Cell Stem Cell Human-derived pluripotent stem cells remodel the midbrain dopamine pathway

Written by | My best friend's old Red Riding Hood's cell therapy for Parkinson's disease is based on the idea that midbrain dopamine neurons are transplanted directly into the brain to partially restore function
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Some previous work has shown that the embryonic ventral mesencephalon contains immature precursor cells of dopamine neurons, and these cells can survive and perform some functions normally when transplanted into the adult brain [1]
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The efficacy of this therapy is reflected in the degree of recovery of motor neuron function and is directly related to the level of nerve endings reconstituted in the striatum by seeded dopamine neurons [2]
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This requires precise localization of the transplanted cells in the striatum
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A number of clinical works have pointed out that this therapy can significantly alleviate the motor dysfunction in patients with long-term Parkinson's disease [3], but the efficacy cannot be said to be completely satisfactory [4,5], which is related to the imprecise positioning of the transplanted cells and the combination with Links outside the striatum are not well established
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Earlier work in rodents mentioned that although embryonic dopamine neurons were implanted in the midbrain, their nerve endings could reach the striatum, but the degree of recovery of motor neurons was much lower than that of direct implantation in the striatum [6] ]
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In recent years, work has successfully achieved the development of dopamine neurons from transplanted human pluripotent stem cells in a mouse model of Parkinson's disease [7]
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Compared with the transplanted embryonic tissue, the density of dopamine neurons produced by this kind of transplantation is higher, the functional reconstruction is more perfect, and the motor function can basically be restored [7]
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However, in the rat model, the remodeling of the dopamine neural pathway was not successful
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This means that as the brain grows, the distance between synapses grows, making it more difficult to rebuild neural function
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Recently, the research group of Lachlan H.
Thompson and Clare L.
Parish from the University of Melbourne, Australia published an article entitled A combined cell and gene therapy approach for homotopic reconstruction of midbrain dopamine pathways using human pluripotent stem cells in Cell Stem Cell, which successfully passed the Pluripotent stem cell transplantation precisely remodeled dopamine neurons and their neural pathways, thereby effectively restoring motor function in Parkinson's disease model mice
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First, to accurately characterize the engraftment and remodeling of midbrain dopamine neurons, the authors established a pluripotent stem cell reporter cell line that expresses green fluorescent protein and is controlled by the regulatory factor PITX3
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26 weeks after transplantation into the midbrain, immunohistochemical results showed that midbrain dopamine neurons grew well, with synapses up to 8 mm long and in contact with the forebrain including the striatum, however, in the absence of GDNF (glue) It is still difficult to extend to the ventral region under the action of cytoplasmic cell line-derived neurotrophic factor) signaling
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Of course, under the action of GDNF, striatal innervation was significantly enhanced
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Defective dopaminergic neuron function can be manifested in motor dysfunction, such as rotational asymmetry or incoordination of the upper limbs
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The authors found that 24 weeks after pluripotent stem cell inoculation under GDNF treatment, the motor function of the Parkinson's disease model mice was basically restored, and the rotational asymmetry and upper limb incoordination were completely corrected
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At the microscopic level, c-Fos-positive cells exhibited increased expression, and striatal dopamine levels were also significantly increased
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In addition, the authors found that, in addition to the striatum, the fibers extending from dopamine neurons had significant contacts with other regions, including different cortical regions, the nucleus accumbens, the septum, the olfactory tubercle ( olfactory tubercle), amygdala (amygdala) and thalamus (thalamus)
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Overexpression of GDNF can significantly increase the proportion and density of dopamine nerve fibers
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Homotopic transplantation refers to the transplantation of cells into the midbrain, while heterotopic transplantation into the striatum
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The authors next compared the similarities and differences between the two transplantation methods
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The authors found that the volume of grafts formed by orthotopic transplantation was significantly larger than that of ectopic transplantation, but the density of dopamine neurons was smaller than that of ectopic transplantation, and the overall number of dopamine neurons was basically the same
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Finally, the authors investigated the effects of the above-described transplantation methods on non-dopamine neurons
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By transplanting both dopamine and non-dopamine neurons at the same time, the authors found that both grew well, but that GDNF only tended to promote the growth of dopamine neurons
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In summary, the authors remodeled the dopamine neural pathway by orthotopic transplantation of human-derived pluripotent stem cell-derived midbrain dopamine neurons by treatment with glial cell line-derived neurotrophic factors
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In this way, the level of dopamine in the striatum of the brain, the contact of dopamine nerve fibers with other areas, and the motor function of the body are restored to a certain extent
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Original link: https://doi.
org/10.
1016/j.
stem.
2022.
01.
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, Kirik, D.
, Bjo ̈ rklund, A.
, and Thompson, LH (2010).
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, and Parmar, M.
(2021).
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Xiong, M.
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( 2019).
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