Kathleen Lonsdale Institute for Human Health Research, Maynooth University, Maynooth, Co. Kildare, Ireland; Department of Biology, Maynooth University, Maynooth, Co. Kildare, Ireland.
Department of Medicine, 226 Health Sciences Research Facility, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA.
Mol Ther. 2023 Nov 1;31(11):3243-3258. doi: 10.1016/j.ymthe.2023.09.013. Epub 2023 Sep 20.
Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodeling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. A polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility to and severity of asthma. We investigated the efficacy of human MSCs in high- vs. low-hMIF environments and the impact of MIF pre-licensing of MSCs using humanized MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodeling in high-MIF-expressing CATT mice but not in CATT or wild-type littermates. Differences in efficacy were correlated with increased MSC retention in the lungs of CATT mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of cyclooxygenase 2 (COX-2) expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT).
目前的哮喘治疗方法侧重于减轻症状，但无法恢复现有的结构损伤。间充质基质细胞（MSC）的给药可以改善气道炎症并逆转气道重塑。然而，患者疾病微环境的差异似乎影响了 MSC 的治疗效果。人类巨噬细胞移动抑制因子（hMIF）基因第 794 位的 CATT 四核苷酸重复多态性与哮喘的易感性和严重程度增加有关。我们研究了高 hMIF 环境与低 hMIF 环境下人类间充质基质细胞的疗效，以及使用人源化 MIF 小鼠在临床相关屋尘螨（HDM）过敏性哮喘模型中对 MSCs 进行 MIF 预许可的影响。间充质基质细胞显著减轻了高 MIF 表达 CATT 小鼠的气道炎症和气道重塑，但对 CATT 或野生型同窝小鼠没有作用。疗效的差异与 CATT 小鼠肺中 MSC 的保留增加有关。MIF 许可增强了间充质基质细胞在以前无效剂量下的抗炎作用。从机制上讲，MIF 与 MSC 上表达的 CD74 结合，导致环氧化酶 2（COX-2）表达上调。在给予 MIF 许可的间充质基质细胞之前，阻断 CD74 或 COX-2 功能会减弱体内 MIF 许可的间充质基质细胞的疗效。这些发现表明，间充质基质细胞的给药可能对高 MIF 基因型（CATT）的严重哮喘患者更有效。
