Generation of hiPSC-derived low threshold mechanoreceptors containing axonal termini resembling bulbous sensory nerve endings and expressing Piezo1 and Piezo2

Stanslowsky, Nancy; Fernández-Trillo, Jorge; Mamo, Tamrat M.; Yu, Pengfei; Kalmbach, Norman; Ritter, Barbara; Eggenschwiler, Reto; Ouwendijk, Werner J. D.; Mzinza, David; Tan, Likai; Leffler, Andreas; Spohn, Michael; Brown, Richard J. P.; Kropp, Kai A.; Kaever, Volkhard; Ha, Teng-Cheong; Narayanan, Pratibha; Grundhoff, Adam; Förster, Reinhold; Schambach, Axel; Verjans, Georges M. G. M.; Schmidt, Manuela; Kispert, Andreas; Cantz, Tobias; Gomis, Ana; Wegner, Florian; Viejo‐Borbolla, Abel

doi:10.1016/j.scr.2021.102535

Cited by 5 publications

(9 citation statements)

References 69 publications

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“…To perform a comparative analysis of SARS-CoV-2 infection in PNS and CNS neurons, we employed protocols developed in our laboratories to differentiate human iPSC into neurons with characteristics of sensory and striatal medium spiny neurons (MSN) (schematic depiction in Figure 1A and 1B) (Kutschenko et al, 2021; Zhu et al, 2021). We will refer to the sensory neurons and MSN as PNS and CNS neurons, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Differentiation of human iPSC-derived CNS and PNS neurons, and their expression profiles of SARS-CoV-2 receptors and entry factors. (A,B) PNS (A) and CNS (B) neurons were differentiated from iPSC adding the indicated supplements at the corresponding time points (Kutschenko et al, 2021; Zhu et al, 2021). (C) Graphs showing relative expression of ACE2, TMPRSS2 and NRP1 in iPSC-derived CNS neurons (left) and PNS neurons (middle) and that of ACE2 in Vero76 cells (right).…”

Section: Resultsmentioning

confidence: 99%

“…Sensory neurons and MSNs were derived from iPSC and maintained as previously described (Kutschenko et al, 2021; Zhu et al, 2021). To differentiate sensory neurons, we employed small molecule derived neuronal precursor cells (smNPCs) generated from cord blood-derived iPSC (Naujock et al, 2014).…”

Section: Methodsmentioning

confidence: 99%

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Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons

Passos

Henkel

Wang

et al. 2022

Preprint

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Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection causes neurological disease in some patients suggesting that infection can affect both the peripheral and central nervous system (PNS and CNS, respectively). It is not clear whether the outcome of SARS-CoV-2 infection of PNS and CNS neurons is similar, and which are the key factors that cause neurological disease: SARS-CoV-2 infection or the subsequent immune response. Here, we addressed these questions by infecting human induced-pluripotent stem cell-derived CNS and PNS neurons with the beta strain of SARS-CoV-2. Our results show that SARS-CoV-2 infects PNS neurons more efficiently than CNS neurons, despite lower expression levels of angiotensin converting enzyme 2. Infected PNS neurons produced interferon lambda 1, several interferon stimulated genes and proinflammatory cytokines. They also displayed neurodegenerative-like alterations, as indicated by increased levels of sterile alpha and Toll/interleukin receptor motif-containing protein 1, amyloid precursor protein and alpha-synuclein and lower levels of nicotinamide mononucleotide adenylyltransferase 2 and beta-III-tubulin. Interestingly, blockade of the Janus kinase and signal transducer and activator of transcription pathway by Ruxolitinib did not increase SARS-CoV-2 infection, but reduced neurodegeneration, suggesting that an exacerbated neuronal innate immune response contributes to pathogenesis in the PNS.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons

Passos

Henkel

Wang

et al. 2022

Preprint

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“…Sensory neurons and striatal medium spiny neurons (MSNs) were derived from iPSC and maintained as previously described. 56,57 To differentiate sensory neurons, we employed small molecule derived neuronal precursor cells (smNPCs) generated from cord bloodderived iPSC. 58 The MSNs were differentiated from a control iPSC line.…”

