Rebamipide Induces Hair Regeneration through EP4-Driven Lipid Metabolism Remodeling
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ABSTRACT:
PROVIDER: PRJNA1257336 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR33387237_1.fastq.gz | Fastqsanger.gz | |||
| SRR33387237_2.fastq.gz | Fastqsanger.gz | |||
| SRR33387238_1.fastq.gz | Fastqsanger.gz | |||
| SRR33387238_2.fastq.gz | Fastqsanger.gz | |||
| SRR33387239_1.fastq.gz | Fastqsanger.gz |
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Project description:Alopecia is a highly prevalent hair loss disorder characterized by abnormality of hair cycling. Induction of autophagy and secretion of growth factors by adipocyte precursors are sufficient to activate quiescent hair follicles. Yet therapies targeting these processes remain limited. Here, we identify rebamipide, a drug initially intended for gastric ulcer treatment, as a promising candidate for hair regeneration by modulating dermal adipocyte metabolism. Topical rebamipide treatment induces autophagy and ATGL-mediated lipolysis in dermal adipocytes. Through primary culture systems, we demonstrate that rebamipide-driven lipolysis triggers adipocyte dedifferentiation, activating HFSCs via elevated PDGFα levels. Mechanistically, computer simulations and target validation experiments confirm that rebamipide directly binds to the prostaglandin E receptor EP4, triggering PI3K/ERK-dependent autophagy and lipolysis. Collectively, our findings highlight EP4 as a novel therapeutic target for alopecia and position rebamipide as an agent that couples lipid metabolism remodeling with HFSC activation.
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Project description:Tight immune defense against environment and a unique ability of self-repair are the hallmarks of epithelia. Here we show that innate immunity Toll like receptor 2 (TLR2) coordinates these key functions thereby promoting hair growth and tissue regeneration. TLR2 is enriched in hair follicle stem cells (HFSCs) and its levels change in hair cycle and skin disorders. The lack of TLR2 in HFSCs diminishes activation and proliferation of HFSCs markedly prolonging the resting phase of hair cycle. Transcriptome profiling of HFSCs revealed that TLR2 regulates main hair regeneration pathways. TLR2 deletion upregulates inhibitory BMP7 signaling, while the blockade by Noggin restores deficient HFSCs proliferation in the absence of TLR2. In injury model TLR2 is required for both, tissue and hair regeneration. While endothelial TLR2 drives wound revascularization and closure, HFSC TLR2 controls hair regrowth. Endogenous TLR2 ligand produced in hair follicles promotes hair regeneration and growth via HFSC TLR2. Together, HFSC TLR2 drives stem cell proliferation, hair cycle and regeneration.
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Project description:To define the mechanisms that underlie regeneration driven by EP4+ macrophages, we transcriptionally compared the WT and Csf1r-EP4-/- mature macrophages isolated from colon by 39 days post DSS treatment.
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Project description:Deafness due to the terminal loss of inner ear hair cells is one of the most common sensory diseases. However, non-mammalian animals (e.g. birds, amphibian and fish) regenerate damaged hair cells. In order to better understand the reasons underpinning such regeneration disparities in vertebrates, we set out to define the changes in gene expression associated with the regeneration of hair cells in the zebrafish lateral line at high resolution. We performed RNA-Seq analyses on regenerating support cells purified by fluorescence activated cell sorting (FACS). The zebrafish lateral line provides an experimentally accessible system to define the complex signaling events triggered by injury and regeneration, because these cells can be acutely killed by exposure to neomycin, after which they regenerate rapidly. Lateral line hair cells are located in the center of a mechanosensory organ known as the neuromast and are surrounded by inner support cells and an outer ring of mantle cells. Tg(sqET20) larvae express GFP strongly in mantle cells and to a lesser degree in inner support cells. We isolated GFP positive and GFP negative cells from 5 days post fertilization (dpf) Tg(sqET20) larvae at 1, 3 and 5 hours post neomycin treatment, as well as from a non-treated control. Transgenic zebrafish Tg(sqET20) larvae at 5 days post fertilization were exposed to neomycin, dissociated, and FACS sorted into GFP positive and GFP negative populations at 1, 3, and 5 hours following treatment, along with a mock treated 1 hr control. The experiment was performed in triplicate, for a total of 24 samples.
