Genipin Crosslinks the Extracellular Matrix to Rescue Developmental and Degenerative Defects, and Accelerates Regeneration of Peripheral Neurons.
Genipin Crosslinks the Extracellular Matrix to Rescue Developmental and Degenerative Defects, and Accelerates Regeneration of Peripheral Neurons.
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Genipin交叉链接细胞外基质以挽救发育和退化性缺陷，并加速周围神经元的再生。
DOI：
10.1101/2023.03.22.533831
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发表时间：
2023-03-24
期刊：
影响因子：
--
通讯作者：
Zeltner N
中科院分区：
文献类型：
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作者：
Saito-Diaz K;Dietrich P;Wu HF;Sun X;Patel AJ;Wzientek CG;Prudden AR;Boons GJ;Chen S;Studer L;Xu B;Dragatsis I;Zeltner N
周围神经系统 (PNS) 对于身体的正常功能至关重要。很大一部分人患有神经退化或外周损伤。例如，超过 40% 的糖尿病患者或接受化疗的患者会出现周围神经病变。尽管如此，人类三七总皂苷发育的知识还存在重大差距，因此没有可用的治疗方法。家族性自主神经功能障碍 (FD) 是一种破坏性疾病，特别影响 PNS，使其成为研究 PNS 功能障碍的理想模型。 FD 是由 ELP1 纯合点突变引起的，导致感觉和自主神经谱系的发育和退行性缺陷。我们之前使用人类多能干细胞 (hPSC) 来证明外周感觉神经元 (SN) 在 FD 中不能有效生成并随着时间的推移而退化。在这里，我们进行了化学筛选，以确定能够挽救这种 SN 分化低效的化合物。我们发现，京尼平（一种中医治疗神经退行性疾病的化合物）可以在 hPSC 模型和 FD 小鼠模型中恢复 FD 的神经嵴和 SN 发育。此外，京尼平可以预防 FD 神经元变性，这表明它可以用于患有 PNS 神经退行性疾病的患者。我们发现京尼平可交联细胞外基质，增加 ECM 的硬度，重组肌动蛋白细胞骨架，并促进 YAP 依赖性基因的转录。最后，我们发现京尼平在体外轴突切除模型中增强健康感觉和交感神经元（PNS 的一部分）和前额皮质神经元（中枢神经系统 CNS 的一部分）的轴突再生。我们的结果表明京尼平可以作为治疗神经发育和神经退行性疾病的有前途的候选药物，并作为神经元再生的增强剂。京尼平可挽救周围神经病家族性自主神经功能障碍的发育和退行性表型，并增强损伤后的神经元再生。
The peripheral nervous system (PNS) is essential for proper body function. A high percentage of the population suffer nerve degeneration or peripheral damage. For example, over 40% of patients with diabetes or undergoing chemotherapy develop peripheral neuropathies. Despite this, there are major gaps in the knowledge of human PNS development and therefore, there are no available treatments. Familial Dysautonomia (FD) is a devastating disorder that specifically affects the PNS making it an ideal model to study PNS dysfunction. FD is caused by a homozygous point mutation in ELP1 leading to developmental and degenerative defects in the sensory and autonomic lineages. We previously employed human pluripotent stem cells (hPSCs) to show that peripheral sensory neurons (SNs) are not generated efficiently and degenerate over time in FD. Here, we conducted a chemical screen to identify compounds able to rescue this SN differentiation inefficiency. We identified that genipin, a compound prescribed in Traditional Chinese Medicine for neurodegenerative disorders, restores neural crest and SN development in FD, both in the hPSC model and in a FD mouse model. Additionally, genipin prevented FD neuronal degeneration, suggesting that it could be offered to patients suffering from PNS neurodegenerative disorders. We found that genipin crosslinks the extracellular matrix, increases the stiffness of the ECM, reorganizes the actin cytoskeleton, and promotes transcription of YAP-dependent genes. Finally, we show that genipin enhances axon regeneration in an in vitro axotomy model in healthy sensory and sympathetic neurons (part of the PNS) and in prefrontal cortical neurons (part of the central nervous system, CNS). Our results suggest genipin can be used as a promising drug candidate for treatment of neurodevelopmental and neurodegenerative diseases, and as a enhancer of neuronal regeneration. Genipin rescues the developmental and degenerative phenotypes of the peripheral neuropathy familial dysautonomia and enhances neuron regeneration after injury.