Dataset Information

High Expression of CD200 and CD200R1 Distinguishes Stem and Progenitor Cell Populations within Mammary Repopulating Units.

ABSTRACT: Aiming to unravel the top of the mammary epithelial cell hierarchy, a subset of the CD49f^highCD24^med mammary repopulating units (MRUs) was identified by flow cytometry, expressing high levels of CD200 and its receptor CD200R1. These MRU^{CD200/CD200R1} repopulated a larger area of de-epithelized mammary fat pads than the rest of the MRUs, termed MRU^{not CD200/CD200R1}. MRU^{CD200/CD200R1} maintained a much lower number of divergently defined, highly expressed genes and pathways that support better cell growth, development, differentiation, and progenitor activity than their MRU^{not CD200/CD200R1} counterparts. A defined profile of hierarchically associated genes supporting a single-lineage hypothesis was confirmed by in vitro mammosphere analysis that assembled 114 genes with decreased expression from MRU^{CD200/CD200R1} via MRU^{not CD200/CD200R1} toward CD200⁺CD200R1^- and CD200R1⁺CD200^- cells. About 40% of these genes were shared by a previously published database of upregulated genes in mammary/breast stem cells and may represent the core genes involved in mammary stemness.

SUBMITTER: Rauner G

PROVIDER: S-EPMC6067058 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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High Expression of CD200 and CD200R1 Distinguishes Stem and Progenitor Cell Populations within Mammary Repopulating Units.

Rauner Gat G Kudinov Tania T Gilad Shlomit S Hornung Gil G Barash Itamar I

Stem cell reports 20180621 1

Aiming to unravel the top of the mammary epithelial cell hierarchy, a subset of the CD49fhighCD24med mammary repopulating units (MRUs) was identified by flow cytometry, expressing high levels of CD200 and its receptor CD200R1. These MRUCD200/CD200R1 repopulated a larger area of de-epithelized mammary fat pads than the rest of the MRUs, termed MRUnot CD200/CD200R1. MRUCD200/CD200R1 maintained a much lower number of divergently defined, highly ...[more]

PMID: 29937142

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Project description:IntroductionThe skin immune system is tightly regulated to prevent inappropriate inflammation in response to harmless environmental substances. This regulation is actively maintained by mechanisms including cytokines and cell surface receptors and its loss results in inflammatory disease. In the case of psoriasis, inappropriate immune activation leads to IL-17-driven chronic inflammation, but molecular mechanisms underlying this loss of regulation are not well understood. Immunoglobulin family member CD200 and its receptor, CD200R1, are important regulators of inflammation. Therefore, we determined if this pathway is dysregulated in psoriasis, and how this affects immune cell activity.MethodsHuman skin biopsies were examined by quantitative polymerase chain reaction, flow cytometry, and immunohistochemistry. The role of CD200R1 in regulating psoriasis-like skin inflammation was examined using CD200R1 blocking antibodies in mouse psoriasis models. CD200R1 blocking antibodies were also used in an in vivo neutrophil recruitment assay and in vitro assays to examine macrophage, innate lymphoid cell, γδ T cell, and neutrophil activity.ResultsWe reveal that CD200 and signaling via CD200R1 are reduced in non-lesional psoriasis skin. In mouse models of psoriasis CD200R1 was shown to limit psoriasis-like inflammation by enhancing acanthosis, CCL20 production and neutrophil recruitment, but surprisingly, macrophage function and IL-17 production were not affected, and neutrophil reactive oxygen species production was reduced.ConclusionCollectively, these data show that CD200R1 affects neutrophil function and limits inflammatory responses in healthy skin by restricting neutrophil recruitment. However, the CD200 pathway is reduced in psoriasis, resulting in a loss of immune control, and increased neutrophil recruitment in mouse models. In conclusion, we highlight CD200R1:CD200 as a pathway that might be targeted to dampen inflammation in patients with psoriasis.

Project description:In the brain of patients with multiple sclerosis, activated microglia/macrophages appear in active lesions and in normal appearing white matter. However, whether they play a beneficial or a detrimental role in the development of the pathology remains a controversial issue. The production of pro-inflammatory molecules by chronically activated microglial cells is suggested to contribute to the progression of neurodegenerative processes in neurological disease. In the healthy brain, neurons control glial activation through several inhibitory mechanisms, such as the CD200-CD200R1 interaction. Therefore, we studied whether alterations in the CD200-CD200R1 system might underlie the neuroinflammation in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. We determined the time course of CD200 and CD200R1 expression in the brain and spinal cord of an EAE mouse model from presymptomatic to late symptomatic stages. We also assessed the correlation with associated glial activation, inflammatory response and EAE severity. Alterations in CD200 and CD200R1 expression were mainly observed in spinal cord regions in the EAE model, mostly a decrease in CD200 and an increase in CD200R1 expression. A decrease in the expression of the mRNA encoding a full CD200 protein was detected before the onset of clinical signs, and remained thereafter. A decrease in CD200 protein expression was observed from the onset of clinical signs. By contrast, CD200R1 expression increased at EAE onset, when a glial reaction associated with the production of pro- and anti-inflammatory markers occurred, and continued to be elevated during the pathology. Moreover, the magnitude of the alterations correlated with severity of the EAE mainly in spinal cord. These results suggest that neuronal-microglial communication through CD200-CD200R1 interaction is compromised in EAE. The early decreases in CD200 expression in EAE suggest that this downregulation might also occur in the initial phases of multiple sclerosis, and that this early neuronal dysfunction might facilitate the development of neuroinflammation. The increased CD200R1 expression in the EAE model highlights the potential use of targeted agonist molecules as therapeutic tools to control neuroinflammation. In summary, the CD200-CD200R1 system is a potential therapeutic target in multiple sclerosis, and CD200R1 agonists are molecules that may be worth developing in this context.

Dataset Information

High Expression of CD200 and CD200R1 Distinguishes Stem and Progenitor Cell Populations within Mammary Repopulating Units.

Publications

High Expression of CD200 and CD200R1 Distinguishes Stem and Progenitor Cell Populations within Mammary Repopulating Units.

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