胰腺星状细胞与导管复合体的crosstalk促进胰腺损伤后修复的机制初探

The injury and regenerative process of pancreas involves both pancreatic acinar cells and pancreatic stellate cells（PSCs), suggesting that PSCs and pancreatic acinar cells represent a structural and functional unit and that they should be studied as a whole. In our preliminary experiments we have shown that PSCs were present around tubular complexes，which derived from injured acinar cells， forming compact periductular sheaths after acute pancreatitis (AP) and gradually disappeared along with pancreatic regeneration. Also, we observed that tubular complexes expressed monocyte chemo-attractant protein 1 (MCP-1) which could chemo-attract PSCs. Furthermore, we found that Shh production increased in PSCs when they were activated, suggesting a role for Hedgehog signaling pathway in the regeneration of pancreas. Thus, we speculate that there exists a crosstalk between PSCs and tubular complexes which could play an important role in the process of pancreatic injury and regeneration. So, the purpose of this study is to establish the relationship between PSCs and tubular complexes through Hedgehog signaling pathway and MCP-1. In order to achieve this goal, the following works are carried out: ①To clarify that PSCs participated in the injury and regenerative process of acute pancreatitis in experimental AP model. ②To investigate that tubular complexes express MCP-1 which was the primary chemo-attractant cytoking for PSCs in cellular and animal level. ③ To identify that Shh served as an autocrine growth factor for PSCs and played a role in Hedgehog signaling in the re-differentiation of tubular complexes. These results will help unravel the molecular mechanism of injury and regeneration of AP and may provide insight into the development of novel therapeutic agent for AP.

胰腺腺泡细胞和胰腺星状细胞（PSC）均参与了急性胰腺炎（AP）损伤和修复过程，两者位置关系紧密，应该作为一个结构和功能单位联系起来研究。我们前期发现，PSC在损伤期会包绕导管复合体（TC）形成鞘样结构并随着胰腺的修复过程逐渐消失，同时TC高表达MCP-1且MCP-1对PSC有趋化作用，PSC活化后高表达Hedgehog通路配体Shh。因此，我们推测PSC可能与TC相互作用从而影响胰腺的损伤和修复过程。本研究将以Hedgehog通路和MCP-1为切入点建立PSC与TC间交互作用的关系。拟解决：①通过左旋半胱氨酸抑制PSC确立其是否参与AP的损伤和修复过程；②验证导管复合体表达MCP-1趋化PSC的聚集。③验证活化的PSC分泌Hedgehog通路中的相关因子激活导管复合体上Hedgehog通路影响胰腺修复过程。以上研究结果将进一步阐明胰腺损伤和修复的分子机制，为AP的治疗提供新思路。

有关急性胰腺炎（acute pancreatitis ，AP）的再生机制目前尚不明确，我们的研究表明胰腺导管复合体（the tubular complexes，TCs）和胰腺星状细胞（pancreatic stellate cells，PSCs）可能作为一个结构和功能单位参与了急性胰腺炎的修复过程。前期研究发现，PSC在损伤期会包绕导管复合体形成鞘样结构并随着胰腺的修复过程逐渐消失。系统性的研究表明导管复合体高表达MCP-1（monocyte chemo-attractant protein 1），且MCP-1能趋化PSC围绕导管复合体。而PSC活化后高表达Hedgehog通路配体Shh从而激活导管复合体上的Hedgehog通路，从而使导管复合体分化为正常的腺泡细胞。以上研究结果将进一步阐明胰腺损伤和修复的分子机制，为AP的治疗提供新思路。