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: email@example.com.Show MeSH
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Mentions: We and others have previously shown that hESC-DA neurons can release DA in vivo (Kirkeby et al., 2012a) and restore a number of motor deficits in 6-OHDA rodent models of PD when assessed 16–18 weeks after grafting (Kirkeby et al., 2012a; Kriks et al., 2011). However, these transplants contained 15,000–18,000 hESC-derived DA neurons, and the high cell number makes it difficult to estimate the efficacy of the cells (Barker, 2014). In previous preclinical and experimental studies using grafts of human fetal VM, it has been shown that normalization of amphetamine-induced rotation after intrastriatal transplantation can be achieved with an average number of 1,200 surviving TH+ neurons (Brundin et al., 1986). On the basis of this information, we performed a potency experiment designed to determine the minimal number of hESC-DA neurons capable of inducing functional recovery in the amphetamine-induced rotation test. We transplanted 6-OHDA lesioned rats, aiming for at least a 10-fold lower number of hESC-DA than the grafts functionally assessed in earlier studies (Kirkeby et al., 2012a; Kriks et al., 2011). The rats were pretested to confirm the completeness of the lesion and immunosuppressed with daily injections of ciclosporin for 18 weeks. At this time point, the rats showed a significant recovery in amphetamine-induced rotation (Figure 2A: t4 = 6.76, p < 0.01; n = 5), despite a much lower number of TH+ neurons in the grafts (Figures 2B and 2C). Quantifications showed that the average number of surviving TH+ neurons was 986 ± 333 per rat (n = 5). Two of the rats had less than 500 surviving hESC-DA neurons and yet showed a complete reduction in rotational bias (Figure 2B). Within TRANSERUO, a EU-funded research consortium formed to develop an efficacious and safe treatment methodology for PD using fetal cell based treatments (http://www.transeuro.org.uk), research groups including our own have optimized and standardized tissue preparation protocols across several centers throughout Europe. A recent report with cells prepared using this protocol show that a significant reduction in amphetamine-induced rotation could be achieved with transplants of human fetal VM with as few 657 ± 199 surviving TH+ neurons (Rath et al., 2013). These results indicate that the functional potency of grafted hESC-DA neurons is on par with that of human DA neurons obtained from fetal VM (Brundin et al., 1986; Rath et al., 2013).
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.