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• W4365795746 abstract "Parkinson’s disease (PD), characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain, is a prototype neurological disease that is suitable for cellular replacement therapy. Levodopa has been utilized to replace the insufficient dopamine released by degenerating DA neurons since the 1960s and it remains the cornerstone of PD treatment. However, as the disease progresses, the diminishing DA neurons become inadequate to convert administered levodopa to functional dopamine, and the affected axonal projections fail to deliver dopamine to target brain regions. As a result, the dopamine replacement eventually loses its efficacy after the initial honeymoon period, and chronic levodopa therapy is associated with debilitating side effects, including motor and non-motor complications. Transplantation of adrenal medulla: With the advancement of modern neurosurgical techniques and better knowledge of the underlying pathobiology, replacing damaged neurons which generate DA has attracted considerable interest. Early attempts at cell transplantation involved the use of adrenal medullary transplants into the caudate, which were reported to alleviate motor symptoms in PD patients. Given that the adrenal medulla produces catecholamines, including dopamine, the transplant was thought to rescue PD phenotypes through dopamine supplements. However, further research showed that the dopamine released by the graft was low and that neuronal fiber outgrowth was poor. More importantly, dopamine was not released tonically by the graft, as seen in autonomous pacemakers of DA neurons. Subsequently, questions were raised about the restorative mechanism of adrenal medullary transplant, suggesting that it promoted the recovery of dopaminergic neurons through neurotrophic action in the host brain, rather than through dopamine release from the graft (Bohn et al., 1987). As little clinical benefit was observed in many patients who received adrenal medullary transplants, this option of cell therapy has been abandoned. Fetal dopaminergic transplantation: Grafting of fetal ventral mesencephalic (fVM) DA neurons utilizes the fetal cells obtained from the ventral mesencephalon of the aborted fetus which contains dopaminergic progenitors. Studies produced favorable results, showing DA neuron survival and outgrowth, and there have been cases in which allografts could survive and adequately function for over 20 years, demonstrating that cell-based therapy is a viable therapeutic option for PD. However, human fVM transplantation trials yielded variable results, with graft-induced dyskinesia frequently reported as a major side effect. The inconsistent efficiency of fVM DA cells in managing PD is due to factors such as the cell types and stages of the graft harvested and transplanted, the nature of the disease in patients, and the immune response of the host to the graft. Dyskinesia is considered to be attributed to the impurity of the graft and aberrant neural circuit formation and regulation (reviewed in Barker et al., 2013). Currently, a European research consortium called TRANSEURO has started an optimized open-label clinical trial to develop a standard methodology for fVM cell-based therapy for PD (ClinicalTrials.gov identifier NCT01898390) (Barker and TRANSEURO consortium, 2019). Nevertheless, fetal tissue grafting will less likely be a routine therapeutic option due to the lack of a standard cell source and ethical concerns. Stem cell-based cell therapy: In 1998, embryonic stem cells (ESCs) were successfully generated from the inner cell mass of a blastocyst. The intrinsic property of self-renewal makes ESCs a sustainable source for cell transplantation, as theoretically they may divide indefinitely provided proper growth conditions are available in a dish. Furthermore, the maintenance of pluripotency during self-renewal enables ESCs to differentiate into any cell type, making them a valuable source for transplantation. Compared with fVM DA neurons, the establishment of ESCs circumvents the shortage of standard sources, but still raises ethnic concerns. Like fVM utilizing aborted fetus, obtaining ESCs involves the arrest of early stages of life by destructing embryos. To address this, technologies have advanced to generate ESCs while preserving the viability of the embryo. However, a better way is to avoid posing any threat to a developing embryo, which has become possible with the discovery of reprogramming differentiated somatic cells into an ESC-like state. The generation of induced pluripotent stem cells (iPSCs) obliviates the need to destroy the early stage of life, representing a better source for transplantation. In addition, when properly prepared, ESC/iPSC-derived DA neurons do not contain serotonin neurons, which were commonly found in fetal midbrain tissue that consists of a heterogeneous cell population. Moreover, optogenetics and chemogenetics (Chen et al., 2016) have been utilized to confirm the motor improvement in the PD model was due to functional grafted neurons and neural networks that were formed. To overcome the existing challenges and establish standard guidelines for cell manufacturing and clinical trial designing, cross-continental collaboration (G-Force-PD) has been initiated, aiming to bring human ESC or human iPSC-derived midbrain DA neurons to the clinic. However, the generation of bona fide DA neurons remains the biggest challenge in the field. DA neurons consist of anatomically and functionally distinct subtypes