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Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease.

Grealish S, Diguet E, Kirkeby A, Mattsson B, Heuer A, Bramoulle Y, Van Camp N, Perrier AL, Hantraye P, Björklund A, Parmar M - Cell Stem Cell (2014)

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.

View Article: PubMed Central - PubMed

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: shane.grealish@med.lu.se.

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Overview of Neuronal Outgrowth of Intranigral Transplants of hESC-DA Neurons 6 Months after Transplantation(A) Schematic overview of hNCAM+ fiber outgrowth from an intranigral transplant of hESC-DA neurons, as visualized under dark-field illumination of DAB-developed sections (see Figure S4A).(B–D) Higher magnification illustrates the hESC-derived innervation patterns of the amygdala (B), caudate-putamen (C), and NAc (D).(E–G) hNCAM+ fiber bundles were seen to extend rostral within the MFB and nigrostriatal pathway (E), and also within the myelinated white matter tracts of the internal capsule (F), over a distance of more than 10 mm from the graft core to innervate parts of the prefrontal cortex (E and G).See also Figure S4. AC, anterior commissure; BLA, basolateral amygdala; CeA, Central Amygdaloid nucleus; CPu, caudate-putamen unit; FM, forceps minor; IC, internal capsule; MeA, medial amygdaloid nucleus; MFB, medial forebrain bundle; NAc, nucleus accumbens; NSP, nigrostriatal pathway; PrL, prelimbic cortex; T, transplant. In (B)–(G), scale bars represent 0.5 mm.
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fig5: Overview of Neuronal Outgrowth of Intranigral Transplants of hESC-DA Neurons 6 Months after Transplantation(A) Schematic overview of hNCAM+ fiber outgrowth from an intranigral transplant of hESC-DA neurons, as visualized under dark-field illumination of DAB-developed sections (see Figure S4A).(B–D) Higher magnification illustrates the hESC-derived innervation patterns of the amygdala (B), caudate-putamen (C), and NAc (D).(E–G) hNCAM+ fiber bundles were seen to extend rostral within the MFB and nigrostriatal pathway (E), and also within the myelinated white matter tracts of the internal capsule (F), over a distance of more than 10 mm from the graft core to innervate parts of the prefrontal cortex (E and G).See also Figure S4. AC, anterior commissure; BLA, basolateral amygdala; CeA, Central Amygdaloid nucleus; CPu, caudate-putamen unit; FM, forceps minor; IC, internal capsule; MeA, medial amygdaloid nucleus; MFB, medial forebrain bundle; NAc, nucleus accumbens; NSP, nigrostriatal pathway; PrL, prelimbic cortex; T, transplant. In (B)–(G), scale bars represent 0.5 mm.

Mentions: Six months posttransplantation we observed robust survival in all hESC grafted animals (n = 8/8), with no signs of overgrowth or necrosis, similar in morphology to the intrastriatal grafts of hESC-DA neurons described above (Figures 1, 2D, and S2A–S2C). As observed with intranigral transplants of fetal VM, large numbers of hNCAM+ fibers projected rostral along the MFB and the adjacent nigrostriatal pathway (Figures 5A, 5F, S4A, and S4B). The axons extending along the MFB continued a distance more than 10 mm from the graft core and gave rise to dense terminal networks in amygdala (Figure 5B); dorsolateral striatum (Figure 5C) and piriform cortex; ventral striatum, including NAc (Figure 5D); olfactory tubercle; lateral septum; and large parts of the frontal lobe (Figures 5A, 5E, and 5G). hNCAM+ cells with a glial morphology were not detected in any of the hESC-grafted rats, consistent with our hypothesis that they are not essential for extensive axonal outgrowth.


Human ESC-derived dopamine neurons show similar preclinical efficacy and potency to fetal neurons when grafted in a rat model of Parkinson's disease.

Grealish S, Diguet E, Kirkeby A, Mattsson B, Heuer A, Bramoulle Y, Van Camp N, Perrier AL, Hantraye P, Björklund A, Parmar M - Cell Stem Cell (2014)

Overview of Neuronal Outgrowth of Intranigral Transplants of hESC-DA Neurons 6 Months after Transplantation(A) Schematic overview of hNCAM+ fiber outgrowth from an intranigral transplant of hESC-DA neurons, as visualized under dark-field illumination of DAB-developed sections (see Figure S4A).(B–D) Higher magnification illustrates the hESC-derived innervation patterns of the amygdala (B), caudate-putamen (C), and NAc (D).(E–G) hNCAM+ fiber bundles were seen to extend rostral within the MFB and nigrostriatal pathway (E), and also within the myelinated white matter tracts of the internal capsule (F), over a distance of more than 10 mm from the graft core to innervate parts of the prefrontal cortex (E and G).See also Figure S4. AC, anterior commissure; BLA, basolateral amygdala; CeA, Central Amygdaloid nucleus; CPu, caudate-putamen unit; FM, forceps minor; IC, internal capsule; MeA, medial amygdaloid nucleus; MFB, medial forebrain bundle; NAc, nucleus accumbens; NSP, nigrostriatal pathway; PrL, prelimbic cortex; T, transplant. In (B)–(G), scale bars represent 0.5 mm.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4232736&req=5

fig5: Overview of Neuronal Outgrowth of Intranigral Transplants of hESC-DA Neurons 6 Months after Transplantation(A) Schematic overview of hNCAM+ fiber outgrowth from an intranigral transplant of hESC-DA neurons, as visualized under dark-field illumination of DAB-developed sections (see Figure S4A).(B–D) Higher magnification illustrates the hESC-derived innervation patterns of the amygdala (B), caudate-putamen (C), and NAc (D).(E–G) hNCAM+ fiber bundles were seen to extend rostral within the MFB and nigrostriatal pathway (E), and also within the myelinated white matter tracts of the internal capsule (F), over a distance of more than 10 mm from the graft core to innervate parts of the prefrontal cortex (E and G).See also Figure S4. AC, anterior commissure; BLA, basolateral amygdala; CeA, Central Amygdaloid nucleus; CPu, caudate-putamen unit; FM, forceps minor; IC, internal capsule; MeA, medial amygdaloid nucleus; MFB, medial forebrain bundle; NAc, nucleus accumbens; NSP, nigrostriatal pathway; PrL, prelimbic cortex; T, transplant. In (B)–(G), scale bars represent 0.5 mm.
Mentions: Six months posttransplantation we observed robust survival in all hESC grafted animals (n = 8/8), with no signs of overgrowth or necrosis, similar in morphology to the intrastriatal grafts of hESC-DA neurons described above (Figures 1, 2D, and S2A–S2C). As observed with intranigral transplants of fetal VM, large numbers of hNCAM+ fibers projected rostral along the MFB and the adjacent nigrostriatal pathway (Figures 5A, 5F, S4A, and S4B). The axons extending along the MFB continued a distance more than 10 mm from the graft core and gave rise to dense terminal networks in amygdala (Figure 5B); dorsolateral striatum (Figure 5C) and piriform cortex; ventral striatum, including NAc (Figure 5D); olfactory tubercle; lateral septum; and large parts of the frontal lobe (Figures 5A, 5E, and 5G). hNCAM+ cells with a glial morphology were not detected in any of the hESC-grafted rats, consistent with our hypothesis that they are not essential for extensive axonal outgrowth.

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.

View Article: PubMed Central - PubMed

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: shane.grealish@med.lu.se.

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Related in: MedlinePlus