“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。