Organoids transplantation as a new modality to design epithelial signature to create a membrane-protective sulfomucin-enriched segment
Organoids transplantation as a new modality to design epithelial signature to create a membrane-protective sulfomucin-enriched segment
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类器官移植作为设计上皮特征以创建膜保护性富含磺粘蛋白片段的新方式
DOI：
10.1007/s00535-023-01959-y
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发表时间：
2023
影响因子：
6.3
通讯作者：
Yui Shiro
中科院分区：
文献类型：
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作者：
Watanabe Satoshi;Ogasawara Nobuhiko;Kobayashi Sakurako;Kirino Sakura;Inoue Masami;Hiraguri Yui;Nagata Sayaka;Shimizu Hiromichi;Ito Go;Mizutani Tomohiro;Nemoto Yasuhiro;Tsuchiya Kiichiro;Okamoto Ryuichi;Watanabe Mamoru;Yui Shiro
背景有机类药物治疗溃疡性结肠炎(UC)的研究进展。重要的是要剖析移植的上皮如何为克服炎症的脆弱性提供好处。我们主要关注磺粘蛋白的递送能力，据报道它在上皮功能中起着重要作用。方法我们分析了结肠上皮的每一段，以确定磺粘蛋白在小鼠和人中产生的差异。随后，我们将从磺基粘蛋白富集区建立的有机类化合物移植到葡聚糖硫酸钠诱导的结肠炎后受损的受体上皮内，并对移植的上皮细胞进行了分析。结果在人正常结肠中，近端结肠的磺粘蛋白产量增加，而UC炎症区的磺粘蛋白产量减少。在小鼠结肠上皮中，与远端小肠和近端结肠相比，盲肠中磺化粘蛋白的产生增加。RNA测序分析表明，在分离的小鼠盲肠隐窝中，与磺化粘蛋白产生相关的几个关键基因，如Papss2和SLc26a1，都得到了丰富的表达。然后，我们建立了小鼠盲肠有机化合物，并将其移植到损伤的远端结肠上皮中。虽然磺化粘蛋白在盲肠器官中的表达暂时减少，但在移植后的移植补片中其分泌又恢复了。最后，我们验证了在人体样本中控制磺基粘蛋白产生的部分机制。结论本研究阐明了磺基粘蛋白在疾病相关移植模型中的输送能力，以设计严重损伤的远端结肠中磺基粘蛋白产生的上皮单位。本研究为更好地推广器官移植治疗难治性UC奠定了基础。
BackgroundThe organoids therapy for ulcerative colitis (UC) is under development. It is important to dissect how the engrafted epithelium can provide benefits for overcoming the vulnerability to inflammation. We mainly focused on the deliverability of sulfomucin, which is reported to play an important role in epithelial function.MethodsWe analyzed each segment of colon epithelium to determine differences in sulfomucin production in both mice and human. Subsequently, we transplanted organoids established from sulfomucin-enriched region into the injured recipient epithelium following dextran sulfate sodium-induced colitis and analyzed the engrafted epithelium in mouse model.ResultsIn human normal colon, sulfomucin production was increased in proximal colon, whereas it was decreased in the inflammatory region of UC. In murine colon epithelium, increased sulfomucin production was found in cecum compared to distal small intestine and proximal colon. RNA sequencing analysis revealed that several key genes associated with sulfomucin production such asPapss2andSlc26a1were enriched in isolated murine cecum crypts. Then we established murine cecum organoids and transplanted them into the injured epithelium of distal colon. Although the expression of sulfomucin was temporally decreased in cecum organoids, its secretion was restored again in the engrafted patches after transplantation. Finally, we verified a part of mechanisms controlling sulfomucin production in human samples.ConclusionThis study illustrated the deliverability of sulfomucin in the disease-relevant grafting model to design sulfomucin-producing epithelial units in severely injured distal colon. The current study is the basis for the better promotion of organoids transplantation therapy for refractory UC.