Cilium induction triggers differentiation of glioma stem cells

Goranci-Buzhala, Gladiola; Mariappan, Aruljothi; Ricci–Vitiani, Lucia; Josipović, Nataša; Pacioni, Simone; Gottardo, Marco; Ptok, Johannes; Schaal, Heiner; Callaini, Giuliano; Rajalingam, Krishnaraj; Dynlacht, Brian David; Hadian, Kamyar; Papantonis, Argyris; Pallini, Roberto; Gopalakrishnan, Jay

doi:10.1016/j.celrep.2021.109656

Cited by 37 publications

(35 citation statements)

References 76 publications

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“…Cilia are key organelles not only involved in cell movement but are also major regulators of cell proliferation [ 40 ]. Most cells begin to disassemble their primary cilia at cell cycle re-entry [ 41 ] and reintroduction of cilia genes in cancer cells can lead to proliferation arrest and differentiation [ 42 ]. Remarkably, GO analysis revealed a significant downregulation of these genes after SCI ( Figure 1 D and Table S1 ) suggesting a link with the concomitant upregulation of genes involved in mitosis ( Figure 1 D).…”

Section: Resultsmentioning

confidence: 99%

RNA Profiling of Mouse Ependymal Cells after Spinal Cord Injury Identifies the Oncostatin Pathway as a Potential Key Regulator of Spinal Cord Stem Cell Fate

Chevreau

Ghazale

Ripoll

et al. 2021

Cells

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Ependymal cells reside in the adult spinal cord and display stem cell properties in vitro. They proliferate after spinal cord injury and produce neurons in lower vertebrates but predominantly astrocytes in mammals. The mechanisms underlying this glial-biased differentiation remain ill-defined. We addressed this issue by generating a molecular resource through RNA profiling of ependymal cells before and after injury. We found that these cells activate STAT3 and ERK/MAPK signaling post injury and downregulate cilia-associated genes and FOXJ1, a central transcription factor in ciliogenesis. Conversely, they upregulate 510 genes, seven of them more than 20-fold, namely Crym, Ecm1, Ifi202b, Nupr1, Rbp1, Thbs2 and Osmr—the receptor for oncostatin, a microglia-specific cytokine which too is strongly upregulated after injury. We studied the regulation and role of Osmr using neurospheres derived from the adult spinal cord. We found that oncostatin induced strong Osmr and p-STAT3 expression in these cells which is associated with reduction of proliferation and promotion of astrocytic versus oligodendrocytic differentiation. Microglial cells are apposed to ependymal cells in vivo and co-culture experiments showed that these cells upregulate Osmr in neurosphere cultures. Collectively, these results support the notion that microglial cells and Osmr/Oncostatin pathway may regulate the astrocytic fate of ependymal cells in spinal cord injury.

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Section: Resultsmentioning

confidence: 99%

RNA Profiling of Mouse Ependymal Cells after Spinal Cord Injury Identifies the Oncostatin Pathway as a Potential Key Regulator of Spinal Cord Stem Cell Fate

Chevreau

Ghazale

Ripoll

et al. 2021

Cells

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“…Further support for the tumor-suppressing role of cilia in GBM was recently reported by Goranci-Buzhala et al (2021) who showed that patient-derived glioblastoma stem cells displayed high levels of proteins that are involved in cilia disassembly such as CPAP, Aurora-A, NEK2, NDE1 and OFD1 that resulted in suppressing ciliogenesis. Furthermore, patient-derived glioblastoma stem cells and clinical glioblastoma tissue displayed reduced primary cilia formation associated with increased cell proliferation.…”

Section: Primary Cilia and Brain Tumorsmentioning

confidence: 65%

“…Furthermore, patient-derived glioblastoma stem cells and clinical glioblastoma tissue displayed reduced primary cilia formation associated with increased cell proliferation. Importantly, rescuing ciliogenesis by depleting the disassembly protein complex restored cilia formation and non-malignant phenotype, as glioma stem cells were able to trigger differentiation ( Goranci-Buzhala et al, 2021 ). Strikingly, ciliogenesis-induced differentiation was critical to prevent infiltration of glioma stem cell organoids into the brain of mice showing that signals from the primary cilia determine glioma stem cell fate ( Goranci-Buzhala et al, 2021 ).…”

