Human stem cell–derived astrocytes replicate human prions in a PRNP genotype–dependent manner

Abstract

Krejciova et al. present the first study demonstrating that CJD prions infect human stem cell–derived astrocytes in vitro. This provides a physiologically relevant model for discovery of key molecular pathogenic events of CJD and facilitates the development of future therapies.

Prion infection, transmission and cytopathology modelled in a low-biohazard human cell line

“…The prions produced may have a reduced propensity to infect humans. Moreover, hovS cells do not require human material (such as CJD brain) for infection, in contrast to all previously reported human prion cell models (Groveman et al, 2019;Krejciova et al, 2017;Ladogana et al, 1995). For these combined reasons, we posit that hovS cells may be adopted by many research laboratories worldwide without requiring biosafety level three (BSL3) precautions.…”

“…Currently, there are only three reports of human cellular models for prion infection and propagation (Groveman et al, 2019;Krejciova et al, 2017;Ladogana et al, 1995). However, the culture and maintenance of these models are costly, extremely laborious and have limited scalability.…”

Concepts toward directing human astroplasticity to promote neuroregeneration

“…For instance, tau‐lowering compounds were screened with induced neurons (iNeurons) from a hPSC line that was generated by inserting an inducible ngn2 cassette into AAVS1 (Wang et al, ). Creating iAstrocytes in a similar fashion, could allow for HTS to discover small molecules that alter reactivity states during various genetic disease paradigms or in response to exogenous insults, such as Zika virus or misfolded prion infection (Retallack et al, ; Krejciova et al, ). Another utility of genetic recombination technology is regulating transcription of target genes by binding nuclease‐deficient Cas9 (dCas9) fused with transcription inhibitors (CRISPRi) or activators (CRISPRa) near start sites (Zhang and McCarty, ).…”

A role for astroglia in prion diseases

“…These limitations have hampered the mechanistic study of human prion diseases and may have also hindered the discovery of human therapies because many antiprion compounds are only effective in specific animal species (Aguzzi and Polymenidou, 2004;Bolognesi and Legname, 2015;Aguzzi et al, 2017). Krejciova et al (2017) have found that human CJD brain extracts can elicit prion replication in astrocytes that were grown out of human induced pluripotent stem cells (iPSCs; see figure). A common Met/Val polymorphism at codon 129 of the PRNP gene controls susceptibility of humans to prion infections, with homozygous individuals (Met/Met and Val/Val) being overrepresented in collectives of CJD patients.…”

“…Although these studies suggested that astrocytes may directly contribute to prion replication and propagation, we deemed them somewhat dubious (including those to which we had contributed) because the GFAP promoter fragment used for the generation of these mice was later found to be ectopically active in certain neuronal populations (Marino et al, 2000;Zhuo et al, 2001;Casper and McCarthy, 2006), thereby sowing doubts whether prion replication occurred truly in astrocytes. The unambiguous replication of CJD prions in human iPSC-derived astrocytes goes a long way toward vin-dicating the Raeber publication, yet the astrocytes used by Krejciova et al (2017), like those from any other iPSC-based systems, may be contaminated with small numbers of neuronal cells. Complete, reliable elimination of all contaminating neurons would be desirable but may not be technically attainable.…”