Abstract
Human neurodegenerative diseases, such as Alzheimer’s disease (AD), are not easily modeled in vitro due to the inaccessibility of brain tissue and the level of complexity required by existing cell culture systems. Three-dimensional (3D) brain organoid systems generated from human pluripotent stem cells (hPSCs) have demonstrated considerable potential in recapitulating key features of AD pathophysiology, such as amyloid plaque- and neurofibrillary tangle-like structures. A number of AD brain organoid models have also been used as platforms to assess the efficacy of pharmacological agents in disease progression. However, despite the fact that stem cell-derived brain organoids mimic early aspects of brain development, they fail to model complex cell-cell interactions pertaining to different regions of the human brain and aspects of natural processes such as cell differentiation and aging. Here, we review current advances and limitations accompanying several hPSC-derived organoid methodologies, as well as recent attempts to utilize them as therapeutic platforms. We additionally discuss comparative benefits and disadvantages of the various hPSC-derived organoid generation protocols and differentiation strategies. Lastly, we provide a comparison of hPSC-derived organoids to primary tissue-derived organoids, examining the future potential and advantages of both systems in modeling neurodegenerative disorders, especially AD.
Highlights
Alzheimer’s disease (AD) constitutes the most prominent cause of late-life dementia, affecting over 50 million individuals
Brain organoid generation attempts have been mostly focused on somatic cell reprogramming, a process in which patient-derived somatic cells are induced to become human pluripotent stem cells (hPSCs) (Amin and Pasca, 2018)
HPSCs can be subsequently differentiated into monolayer neuronal cultures or brain organoids, which are 3D neural cell aggregates resembling various brain regions
Summary
Alzheimer’s disease (AD) constitutes the most prominent cause of late-life dementia, affecting over 50 million individuals. HPSC-derived organoids predominantly rely on the process of somatic cell reprogramming, which has been extensively linked to increased risk of genomic instability, as iPSCs may often carry mutations related to known tumorigenic loci (Mayshar et al, 2010; Hussein et al, 2011; Laurent et al, 2011) This implication poses serious limitations to the use of hPSC-derived organoids in modeling human disease. Genomic analyses of early passage iPSCs have indicated that they might retain “epigenetic memory” related to their previous fate, by displaying DNA methylation patterns encountered in somatic cells, at regions proximal to CpG islands This leads to variations in gene expression which might affect hPSC usage as organoid generation templates (Doi et al, 2009; Kim et al, 2010; Polo et al, 2010; Bar-Nur et al, 2011; Puri and Nagy, 2012). Due to the above limitations, hPSC-derived organoid cultures need to be constantly compared to independent batches of multiple hPSC lines and adequately assessed for their capacity to produce consistent results, before being put forward as powerful disease model systems
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