Human ESC-Derived Dopamine Neurons Show Similar Preclinical Efficacy and Potency to Fetal Neurons when Grafted in a Rat Model of Parkinson’s Disease

摘要

class="head no_bottom_margin" id="sec1title">IntroductionCell replacement therapy in Parkinson’s disease (PD) is based on the premise that transplanted midbrain dopamine (DA) neurons can restore dopaminergic neurotransmission when transplanted to the DA-depleted striatum, providing a functionally efficient substitute for the neurons that are lost in the disease. Clinical trials using cells derived from human fetal ventral mesencephalon (VM) have shown that transplanted DA neurons can functionally reinnervate the denervated striatum, restore DA release, and at least in some PD patients, provide substantial long-term clinical improvement (). However, the use of tissue from aborted human embryos presents several ethical and logistical issues that hamper the effective translation of fetal tissue transplantation as a realistic therapeutic option.In order to move to large-scale clinical applications, a readily available, renewable, and bankable source of cells with the potential to differentiate into fully functional DA neurons after transplantation is an absolute requirement. Among the different stem cell sources available, human pluripotent stem cells, in particular human embryonic stem cells (hESCs), have advanced the furthest (). Using protocols entirely based on extrinsic patterning cues that mimic fetal midbrain development, it is now possible to generate DA neurons with an authentic midbrain phenotype from human pluripotent stem cells that survive transplantation and that can restore motor deficits in animal models of PD ().However, a number of crucial issues need to be addressed in preclinical studies before these cells can be considered for clinical use: it is important to verify that their functional efficacy is robust, reproducible, and stable over significant time periods; that the transplanted cells have the capacity to grow axons and reinnervate the DA-denervated host striatum over distances that are relevant for the size of the human brain; and that they function with equal potency to human fetal VM DA neurons that have previously been used in clinical trials ().Here we have performed a rigorous preclinical assessment of long-term in vivo functionality and axonal outgrowth capacity of hESC-derived midbrain DA neurons, critical for their translation to the clinic. We show long-term survival and functionality using clinically relevant MRI and positron emission tomography (PET) imaging techniques and efficacy in restoration of motor function that is comparable to that seen with human fetal cells. Importantly, we provide a direct comparison of human DA neurons sourced from either hESCs or fetal VM and show that hESC-derived neurons, like their fetal counterparts, can project over long distances in the lesioned adult rodent brain and regenerate axonal projections with cell-type specific innervation of correct target structures. These data represent an important milestone in the preclinical assessment of hESC-derived DA neurons and provide essential support for their usefulness in cell replacement therapy for PD.