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Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair

Cell therapy for Parkinson’s disease (PD) is aimed to replace the degenerated midbrain dopamine (mDA) neurons and restore DA neurotransmission in the denervated forebrain targets. A limitation of the intrastriatal grafting approach, which is currently used in clinical trials, is that the mDA neurons...

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Autores principales: Björklund, Anders, Parmar, Malin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543294/
https://www.ncbi.nlm.nih.gov/pubmed/33814467
http://dx.doi.org/10.3233/JPD-212609
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author Björklund, Anders
Parmar, Malin
author_facet Björklund, Anders
Parmar, Malin
author_sort Björklund, Anders
collection PubMed
description Cell therapy for Parkinson’s disease (PD) is aimed to replace the degenerated midbrain dopamine (mDA) neurons and restore DA neurotransmission in the denervated forebrain targets. A limitation of the intrastriatal grafting approach, which is currently used in clinical trials, is that the mDA neurons are implanted into the target area, in most cases the putamen, and not in the ventral midbrain where they normally reside. This ectopic location of the cells may limit their functionality due to the lack of appropriate afferent regulation from the host. Homotopic transplantation, into the substantia nigra, is now being pursued in rodent PD models as a way to achieve more complete circuitry repair. Intranigral grafts of mDA neurons, derived from human embryonic stem cells, have the capacity to re-establish the nigrostriatal and mesolimbic pathways in their entirety and restore dense functional innervations in striatal, limbic and cortical areas. Tracing of host afferent inputs using the rabies tracing technique shows that the afferent connectivity of grafts implanted in the nigra matches closely that of the intrinsic mDA system, suggesting a degree of circuitry reconstruction that exceeds what has been achieved before. This approach holds great promise, but to match the larger size of the human brain, and the 10 times greater distance between substantia nigra and its forebrain targets, it may be necessary to find ways to improve the growth capacity of the grafted mDA neurons, pointing to a combined approach where growth promoting factors are used to enhance the performance of mDA neuron grafts.
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spelling pubmed-85432942021-11-10 Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair Björklund, Anders Parmar, Malin J Parkinsons Dis Review Cell therapy for Parkinson’s disease (PD) is aimed to replace the degenerated midbrain dopamine (mDA) neurons and restore DA neurotransmission in the denervated forebrain targets. A limitation of the intrastriatal grafting approach, which is currently used in clinical trials, is that the mDA neurons are implanted into the target area, in most cases the putamen, and not in the ventral midbrain where they normally reside. This ectopic location of the cells may limit their functionality due to the lack of appropriate afferent regulation from the host. Homotopic transplantation, into the substantia nigra, is now being pursued in rodent PD models as a way to achieve more complete circuitry repair. Intranigral grafts of mDA neurons, derived from human embryonic stem cells, have the capacity to re-establish the nigrostriatal and mesolimbic pathways in their entirety and restore dense functional innervations in striatal, limbic and cortical areas. Tracing of host afferent inputs using the rabies tracing technique shows that the afferent connectivity of grafts implanted in the nigra matches closely that of the intrinsic mDA system, suggesting a degree of circuitry reconstruction that exceeds what has been achieved before. This approach holds great promise, but to match the larger size of the human brain, and the 10 times greater distance between substantia nigra and its forebrain targets, it may be necessary to find ways to improve the growth capacity of the grafted mDA neurons, pointing to a combined approach where growth promoting factors are used to enhance the performance of mDA neuron grafts. IOS Press 2021-09-22 /pmc/articles/PMC8543294/ /pubmed/33814467 http://dx.doi.org/10.3233/JPD-212609 Text en © 2021 – The authors. Published by IOS Press https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review
Björklund, Anders
Parmar, Malin
Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair
title Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair
title_full Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair
title_fullStr Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair
title_full_unstemmed Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair
title_short Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair
title_sort dopamine cell therapy: from cell replacement to circuitry repair
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8543294/
https://www.ncbi.nlm.nih.gov/pubmed/33814467
http://dx.doi.org/10.3233/JPD-212609
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