Reprogramming lineage identity through cell–cell fusion

Brown, Karen E.; Fisher, Amanda G.

doi:10.1016/j.gde.2021.04.004

Cited by 13 publications

(7 citation statements)

References 103 publications

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“…In this regard, FAST-containing oncolytic viruses were shown to decrease tumor growth by inducing tumor cell fusion and senescence ( Jeon and Jung, 2022 ). FAST proteins p10, p14, and p15 are promising candidates for cancer gene therapy, but their role in viral infections and neurodegeneration is currently unknown ( Del Papa et al., 2021 ; Brown and Fisher, 2021 ).…”

Section: Harnessing Fusionmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a “decentralized” information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

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Section: Harnessing Fusionmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Some of our findings are, however, reminiscent of the previously proposed "seesaw model" (Shu et al, 2013), in which opposing lineage factors are thought to cancel each other out, stabilizing a pluripotent stem cell identity. Conceptually close as well are cell fusion experiments (Cowan et al, 2005;Brown & Fisher, 2021). Such experiments showed that pluripotency is often dominant over somatic cell identities.…”

Section: Discussionmentioning

confidence: 83%

Probing cell identity hierarchies by fate titration and collision during direct reprogramming

Hersbach

Fischer

Masserdotti

et al. 2022

Molecular Systems Biology

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Despite the therapeutic promise of direct reprogramming, basic principles concerning fate erasure and the mechanisms to resolve cell identity conflicts remain unclear. To tackle these fundamental questions, we established a single‐cell protocol for the simultaneous analysis of multiple cell fate conversion events based on combinatorial and traceable reprogramming factor expression: Collide‐seq. Collide‐seq revealed the lack of a common mechanism through which fibroblast‐specific gene expression loss is initiated. Moreover, we found that the transcriptome of converting cells abruptly changes when a critical level of each reprogramming factor is attained, with higher or lower levels not contributing to major changes. By simultaneously inducing multiple competing reprogramming factors, we also found a deterministic system, in which titration of fates against each other yields dominant or colliding fates. By investigating one collision in detail, we show that reprogramming factors can disturb cell identity programs independent of their ability to bind their target genes. Taken together, Collide‐seq has shed light on several fundamental principles of fate conversion that may aid in improving current reprogramming paradigms.

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“…Given that EPSCs have distinct epigenomic networks compared to naïve ESCs [ 11 , 46 ], observing time-course changes during cell-fusion-induced reprogramming may provide novel epigenetic and mechanistic insights into a totipotent state. For example, Mai et al identified a novel transient reprogramming regulator, NKX3-1, using a cell-fusion-mediated heterokaryon model [ 47 ], suggesting that fusion-induced reprogramming could be a promising model for identifying early reprogramming factors [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Developmental Potency and Metabolic Traits of Extended Pluripotency Are Faithfully Transferred to Somatic Cells via Cell Fusion-Induced Reprogramming

Song

Choi

Hong

et al. 2022

Cells

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As a novel cell type from eight-cell-stage embryos, extended pluripotent stem cells (EPSCs) are known for diverse differentiation potency in both extraembryonic and embryonic lineages, suggesting new possibilities as a developmental research model. Although various features of EPSCs have been defined, their ability to directly transfer extended pluripotency to differentiated somatic cells by cell fusion remains to be elucidated. Here, we derived EPSCs from eight-cell mouse embryos and confirmed their extended pluripotency at the molecular level and extraembryonic differentiation ability. Then, they were fused with OG2+/− ROSA+/− neural stem cells (NSCs) by the polyethylene-glycol (PEG)-mediated method and further analyzed. The resulting fused hybrid cells exhibited pluripotential markers with upregulated EPSC-specific gene expression. Furthermore, the hybrid cells contributed to the extraembryonic and embryonic lineages in vivo and in vitro. RNA sequencing analysis confirmed that the hybrid cells showed distinct global expression patterns resembling EPSCs without parental expression of NSC markers, indicating the complete acquisition of extended pluripotency and the erasure of the somatic memory of NSCs. Furthermore, ultrastructural observation and metabolic analysis confirmed that the hybrid cells rearranged the mitochondrial morphology and bivalent metabolic profile to those of EPSCs. In conclusion, the extended pluripotency of EPSCs could be transferred to somatic cells through fusion-induced reprogramming.

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Reprogramming lineage identity through cell–cell fusion

Cited by 13 publications

References 103 publications

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Probing cell identity hierarchies by fate titration and collision during direct reprogramming

Developmental Potency and Metabolic Traits of Extended Pluripotency Are Faithfully Transferred to Somatic Cells via Cell Fusion-Induced Reprogramming

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