WNTs regulate myriad biological processes during embryonic development and are key regulators of stem cell function, tissue homeostasis, and injury repair in adults. The creation of WNT-based therapies has been hampered by challenges in developing soluble, potent, and selective WNT molecules. Soluble WNT surrogates have been reported, but they demonstrate relatively weak WNT signaling activity. Here, we describe a platform for potent, selective WNT surrogate generation. We identify multivalent binding to Frizzleds (FZDs) and low-density lipoprotein receptor-related proteins (LRPs) to be a requirement for maximal WNT/β-catenin activation. Furthermore, we show that recruitment of two different FZDs together with LRP causes efficient signaling. Surrogate WNT targeting either FZD1,2,7 or FZD5,8 induces expansive growth of intestinal organoids. This flexible WNT surrogate platform yields potent agonists with any desired receptor specificity and will be useful for research and therapeutic applications for tissue regeneration.

中文翻译：

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有力，选择性的替代WNT分子的开发及其在定义毛躁要求中的应用。

WNTs调节胚胎发育过程中的无数生物学过程，并且是成人干细胞功能，组织稳态和损伤修复的关键调节剂。在开发可溶性，有效和选择性WNT分子方面面临的挑战阻碍了基于WNT疗法的创建。已经报道了可溶的WNT替代物，但是它们显示出相对弱的WNT信号传导活性。在这里，我们描述了一个有效的，选择性的WNT替代物产生的平台。我们确定对Frizzleds（FZDs）和低密度脂蛋白受体相关蛋白（LRPs）的多价结合是最​​大WNT /β-catenin激活的要求。此外，我们表明，两个不同的FZD与LRP一起募集会导致有效的信号传递。以FZD1,2,7或FZD5,8为目标的替代WNT诱导肠道类器官的广泛生长。