Midbrain Dopaminergic Neurons Differentiated from Human-Induced Pluripotent Stem Cells

Tofoli, Fabiano A.; Semeano, Ana Teresa Silva; Oliveira-Giacomelli, Ágatha; Gonçalves, Maria Carolina Bittencourt; Ferrari, Merari F. R.; Pereira, Lygia V.; Ulrich, Henning

doi:10.1007/978-1-4939-9007-8_8

Cited by 19 publications

(8 citation statements)

References 48 publications

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“…We derived hMOs from different iPSC lines using classical midbrain patterning factors [14,[54][55][56][57][58][59][60], following our previously published timeline [7] (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Microfabricated disk technology: rapid scale up in midbrain organoid generation

Mohamed

Lépine

Lacalle‐Aurioles

et al. 2021

Preprint

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By providing a three-dimensional in vitro culture system with key features of the substantia nigra region in the brain, 3D neuronal organoids derived from human induced pluripotent stem cells (iPSCs) provide living neuronal tissue resembling the midbrain region of the brain. However, a major limitation of conventional brain organoid culture is that it is often labor-intensive, requiring highly specialized personnel for moderate throughput. Additionally, the methods published for long-term cultures require time-consuming maintenance to generate brain organoids in large numbers. With the increasing need for human midbrain organoids (hMOs) to better understand and model Parkinson′s disease (PD) in a dish, there is a need to implement new workflows and methods to both generate and maintain hMOs, while minimizing batch to batch variation. In this study, we developed a method with microfabricated disks to scale up the generation of hMOs. This opens up the possibility to generate larger numbers of hMOs, in a manner that minimizes the amount of labor required, while decreasing variability and maintaining the viability of these hMOs over time. Taken together, producing hMOs in this manner opens up the potential for these to be used to further PD studies.

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“…We derived hMOs from different iPSC lines using classical midbrain patterning factors [14,[54][55][56][57][58][59][60], following our previously published timeline [7] (Fig. 1A).…”

Section: Resultsmentioning

confidence: 99%

Microfabricated disk technology: rapid scale up in midbrain organoid generation

Mohamed

Lépine

Lacalle‐Aurioles

et al. 2021

Preprint

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“…Following our previously published methods 30 , we derived hMOs from the SNCA iPSC lines using classical midbrain patterning factors 26,[39][40][41][42][43][44][45] (Fig. 1A).…”

Section: Generation Of Midbrain Organoids From Patient-derived Ipscs With An Snca Triplicationmentioning

confidence: 99%

Midbrain organoids with anSNCAgene triplication model key features of synucleinopathy

Mohamed

Sirois

Ramamurthy

et al. 2021

Preprint

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SNCA, the first gene associated with Parkinson′s disease, encodes the α-synuclein (α-syn) protein, the predominant component within pathological inclusions termed Lewy bodies (LBs). The presence of LBs is one of the classical hallmarks found in the brain of patients with Parkinson′s disease, and LBs have also been observed in patients with other synucleinopathies. However, the study of α-syn pathology in cells has relied largely on two-dimensional culture models, which typically lack the cellular diversity and complex spatial environment found in the brain. Here, to address this gap, we use 3D midbrain organoids (hMOs), differentiated from human induced pluripotent stem cells derived from patients carrying a triplication of the SNCA gene and from CRISPR/Cas9 corrected isogenic control iPSCs. These hMOs recapitulate key features of α-syn pathology observed in the brains of patients with synucleinopathies. In particular, we find that SNCA triplication hMOs express elevated levels of α-syn and exhibit an age-dependent increase in α-syn aggregation, manifested by the presence of both oligomeric and phosphorylated forms of α-syn. These phosphorylated α-syn aggregates were found in both neurons and glial cells and their time-dependent accumulation correlated with a selective reduction in dopaminergic neuron numbers. Thus, hMOs from patients carrying SNCA gene multiplication can reliably model key pathological features of Parkinson′s disease and provide a powerful system to study the pathogenesis of synucleinopathies.

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“…One of the key benefits of using hiPSCs is the possibility of autologous transplantation. Similarly to hESC-derived DA neurons, midbrain identity has been achieved in differentiated hiPSCs (Niclis et al, 2017;Tofoli et al, 2019). Transplants of hiPSC-derived DA progenitors in rodent and non-human primate models of PD have resulted in graft integration into existing neural networks with associated motor improvement (Hallett et al, 2015;Kikuchi et al, 2017;Niclis et al, 2017).…”

Section: Induced Pluripotent Stem Cellsmentioning

confidence: 99%

Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases?

Salado-Manzano

Perpiñá

Straccia³

et al. 2020

Front. Cell. Neurosci.

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Neurodegenerative disorders such as Parkinson's (PD) and Huntington's disease (HD) are characterized by a selective detrimental impact on neurons in a specific brain area. Currently, these diseases have no cures, although some promising trials of therapies that may be able to slow the loss of brain cells are underway. Cell therapy is distinguished by its potential to replace cells to compensate for those lost to the degenerative process and has shown a great potential to replace degenerated neurons in animal models and in clinical trials in PD and HD patients. Fetal-derived neural progenitor cells, embryonic stem cells or induced pluripotent stem cells are the main cell sources that have been tested in cell therapy approaches. Furthermore, new strategies are emerging, such as the use of adult stem cells, encapsulated cell lines releasing trophic factors or cell-free products, containing an enriched secretome, which have shown beneficial preclinical outcomes. One of the major challenges for these potential new treatments is to overcome the host immune response to the transplanted cells. Immune rejection can cause significant alterations in transplanted and endogenous tissue and requires immunosuppressive drugs that may produce adverse effects. T-, B-lymphocytes and microglia have been recognized as the main effectors in striatal graft rejection. This review aims to summarize the preclinical and clinical studies of cell therapies in PD and HD. In addition, the precautions and strategies to ensure the highest quality of cell grafts, the lowest risk during transplantation and the reduction of a possible immune rejection will be outlined. Altogether, the wide-ranging possibilities of advanced therapy medicinal products (ATMPs) could make therapeutic treatment of these incurable diseases possible in the near future.

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Midbrain Dopaminergic Neurons Differentiated from Human-Induced Pluripotent Stem Cells

Cited by 19 publications

References 48 publications

Microfabricated disk technology: rapid scale up in midbrain organoid generation

Microfabricated disk technology: rapid scale up in midbrain organoid generation

Midbrain organoids with anSNCAgene triplication model key features of synucleinopathy

Is the Immunological Response a Bottleneck for Cell Therapy in Neurodegenerative Diseases?

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