SPIB

利用细胞类型特异性报告类器官和CRISPR介导的基因修饰，研究团队发现Notch信号通路和一种名为SPIB的主调节因子对这些细胞的发育至关重要。 来自荷兰胡布勒支研究所类器官小组的研究人员发现，特定的肠道细胞BEST4/CA7+细胞调节电解质和水平衡，以应对引起腹泻的细菌毒素。他们的研究结果表明当暴露于细胞因子干扰素-γ（IFNγ）时，这些肠道细胞的数量会大大增加，为治疗策略提供了一种有前景的靶点。相关研究结果发表在Cell Stem Cell期刊上。 在肠道中，多种细胞类型协同作用以保持电解质和水的平衡。细菌感染会破坏这种平衡，导致腹泻。然而，目前尚不清楚哪些细胞主要受到这些毒素的影响。 论文第一作者Daisong Wang说，“在这项研究中，我们研究了最近发现的BEST4/CA7+细胞，这是肠道内壁中一种特定类型的高度表达CFTR的细胞，其中CFBEST4/CA7+细胞TR是一种实现电解质平衡的重要离子通道” 了解BEST4/CA7+细胞如何发育 虽然研究人员之前已经发现了BEST4/CA7+细胞的存在，但由于缺乏研究模型，它们的发育和功能尚不清楚。Wang 和他的同事们通过在培养皿中培养人类肠道类器官，即微型器官状结构，克服了这一点。他们使用这些类器官来实验评估BEST4/CA7+细胞对各种特定信号的反应。 Wang 指出：“利用细胞类型特异性报告类器官和CRISPR介导的基因修饰，我们发现Notch信号通路和一种名为SPIB的主调节因子对这些细胞的发育至关重要。” 该团队之前观察到，当离子通道CFTR被激活时，肠道类器官会肿胀。Wang 解释说：“然而，我们发现缺乏BEST4/CA7+细胞的肠道类器官没有出现这种肿胀，这证实了这些细胞在控制体液平衡方面的重要作用。”这表明BEST4/CA7+细胞是腹泻的关键靶点。 针对IFNγ反应的意外生长 Wang 团队随后添加了一种名为IFNγ的I型免疫因子，该因子在细菌感染期间存在。他们观察到尽管这些细胞只代表肠道内壁的一小部分，但时在暴露于IFNγ的肠道类器官中。 这是首次在人类肠道中鉴定出I型免疫反应细胞类型，而BEST4/CA7+细胞的显著生长突显了它们在免疫中的作用。另一方面，当用一种名为雷帕霉素（rapamycin）的药物处理时，这些细胞的数量减少了。这可能表明一种有前景的药理学策略，可以自然调节BEST4/CA7+细胞的数量。 这项研究提供的新见解不仅深化了人们对肠道生物学的理解，也为治疗策略打开了新的大门。Wang 指出：“将BEST4/CA7+细胞确定为细菌毒素的主要靶标，可能使我们能够通过改变BEST4/CA7+细胞的数量或靶向其细胞内功能机制，更有效地控制液体释放。” 虽然这些初步的实验室结果很有希望，但需要进一步的研究来确定这些策略在现实世界应用中的有效性。（生物谷 Bioon.com） 参考资料： Daisong Wang et al, Interferon-responsive intestinal BEST4/CA7+ cells are targets of bacterial diarrheal toxins, Cell Stem Cell (2025). DOI: 10.1016/j.stem.2025.02.003.

Researchers have found that specific gut cells, BEST4/CA7+ cells, regulate electrolyte and water balance in response to bacterial toxins that cause diarrhea. Their findings show that these cells greatly increase in number when exposed to the cytokine interferon- (IFN ), presenting a promising target for therapeutic strategies. Researchers from the Organoid group at the Hubrecht Institute have found that specific gut cells, BEST4/CA7+ cells, regulate electrolyte and water balance in response to bacterial toxins that cause diarrhea. Their findings, published in Cell Stem Cell, show that these cells greatly increase in number when exposed to the cytokine interferon-γ (IFNγ), presenting a promising target for therapeutic strategies. In the gut, a variety of cell types collaborate to keep a balance of electrolyte and water. Bacterial infections can disrupt this balance, leading to diarrhea. Yet, it was unclear which cells were mainly affected by these toxins. "In this study, we looked at the recently identified BEST4/CA7+ cells, a specific type of cell in the intestinal lining that highly expresses CFTR, an important ion channel for electrolyte balance," says Daisong Wang, lead author of the study. Understanding how BEST4/CA7+ cells develop While researchers previously identified the presence of BEST4/CA7+ cells, their development and function are not well understood due to the lack of study models. Wang and his colleagues overcame this by creating human intestinal organoids, mini organ-like structures cultured in a dish. They used these organoids to experimentally assess the response of BEST4/CA7+ cells to various specific signals. "Using cell-type specific reporter organoids and CRISPR-mediated genetic modifications, we found that the Notch signaling pathway and a master regulator named SPIB are crucial for these cells' development," Wang notes. BEST4/CA7+ cells: key targets in diarrhea The team previously observed swelling of the organoid when the ion channel CFTR was activated. "However, we saw that organoids lacking BEST4/CA7+ cells did not show this swelling, confirming the vital role of these cells in controlling fluid balance," Wang explains. This shows that BEST4/CA7+ cells are key targets in diarrhea. Unexpected growth in response to IFNγ The researchers then added the type I immune factor called IFNγ which is present during bacterial infections. What they observed was remarkable: "Though these cells only represent a small portion of the intestinal lining, we observed their numbers increase over eightfold in organoids exposed to IFNγ," Wang explains. "This is the first time that a type I immune-responsive cell type has been identified in the human gut and the significant growth of BEST4/CA7+ cells underscore their roles in immunity. On the other hand, when treated with a drug called rapamycin, we saw that the number of these cells goes down." he adds. This could suggest a promising pharmacological strategy for naturally regulating the number of BEST4/CA7+ cell. Future implications The insights from this study not only advance our understanding of gut biology but also open new doors for therapeutic strategies. "Identifying BEST4/CA7+ cells as the primary targets of bacterial toxins might allow us to control fluid release more effectively, either by changing the number of BEST4/CA7+ cells or by targeting their intracellular functional mechanisms." Wang notes. While initial laboratory results are promising, further research is necessary to determine the efficacy of these strategies in real-world applications.

