CXCR5-Overexpressing Mesenchymal Stromal Cells Exhibit Enhanced Homing and Can Decrease Contact Hypersensitivity.
CXCR5-Overexpressing Mesenchymal Stromal Cells Exhibit Enhanced Homing and Can Decrease Contact Hypersensitivity.
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DOI：
10.1016/j.ymthe.2017.04.004
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Xiaoran Zhang;Weijun Huang;Xiaoyong Chen;Yufan Lian;Jiancheng Wang;Chuang Cai;Li Huang;Tao Wang;Jie Ren;A. Xiang
中科院分区：
文献类型：
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作者：
Xiaoran Zhang;Weijun Huang;Xiaoyong Chen;Yufan Lian;Jiancheng Wang;Chuang Cai;Li Huang;Tao Wang;Jie Ren;A. Xiang
间充质基质细胞(MSCs)可以调节炎症和促进组织再生，因此成为细胞治疗的一种有前途的选择。然而，MSCs向损伤组织迁移的能力仍有待提高。在这项研究中，我们调查了基因工程的MSCs是否可以表现出更多的迁移特性和改善的治疗效果。利用小鼠接触性超敏反应(CHS)模型，趋化因子基因表达筛选显示，CXCL13在损伤组织中的变化最为显著。不幸的是，MSCs几乎不表达相应的受体CXCR5。因此，产生了高表达CXCR5的MSCs(MSCCXCR5)，并保留了其增殖、分化和免疫调节的能力。此外，MSCCXCR5对CXCL13的迁移能力显著增强。重要的是，系统性输注MSCCXCR5显著抑制了小鼠的CHS，炎性细胞浸润和促炎细胞因子的产生水平下降证明了这一点。大量MSCCXCR5迁移到炎症的耳朵，定位于T细胞，抑制T细胞的增殖，促进T细胞的凋亡，抑制T细胞衍生的促炎因子的产生。综上所述，这些发现表明，CXCR5过表达增强了MSCs对迁移刺激的反应能力，并在体内高度增强了它们的免疫调节作用。这种增强定向干细胞/祖细胞归巢的策略可能会提高基于MSC的治疗效果。
Mesenchymal stromal cells (MSCs) can modulate inflammation and contribute to tissue regeneration and, thus, have emerged as a promising option for cell-based therapy. However, the ability of MSCs to migrate to injured tissues still needs to be improved. In this study, we investigated whether genetically engineered MSCs could exhibit increased migratory properties and improved therapeutic efficacy. Using a mouse model of contact hypersensitivity (CHS), chemokine gene expression screening revealed that CXCL13 changed most significantly in injured tissue. Unfortunately, MSCs hardly express the corresponding receptor, CXCR5. Thus, CXCR5-overexpressing MSCs (MSCCXCR5) were generated that retained their abilities of proliferation, differentiation, and immunomodulation. Furthermore, MSCCXCR5showed significantly increased migrating ability toward CXCL13. Importantly, systemic infusion of MSCCXCR5dramatically suppressed CHS in mice, as evidenced by decreased levels of inflammatory cell infiltration and pro-inflammatory cytokine production. Numerous MSCCXCR5migrated into inflamed ears, localized with T cells, inhibited T cell proliferation, promoted T cell apoptosis, and suppressed the production of T cell-derived pro-inflammatory factors. Collectively, these findings demonstrate that CXCR5 overexpression increases the ability of MSCs to respond to migratory stimuli and highly intensifies their immunomodulatory effects in vivo. This strategy for enhancing targeted stem/progenitor cell homing may improve the efficacy of MSC-based therapies.