Section: Primary Cilia and Brain Tumorsmentioning

confidence: 99%

“…Importantly, rescuing ciliogenesis by depleting the disassembly protein complex restored cilia formation and non-malignant phenotype, as glioma stem cells were able to trigger differentiation ( Goranci-Buzhala et al, 2021 ). Strikingly, ciliogenesis-induced differentiation was critical to prevent infiltration of glioma stem cell organoids into the brain of mice showing that signals from the primary cilia determine glioma stem cell fate ( Goranci-Buzhala et al, 2021 ). Collectively, these studies highlight the importance of primary cilia in regulating neuronal differentiation, cell proliferation and, consequently, GBM tumorigenesis as cilia formation is impaired in GBM ( Sarkisian and Semple-Rowland, 2019 ).…”

Section: Primary Cilia and Brain Tumorsmentioning

confidence: 99%

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Post-transcriptional and Post-translational Modifications of Primary Cilia: How to Fine Tune Your Neuronal Antenna

Rocha

Prinos

2022

Front. Cell. Neurosci.

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Primary cilia direct cellular signaling events during brain development and neuronal differentiation. The primary cilium is a dynamic organelle formed in a multistep process termed ciliogenesis that is tightly coordinated with the cell cycle. Genetic alterations, such as ciliary gene mutations, and epigenetic alterations, such as post-translational modifications and RNA processing of cilia related factors, give rise to human neuronal disorders and brain tumors such as glioblastoma and medulloblastoma. This review discusses the important role of genetics/epigenetics, as well as RNA processing and post-translational modifications in primary cilia function during brain development and cancer formation. We summarize mouse and human studies of ciliogenesis and primary cilia activity in the brain, and detail how cilia maintain neuronal progenitor populations and coordinate neuronal differentiation during development, as well as how cilia control different signaling pathways such as WNT, Sonic Hedgehog (SHH) and PDGF that are critical for neurogenesis. Moreover, we describe how post-translational modifications alter cilia formation and activity during development and carcinogenesis, and the impact of missplicing of ciliary genes leading to ciliopathies and cell cycle alterations. Finally, cilia genetic and epigenetic studies bring to light cellular and molecular mechanisms that underlie neurodevelopmental disorders and brain tumors.

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“…The cancer stem cell hypothesis predates human pluripotent stem cell technology though still remains controversial (see Gimple et al, 2019 for a recent review). Methods for isolation and culture of CNS solid tumor stem cells are established and can be used for examining the first steps of cancer formation (see Goranci-Buzhala et al, 2021 for a recent example). Human stem cells (endogenous and PSC-derived) make excellent complimentary models for studying the cell of origin, cellular heterogeneity, and mechanisms of progression of multiple types of brain cancers, particularly since dedifferentiation and re-activation of an embryonic stem-like state is a hallmark of many cancers.…”

Section: Complementing and Building On Animal Models With Human Stem Cell Modelsmentioning

confidence: 99%

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

Knock

Julian

2021

Front. Cell. Neurosci.

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The brain is our most complex and least understood organ. Animal models have long been the most versatile tools available to dissect brain form and function; however, the human brain is highly distinct from that of standard model organisms. In addition to existing models, access to human brain cells and tissues is essential to reach new frontiers in our understanding of the human brain and how to intervene therapeutically in the face of disease or injury. In this review, we discuss current and developing culture models of human neural tissue, outlining advantages over animal models and key challenges that remain to be overcome. Our principal focus is on advances in engineering neural cells and tissue constructs from human pluripotent stem cells (PSCs), though primary human cell and slice culture are also discussed. By highlighting studies that combine animal models and human neural cell culture techniques, we endeavor to demonstrate that clever use of these orthogonal model systems produces more reproducible, physiological, and clinically relevant data than either approach alone. We provide examples across a range of topics in neuroscience research including brain development, injury, and cancer, neurodegenerative diseases, and psychiatric conditions. Finally, as testing of PSC-derived neurons for cell replacement therapy progresses, we touch on the advancements that are needed to make this a clinical mainstay.

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Cilium induction triggers differentiation of glioma stem cells

Cited by 37 publications

References 76 publications

RNA Profiling of Mouse Ependymal Cells after Spinal Cord Injury Identifies the Oncostatin Pathway as a Potential Key Regulator of Spinal Cord Stem Cell Fate

RNA Profiling of Mouse Ependymal Cells after Spinal Cord Injury Identifies the Oncostatin Pathway as a Potential Key Regulator of Spinal Cord Stem Cell Fate

Post-transcriptional and Post-translational Modifications of Primary Cilia: How to Fine Tune Your Neuronal Antenna

Building on a Solid Foundation: Adding Relevance and Reproducibility to Neurological Modeling Using Human Pluripotent Stem Cells

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