治疗性间充质基质细胞 (MSC) 的免疫调节是通过单核细胞对 MSC 的吞噬作用触发的,STEM CELLS

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治疗性间充质基质细胞 (MSC) 的免疫调节是通过单核细胞对 MSC 的吞噬作用触发的
STEM CELLS ( IF 4.0 ) Pub Date : 2018-02-01 , DOI: 10.1002/stem.2779
Samantha F.H. de Witte ₁ , Franka Luk ₁ , Jesus M. Sierra Parraga ₁ , Madhu Gargesha ₂ , Ana Merino ₁ , Sander S. Korevaar ₁ , Anusha S. Shankar ₁ , Lisa O'Flynn ₃ , Steve J. Elliman ₃ , Debashish Roy ₂ , Michiel G.H. Betjes ₁ , Philip N. Newsome _{4,

5,

6} , Carla C. Baan ₁ , Martin J. Hoogduijn ₁

Affiliation

间充质干细胞或基质细胞 (MSC) 正在研究作为一种潜在的免疫疗法。MSC 通常通过静脉输注给药，之后它们会被困在肺部并在一天内死亡并消失。MSC 从肺部消失后的命运尚不清楚，也不清楚 MSC 如何在其短暂的生命周期内实现其免疫调节作用。我们检查了决定输注 MSC 命运的免疫学机制以及与之相关的免疫调节反应。使用 Qtracker 珠（包含在活细胞中）和 Hoechst33342（染色所有细胞）跟踪小鼠中活的和死的人脐带 MSC (ucMSC) 显示，输注后立即在肺中存在活的 ucMSC。二十四小时后，大多数 ucMSC 已经死亡，并在肺和肝脏中发现，它们包含在主要为非经典 Ly6Clow 表型的单核细胞中。还系统地检测到含有 ucMSC 的单核细胞。体外实验证实，人 CD14++/CD16-经典单核细胞在吞噬 ucMSC 后向非经典 CD14++CD16+CD206+ 表型极化，并表达程序性死亡配体-1 和 IL-10，而 TNF-α 减少。ucMSC 引发的单核细胞在混合淋巴细胞反应中诱导 Foxp3+ 调节性 T 细胞形成。这些结果表明，注入的 MSC 被单核细胞迅速吞噬，随后从肺部迁移到其他身体部位。ucMSC 的吞噬作用诱导单核细胞的表型和功能变化，随后调节适应性免疫系统的细胞。可以得出结论，单核细胞在介导、分布和转移 MSC 的免疫调节作用中起着至关重要的作用。干细胞 2018；36：602–615

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Immunomodulation by Therapeutic Mesenchymal Stromal Cells (MSC) is Triggered Through Phagocytosis of MSC by Monocytic Cells

Mesenchymal stem or stromal cells (MSC) are under investigation as a potential immunotherapy. MSC are usually administered via intravenous infusion, after which they are trapped in the lungs and die and disappear within a day. The fate of MSC after their disappearance from the lungs is unknown and it is unclear how MSC realize their immunomodulatory effects in their short lifespan. We examined immunological mechanisms determining the fate of infused MSC and the immunomodulatory response associated with it. Tracking viable and dead human umbilical cord MSC (ucMSC) in mice using Qtracker beads (contained in viable cells) and Hoechst33342 (staining all cells) revealed that viable ucMSC were present in the lungs immediately after infusion. Twenty‐four hours later, the majority of ucMSC were dead and found in the lungs and liver where they were contained in monocytic cells of predominantly non‐classical Ly6Clow phenotype. Monocytes containing ucMSC were also detected systemically. In vitro experiments confirmed that human CD14++/CD16‐ classical monocytes polarized toward a non‐classical CD14++CD16+CD206+ phenotype after phagocytosis of ucMSC and expressed programmed death ligand‐1 and IL‐10, while TNF‐α was reduced. ucMSC‐primed monocytes induced Foxp3+ regulatory T cell formation in mixed lymphocyte reactions. These results demonstrate that infused MSC are rapidly phagocytosed by monocytes, which subsequently migrate from the lungs to other body sites. Phagocytosis of ucMSC induces phenotypical and functional changes in monocytes, which subsequently modulate cells of the adaptive immune system. It can be concluded that monocytes play a crucial role in mediating, distributing, and transferring the immunomodulatory effect of MSC. Stem Cells 2018;36:602–615

更新日期：2018-02-01

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