Human Stem Cell Models to Study Host–Virus Interactions in the Central Nervous System
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REVIEWS Human stem cell models to study host–virus interactions in the central nervous system Oliver Harschnitz 1,2 ✉ and Lorenz Studer 1,2 Abstract | Advancements in human pluripotent stem cell technology offer a unique opportunity for the neuroimmunology field to study host–virus interactions directly in disease-relevant cells of the human central nervous system (CNS). Viral encephalitis is most commonly caused by herpesviruses, arboviruses and enteroviruses targeting distinct CNS cell types and often leading to severe neurological damage with poor clinical outcomes. Furthermore, different neurotropic viruses will affect the CNS at distinct developmental stages, from early prenatal brain development to the aged brain. With the unique flexibility and scalability of human pluripotent stem cell technology, it is now possible to examine the molecular mechanisms underlying acute infection and latency, determine which CNS subpopulations are specifically infected, study temporal aspects of viral susceptibility, perform high-throughput chemical or genetic screens for viral restriction factors and explore complex cell-non-autonomous disease mechanisms. Therefore, human pluripotent stem cell technology has the potential to address key unanswered questions about antiviral immunity in the CNS, including emerging questions on the potential CNS tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). embryonic stem cells1 Embryonic stem cells The isolation of human and tran- immune system. Animal models can be genetically Pluripotent stem cells scription factor-based reprogramming of somatic cells altered, and disease phenotypes can be studied within that are capable of giving into human induced pluripotent stem cells (iPSCs)2 are an entire organism to dissect complex interactions rise to all lineages, but not important breakthroughs in the stem cell field. The between organ systems and diverse cell types. However, to extraembryonic tissues. directed differentiation They are derived from of human pluripotent stem cells there are considerable species-specific differences of the inner cell mass of the (hPSCs; a term referring to both human embryonic stem the immune system that complicate the translation developing embryo. cells and human iPSCs) along the three germ layers ena- of findings in animal models to human disease. General bles the derivation, study and perturbation of potentially differences in metabolism and cell turnover may play a any human cell type. Key applications of hPSCs include role, but species-specific differences of the immune sys- the study of human development3–7, modelling human tem are also profound. Comparing mice and humans, disease8–11 and the development of cell-based therapies we find key differences in many immune components, in regenerative medicine12–18. Past human studies on including in the cellular composition of leukocytes, in neurological and neuroimmunological disease relied signalling components of B cells and T cells, in Toll-like on autopsy or biopsy materials, the isolation of cere- receptors (TLRs), in cytokines and cytokine receptors brospinal fluid or peripheral blood samples. The lack of and in immunoglobulin class switching19,20. In the brain, 1Developmental Biology routine access to primary human central nervous system microglia show species-specific divergence at physio- Program, Sloan Kettering (CNS) cell types has precluded most mechanistic studies, logical levels (for example, in proliferation and in the Institute for Cancer Research, prevented the establishment of robust in vitro disease expression of sialic acid-binding immunoglobulin-like New York, NY, USA. models and made it impossible to perform high-content lectins (SIGLECs)) and in their neuroinflammatory 2 The Center for Stem Cell chemical or genetic screens directly in human cells. and disease states (for example, responses to trans- Biology, Sloan Kettering Institute for Cancer Research, Therefore, hPSC technology offers a particularly attrac- forming growth factor-β (TGFβ) signalling in models 21 New York, NY, USA. tive approach for studying CNS disease and is an ideal of Alzheimer disease) . The use of hPSC-derived cell ✉e-mail: [email protected] tool to probe neuroimmunological disorders. types provides a tractable human in vitro disease plat- https://doi.org/10.1038/ Animal models have yielded important insights form for mechanistic studies, for identifying novel thera- s41577-020-00474-y into the physiology and dysfunction of the mammalian peutic targets and for translating targets into compounds NATURE REVIEWS | IMMUNOLOGY VOLUME 21 | JULY 2021 | 441 REVIEWS Induced pluripotent for therapeutic intervention. In addition to capturing