forming separate neural circuits that mediate distinct functions. The A9 DA neurons are located in the SNpc, forming nigrostriatal circuit to regulate motor functions. PD becomes clinically detectable when over 50–60% of such neurons are lost due to neurodegeneration. In contrast, A10 DA neurons reside in the ventral tegmental area, innervating broader brain regions, including nucleus accumbens, and are involved in emotion processing and other non-motor functions. Current protocols for DA neuron differentiation require dual suppressor of mothers against decapentaplegic (SMAD) inhibition (inhibition of bone morphogenetic protein (BMP) and transforming growth factor beta (TGFβ) signaling) for neural induction before activating Sonic hedgehog (SHH), Wnt, and FGF8b signaling under fine control to generate floor-plate derived DA neurons (Nolbrant et al., 2017). Latest single-cell transcriptional profiling categorized DA neurons in the SN into 10 subpopulations, among which a particular subtype with a signature of SOX6 and AGTR1 gene expression confined to the ventral SNpc was most susceptible in PD (Kamath et al., 2022). Induction of SOX6 has been employed to improve SN DA neuron development during human iPSC differentiation, and it warrants further investigation if boosting AGTR1 gene expression will benefit the generation of SNpc DA neurons. With a deeper understanding of signaling involved and concerted effects for optimization, a standard protocol will be established to obtain authentic DA neurons with maximum benefits and minimum side effects for grafting. Cell sorting with specific markers has been shown to provide better graft outcomes by removing other neurons starting from the same graft, as those neurons may connect with the differentiated DA neurons anatomically and functionally, affecting the functions of the graft and its communication with surrounding neurons of the host. Host immune response not only compromises the survival of graft, but also imposes extra stress on the vulnerable host neurons near the site of transplantation. Autologous transplantation induces minimum immune response with little CD4 activation, and the grafts have been shown to survive well in animal models. In a clinical case of autologous transplantation, gradual clinical improvement was reported, along with a better response to levodopa treatment (Schweitzer et al., 2020). However, it should be noted that generating clinical-grade autologous grafts for an individual requires significant amounts of resources and efforts. Moreover, since genetic risks are a major cause of PD, an autologous graft may carry genetic mutations or risk variants that predispose the graft to neurodegeneration with increased susceptibility to α synuclein transmission through tunneling nanotubes or extracellular vesicles. Lewy bodies have been identified in human fetal tissue grafts years after cell therapy, providing clinical evidence of host-to-graft disease propagation (Barker et al., 2013). Alternatively, transplantation of human leucocyte antigen-matched iPSC-derived DA neurons could attenuate the risk of allograft rejection, reducing the amount of immunosuppressant needed (Morizane et al., 2017). It should be noted that tacrolimus, a standard immunosuppressant used widely in transplantation, has been reported to induce Parkinsonism in transplantation recipients. human leucocyte antigen-matched iPSCs or even neural progenitor cells could be produced conforming to current Good Manufacturing Practices standards as a readily accessible transplant source that has passed preclinical safety and efficacy test. Moreover, human leucocyte antigen-matched iPSCs can undergo genetic test to exclude graft sources with genetic defects for PD, which could extend the effective duration of cell therapy. The optimal graft location is still under investigation and debate. Traditionally, grafts are seeded in the striatum region to ensure dopamine released by the graft can be utilized proximately. The grafts at this site have successfully restored motor deficits in PD models. However, the A9 DA neurons are originally located in SNpc where proper support is provided for the development of the grafted immature DA neurons to ensure their integration into neural circuits by projecting neurites to their destined targets and receiving afferent innervation to fine-tune their functions. Thus, intranigral grafting may lead to better restoration of complex motor behaviors with proper synaptic input regulations. However, this approach requires axonal branching of the intranigral graft to cover a distance of a few centimeters to innervate the striatum area in humans. In monkey models of PD, fibers from grafted neurons were observed to extend over 2000 µm away from the graft, and their density decreased with distance. The first PD patient who received an autologous graft experienced a gradual improvement in their clinical symptoms over a period of time, which is consistent with the process of reinnervation of the putamen by projections from the graft. It would, therefore, take years for intranigral graft to properly innervate its targets and rescue motor deficits in PD patients. To promote graft innervation, glial-derived neurotrophic factor has been combined with cell therapy and showed significantly increased projection of grafted DA neurons to the targets that are innervated by endogenous DA neurons (Moriarty et al., 2022). Cell therapy using direct conversion: Recent studies have shown that glia, which share a common ancestor with neurons, have