Doublecortin and CaM kinase-like-1 and leucine-rich-repeat-containing G-protein-coupled receptor mark quiescent and cycling intestinal stem cells, respectively.
Doublecortin and CaM kinase-like-1 and leucine-rich-repeat-containing G-protein-coupled receptor mark quiescent and cycling intestinal stem cells, respectively.
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DOI：
10.1002/stem.193
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发表时间：
2009-10
期刊：
影响因子：
5.2
通讯作者：
Houchen, Courtney W.
中科院分区：
文献类型：
--
作者：
May, Randal;Sureban, Sripathi M.;Hoang, Nguyet;Riehl, Terrence E.;Lightfoot, Stan A.;Ramanujam, Rama;Wyche, James H.;Anant, Shrikant;Houchen, Courtney W.
关键词：
人们认为，小肠上皮（IE）之所以能够持续自我更新，主要是由于其未分化干细胞群的作用。这些干细胞产生转运放大（子细胞/祖细胞）细胞，可以分化成正常肠道功能所需的所有成熟细胞类型。 IE 中干细胞的鉴定对于充分理解这一更新过程至关重要。胃肠道干细胞生物学的一个主要障碍是缺乏识别小肠干细胞（ISC）的明确标记。在这里，我们证明了新型假定的 ISC 标记物双皮质素和 CaM 激酶样 1 (DCAMKL-1) 主要在肠隐窝上皮下三分之二的静止细胞中表达，偶尔在隐窝柱状细胞 (CBC) 中表达。相比之下，在快速循环的 CBC 和偶尔的隐窝上皮细胞中观察到新的假定干细胞标记物富含亮氨酸重复序列的 G 蛋白偶联受体 (LGR5)。此外，功能静止的 DCAMKL-1+ 隐窝上皮细胞在改良的标记保留测定中保留了溴脱氧尿苷。此外，我们证明DCAMKL-1是一种细胞表面表达蛋白；通过荧光激活细胞分选从成年小鼠小肠中分离出的 DCAMKL-1+ 细胞能够自我更新，并最终在悬浮培养物中形成球体。这些球体在无胸腺裸鼠的侧腹形成腺上皮结构，表达肠道上皮谱系的多种标记物。因此，DCAMKL-1 是静止 ISC 的标记，可以与循环干细胞/祖细胞 (LGR51) 区分开来。此外，DCAMKL-1可用于分离正常小肠干细胞，代表了再生医学和癌症治疗的新型研究工具。
It is thought that small intestinal epithelia (IE) undergo continuous self-renewal primarily due to their population of undifferentiated stem cells. These stem cells give rise to transit amplifying (daughter/progenitor) cells, which can differentiate into all mature cell types required for normal gut function. Identification of stem cells in IE is paramount to fully understanding this renewal process. One major obstacle in gastrointestinal stem cell biology has been the lack of definitive markers that identify small intestinal stem cells (ISCs). Here we demonstrate that the novel putative ISC marker doublecortin and CaM kinase-like-1 (DCAMKL-1) is predominantly expressed in quiescent cells in the lower two-thirds of intestinal crypt epithelium and in occasional crypt-based columnar cells (CBCs). In contrast, the novel putative stem cell marker leucine-rich-repeat-containing G-protein-coupled receptor (LGR5) is observed in rapidly cycling CBCs and in occasional crypt epithelial cells. Furthermore, functionally quiescent DCAMKL-1+ crypt epithelial cells retain bromo-deoxyuridine in a modified label retention assay. Moreover, we demonstrate that DCAMKL-1 is a cell surface expressing protein; DCAMKL-1+ cells, isolated from the adult mouse small intestine by fluorescence activated cell sorting, self-renew and ultimately form spheroids in suspension culture. These spheroids formed glandular epithelial structures in the flanks of athymic nude mice, which expressed multiple markers of gut epithelial lineage. Thus, DCAMKL-1 is a marker of quiescent ISCs and can be distinguished from the cycling stem/progenitors (LGR51). Moreover, DCAMKL-1 can be used to isolate normal small intestinal stem cells and represents a novel research tool for regenerative medicine and cancer therapy.
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