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Review
. 2023 Nov 29;13(12):1654.
doi: 10.3390/brainsci13121654.

Cell Replacement Therapy for Brain Repair: Recent Progress and Remaining Challenges for Treating Parkinson's Disease and Cortical Injury

Paul M Harary  1 , Dennis Jgamadze  1 , Jaeha Kim  1 , John A Wolf  1   2 , Hongjun Song  3   4   5   6 , Guo-Li Ming  3   4   5   7 , D Kacy Cullen  1   2   4   8 , H Isaac Chen  1   2   4
Affiliations
Review

Cell Replacement Therapy for Brain Repair: Recent Progress and Remaining Challenges for Treating Parkinson's Disease and Cortical Injury

Paul M Harary et al. Brain Sci. .

Abstract

Neural transplantation represents a promising approach to repairing damaged brain circuitry. Cellular grafts have been shown to promote functional recovery through "bystander effects" and other indirect mechanisms. However, extensive brain lesions may require direct neuronal replacement to achieve meaningful restoration of function. While fetal cortical grafts have been shown to integrate with the host brain and appear to develop appropriate functional attributes, the significant ethical concerns and limited availability of this tissue severely hamper clinical translation. Induced pluripotent stem cell-derived cells and tissues represent a more readily scalable alternative. Significant progress has recently been made in developing protocols for generating a wide range of neural cell types in vitro. Here, we discuss recent progress in neural transplantation approaches for two conditions with distinct design needs: Parkinson's disease and cortical injury. We discuss the current status and future application of injections of dopaminergic cells for the treatment of Parkinson's disease as well as the use of structured grafts such as brain organoids for cortical repair.

Keywords: Parkinson’s disease; brain organoids; neural replacement; tissue engineering.

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Conflict of interest statement

D.K.C. is a scientific co-founder of Innervace Inc., a University of Pennsylvania spin-out company focused on the translation of advanced regenerative therapies to treat central nervous system disorders. Multiple patents relate to the composition, methods, and use of constructs mentioned in this article, including U.S. Patent App. 15/032,677 (D.K.C.), U.S. Patent App. 16/093,036 (D.K.C., J.A.W., H.I.C.), and U.S. Provisional Patent App. 63/190,581 (D.K.C., H.I.C.). No other authors declare a competing financial interest.

Figures

Figure 1
Figure 1
Design needs of neural replacement approaches for different neurological conditions. Many classical symptoms of Parkinson’s disease are caused by a decrease in dopaminergic innervation of the striatum due to loss of dopaminergic cells in the substantia nigra pars compacta. Dashed arrows represent the nigrostriatal pathway. By comparison, the cerebral cortex has an elaborate cytoarchitecture comprising six layers, which is disrupted in conditions such as traumatic brain injury and stroke. L1 represents the most superficial cortical layer, while L6 represents the deepest layer. In Alzheimer’s disease (AD) the hippocampus is significantly affected, often accompanied by ventricular enlargement and cortical shrinkage. Therefore, neural replacement strategies for each of these conditions should reflect the structure of the damaged tissue.
Figure 2
Figure 2
Workflow for iPSC-derived dopaminergic progenitor cell treatment for Parkinson’s disease: Injection of dissociated cells and implantation of engineered microcolumns. (a) A representation of the generation of midbrain dopaminergic (DA) progenitor cells by human pluripotent stem cell (PSC) culture, followed by quality control and cell intrastriatal (green arrow) or intranigral (red arrow) injection. (b) Tissue-engineered nigrostriatal pathway (TE-NSP) technology may be used to deliver DA cells to more specifically reconstitute nigrostriatal circuitry.
Figure 3
Figure 3
Obstacles to the use of organoids in transplantation-based cortical repair. Brain organoids currently lack vascularization, leading to internal necrosis due to lack of sufficient oxygen perfusion and nutrient supply. Organoid culture protocols produce morphologically heterogeneous organoids which are highly variable in size and number of neural progenitor zones. An optimal organoid age for specific cortical repair applications must be more precisely identified. A stronger understanding of organoid microcircuitry, such as the presence of a cortical microcircuit, is important for improving the utility of organoids in neural repair.
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