PDF(Pubmed)
Abstract：
Mesenchymal stem cells (MSCs) have shown great potential for the treatment of liver injuries, and the therapeutic efficacy greatly depends on their homing to the site of injury. In the present study, we detected significant upregulation of hepatocyte growth factor (HGF) in the serum and liver in mice with acute or chronic liver injury. In vitro study revealed that upregulation of miR-9-5p or miR-221-3p promoted the migration of human MSCs (hMSCs) toward HGF. Moreover, overexpression of miR-9-5p or miR-221-3p promoted hMSC homing to the injured liver and resulted in significantly higher engraftment upon peripheral infusion. hMSCs reduced hepatic necrosis and inflammatory infiltration but showed little effect on extracellular matrix (ECM) deposition. By contrast, hMSCs overexpressing miR-9-5p or miR-221-3p resulted in not only less centrilobular necrosis and venous congestion but also a significant reduction of ECM deposition, leading to obvious improvement of hepatocyte morphology and alleviation of fibrosis around central vein and portal triads. Further studies showed that hMSCs inhibited the activation of hepatic stellate cells (HSCs) but could not decrease the expression of TIMP-1 upon acute injury and the expression of MCP-1 and TIMP-1 upon chronic injury, while hMSCs overexpressing miR-9-5p or miR-221-3p led to further inactivation of HSCs and downregulation of all three fibrogenic and proinflammatory factors TGF-β, MCP-1, and TIMP-1 upon both acute and chronic injuries. Overexpression of miR-9-5p or miR-221-3p significantly downregulated the expression of α-SMA and Col-1α1 in activated human hepatic stellate cell line LX-2, suggesting that miR-9-5p and miR-221-3p may partially contribute to the alleviation of liver injury by preventing HSC activation and collagen expression, shedding light on improving the therapeutic efficacy of hMSCs via microRNA modification.
摘要：
间充质干细胞（MSCs）在肝损伤的治疗中显示出巨大的潜力，治疗效果在很大程度上取决于它们归巢到损伤部位。在本研究中,我们检测到急性或慢性肝损伤小鼠血清和肝脏中肝细胞生长因子（HGF）的显着上调。体外研究显示miR-9-5p或miR-221-3p的上调促进了人MSCs(hMSCs)向HGF的迁移。此外，miR-9-5p或miR-221-3p的过表达可促进hMSC归巢至受损肝脏,并导致外周输注后植入显著增加.hMSCs减少了肝坏死和炎性浸润，但对细胞外基质（ECM）沉积影响很小。相比之下,过表达miR-9-5p或miR-221-3p的hMSCs不仅减少了小叶中心坏死和静脉充血，而且还显著减少了ECM沉积，导致肝细胞形态明显改善，中央静脉和门静脉三联体周围纤维化减轻。进一步的研究表明，hMSCs可抑制肝星状细胞（HSCs）的活化，但不能降低急性损伤时TIMP-1的表达和慢性损伤时MCP-1和TIMP-1的表达。而过表达miR-9-5p或miR-221-3p的hMSCs导致HSCs进一步失活，并下调所有三种纤维化和促炎因子TGF-β，急性和慢性损伤时的MCP-1和TIMP-1。miR-9-5p或miR-221-3p的过表达显著下调激活的人肝星状细胞系LX-2中α-SMA和Col-1α1的表达，提示miR-9-5p和miR-221-3p可能通过阻止HSC活化和胶原表达而部分减轻肝损伤，通过microRNA修饰提高hMSCs的治疗效果。