the potential to be directly converted into neurons. Regional identity of host astrocytes can facilitate the conversion to neurons of the same region after neural induction. In a chemically induced PD model, depletion of PTB gene in astrocytes of the SN resulted in astrocytes being reprogrammed into functional dopaminergic neurons that rescued PD motor dysfunctions. Interestingly, the higher conversion efficiency in the mouse midbrain was observed than in cultured midbrain astrocytes. Programmed DA neurons expressed a high level of Sox6 in the SN and Otx2 in the ventral tegmental area, consistent with the endogenous subtype-specific expression pattern. This evidence indicates that the local microenvironment is conducive to direct conversion, which may partially explain why a single gene manipulation resulted in specific changes in cell fate (Qian et al., 2020). However, there have been reports using the linage tracing strategy to show that genetically labeled astrocytes were not converted into neurons upon depletion of PTBP1 in vivo (Wang et al., 2021). Despite the debate, it would be helpful to investigate if small molecules that activate the SHH, Wnt, and FGF8b signaling pathways could improve reprogramming efficiency, as these pathways play a crucial role in differentiating stem cells to DA neurons. Moreover, a balance has to be reached to fine-tune the number of astrocytes converted to sufficiently compensate for the DA neuronal functions while maintaining the roles of astrocytes in blood-brain barrier homeostasis, brain structural support, and other physiological processes. Brain organoid transplantation: The 2D-grown DA neurons derived from stem cells are interspersed by uncharacterized neurons, and fail to form functional neural circuits. In contrast, human midbrain-like organoids (hMLOs) have been established to form a 3D architecture with DA secretion and synapse formation. The neurons in organoids are more mature, exhibiting similarity to the prenatal midbrain, characterized by the expression of the dopamine transporter. The hMLOs recapitulated both physiological and pathological features of the human brain, such as neuromelanin which is specifically expressed in the SNpc of humans and pathological α synuclein that aberrantly accumulates in the Lewy bodies (Jo et al., 2021). In midbrain organoids, other neuronal and glial cells also developed along with spatially-organized DA neurons, displaying synaptic connections and electrophysiological properties. Recently, cortical organoids were transplanted into the cortex of newborn rodents with mature cells successfully integrated into neural circuits (Revah et al., 2022). It is potentially possible to transplant hMLOs into the SN or striatum of the PD model to examine whether they can rescue the motor deficits. However, it will be a major challenge for the DA neurons in mature hMLOs to cross the organoid barrier to innervate the targets in the host brain. Carefully determining the development stages for hMLOs as potential transplantation sources is warranted. Historically, the transplantation of fVM DA cells marked a major breakthrough in cell therapy for PD and provided proof of concept for its therapeutic potential. Today, there is a concerted effort to translate iPSC-derived neurons into a clinically accessible option for cell therapy. We look forward to the findings of the ongoing clinical trials of transplantation of iPSC-derived DA neurons from multiple groups (summarized in Kim et al., 2022), which will help move cell therapy for PD forward. In the future, there is promising potential for the direct conversion and transplantation of midbrain organoids for PD therapy (Figure 1). With continued research, cell therapy may provide a viable therapeutic option for managing PD in the foreseeable future.Figure 1: Sources of cell therapy for PD.The field of cell therapy for PD has been constantly evolving. Historically, it started with transplantation of the adrenal medulla which has been abandoned in clinical practice. Transplantation of fetal ventral mesencephalic neurons has yielded mixed clinical outcomes with some patients enjoying long-term disease-free life. It provides proof-of-concept evidence for cell therapy as a viable option for PD but will less likely become a therapeutic norm for the general PD population. Currently, cell therapy utilizing human induced pluripotent stem cells (iPSCs)-derived graft overcomes the major hurdles that embryonic stem cells (ESCs)-based therapy encounters and holds great potential as a routine therapeutic option for PD. In the future, the direct conversion and transplantation of midbrain organoids for PD therapy are promising areas of research. PD: Parkinson’s disease. Created with BioRender.com.The authors thank the Singapore Ministry of Health’s National Medical Research Council (Open Fund Large Collaborative Grant (MOH-000207) and Singapore Translational Research (STaR) Investigator Award (NMRC/STaR/0030/2018) to EKT, CS-IRG-NIG, OF-YIRG and TA award to BX) for their support. The authors apologize for not being able to cite most of the relevant work, owing to reference limitations. C-Editors: Zhao M, Liu WJ, Li CH; T-Editor: Jia Y" @default.
• W4365795746 created "2023-04-16" @default.
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• W4365795746 date "2023-04-20" @default.
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• W4365795746 title "Cell replacement for Parkinson’s disease: advances and challenges" @default.
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