重编程是组织再生的重要途径。c-Jun重编程雪旺细胞。我们在以往长期口服大剂量辛伐他汀促进神经修复研究基础上，进一步发现壳聚糖导管填充小剂量辛伐他汀水凝胶修复周围神经缺损，c-Jun表达增高。.由此推测：局部施用辛伐他汀通过上调c-Jun重编程雪旺细胞，促进髓鞘崩解碎片清除、诱导内源性神经营养因子分泌、维持神经元存活，诱导神经再生。研究拟结合雪旺细胞特异性c-Jun基因敲除小鼠及siRNA技术，分别通过行为学、神经电生理、组织学、细胞学及分子生物学等技术多维度进行验证；应用自主研发的温敏性辛伐他汀水凝胶调控降解时间，通过持续上调c-Jun，重编程自身雪旺细胞，诱导神经再生。.这种通过局部缓释辛伐他汀“化学重编程”雪旺细胞的方法，绕开了遗传学及组织工程学的伦理问题与技术障碍，不仅为神经再生提供新策略，还将为辛伐他汀“老药新用”制备诱导神经再生的生物材料提供依据，具有重要的理论意义和应用价值。

The ultimate goal of regenerative medicine is to replace lost or damaged cells. This can potentially be accomplished using the processes of dedifferentiation, transdifferentiation or reprogramming. Unlike the reprogramming somatic into iPSCs, where c-Jun is a powerful inhibitor of somatic cell reprogramming. The transcription factor c-Jun reprograms Schwann cells of injured nerves to generate a special repair Bungner Schwann cells, which are essential for regeneration, plays an important role in the process of nerve regeneration. The Bungner cells have different phenotype and function with the Schwann precursor cells and immature Schwann cells. This direct induction of functional cell types from one lineage to another lineage without passing through an intermediate pluripotent stage is defined as lineage reprogramming. .In our previous study, we have found that oral administration of high-dose simvastatin promote spinal cord injury repair. Statins, as the lipid lower, the primary target organ of statins is the liver, and less than 5 % of orally administered statins reach systemic circulation after the first-pass hepatic metabolism, even lower concentrations are found in the injured nerve. We postulated that local use of small doses of simvastatin promote nerve regeneration. In the recent research of our team, we developed a novel composite chitosan conduit filled with simvastatin/poloxamer 407 hydrogel and bridged a 10mm sciatic nerve gap in rats. We found that that filling chitosan conduit with simvastatin hydrogel improved transected sciatic nerve regeneration and functional recovery in rats, with the potential mechanism of promoting the endogenous expression of neurophic factors such as GDNF (also as marker of repair Bungner Schwann cells), PTN, HGF and VEGF. The c-Jun is also up-regulated after 2 weeks of treatment..In this study, we suppose that simvastatin could reprogram Schwann cells, transdifferentiated into Bungner Schwann cells by up-regulating the c-Jun level. The reprogramed Schwann cell could recruit macrophages to clear damaged myelin debris, secretes GDNF and other endogenous neurotrophic factors to maintain the neuron survival, then form axon regeneration channels, and ultimately promote nerve regeneration. By using the conditional deletion of c-Jun in Schwann cells (c-Jun mutant mice) and siRNA technology, behavior, nerve electrophysiology, histology, cytology and molecular biology methods to verify that simvastatin reprogramming Schwann cells by increasing c-Jun, and finally promoting peripheral nerve regeneration. In this study, we also plan to modify simvastatin release time using we previously developed hydrogels with independent intellectual property rights to prolong the release time of simvastatin, consciously up-regulate c-Jun and lineage reprogram injured Schwann cells to promote peripheral nerve regeneration..This small molecule compounds regulate Schwann cell reprogramming bypass safety ethics and technical barriers of genetic and tissue engineering methods, provides a new strategies for nerve regeneration. Also, this study will provides the basis for using simvastatin as compound as inducible regeneration biomaterials to promote the regeneration of peripheral nerve.

神经再生与修复是临床急需解决的难题。我们通过辛伐他汀/泊洛沙姆407水凝胶的壳聚糖导管填充神经缺损，促进大鼠坐骨神经缺损后的神经再生和运动功能恢复，并对其作用机制进行了深入探索。体视显微镜、扫描电镜、体外降解实验和流变学检测发现，壳聚糖导管半透明并具有通透性，扫描电镜下展示出良好的微观结构；泊洛沙姆407水凝胶呈微孔状，在14天左右降解完全，且于20℃左右呈现出液相-固相的转变。通过制备的复合材料修复大鼠坐骨神经缺损，于术后不同时期进行坐骨神经指数（SFI）、神经电生理、荧光金逆行示踪、腓肠肌的检测来观察其促进神经缺损后运动功能恢复的作用。术后10周取材进行H&E染色、免疫荧光双标、透射电镜观察再生神经的形态学, 并对再生神经的轴突数量、髓鞘厚度、G-ratio等进行定量分析。发现术后4、6、8、10周辛伐他汀治疗组（0.5，1mg）的SFI明显优于对照组（p<0.05）；术后10周辛伐他汀治疗组再生神经形态、电生理指标、荧光金标记的阳性神经元数量、腓肠肌相对湿重及运动终板的恢复均显著优于对照组（p<0.05）。我们进一步对再生神经中神经营养因子及神经标志物进行了研究，结果显示壳聚糖导管复合辛伐他汀/泊洛沙姆407水凝胶促进内源性神经营养因子PTN、HGF、VEGF和GDNF呈现高表达。并且促进神经再生修复导管的血管新生。综上，壳聚糖导管复合辛伐他汀/泊洛沙姆407水凝胶显著促进神经缺损组织学的重建及其功能恢复，作用且机制与其促进内源性神经营养因子高表达、再生导管周围血管新生有关。研究不仅为周围神经再生提供新的视角和研究方向，还将为辛伐他汀“老药新用”作为神经修复的复合生物材料提供依据，具有重要的理论意义和应用价值。已申请国家发明专利1项；发表SCI论文4篇（均标注基金资助，IF总计13.927），核心期刊1篇，培养培养硕士生毕业3名，博士生毕业1名。