Li Qiaojia, Lian Yufan, Deng Yiwen, Chen Jieying, Wu Tao, Lai Xinqiang, Zheng Bowen, Qiu Chen, Peng Yanwen, Li Weiqiang, Xiang Andy Peng, Zhang Xiaoran, Ren Jie
Department of Medical Ultrasonic, The Third Affiliated Hospital, Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou 510630, China.
Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, China.
Mol Ther Nucleic Acids. 2021 Jul 21;26:222-236. doi: 10.1016/j.omtn.2021.07.009. eCollection 2021 Dec 3.
Mesenchymal stromal cells (MSCs) have shown significant heterogeneity in terms of therapeutic efficacy for inflammatory bowel disease (IBD) treatment, which may be due to an insufficient number of MSCs homing to the damaged tissue of the colon. Engineering MSCs with specific chemokine receptors can enhance the homing ability by lentiviral transduction. However, the unclear specific chemokine profile related to IBD and the safety concerns of viral-based gene delivery limit its application. Thus, a new strategy to modify MSCs to express specific chemokine receptors using mRNA engineering is developed to evaluate the homing ability of MSCs and its therapeutic effects for IBD. We found that CXCL2 and CXCL5 were highly expressed in the inflammatory colon, while MSCs minimally expressed the corresponding receptor CXCR2. Transient expression of CXCR2 in MSC was constructed and exhibited significantly enhanced migration to the inflamed colons, leading to a robust anti-inflammatory effect and high efficacy. Furthermore, the high expression of semaphorins7A on MSCs were found to induce the macrophages to produce IL-10, which may play a critical therapeutic role. This study demonstrated that the specific chemokine receptor mRNA-engineered MSCs not only improves the therapeutic efficacy of IBD but also provides an efficient and safe MSC modification strategy.
间充质基质细胞（MSCs）在炎症性肠病（IBD）治疗的疗效方面表现出显著的异质性，这可能是由于归巢至结肠受损组织的MSCs数量不足所致。通过慢病毒转导用特定趋化因子受体对MSCs进行工程改造可增强其归巢能力。然而，与IBD相关的特定趋化因子谱尚不明确，且基于病毒的基因递送的安全性问题限制了其应用。因此，开发了一种利用mRNA工程改造MSCs以表达特定趋化因子受体的新策略，以评估MSCs的归巢能力及其对IBD的治疗效果。我们发现CXCL2和CXCL5在炎症性结肠中高表达，而MSCs中相应受体CXCR2的表达极低。构建了CXCR2在MSCs中的瞬时表达，其向炎症结肠的迁移显著增强，从而产生强大的抗炎作用和高效性。此外，发现MSCs上信号素7A的高表达可诱导巨噬细胞产生IL-10，这可能发挥关键的治疗作用。本研究表明，特定趋化因子受体mRNA工程改造的MSCs不仅提高了IBD的治疗效果，还提供了一种高效且安全的MSCs改造策略。
