Surrozen, South San Francisco, California.
Surrozen, South San Francisco, California.
Cell Mol Gastroenterol Hepatol. 2022;14(2):435-464. doi: 10.1016/j.jcmgh.2022.05.003. Epub 2022 May 13.
Current management of inflammatory bowel disease leaves a clear unmet need to treat the severe epithelial damage. Modulation of Wnt signaling might present an opportunity to achieve histological remission and mucosal healing when treating IBD. Exogenous R-spondin, which amplifies Wnt signals by maintaining cell surface expression of Frizzled (Fzd) and low-density lipoprotein receptor-related protein receptors, not only helps repair intestine epithelial damage, but also induces hyperplasia of normal epithelium. Wnt signaling may also be modulated with the recently developed Wnt mimetics, recombinant antibody-based molecules mimicking endogenous Wnts.
We first compared the epithelial healing effects of RSPO2 and a Wnt mimetic with broad Fzd specificity in an acute dextran sulfate sodium mouse colitis model. Guided by Fzd expression patterns in the colon epithelium, we also examined the effects of Wnt mimetics with subfamily Fzd specificities.
In the DSS model, Wnt mimetics repaired damaged colon epithelium and reduced disease activity and inflammation and had no apparent effect on uninjured tissue. We further identified that the FZD5/8 and LRP6 receptor-specific Wnt mimetic, SZN-1326-p, was associated with the robust repair effect. Through a range of approaches including single-cell transcriptome analyses, we demonstrated that SZN-1326-p directly impacted epithelial cells, driving transient expansion of stem and progenitor cells, promoting differentiation of epithelial cells, histologically restoring the damaged epithelium, and secondarily to epithelial repair, reducing inflammation.
It is feasible to design Wnt mimetics such as SZN-1326-p that impact damaged intestine epithelium specifically and restore its physiological functions, an approach that holds promise for treating epithelial damage in inflammatory bowel disease.
目前炎症性肠病的治疗方法明显未能满足治疗严重上皮损伤的需求。调节 Wnt 信号可能为治疗 IBD 时实现组织学缓解和黏膜愈合提供机会。外源性 R-spondin 通过维持Frizzled（Fzd）和低密度脂蛋白受体相关蛋白受体的细胞表面表达来放大 Wnt 信号，不仅有助于修复肠道上皮损伤，还诱导正常上皮的增生。Wnt 信号也可以通过最近开发的 Wnt 模拟物来调节，Wnt 模拟物是模拟内源性 Wnts 的基于重组抗体的分子。
我们首先在急性葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎模型中比较了 RSPO2 和具有广泛 Fzd 特异性的 Wnt 模拟物的上皮愈合作用。根据结肠上皮中 Fzd 的表达模式，我们还研究了具有亚家族 Fzd 特异性的 Wnt 模拟物的作用。
在 DSS 模型中，Wnt 模拟物修复受损的结肠上皮，降低疾病活动度和炎症，对未受损的组织没有明显影响。我们进一步确定了 FZD5/8 和 LRP6 受体特异性 Wnt 模拟物 SZN-1326-p 与强大的修复作用相关。通过一系列方法，包括单细胞转录组分析，我们证明了 SZN-1326-p 直接作用于上皮细胞，驱动干细胞和祖细胞的短暂扩增，促进上皮细胞的分化，在组织学上恢复受损的上皮，其次是上皮修复，减少炎症。
设计 SZN-1326-p 等靶向损伤肠道上皮的 Wnt 模拟物并恢复其生理功能是可行的，这种方法有望治疗炎症性肠病中的上皮损伤。