ZIKV preferentially targets NPCs and microglia, lead- stem cells the patient’s genetic information via iPSC technology, ing to impaired prenatal brain development resulting (iPSCs). Pluripotent stem powerful genome editing tools are used routinely in in microcephaly41,42. In addition to direct CNS tropism, cells derived from terminally hPSCs to genetically correct or induce the expression of viral infections can lead to systemic inflammatory differentiated somatic cells through cellular reprogramming disease-linked alleles. responses that may harm CNS-resident cell types either via the transient expression of To date, hPSC technology has been mostly applied directly or through migration of immune cells into the a defined set of transcription to neurodevelopmental and neurodegenerative disor- CNS43. One such example is the development of post- factors. ders, such as microcephaly22, spinal muscular atrophy23, encephalitic parkinsonism that followed the influenza familial dysautonomia24, amyotrophic lateral sclerosis8, pandemic in 1918. The cause of the resulting parkin- Directed differentiation 9 25 The guided differentiation of Alzheimer disease and Parkinson disease . However, sonism remains unclear, with several potential mech- pluripotent stem cells towards hPSC technology is also increasingly used to study anisms proposed, such as chronic CNS inflammation a desired somatic cell state autoimmune-induced or virus-induced diseases of the following acute viral infection, invasion of peripheral using morphogens and small nervous system26. Such studies have examined how immune cells into the CNS following loss of integrity molecules. autoantibodies target neuronal epitopes leading to of the blood–brain barrier (BBB) or damage due to 44,45 Cerebellar granule cell neuronal dysfunction that closely recapitulates clinical postinfectious autoimmunity . neurons phenotypes and treatment responsiveness27–29. Studies Why certain neuronal or glial cell types show resist- The most numerous neurons on host–virus interactions in hPSC-derived neural lin- ance or susceptibility to a given virus remains largely in the human brain. They are eages include work on herpes simplex virus 1 (HSV-1) unknown. To probe cell type-specific innate immune found in the thick granular layer of the cerebellar cortex. and Zika virus (ZIKV), which affect distinct subpopu- responses, it is imperative to obtain purified neural lations, such as postmitotic neurons versus neural pro- lineages on demand. The derivation of highly enriched Purkinje neurons genitor cells (NPCs), providing important insights into CNS subtypes from hPSCs allows modelling of selec- A class of GABAergic neurons virus-induced CNS pathophysiology30–33. This Review tive vulnerabilities in vitro and the identification of cell located within the Purkinje layer of the cerebellum. They presents an overview of hPSC-based studies of CNS type-specific innate immune mechanisms. Furthermore, arise from progenitors in the host–virus interactions and explores how this technol- by combining several distinct cell types in co-culture sys- ventricular neuroepithelium ogy can address key outstanding questions in the neuro- tems, either in two or three dimensions, one can study of the cerebellar primordium immunology field. In the final section of the Review, the role of cell-non-autonomous signalling in anti viral during embryogenesis. we discuss how such studies may also help to address immunity46. Those may include anti-inflammatory emerging questions concerning CNS involvement and mechanisms during the acute phase47,48, but also pro- neurological complications in severe acute respiratory inflammatory cascades leading to chronic inflamma- syndrome coronavirus 2 (SARS-CoV-2) infection. tion and long-term neurological deficits43,49–51. Systemic inflammatory signals that negatively impact CNS Using hPSCs to model CNS-resident cell types function, such as virus-induced brain endothelial cell CNS-resident cells show differential susceptibility to inflammation52 or T cell-mediated synaptic pruning43, viral infection. The brain comprises numerous neuronal could also be modelled with hPSC technology by and glial cell types that are essential for CNS function. establishing relevant co-culture systems of neural and The extensive cellular heterogeneity in the CNS entails non-neural cell types. vast heterogeneity in cell type-specific immunologi- cal responses. Astrocytes and microglia play key roles Neural induction and differentiation of hPSCs. in antiviral immunity, and neurons themselves are Sophisticated differentiation strategies have been devel- not mere bystanders. Neurons exhibit innate antiviral oped to yield region-specific neuronal subtypes12,35,53–60, immune responses and produce various interferons and astrocytes61–64 and oligodendrocytes65. The first