Dataset Information

Sonic Hedgehog Is a Determinant of ?? T-Cell Differentiation in the Thymus.

ABSTRACT: Here we investigate the function of Hedgehog (Hh) signaling in thymic ?? T-cell maturation and subset differentiation. Analysis of Hh mutants showed that Hh signaling promotes ?? T-cell development in the thymus and influences ?? T-cell effector subset distribution. Hh-mediated transcription in thymic ?? cells increased ?? T-cell number, and promoted their maturation and increased the ??NKT subset, whereas inhibition of Hh-mediated transcription reduced the thymic ?? T-cell population and increased expression of many genes that are normally down-regulated during ?? T-cell maturation. These changes were also evident in spleen, where increased Hh signaling increased ??NKT cells, but reduced CD27-CD44+ and V?2+ populations. Systemic in vivo pharmacological Smoothened-inhibition reduced ?? T-cell and ??NKT cells in the thymus, and also reduced splenic ?? T-cell and ??NKT populations, indicating that Hh signaling also influences homeostasis of peripheral ?? T-cell populations. Taken together our data indicate that Sonic Hedgehog is an important determinant of ?? T-cell effector subset differentiation.

SUBMITTER: Mengrelis K

PROVIDER: S-EPMC6658896 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Sonic Hedgehog Is a Determinant of γδ T-Cell Differentiation in the Thymus.

Mengrelis Konstantinos K Lau Ching-In CI Rowell Jasmine J Solanki Anisha A Norris Sonia S Ross Susan S Ono Masahiro M Outram Susan S Crompton Tessa T

Frontiers in immunology 20190719

Here we investigate the function of Hedgehog (Hh) signaling in thymic γδ T-cell maturation and subset differentiation. Analysis of Hh mutants showed that Hh signaling promotes γδ T-cell development in the thymus and influences γδ T-cell effector subset distribution. Hh-mediated transcription in thymic γδ cells increased γδ T-cell number, and promoted their maturation and increased the γδNKT subset, whereas inhibition of Hh-mediated transcription reduced the thymic γδ T-cell population and increa ...[more]

PMID: 31379834

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Project description:BackgroundIndian hedgehog (IHH) and Sonic hedgehog (SHH) are important regulators of chondrogenesis. However, activation of IHH and SHH also promotes chondrocyte hypertrophy and ossification during chondrogenesis. The aims of this study were to investigate the effect of microgravity on IHH- and SHH-induced chondrogenic differentiation and to elucidate the role of microgravity in this process.MethodsAdenovirus plasmids encoding the rabbit IHH gene and SHH genes were constructed in vitro and transfected into rabbit bone marrow-derived mesenchymal stem cells (BMSCs). A rotary cell culture system (RCCS), in which a dynamic three-dimensional culture system combines the mechanical environment with a three-dimensional culture surface, was used for cell culture and differentiation. During the induction of differentiation, expression levels of cartilage-related and cartilage hypertrophy-related genes and proteins were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Toluidine blue and collagen II immunohistochemical staining and annexin V-Cy3 staining were used to indicate investigate cartilage matrix synthesis and hypertrophic hypertrophy, respectively, on day 21 after induction of differentiation.ResultsIn this study, IHH and SHH were shown to be equipotent inducers of chondrogenesis in rabbit BMSCs, as evidenced by strong staining for proteoglycans and collagen II, and increased expression of mRNAs and proteins associated with chondrogenesis in an RCCS environment. More importantly, chondrogenic hypertrophy and aging were effectively inhibited in the RCCS environment. In addition, levels of cartilage-related markers in the IHH and SHH transfection groups were initially increased and later decreased in the traditional two-dimensional environment, while cartilage hypertrophy-related factors revealed higher mRNA expression levels during induction.ConclusionsIn summary, microgravity significantly promoted chondrogenic differentiation of BMSCs induced by IHH and SHH and attenuated chondrogenic hypertrophy and aging during chondrogenesis. Furthermore, exogenous IHH and SHH had the same effect on chondrogenic differentiation of BMSCs in the RCCS environment. This study provides further evidence of chondrogenic induction of BMSCs in vitro via IHH and SHH gene delivery.

Project description:Differentiating cerebellar organoids can be challenging due to complex cell organization and structure in the cerebellum. Different approaches were investigated to recapitulate differentiation process of the cerebellum from human-induced pluripotent stem cells (hiPSCs) without high efficiency. This study was carried out to test the hypothesis that the combination of different signaling factors including retinoic acid (RA), Wnt activator, and sonic hedgehog (SHH) activator promotes the cerebellar differentiation of hiPSCs. Wnt, RA, and SHH pathways were activated by CHIR99021 (CHIR), RA, and purmorphamine (PMR), respectively. Different combinations of the morphogens (RA/CHIR, RA/PMR, CHIR/PMR, and RA/CHIR/PMR) were utilized, and the spheroids (day 35) were characterized for the markers of three cerebellum layers (the molecular layer, the Purkinje cell layer, and the granule cell layer). Of all the combinations tested, RA/CHIR/PMR promoted both the Purkinje cell layer and the granule cell layer differentiation. The cells also exhibited electrophysiological characteristics using whole-cell patch clamp recording, especially demonstrating Purkinje cell electrophysiology. This study should advance the understanding of different signaling pathways during cerebellar development to engineer cerebellum organoids for drug screening and disease modeling. Impact statement This study investigated the synergistic effects of retinoic acid, Wnt activator, and sonic hedgehog activator on cerebellar patterning of human-induced pluripotent stem cell (hiPSC) spheroids and organoids. The results indicate that the combination promotes the differentiation of the Purkinje cell layer and the granule cell layer. The cells also exhibit electrophysiological characteristics using whole-cell patch clamp recording, especially demonstrating Purkinje cell electrophysiology. The findings are significant for understanding the biochemical signaling of three-dimensional microenvironment on neural patterning of hiPSCs for applications in organoid engineering, disease modeling, and drug screening.

Dataset Information

Sonic Hedgehog Is a Determinant of ?? T-Cell Differentiation in the Thymus.

Publications

Sonic Hedgehog Is a Determinant of γδ T-Cell Differentiation in the Thymus.

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