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The A9 dopamine neuron component in grafts of ventral mesencephalon is an important determinant for recovery of motor function in a rat model of Parkinson's disease.

Grealish S, Jönsson ME, Li M, Kirik D, Björklund A, Thompson LH - Brain (2010)

Bottom Line: Here, we report results from a series of grafting experiments where the anatomical and functional properties of grafts either selectively lacking in A9 neurons, or with a typical A9/A10 composition were compared.The findings highlight dopamine neuronal subtype composition as a potentially important parameter to monitor in order to understand the variable nature of functional outcome better in transplantation studies.Furthermore, the results have interesting implications for current efforts in this field to generate well-characterized and standardized preparations of transplantable dopamine neuronal progenitors from stem cells.

View Article: PubMed Central - PubMed

Affiliation: Wallenberg Neuroscience Centre, Lund University, Lund, Sweden.

ABSTRACT
Grafts of foetal ventral mesencephalon, used in cell replacement therapy for Parkinson's disease, are known to contain a mix of dopamine neuronal subtypes including the A9 neurons of the substantia nigra and the A10 neurons of the ventral tegmental area. However, the relative importance of these subtypes for functional repair of the brain affected by Parkinson's disease has not been studied thoroughly. Here, we report results from a series of grafting experiments where the anatomical and functional properties of grafts either selectively lacking in A9 neurons, or with a typical A9/A10 composition were compared. The results show that the A9 component of intrastriatal grafts is of critical importance for recovery in tests on motor performance, in a rodent model of Parkinson's disease. Analysis at the histological level indicates that this is likely to be due to the unique ability of A9 neurons to innervate and functionally activate their target structure, the dorsolateral region of the host striatum. The findings highlight dopamine neuronal subtype composition as a potentially important parameter to monitor in order to understand the variable nature of functional outcome better in transplantation studies. Furthermore, the results have interesting implications for current efforts in this field to generate well-characterized and standardized preparations of transplantable dopamine neuronal progenitors from stem cells.

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Related in: MedlinePlus

Expression of the GFP reporter in intrastriatal ventral mesencephalon grafts. Immunohistochemistry for GFP (green; A–C) and TH (red; A–C) in a coronal section through the striatum from a representative animal 12 weeks after transplantation of ventral mesencephalon cells from the Pitx3WT/GFP donor group. The boxed areas are shown in greater detail on the left as individual and merged colour channels and illustrate the overlap between TH and GFP that is the case for the vast majority of GFP+ cells (B) and also the population of small TH−/GFP+ cells that tended to cluster in more central parts of the grafts (C). Scale: 200 µm.
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Figure 5: Expression of the GFP reporter in intrastriatal ventral mesencephalon grafts. Immunohistochemistry for GFP (green; A–C) and TH (red; A–C) in a coronal section through the striatum from a representative animal 12 weeks after transplantation of ventral mesencephalon cells from the Pitx3WT/GFP donor group. The boxed areas are shown in greater detail on the left as individual and merged colour channels and illustrate the overlap between TH and GFP that is the case for the vast majority of GFP+ cells (B) and also the population of small TH−/GFP+ cells that tended to cluster in more central parts of the grafts (C). Scale: 200 µm.

Mentions: Twelve weeks after transplantation, immunohistochemistry for GFP showed 8/8 and 7/8 surviving grafts in animals transplanted with Pitx3WT/GFP or Pitx3GFP/GFP cells, respectively. The vast majority of GFP expressing cells in the grafts were also TH-positive (Fig. 5A–C). As in the intact Pitx3-GFP midbrain, we also observed a minor population of small (<10 µm) GFP+ cells that were not immunoreactive for TH (Fig. 5C). These cells had few, if any, dendritic processes and were predominately located in the central part of the graft. Counting of GFP+ cells revealed that the total number of surviving midbrain dopamine neurons was not different between Pitx3WT/GFP (2517 ± 215; 3.1 ± 0.3% of cells injected) and Pitx3GFP/GFP (2079 ± 405; 1.4 ± 0.3%) grafts (P = 0.95).


