiate to mature islets with β cells and α cells.Key words: cell cycle regulation, adult pancreatic progenitor cells, proliferation, differentiation, islets regeneration, diabetes 相似文献
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Maryline Paris Cécile Tourrel-Cuzin Cédric Plachot Alain Ktorza 《Experimental diabetes research》2004,5(2):111-121
β-cell neogenesis triggers the generation of new β-cells
from precursor cells. Neogenesis from duct epithelium is the
most currently described and the best documented process
of differentiation of precursor cells into β-cells. It is contributes
not only to β-cell mass expansion during fetal and
nonatal life but it is also involved in the maintenance of the
β-cell mass in adults. It is also required for the increase in
β-cell mass in situations of increase insulin demand (obesity,
pregnancy). A large number of factors controlling the differentiation
of β-cells has been identified. They are classified
into the following main categories: growth factors, cytokine
and inflamatory factors, and hormones such as PTHrP and
GLP-1. The fact that intestinal incretin hormone GLP-1
exerts a major trophic role on pancreatic β-cells provides
insights into the possibility to pharmacologically stimulate
β-cell neogenesis. This could have important implications
for the of treatment of type 1 and type 2 diabetes. Transdifferentiation,
that is, the differentiation of already differentiated
cells into β-cells, remains controversial.However, more
and more studies support this concept. The cells, which can
potentially “transdifferentiate” into β-cells, can belong to
the pancreas (acinar cells) and even islets, or originate from
extra-pancreatic tissues such as the liver. Neogenesis from intra-islet precursors also have been proposed and subpopulations
of cell precursors inside islets have been described
by some authors. Nestin positive cells, which have been considered
as the main candidates, appear rather as progenitors
of endothelial cells rather than β-cells and contribute to
angiogenesis rather than neogenesis. To take advantage of
the different differentiation processes may be a direction for
future cellular therapies. Ultimately, a better understanding
of the molecular mechanisms involved in β-cell neogenesis
will allow us to use any type of differentiated and/or undifferentiated
cells as a source of potential cell precursors. 相似文献
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