Year: 2021
Type: article
Abstract: The rapid development of induced pluripotent stem cell (iPSC) technology has considerably expanded the range of human cell and tissue models available for investigators.IPSCs can be used to generate a variety of cells and tissues, with examples ranging from directed differentiation of cell populations for studying homogenous cultures to more complex three-dimensional (3D) structures.One especially advantageous innovation was the development of mini-tissues termed "organoids."Organoids allow cells to be studied in a 3D environment that loosely mimics how they would interact with neighboring cells in an organism.This is critical because cells inside an organ are structured as part of their function, something that is rarely achievable when cells are cultured in vitro.Human brain has proven difficult to model, and this tissue is not widely available for study.Therefore, the application of organoid technology to produce 3D cultures of self-patterning brain tissue, human cerebral organoids (hCOs), offers great promise for investigating how brain cells become dysfunctional and die in neurodegenerative conditions.Prions diseases (PrDs), or transmissible spongiform encephalopathies, encompass a family of aggressive neurodegenerative conditions that affect both humans and animals.These diseases are caused by misfolding of a cellular protein, the prion protein (PrP), into misfolded conformers (prions or PrP Sc ) that can then template conversion of more misfolded PrP Sc .This templated misfolding results in transmissibility of PrDs within a species and, under certain circumstances, across species.Certain hallmark features are common to most PrDs, including deposition of PrP Sc in the brain, vacuolation giving the brain a spongy appearance, and astrogliosis.In human PrDs, different subtypes of disease have different clinical presentations and different biochemistry.The subtypes can be modeled in mice but only recently, with the development of new iPSC-based models, has it been possible to consider the pathogenesis of human PrDs in a fully human cell system.Below and within Fig 1, we outline current progress and future possibilities of hCO systems for the investigation of PrDs. OAU : Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly: rganoids become infected with and accumulate human prionsUntil 2017, no reproducible human cell model of prion infection existed.There was precedent in the literature from mouse models that neural stem cells (NSCs), and mature cultures differentiated from NSCs, would be permissible to infection [1-3].Thus, iPSCs were a prime technology to apply to this problem.The first system derived from human iPSC lines for PrD research studied astrocytes [4].Transmission from human brain tissue to cultures of iPSCderived astrocytes demonstrated that it was feasible to transmit prions from human tissue to human tissue cultures and that the biochemical features of the subtypes were preserved [4].Using hCO cultures differentiated from iPSCs employing the method described by Lancaster
Source: PLoS Pathogens
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,575
OpenAlex ID: W3184018023