The A9 dopamine neuron component in grafts of ventral mesencephalon is an important determinant for recovery of motor function in a rat model of Parkinson's disease.

Grealish S, Jönsson ME, Li M, Kirik D, Björklund A, Thompson LH - Brain (2010)

Expression of the GFP reporter in intrastriatal ventral mesencephalon grafts. Immunohistochemistry for GFP (green; A–C) and TH (red; A–C) in a coronal section through the striatum from a representative animal 12 weeks after transplantation of ventral mesencephalon cells from the Pitx3WT/GFP donor group. The boxed areas are shown in greater detail on the left as individual and merged colour channels and illustrate the overlap between TH and GFP that is the case for the vast majority of GFP+ cells (B) and also the population of small TH−/GFP+ cells that tended to cluster in more central parts of the grafts (C). Scale: 200 µm.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2822634&req=5

Figure 5: Expression of the GFP reporter in intrastriatal ventral mesencephalon grafts. Immunohistochemistry for GFP (green; A–C) and TH (red; A–C) in a coronal section through the striatum from a representative animal 12 weeks after transplantation of ventral mesencephalon cells from the Pitx3WT/GFP donor group. The boxed areas are shown in greater detail on the left as individual and merged colour channels and illustrate the overlap between TH and GFP that is the case for the vast majority of GFP+ cells (B) and also the population of small TH−/GFP+ cells that tended to cluster in more central parts of the grafts (C). Scale: 200 µm.
Mentions: Twelve weeks after transplantation, immunohistochemistry for GFP showed 8/8 and 7/8 surviving grafts in animals transplanted with Pitx3WT/GFP or Pitx3GFP/GFP cells, respectively. The vast majority of GFP expressing cells in the grafts were also TH-positive (Fig. 5A–C). As in the intact Pitx3-GFP midbrain, we also observed a minor population of small (<10 µm) GFP+ cells that were not immunoreactive for TH (Fig. 5C). These cells had few, if any, dendritic processes and were predominately located in the central part of the graft. Counting of GFP+ cells revealed that the total number of surviving midbrain dopamine neurons was not different between Pitx3WT/GFP (2517 ± 215; 3.1 ± 0.3% of cells injected) and Pitx3GFP/GFP (2079 ± 405; 1.4 ± 0.3%) grafts (P = 0.95).

Bottom Line: Here, we report results from a series of grafting experiments where the anatomical and functional properties of grafts either selectively lacking in A9 neurons, or with a typical A9/A10 composition were compared.The findings highlight dopamine neuronal subtype composition as a potentially important parameter to monitor in order to understand the variable nature of functional outcome better in transplantation studies.Furthermore, the results have interesting implications for current efforts in this field to generate well-characterized and standardized preparations of transplantable dopamine neuronal progenitors from stem cells.

View Article: PubMed Central - PubMed

Affiliation: Wallenberg Neuroscience Centre, Lund University, Lund, Sweden.

ABSTRACT
Grafts of foetal ventral mesencephalon, used in cell replacement therapy for Parkinson's disease, are known to contain a mix of dopamine neuronal subtypes including the A9 neurons of the substantia nigra and the A10 neurons of the ventral tegmental area. However, the relative importance of these subtypes for functional repair of the brain affected by Parkinson's disease has not been studied thoroughly. Here, we report results from a series of grafting experiments where the anatomical and functional properties of grafts either selectively lacking in A9 neurons, or with a typical A9/A10 composition were compared. The results show that the A9 component of intrastriatal grafts is of critical importance for recovery in tests on motor performance, in a rodent model of Parkinson's disease. Analysis at the histological level indicates that this is likely to be due to the unique ability of A9 neurons to innervate and functionally activate their target structure, the dorsolateral region of the host striatum. The findings highlight dopamine neuronal subtype composition as a potentially important parameter to monitor in order to understand the variable nature of functional outcome better in transplantation studies. Furthermore, the results have interesting implications for current efforts in this field to generate well-characterized and standardized preparations of transplantable dopamine neuronal progenitors from stem cells.

Show MeSH
Related in: MedlinePlus