Section: Cells and Virusesmentioning

confidence: 99%

Innate immune response to SARS‐CoV‐2 infection contributes to neuronal damage in human iPSC‐derived peripheral neurons

Passos,

Henkel,

Wang

et al. 2024

Journal of Medical Virology

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Severe acute respiratory coronavirus 2 (SARS‐CoV‐2) causes neurological disease in the peripheral and central nervous system (PNS and CNS, respectively) of some patients. It is not clear whether SARS‐CoV‐2 infection or the subsequent immune response are the key factors that cause neurological disease. Here, we addressed this question by infecting human induced pluripotent stem cell‐derived CNS and PNS neurons with SARS‐CoV‐2. SARS‐CoV‐2 infected a low number of CNS neurons and did not elicit a robust innate immune response. On the contrary, SARS‐CoV‐2 infected a higher number of PNS neurons. This resulted in expression of interferon (IFN) λ1, several IFN‐stimulated genes and proinflammatory cytokines. The PNS neurons also displayed alterations characteristic of neuronal damage, as increased levels of sterile alpha and Toll/interleukin receptor motif‐containing protein 1, amyloid precursor protein and α‐synuclein, and lower levels of cytoskeletal proteins. Interestingly, blockade of the Janus kinase and signal transducer and activator of transcription pathway by Ruxolitinib did not increase SARS‐CoV‐2 infection, but reduced neuronal damage, suggesting that an exacerbated neuronal innate immune response contributes to pathogenesis in the PNS. Our results provide a basis to study coronavirus disease 2019 (COVID‐19) related neuronal pathology and to test future preventive or therapeutic strategies.

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“…It is likely we will see more studies using α-HV latency models based on geneticallyisogenic populations of human neurons exhibiting transcriptomes resembling those of bona fide sensory or sympathetic neurons. Because of the perceived value in regenerative medicine, directed reprogramming techniques capable of converting untransformed cells such as primary fibroblasts into functional neurons are becoming more efficient and more nuanced in terms of the neuronal subtypes generated, and do not require cells to pass through an embryonic phenotype [93][94][95][96]. However, there are still significant challenges relating to the length of time required to generate usable cultures and unresolved difficulties in achieving desirable uniformity in sufficient quantity.…”

Section: Next Generation Modelsmentioning

confidence: 99%

Impact of Cultured Neuron Models on α-Herpesvirus Latency Research

Wilson

2022

Viruses

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A signature trait of neurotropic α-herpesviruses (α-HV) is their ability to establish stable non-productive infections of peripheral neurons termed latency. This specialized gene expression program is the foundation of an evolutionarily successful strategy to ensure lifelong persistence in the host. Various physiological stresses can induce reactivation in a subset of latently-infected neurons allowing a new cycle of viral productive cycle gene expression and synthesis of infectious virus. Recurring reactivation events ensure transmission of the virus to new hosts and contributes to pathogenesis. Efforts to define the molecular basis of α-HV latency and reactivation have been notoriously difficult because the neurons harboring latent virus in humans and in experimentally infected live-animal models, are rare and largely inaccessible to study. Increasingly, researchers are turning to cultured neuron infection models as simpler experimental platforms from which to explore latency and reactivation at the molecular level. In this review, I reflect on the strengths and weaknesses of existing neuronal models and briefly summarize the important mechanistic insights these models have provided. I also discuss areas where prioritization will help to ensure continued progress and integration.

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Generation of hiPSC-derived low threshold mechanoreceptors containing axonal termini resembling bulbous sensory nerve endings and expressing Piezo1 and Piezo2

Cited by 5 publications

References 69 publications

Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons

Innate immune response to SARS-CoV-2 infection contributes to neuronal damage in human iPSC-derived peripheral neurons

Innate immune response to SARS‐CoV‐2 infection contributes to neuronal damage in human iPSC‐derived peripheral neurons

Impact of Cultured Neuron Models on α-Herpesvirus Latency Research

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