Essential Roles of Thyroid Hormone-Regulated Hyaluronan/CD44 Signaling in Adult Stem Cell Development During Xenopus laevis Intestinal Remodeling
Essential Roles of Thyroid Hormone-Regulated Hyaluronan/CD44 Signaling in Adult Stem Cell Development During Xenopus laevis Intestinal Remodeling
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DOI：
10.1002/stem.2671
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发表时间：
2017-10-01
期刊：
影响因子：
5.2
通讯作者：
Ishizuya-Oka, Atsuko
中科院分区：
文献类型：
--
作者：
Hasebe, Takashi;Fujimoto, Kenta;Ishizuya-Oka, Atsuko
在两栖动物变态期的肠道中，甲状腺激素（TH）诱导一些幼虫上皮细胞去分化为干细胞，这些干细胞产生类似于哺乳动物肠道上皮的成体上皮。我们以前已经表明，典型的Wnt信号通路参与成年非洲爪蟾肠上皮发育。为了更准确地理解这一通路的功能，我们在这里集中于CD 44，一个主要的Wnt靶点，它已被确定为X中的TH应答基因。左肠我们的原位杂交分析表明，CD 44 mRNA是可检测的成人上皮原基组成的成人干/祖细胞，并强烈表达在周围的结缔组织（CT）细胞。有趣的是，当CD 44 mRNA的表达是最高的，透明质酸（HA），CD 44的主要配体，是新合成的，并成为最丰富的分布在CT正下方的成人上皮原基活跃增殖。此后，随着成体原基分化为单层柱状上皮，CD 44 mRNA的表达逐渐下调。更重要的是，利用X.在TH存在的情况下，我们已经通过实验表明，通过4-甲基伞形酮抑制HA合成不仅抑制CT的发育，而且抑制上皮干细胞的发育，导致不能产生AE。我们的研究结果强烈表明，TH上调HA/CD 44信号在脊椎动物胚胎后发育过程中肠道干细胞龛的形成中起着至关重要的作用。
In the amphibian intestine during metamorphosis, thyroid hormone (TH) induces some larval epithelial cells to dedifferentiate into stem cells, which generate the adult epithelium analogous to the mammalian intestinal epithelium. We have previously shown that the canonical Wnt signaling pathway is involved in adult epithelial development in the Xenopus laevis intestine. To understand the function of this pathway more precisely, we here focused on CD44, a major Wnt target, which has been identified as a TH response gene in the X. laevis intestine. Our in situ hybridization analysis indicated that CD44 mRNA is detectable in adult epithelial primordia consisting of the adult stem/progenitor cells and is strongly expressed in the connective tissue (CT) cells surrounding them. Interestingly, when the expression of CD44 mRNA is the highest, hyaluronan (HA), a principle ligand of CD44, is newly synthesized and becomes most abundantly distributed in the CT just beneath the adult epithelial primordia that are actively proliferating. Thereafter, as the adult primordia differentiate into the simple columnar epithelium, the expression of CD44 mRNA is gradually downregulated. More importantly, using organ cultures of the X. laevis tadpole intestine in the presence of TH, we have experimentally shown that inhibition of HA synthesis by 4-methylumbelliferone suppresses development of not only the CT but also the epithelial stem cells, resulting in failure to generate the AE. Our findings strongly suggest that TH-upregulated HA/CD44 signaling plays an essential role in formation of the intestinal stem cell niche during vertebrate postembryonic development.