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Vimentin protects differentiating stem cells from stress.

ABSTRACT: Vimentin is one of the first cytoplasmic intermediate filaments to be expressed in mammalian cells during embryogenesis, but its role in cellular fitness has long been a mystery. Vimentin is acknowledged to play a role in cell stiffness, cell motility, and cytoplasmic organization, yet it is widely considered to be dispensable for cellular function and organismal development. Here, we show that Vimentin plays a role in cellular stress response in differentiating cells, by recruiting aggregates, stress granules, and RNA-binding proteins, directing their elimination and asymmetric partitioning. In the absence of Vimentin, pluripotent embryonic stem cells fail to differentiate properly, with a pronounced deficiency in neuronal differentiation. Our results uncover a novel function for Vimentin, with important implications for development, tissue homeostasis, and in particular, stress response.

SUBMITTER: Pattabiraman S

PROVIDER: S-EPMC7658978 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Vimentin protects differentiating stem cells from stress.

Pattabiraman Sundararaghavan S Azad Gajendra Kumar GK Amen Triana T Brielle Shlomi S Park Jung Eun JE Sze Siu Kwan SK Meshorer Eran E Kaganovich Daniel D

Scientific reports 20201111 1

Vimentin is one of the first cytoplasmic intermediate filaments to be expressed in mammalian cells during embryogenesis, but its role in cellular fitness has long been a mystery. Vimentin is acknowledged to play a role in cell stiffness, cell motility, and cytoplasmic organization, yet it is widely considered to be dispensable for cellular function and organismal development. Here, we show that Vimentin plays a role in cellular stress response in differentiating cells, by recruiting aggregates, ...[more]

PMID: 33177544

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Project description:Environmental genotoxic factors pose a challenge to the genomic integrity of epithelial cells at barrier surfaces that separate host organisms from the environment. They can induce mutations that, if they occur in epithelial stem cells, contribute to malignant transformation and cancer development1-3. Genome integrity in epithelial stem cells is maintained by an evolutionarily conserved cellular response pathway, the DNA damage response (DDR). The DDR culminates in either transient cell-cycle arrest and DNA repair or elimination of damaged cells by apoptosis4,5. Here we show that the cytokine interleukin-22 (IL-22), produced by group 3 innate lymphoid cells (ILC3) and γδ T cells, is an important regulator of the DDR machinery in intestinal epithelial stem cells. Using a new mouse model that enables sporadic inactivation of the IL-22 receptor in colon epithelial stem cells, we demonstrate that IL-22 is required for effective initiation of the DDR following DNA damage. Stem cells deprived of IL-22 signals and exposed to carcinogens escaped DDR-controlled apoptosis, contained more mutations and were more likely to give rise to colon cancer. We identified metabolites of glucosinolates, a group of phytochemicals contained in cruciferous vegetables, to be a widespread source of genotoxic stress in intestinal epithelial cells. These metabolites are ligands of the aryl hydrocarbon receptor (AhR)6, and AhR-mediated signalling in ILC3 and γδ T cells controlled their production of IL-22. Mice fed with diets depleted of glucosinolates produced only very low levels of IL-22 and, consequently, the DDR in epithelial cells of mice on a glucosinolate-free diet was impaired. This work identifies a homeostatic network protecting stem cells against challenge to their genome integrity by AhR-mediated 'sensing' of genotoxic compounds from the diet. AhR signalling, in turn, ensures on-demand production of IL-22 by innate lymphocytes directly regulating components of the DDR in epithelial stem cells.

Project description:Stem cell transplantation has recently demonstrated a significant therapeutic efficacy in various diseases. Multilineage-differentiating stress-enduring (Muse) cells are stress-tolerant endogenous pluripotent stem cells that were first reported in 2010. Muse cells can be found in the peripheral blood, bone marrow and connective tissue of nearly all body organs. Under basal conditions, they constantly move from the bone marrow to peripheral blood to supply various body organs. However, this rate greatly changes even within the same individual based on physical status and the presence of injury or illness. Muse cells can differentiate into all three-germ-layers, producing tissue-compatible cells with few errors, minimal immune rejection and without forming teratomas. They can also endure hostile environments, supporting their survival in damaged/injured tissues. Additionally, Muse cells express receptors for sphingosine-1-phosphate (S1P), which is a protein produced by damaged/injured tissues. Through the S1P-S1PR2 axis, circulating Muse cells can preferentially migrate to damaged sites following transplantation. In addition, Muse cells possess a unique immune privilege system, facilitating their use without the need for long-term immunosuppressant treatment or human leucocyte antigen matching. Moreover, they exhibit anti-inflammatory, anti-apoptotic and tissue-protective effects. These characteristics circumvent all challenges experienced with mesenchymal stem cells and induced pluripotent stem cells and encourage the wide application of Muse cells in clinical practice. Indeed, Muse cells have the potential to break through the limitations of current cell-based therapies, and many clinical trials have been conducted, applying intravenously administered Muse cells in stroke, myocardial infarction, neurological disorders and acute respiratory distress syndrome (ARDS) related to novel coronavirus (SARS-CoV-2) infection. Herein, we aim to highlight the unique biological properties of Muse cells and to elucidate the advantageous difference between Muse cells and other types of stem cells. Finally, we shed light on their current therapeutic applications and the major obstacles to their clinical implementation from laboratory to clinic.

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Vimentin protects differentiating stem cells from stress.

Publications

Vimentin protects differentiating stem cells from stress.

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