BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice
BHLHA15-Positive Secretory Precursor Cells Can Give Rise to Tumors in Intestine and Colon in Mice
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DOI：
10.1053/j.gastro.2018.11.024
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发表时间：
2019-03-01
期刊：
影响因子：
29.4
通讯作者：
Wang, Timothy C.
中科院分区：
文献类型：
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作者：
Hayakawa, Yoku;Tsuboi, Mayo;Wang, Timothy C.
背景与目的：肠上皮由位于隐窝基部附近的长寿命肠干细胞（ISCs）维持。在ISC区以上，存在短寿祖细胞，通常产生谱系特异性分化细胞类型，但在某些情况下可以退分化为ISCs。然而，上皮去分化在癌症发展中的作用尚未完全阐明。方法：对小鼠Bhlha15-CreERT、Lgr5-DTR-GFP、Apc（flox/flox）、LSL-Notch （IC）和r26报告菌株进行研究。部分小鼠给予白喉毒素消融lgr5阳性细胞，辐照或给予5-氟尿嘧啶、羟基脲、阿霉素、葡聚糖硫酸钠诱导肠道或结肠组织损伤。在肠组织中，我们分析了表达Bhlha15的后代的命运。我们使用微阵列和反转录PCR分析了健康和受损肠道组织以及肿瘤中的基因表达模式。我们使用Cancer Genome Atlas数据集分析了人类结直肠肿瘤的基因表达模式。结果：bhha15鉴定出位于肠上皮ISC区上方的Paneth细胞和短寿命分泌前体细胞（包括前Paneth标签保留细胞）。lgr5阳性细胞丢失或辐照后，Bhlha15（+）细胞无可塑性。然而，在阿霉素诱导的上皮损伤后，Bhlha15（+）分泌前体开始以notch依赖的方式供应肠细胞谱系。Notch的持续激活将Bhlha15（+）分泌前体转化为长寿的肠细胞祖细胞。阿霉素和激活形式Notch的表达导致与肠细胞祖细胞相关的基因表达模式，而只有Notch的持续激活才能改变Bhlha15（+）前体向ISCs的基因表达模式。Notch持续激活的Bhlha15（+）肠细胞祖细胞在Apc破坏小鼠中形成具有锯齿状特征的肠肿瘤。在结肠中，Bhlha15通过激活Src和YAP信号，在葡聚糖硫酸钠诱导的损伤后，标记分泌前体细胞成为干细胞样的癌起始细胞。在人类结直肠肿瘤的分析中，我们将Notch的激活与左结肠具有锯齿状特征的染色体不稳定型肿瘤联系起来。结论：在小鼠中，我们发现短寿命前体可以通过激活Notch和YAP信号进行永久性重编程。除了传统的ISCs外，这些细胞还可以介导肿瘤的形成。
BACKGROUND & AIMS: The intestinal epithelium is maintained by long-lived intestinal stem cells (ISCs) that reside near the crypt base. Above the ISC zone, there are short-lived progenitors that normally give rise to lineage-specific differentiated cell types but can dedifferentiate into ISCs in certain circumstances. However, the role of epithelial dedifferentiation in cancer development has not been fully elucidated. METHODS: We performed studies with Bhlha15-CreERT, Lgr5-DTR-GFP, Apc(flox/flox), LSL-Notch (IC), and R26-reporter strains of mice. Some mice were given diphtheria toxin to ablate Lgr5-positive cells, were irradiated, or were given 5-fluorouracil, hydroxyurea, doxorubicin, or dextran sodium sulfate to induce intestinal or colonic tissue injury. In intestinal tissues, we analyzed the fate of progeny that expressed Bhlha15. We used microarrays and reverse-transcription PCR to analyze gene expression patterns in healthy and injured intestinal tissues and in tumors. We analyzed gene expression patterns in human colorectal tumors using The Cancer Genome Atlas data set. RESULTS: Bhlha15 identified Paneth cells and short-lived secretory precursors (including pre-Paneth label-retaining cells) located just above the ISC zone in the intestinal epithelium. Bhlha15(+) cells had no plasticity after loss of Lgr5-positive cells or irradiation. However, Bhlha15(+) secretory precursors started to supply the enterocyte lineage after doxorubicin-induced epithelial injury in a Notch-dependent manner. Sustained activation of Notch converts Bhlha15(+) secretory precursors to long-lived enterocyte progenitors. Administration of doxorubicin and expression of an activated form of Notch resulted in a gene expression pattern associated with enterocyte progenitors, whereas only sustained activation of Notch altered gene expression patterns in Bhlha15(+) precursors toward those of ISCs. Bhlha15(+) enterocyte progenitors with sustained activation of Notch formed intestinal tumors with serrated features in mice with disruption of Apc. In the colon, Bhlha15 marked secretory precursors that became stem-like, cancer-initiating cells after dextran sodium sulfate-induced injury, via activation of Src and YAP signaling. In analyses of human colorectal tumors, we associated activation of Notch with chromosome instability-type tumors with serrated features in the left colon. CONCLUSIONS: In mice, we found that short-lived precursors can undergo permanent reprogramming by activation of Notch and YAP signaling. These cells could mediate tumor formation in addition to traditional ISCs.