Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease.
Bottom Line: Considerable progress has been made in generating fully functional and transplantable dopamine neurons from human embryonic stem cells (hESCs).We show long-term survival and functionality using clinically relevant MRI and PET imaging techniques and demonstrate efficacy in restoration of motor function with a potency comparable to that seen with human fetal dopamine neurons.Furthermore, we show that hESC-derived dopamine neurons can project sufficiently long distances for use in humans, fully regenerate midbrain-to-forebrain projections, and innervate correct target structures.
Affiliation: Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. Electronic address: firstname.lastname@example.org.Show MeSH
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Mentions: We next performed a direct histological comparison between hESC-DA neurons and authentic human fetal DA neurons prepared according to Rath et al. (2013), grafted in parallel, in order to validate the morphology, maturation, and phenotypic properties of the transplanted DA neurons (Figures 2D and 2E). In this analysis, we observed the presence of TH+ neurons with two distinct morphologies in the hESC-grafted animals (Mendez et al., 2005; Thompson et al., 2005): A9-like nigral neurons characterized by large angular somata and A10-like VTA neurons with small, round somata (Figure 3A). The morphology of the hESC-derived neurons was identical to that observed with intrastriatal transplants of fetal VM when analyzed at 6 months posttransplantation (Figure 3C) and consistent with graft appearance from previous postmortem reports from transplanted PD patients (Mendez et al., 2005). When staining the cells for markers commonly used to distinguish between SN (A9) and VTA (A10) neurons, TH+ neurons expressing GIRK2 (A9), Calbindin (A10), or both markers were readily detected (Figures 3B and 3D). Quantifications showed that TH+/GIRK2+ neurons were the most abundant subtype in both hESC-derived and fetal grafts (Figure 3I) and that the proportion was similar in both hESC- and fetal-derived grafts (Figure 3J). Taken together, this analysis shows that hESC-DA neurons are indistinguishable from their fetal counterparts on the basis of graft appearance, morphology, and marker expression 6 months after grafting and that the hESC-derived grafts are rich in both A9-like and A10-like DA neurons.
Affiliation: Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Lund University, 22184 Lund, Sweden; Lund Stem Cell Center, Lund University, 22184 Lund, Sweden. Electronic address: email@example.com.