The homing capacity of human mesenchymal stem cells (hMSCs) to the injured sites enables systemic administration of hMSCs in clinical practice. In reality, only a small proportion of MSCs are detected in the target tissue, which is a major bottleneck for MSC-based therapies. We still don’t know the mechanism how MSCs are chemo-attracted to certain target organ and engrafted through trans-endothelial migration. In this study, we aimed to determine the mechanism how the circulating hMSCs home to the injured liver. When we compare the cytokine array between normal and injured mouse liver at 1-day thioacetamide (TAA)-treatment, we found that chemerin, CXCL2, and CXCL10 were higher in the injured liver than normal one. Among three, only chemerin was the chemoattractant of hMSCs in 2D- and 3D-migration assay. Analysis of the signal transduction pathways in hMSCs showed that chemerin activated the phosphorylation of JNK1/2, ERK1/2 and p38, and finally upregulated CD44, ITGA4, and MMP-2 that are involved in the transendothelial migration and extravasation of MSCs. Upstream transcription regulators of CD44, ITGA4, and MMP-2 after chemerin treatment were MZF1, GATA3, STAT3, and STAT5A. To develop chemerin as a chemoattractant tool, we cloned gene encoding the active chemerin under the CMV promoter (CMV-aChemerin). We analyzed the migration of hMSCs in the 3D model for space of the Disse, which mimics transmigration of hMSCs in the liver. CMV-aChemerin-transfected hepatocytes were more effective to attract hMSC than control hepatocytes, leading to the enhanced transendothelial migration and homing of hMSCs to liver. The homing efficiency of the intravascularly-delivered hMSCs to liver was evaluated after systemic introduction of the CMV-aChemerin plasmid packed in liposome-vitamin A conjugates which target liver. CMV-aChemerin plasmid targeting liver significantly enhanced homing efficiency of hMSCs to liver compared with control plasmid vector. Chemerin is the newly found chemoattractant of hMSCs and may be a useful tool to manipulate the homing of the intravascularly-administered hMSC to the specific target organ.

中文翻译：

---

发现chemerin作为人类间充质干细胞的新趋化剂

人类间充质干细胞 (hMSCs) 对损伤部位的归巢能力使 hMSCs 在临床实践中的全身给药成为可能。实际上，在目标组织中仅检测到一小部分 MSC，这是基于 MSC 疗法的主要瓶颈。我们仍然不知道MSCs如何被化学吸引到某些靶器官并通过跨内皮迁移移植的机制。在这项研究中，我们的目的是确定循环 hMSCs 如何返回受损肝脏的机制。当我们在 1 天硫代乙酰胺 (TAA) 治疗时比较正常和受损小鼠肝脏之间的细胞因子阵列时，我们发现受损肝脏中的凯莫瑞、CXCL2 和 CXCL10 高于正常肝脏。在这三个中，在 2D 和 3D 迁移测定中，只有 chemerin 是 hMSCs 的化学引诱剂。hMSCs 信号转导通路分析表明，chemerin 激活 JNK1/2、ERK1/2 和 p38 的磷酸化，最终上调参与 MSCs 跨内皮迁移和外渗的 CD44、ITGA4 和 MMP-2。chemerin 处理后 CD44、ITGA4 和 MMP-2 的上游转录调节因子是 MZF1、GATA3、STAT3 和 STAT5A。为了开发 chemerin 作为化学引诱工具，我们在 CMV 启动子 (CMV-aChemerin) 下克隆了编码活性 chemerin 的基因。我们在 Disse 空间的 3D 模型中分析了 hMSCs 的迁移，该模型模拟了 hMSCs 在肝脏中的迁移。CMV-aChemerin 转染的肝细胞比对照肝细胞更有效地吸引 hMSC，导致增强的跨内皮迁移和 hMSC 向肝脏的归巢。在系统引入包装在脂质体-维生素 A 缀合物中的 CMV-aChemerin 质粒后，评估血管内递送的 hMSCs 到肝脏的归巢效率。与对照质粒载体相比，靶向肝脏的 CMV-aChemerin 质粒显着提高了 hMSC 对肝脏的归巢效率。Chemerin 是新发现的 hMSCs 化学引诱剂，可能是操纵血管内给药的 hMSC 归巢至特定靶器官的有用工具。