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Project description:The exogen phase of the hair follicle cycle, during which club hairs are shed and new hairs emerge, represents a pivotal yet understudied transition marked by structural remodeling and cell fate changes. This study investigates the role of the transcription factor Msx2 in regulating hair anchoring, hair follicle stem cell (HFSC) lineage commitment, and extracellular matrix (ECM) remodeling during exogen. Using Msx2-knockout (KO) mice, we integrated transcriptomic, epigenomic, and functional assays to reveal Msx2 as a key regulator of exogen, critical for maintaining HFSC niche integrity, preserving bulge architecture, and coordinating lineage progression during hair regeneration. By modulating the balance between TGF-β and Wnt signaling pathways, Msx2 ensures proper HFSC activation and prevents premature epidermal differentiation and hair shedding. These findings provide mechanistic insights into the molecular control of hair cycling and highlight Msx2 dysfunction as a potential contributor to hair loss disorders, positioning it as a promising therapeutic target in regenerative dermatology.
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Project description:The exogen phase of the hair follicle cycle, during which club hairs are shed and new hairs emerge, represents a pivotal yet understudied transition marked by structural remodeling and cell fate changes. This study investigates the role of the transcription factor Msx2 in regulating hair anchoring, hair follicle stem cell (HFSC) lineage commitment, and extracellular matrix (ECM) remodeling during exogen. Using Msx2-knockout (KO) mice, we integrated transcriptomic, epigenomic, and functional assays to reveal Msx2 as a key regulator of exogen, critical for maintaining HFSC niche integrity, preserving bulge architecture, and coordinating lineage progression during hair regeneration. By modulating the balance between TGF-β and Wnt signaling pathways, Msx2 ensures proper HFSC activation and prevents premature epidermal differentiation and hair shedding. These findings provide mechanistic insights into the molecular control of hair cycling and highlight Msx2 dysfunction as a potential contributor to hair loss disorders, positioning it as a promising therapeutic target in regenerative dermatology.
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Project description:Significant changes in the expression of synaptic and inflammatory genes were observed early after damage, during regeneration of the fibers and synapses, and after completion of in vitro regeneration between afferent neurons and cochlear hair cells.
2020-09-14 | GSE130495 | GEO
Project description:Loss of sensory hair cells leads to deafness and balance deficiencies. In contrast to mammalian hair cells, zebrafish ear and lateral line hair cells regenerate from poorly characterized, proliferating support cells. Equally ill-defined is the gene regulatory network underlying the progression of support cells to cycling hair cell progenitors and differentiated hair cells. We used single-cell RNA-Sequencing (scRNA-Seq) of lateral line sensory organs and uncovered five different support cell types, including quiescent and activated stem cells. In silico ordering of support cells along a developmental trajectory identified cells that self-renew and new groups of genes required for hair cell differentiation. scRNA-Seq analyses of fgf3 mutants, in which hair cell regeneration is increased demonstrates that Fgf and Notch signaling inhibit proliferation of support cells in parallel by inhibiting Wnt signaling. Our scRNA-Seq analyses set the foundation for mechanistic studies of sensory organ regeneration and is crucial for identifying factors to trigger hair cell production in mammals.
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Project description:Sensorineural hearing loss is included in the most common disabilities, and often caused by loss of sensory hair cells in the cochlea. Hair cell regeneration has long been a main target for developing novel therapeutics for sensorineural hearing loss. In the mammalian cochlea, hair cell regeneration occurs in very limited situations, while auditory epithelia of non-mammalians retain the capacity for hair cell regeneration. In the avian basilar papilla, an auditory sensory epithelium, supporting cells, which are sources for regenerated hair cells, are usually quiescent, while hair cell loss induces both direct transdifferentiation of supporting cells and mitotic division of supporting cells. In the present study, we aimed to establish an explant culture model for hair cell regeneration in chick basilar papillae, and validated usefulness of our model to investigate the initial phase of hair cell regeneration. Histological assessments demonstrated that hair cell regeneration via direct transdifferentiation of supporting cells occurred in our model. Labeling assay using 5-ethynyl-2'-deoxyuridine (EdU) revealed the occurrence of mitotic division of supporting cells in the specific location in basilar papillae, while no EdU labeling was identified in newly generated HCs. RNA sequencing indicated alterations in known signaling pathways associated with hair cell regeneration, which is consistent with previous findings. In addition, unbiased analyses of RNA sequencing data indicated novel genes and signaling pathways that could be related to the ignition of supporting cell activation in chick basilar papillae. These results indicate the advantages of our model using explant cultures of chick basilar papillae for exploring molecular mechanisms for hair cell regeneration. Further studies such as single-cell RNA sequencing will allow us to capture the spatiotemporal information by using our explant culture model.
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