Nguyen Huy, Fletcher Russell B, Lopez Tom, Whisler Elizabeth, Logas Kelsey R, Dhaliwal Navrose, Suen Timothy, Zhang Mengrui, Dilip Archana, Yuan Tom Z, Go Hayoung, Ye Jay, Sampathkumar Parthasarathy, Suen Nick, Chen Hui, Yeh Wen-Chen, Li Yang, Post Yorick
Surrozen Inc., South San Francisco, CA, USA.
Transl Vis Sci Technol. 2025 Jun 2;14(6):19. doi: 10.1167/tvst.14.6.19.
Dry eye disease is characterized by abnormal tear film composition and inflammation. Disruptions in the presence or secretory function of acinar cells can result in dry eye, leading to discomfort, damage, and vision loss. Although tear replacement and anti-inflammatory treatments have been investigated thoroughly, a method to induce epithelial restoration is lacking. Here, we asked whether WNT signaling activation via an antibody-based WNT mimetic platform might activate lacrimal gland acinar cells and restore tear secretion.
Primary murine lacrimal gland cells were used to establish three-dimensional acinar cell organoids. Dry eye disease was modeled in mice using a lacrimal gland excretory duct ligation. Transcriptional and cellular changes were investigated using single-cell sequencing.
Frizzled and LRP5/6 receptors, which are essential for WNT signal transduction, are expressed in glandular acinar cells in vivo. We showed that murine acinar cells can be expanded as organoids by using WNT signaling activation. Here, we demonstrate that WNT signaling is an essential factor for acinar cell proliferation ex vivo. In a mouse model of dry eye disease, and intra-lacrimal gland treatment with a WNT mimetic targeting FZD1, 2, and 7 reversed aqueous tear deficiency. After excretory duct ligation damage, WNT mimetic treatment promoted acinar cell restoration and increased detectable tear volume production.
We demonstrate a role for WNT signaling in acinar cell proliferation. Our findings extend the potential for WNT pathway activation via a ligand mimetic platform to lacrimal gland regeneration. Pathway activation results in adult acinar cell proliferation in vitro and in vivo and tissue recovery.
Our novel WNT mimetic platform offers a promising alternative to symptom-focused treatments by actively stimulating acinar cell proliferation and restoration.
干眼症的特征是泪膜成分异常和炎症。腺泡细胞存在或分泌功能的破坏可导致干眼症，进而引起不适、损伤和视力丧失。尽管泪液替代和抗炎治疗已得到充分研究，但缺乏诱导上皮修复的方法。在此，我们探究了通过基于抗体的WNT模拟平台激活WNT信号是否可能激活泪腺腺泡细胞并恢复泪液分泌。
使用原代小鼠泪腺细胞建立三维腺泡细胞类器官。通过泪腺排泄管结扎在小鼠中建立干眼症模型。使用单细胞测序研究转录和细胞变化。
WNT信号转导所必需的卷曲蛋白和低密度脂蛋白受体相关蛋白5/6受体在体内腺泡细胞中表达。我们表明，通过激活WNT信号，小鼠腺泡细胞可以作为类器官进行扩增。在此，我们证明WNT信号是体外腺泡细胞增殖的关键因素。在干眼症小鼠模型中，用靶向卷曲蛋白1、2和7的WNT模拟物进行泪腺内治疗可逆转水样泪液缺乏。排泄管结扎损伤后，WNT模拟物治疗促进了腺泡细胞的恢复并增加了可检测到的泪液量产生。
我们证明了WNT信号在腺泡细胞增殖中的作用。我们的研究结果将通过配体模拟平台激活WNT通路的潜力扩展到泪腺再生。通路激活导致体外和体内成年腺泡细胞增殖以及组织恢复。
我们新颖的WNT模拟平台通过积极刺激腺泡细胞增殖和恢复，为以症状为重点的治疗提供了一种有前景的替代方法。
