“代谢转换障碍/铁死亡”限制脊髓星形胶质细胞体内重编程的作用及机制研究

Difficult to treat and bad prognosis of spinal cord injury (SCI) make it a heavy burden for society. In the manner of generating scar-forming cells to neurons in vivo, reprogramming of astrocytes is promising to treat SCI, with the ability to alleviate the inhibition of scar on nerve regeneration and increase the neurons bridging the circuits. Nevertheless, the inefficiency of reprogramming has restricted its utilization. Our team believe that the main reason for inefficiency is “Uncoordinated Metabolic Transition/Ferroptosis”, with in vivo tests of brain astrocytes reprogramming supporting us. As there exist regional heterogeneity and transcription difference between spine and brain, it’s necessary to verify its feasibility for SCI treatment. Our previously findings showed that uncoordinated metabolic transition and ferroptosis exist in the in vivo reprogramming process of spinal astrocytes, meanwhile, antioxidant therapy significantly elevating the efficiency of reprogramming. Our works preliminarily revealed that uncoordinated metabolic transition/ferroptosis play a vital role in inhibiting astrocytes reprogramming, as lipid peroxidation is the characteristic of ferroptosis. Our task is to clarify the effect and mechanism of uncoordinated metabolic transition in reprogramming while considering uncoordinated metabolic transition and ferroptosis as inhibitory checkpoints, and those of lipid peroxidation to activate ferroptosis in inhibiting reprogramming. With these problems having been clarified, we can update the molecular mechanism of reprogramming, and offer a new therapeutic strategy for SCI.

脊髓损伤（SCI）治疗难、效果差，给社会带来沉重负担。星形胶质细胞体内重编程是SCI有希望的治疗方法，利用体内瘢痕形成细胞来再生新神经元，既减轻瘢痕对神经再生的抑制，又增加神经元来桥接回路，但目前重编程效率低。课题组认为：重编程过程中代谢转换障碍/铁死亡是效率低下的主要原因。脑星形胶质细胞体内重编程的研究支持这一观点，但由于区域异质性且脊髓重编程转录子为SOX2与脑不同，有必要验证是否适用于SCI。课题组前期发现：脊髓星形胶质细胞体内重编程存在代谢转换障碍，脂质过氧化，同时抗氧化治疗能显著提高效率。而脂质过氧化是铁死亡的特征，初步揭示代谢转换障碍/铁死亡的关键作用。下一步本课题拟：以代谢转换障碍和铁死亡为抑制性检查点，阐明重编程过程中代谢转换障碍的作用和机制；明确代谢转换障碍通过脂质过氧化进一步激活铁死亡限制重编程的作用及机制。阐明这些问题，将丰富重编程的分子机制，为SCI治疗提供新策略。

脊髓损伤（SCI）是一种致残率高、预后极差的中枢神经系统创伤性疾病。创伤后大量的神经元细胞丢失和致密神经胶质瘢痕的形成是影响SCI修复和神经再生的主要原因。星形胶质细胞体内重编程是目前SCI修复治疗方法中十分具有前景的治疗方式，但目前重编程效率低不足以满足脊髓功能恢复的要求。基于“体内重编程过程中代谢转换障碍/ 铁死亡是脊髓星形胶质细胞细胞体内重编程效率低下的主要原因”的研究假设，本研究建立小鼠脊髓损伤模型，采用慢病毒载体将Sox 2基因导入到脊髓星形胶质细胞中，诱导星形胶质细胞体内重编程。研究发现，在体内重编程过程中，细胞氧化应激水平以及脂质过氧化显著提高，给予抗氧化剂处理可有效地提高重编程效率；用透射电子显微镜可在脊髓星形胶质细胞体内重编程过程中观察到线粒体出现铁死亡特征性改变。进一步研究发现，体内重编程中铁死亡的相关指标均发生了显著变化，并且抑制铁死亡可以改善重编程细胞存活率，提高重编程效率，提示铁死亡可能是体内重编程细胞主要死亡模式。并且抗氧化剂和铁死亡抑制剂均可以有效地降低神经胶质瘢痕的密度以促进神经轴突再生。本研究对铁死亡抑制脊髓星形胶质细胞体内重编程效率机制的研究对该技术临床应用于SCI治疗具有指导意义。