癌基因c-MYC在约70%的人类癌症中异常高表达，如伯基特淋巴瘤（BL）。 癌基因c-MYC在约70%的人类癌症中异常高表达，如伯基特淋巴瘤（BL）。由于BL和其他淋巴系统恶性肿瘤的发展需要额外的遗传或表观遗传学畸变，这些畸变与失调的c-MYC表达协同作用，研究者之前在体内进行无偏见的全基因组功能性遗传筛选，确定转录因子TFAP4（也称为AP-4）是最热门的基因之一。 TFAP4是一种碱性螺旋-环-螺旋-亮氨酸拉链转录因子，Tfap4的表达本身受到c-MYC的直接调控。TFAP4通过与c-MYC的功能相互作用，包括与相同的基因启动子元件的结合，有助于几种c-MYC调节的细胞过程。 值得注意的是，TFAP4通过结合和调节相同的基因启动子，在感染性攻击后维持生发中心B细胞中c-MYC驱动的增殖和成熟信号至关重要。因此，TFAP4是一种重要的转录因子，作用于c-MYC的下游和/或与c-MYC平行，调节成熟B淋巴细胞的增殖和Ig类转换。 图片来源：https://doi.org/10.1038/s41418-023-01145-w 近日，来自沃尔特和伊丽莎.霍尔医学研究所的研究者们在Cell Death Differ.杂志上发表了题为“Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis”的文章，该研究发现TFAP4的缺失导致B细胞早期发育过程中分化受阻，从而加速c-MYC驱动的淋巴瘤发展。 许多淋巴系统恶性肿瘤是由c-MYC表达失调与其他遗传病变共同作用引起的。虽然已经发现了许多这种协同遗传病变，并对其功能进行了表征，但主要患者样本的DNA序列数据表明，还存在更多的协同遗传病变。 然而，他们对c-MYC驱动的淋巴瘤的贡献的性质尚未得到研究。在先前的全基因组CRISPR敲除体内原代细胞筛选中，研究者确定TFAP4是c-MYC驱动的淋巴瘤发展的有效抑制剂。Eµ-MYC转基因造血干细胞和祖细胞（HSPCs）中TFAP4的CRISPR缺失，以及将这些操纵的HSPCs移植到致命辐照的动物中，显著加速了cMYC驱动的淋巴瘤的发展。 有趣的是，TFAP4缺陷型Eµ-MYC淋巴瘤都发生在B细胞发育的前B细胞阶段。这一观察结果促使研究者对移植有Eµ-MYC/Cas9 HSPCs的白血病前期小鼠的前B细胞的转录谱进行表征，这些HSPCs已用靶向TFAP4的sgRNA转导。该分析显示，TFAP4缺失降低了B细胞分化的几种主要调节因子的表达，如Spi1、SpiB和Pax5，它们是TFAP4和MYC的直接靶基因。 Tfap4的缺失加速了c-MYC驱动的淋巴结肿瘤 图片来源：https://doi.org/10.1038/s41418-023-01145-w 综上所述，在c-MYC驱动的血癌中恢复TFAP4的表达，可能不是通过杀死肿瘤细胞，而是通过诱导自我更新的前B淋巴瘤细胞库正常分化为增殖性较低的未成熟/成熟B细胞来改善疾病进展，尽管前提是这些细胞依赖于TFAP4持续缺失来维持淋巴瘤，而不仅仅是淋巴瘤的发展。（生物谷 Bioon.com） 参考文献 Margaret A. Potts et al. Deletion of the transcriptional regulator TFAP4 accelerates c-MYC-driven lymphomagenesis. Cell Death Differ. 2023 Mar 9. doi: 10.1038/s41418-023-01145-w.