FAK signaling suppression by OCT4-ITGA6 mediates the effectively removal of residual pluripotent stem cells and enhances application safety.

IF 12.4 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-06-12 eCollection Date: 2025-01-01 DOI:10.7150/thno.111198
Wenpeng Song, Jian Wang, Shixin Gong, Xiaoyan Wang, Junji Xu, Ruiqing Wu, Zongmin Jiang, Huiyuan Zhang, Lida Wu, Yilong Wang, Yingying Su, Hao Wang, Yuchun Gu
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引用次数: 0

Abstract

Rationale: Pluripotent stem cells (PSCs) serve as a critical source of seed cells for regenerative therapies due to their unlimited proliferative capacity and ability to differentiate into all three germ layers. Despite their potential, the risk of teratoma formation caused by residual PSCs within differentiated cell populations poses a significant barrier to clinical applications. This study aims to develop a novel strategy to selectively remove residual PSCs while preserving the safety and functionality of PSC-derived differentiated cells (iDCs). Methods: The calcium- and magnesium-free balanced salt solution (BSS(Ca-Mg-)) was employed to selectively target PSCs in a co-culture system comprising PSCs and four types of iDCs. The effect of BSS(Ca-Mg-) treatment on teratoma formation was evaluated in immunodeficient mice following cell transplantation. Comparative analysis and gene knockdown experiments were conducted to explore the molecular mechanisms underlying the differential response of PSCs and iDCs to BSS(Ca-Mg-), focusing on FAK signaling and its interaction with OCT4 and ITGA6. Results: The BSS(Ca-Mg-) treatment effectively induced the detachment of PSCs in the co-culture system without disrupting iDC adhesion. In vivo experiments confirmed that cells treated with BSS(Ca-Mg-) did not form teratomas upon implantation into immunodeficient mice. Mechanistic studies revealed that PSCs exhibit lower activation of FAK signaling compared to iDCs, contributing to their selective detachment. Additionally, OCT4 and ITGA6 were found to maintain each other's protein expression, forming a feedback loop that suppressed FAK signaling, while FAK suppression further enhanced OCT4 expression. Conclusions: The study presents a safe, effective, and cost-efficient method for the selective removal of residual PSCs. This approach enhances existing safety measures for iDC applications, improving the clinical feasibility of iDC-based cell therapies.

OCT4-ITGA6对FAK信号的抑制可有效地介导残余多能干细胞的清除,提高应用安全性。
原理:多能干细胞(PSCs)由于其无限的增殖能力和分化成所有三种胚层的能力而成为再生治疗种子细胞的重要来源。尽管它们具有潜力,但分化细胞群中残留的PSCs导致畸胎瘤形成的风险对临床应用构成了重大障碍。本研究旨在开发一种新的策略来选择性地去除残留的psc,同时保持psc衍生分化细胞(idc)的安全性和功能。方法:采用无钙无镁平衡盐溶液(BSS(Ca-Mg-))选择性靶向PSCs,在由PSCs和4种类型的adc组成的共培养体系中培养。在免疫缺陷小鼠细胞移植后,评价了钙镁离子对畸胎瘤形成的影响。通过对比分析和基因敲低实验,探讨PSCs和idc对BSS(Ca-Mg-)差异反应的分子机制,重点研究FAK信号及其与OCT4和ITGA6的相互作用。结果:BSS(Ca-Mg-)处理在不破坏iDC粘附的情况下有效诱导PSCs在共培养体系中脱离。体内实验证实,经BSS(Ca-Mg-)处理的细胞在植入免疫缺陷小鼠体内后不会形成畸胎瘤。机制研究表明,与iDCs相比,PSCs表现出较低的FAK信号激活,有助于其选择性脱离。此外,OCT4和ITGA6相互维持蛋白表达,形成抑制FAK信号的反馈回路,而FAK的抑制进一步增强了OCT4的表达。结论:本研究提出了一种安全、有效、经济的选择性去除残留psc的方法。这种方法增强了iDC应用的现有安全措施,提高了基于iDC的细胞疗法的临床可行性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
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