Moriarty Niamh, Fraser Tyra D, Hunt Cameron P J, Eleftheriou Georgia, Kauhausen Jessica A, Thompson Lachlan H, Parish Clare L
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia; Charles Perkins Institute, The University of Sydney, Sydney, NSW, Australia.
Stem Cell Reports. 2025 May 13;20(5):102480. doi: 10.1016/j.stemcr.2025.102480. Epub 2025 Apr 24.
Human pluripotent stem cell (hPSC)-derived dopamine neurons can functionally integrate and reverse motor symptoms in Parkinson's disease models, motivating current clinical trials. However, dopamine neuron proportions remain low and their plasticity inferior to fetal tissue grafts. Evidence shows exercise can enhance neuron survival and plasticity, warranting investigation for hPSC-derived neural grafts. We show voluntary exercise (wheel running) significantly increases graft plasticity, accelerating motor recovery in animals receiving ectopic, but not homotopic, placed grafts, suggestive of threshold requirements. Plasticity was accompanied by increased phosphorylated extracellular signal-regulated kinase (ERK+) cells in the graft (and host), reflective of mitogen-activated protein kinase (MAPK)-ERK signaling, a downstream target of glial cell-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), proteins that were also elevated. Verifying improved graft integration was the increase in cFos+ postsynaptic striatal neurons. These findings have direct implications for the adoption of physical therapy-based approaches to enhance neural transplantation outcomes in future Parkinson's disease clinical trials.
人多能干细胞（hPSC）衍生的多巴胺神经元在帕金森病模型中能够实现功能整合并逆转运动症状，这推动了当前的临床试验。然而，多巴胺神经元的比例仍然很低，并且其可塑性不如胎儿组织移植物。有证据表明运动可以提高神经元的存活率和可塑性，因此有必要对hPSC衍生的神经移植物进行研究。我们发现，自愿运动（转轮跑步）显著提高了移植物的可塑性，加速了接受异位（而非同位）移植的动物的运动恢复，这表明存在阈值要求。可塑性伴随着移植物（和宿主）中磷酸化细胞外信号调节激酶（ERK+）细胞的增加，这反映了丝裂原活化蛋白激酶（MAPK）-ERK信号传导，而胶质细胞源性神经营养因子（GDNF）和脑源性神经营养因子（BDNF）的下游靶点蛋白水平也有所升高。cFos+突触后纹状体神经元的增加证实了移植物整合得到改善。这些发现对于在未来帕金森病临床试验中采用基于物理治疗的方法来提高神经移植效果具有直接意义。
