Dopamine Cell Therapy: From Cell Replacement to Circuitry Repair

Author:

Björklund Anders1,Parmar Malin1

Affiliation:

1. Department of Experimental Medical Science, Developmental and Regenerative Neurobiology, Wallenberg Neuroscience Center, Lund University, Lund, Sweden

Abstract

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.

Publisher

IOS Press

Subject

Cellular and Molecular Neuroscience,Neurology (clinical)

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1. Glial cell transplant for brain diseases: the supportive saviours?;Translational Medicine Communications;2024-07-13

2. Alpha-Synuclein Gene Alterations Modulate Tyrosine Hydroxylase in Human iPSC-Derived Neurons in a Parkinson’s Disease Animal Model;Life;2024-06-05

3. Non-Neuronal GABA in Neocortical Neurografts of the Rats;Российский физиологический журнал им  И  М  Сеченова;2023-12-01

4. Non-Neuronal GABA in Neocortical Neurografts of the Rats;Journal of Evolutionary Biochemistry and Physiology;2023-11

5. Patients accept therapy using embryonic stem cells for Parkinson’s disease: a discrete choice experiment;BMC Medical Ethics;2023-10-12

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