{"gene":"THY1","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2014,"finding":"Thy1 (CD90) blocks adipogenesis by inhibiting the activity of the Src family kinase Fyn, which in turn decreases PPARγ transcriptional activity by more than 60%. Thy1-null mice gained 30% more weight than controls on a high-fat diet, and overexpression of Thy1 in 3T3-L1 cells blocked adipocyte formation and reduced FABP4 expression 5-fold.","method":"Thy1 overexpression/knockout in mouse model, PPARγ reporter assays, genetic and pharmacologic Fyn inhibition (siRNA + PP2 inhibitor), Western blotting","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (KO mouse, OE, reporter assay, siRNA, pharmacologic inhibition) in single rigorous study identifying Fyn as the kinase mediator","pmids":["25416548"],"is_preprint":false},{"year":2008,"finding":"Thy-1 activation in lung myofibroblasts up-regulates FasL expression via Src family kinases, specifically Fyn. Thy-1 activation first causes translocation of FasL to the membrane surface, then induces de novo synthesis of FasL at mRNA and protein levels. Src family kinase inhibitor PP2 and Fyn-specific siRNA both blocked this induction.","method":"Anti-Thy1 antibody activation, SFK inhibitor PP2, Fyn-specific siRNA knockdown, flow cytometry, RT-PCR, Western blot","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal genetic and pharmacologic inhibition of Fyn, direct Thy-1 activation assay with multiple readouts in single lab","pmids":["18676775"],"is_preprint":false},{"year":2006,"finding":"Thy-1 expression predetermines fibroblast lineage commitment: only Thy-1(+) human myometrial and orbital fibroblasts differentiated into myofibroblasts (assessed by α-SMA expression) in response to TGF-β or platelet concentrate, whereas only Thy-1(−) fibroblasts differentiated into lipofibroblasts after treatment with PPARγ agonists.","method":"FACS-sorted fibroblast subsets, TGF-β treatment, PPARγ agonist treatment, α-SMA immunostaining, lipid droplet accumulation assay","journal":"The American journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — sorted cell populations with defined differentiation stimuli and phenotypic readouts, single lab","pmids":["14507638"],"is_preprint":false},{"year":2006,"finding":"Thy-1(−) lung fibroblasts show significantly greater myofibroblast differentiation, collagen matrix contraction, and resistance to apoptosis compared with Thy-1(+) cells. Transfection of Thy-1 into Thy-1(−) cells inhibited collagen matrix contraction and reduced cell survival, directly demonstrating that Thy-1 regulates myogenic gene expression and myofibroblastic differentiation.","method":"FACS-sorted rat lung fibroblasts, TGF-β/ET-1/CTGF stimulation, floating collagen matrix contraction assays, apoptosis assays, Thy-1 transfection into Thy-1(−) cells, RT-PCR, immunoblotting","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — gain-of-function transfection with functional rescue, sorted cell populations, multiple orthogonal assays","pmids":["16960126"],"is_preprint":false},{"year":2008,"finding":"Thy-1 promoter CpG islands are hypermethylated in Thy-1(−) lung fibroblasts and in fibroblastic foci of IPF tissue, silencing Thy-1 expression. Treatment with DNA methyltransferase inhibitors restores Thy-1 expression in Thy-1(−) fibroblasts, establishing promoter hypermethylation as a mechanism of Thy-1 silencing in pulmonary fibrosis.","method":"RT-PCR, methylation-specific PCR, bisulfite genomic sequencing, MSP-in situ hybridization on fibrotic tissue, DNMT inhibitor treatment","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — bisulfite sequencing, MSP, in situ validation in tissue, pharmacologic reversal with DNMT inhibitors, multiple orthogonal methods","pmids":["18556592"],"is_preprint":false},{"year":2010,"finding":"Histone deacetylase inhibitor trichostatin A (TSA) restores Thy-1 expression in Thy-1(−) lung fibroblasts by enriching histone H3K4 trimethylation and H4 acetylation at the Thy-1 locus, while depleting repressive H3K27 trimethylation. TSA treatment also caused demethylation of previously hypermethylated CpG sites in the Thy-1 promoter, indicating that histone modifications regulate DNA methylation at this locus.","method":"TSA treatment, chromatin immunoprecipitation (ChIP) for histone marks, bisulfite sequencing, RT-PCR, global DNA methylation assays","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP with multiple histone marks, bisulfite sequencing, pharmacologic intervention, multiple orthogonal methods in single study","pmids":["20724553"],"is_preprint":false},{"year":2015,"finding":"TGF-β1 epigenetically suppresses Thy-1 expression in primary lung fibroblasts by activating DNMT1 and inducing Thy-1 promoter methylation. siRNA knockdown of DNMT1 attenuated TGF-β1-induced DNMT activity and rescued Thy-1 expression, also inhibiting downstream α-SMA and collagen Col1A1 expression.","method":"TGF-β1 treatment, 5-AZA co-treatment, DNMT1 siRNA knockdown, quantitative methyl PCR, RT-PCR, Western blot, immunofluorescence","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — genetic (siRNA) and pharmacologic DNMT1 inhibition with promoter methylation confirmation by qMethyl-PCR, replicated TGF-β1 induction mechanism","pmids":["26333597"],"is_preprint":false},{"year":2009,"finding":"Loss of Thy-1 in Thy-1(−/−) mice leads to impaired alveolarization, increased TGF-β signaling, altered cell proliferation, and increased collagen/elastin deposition. Administration of TGF-β neutralizing antibody (1D11) to Thy-1(−/−) mice improved alveolar development, establishing that Thy-1-expressing fibroblasts inhibit TGF-β activation and thereby support normal alveolar development.","method":"Thy-1 null mouse model, hypoxia exposure, lung histology, lung function measurement, TGF-β neutralizing antibody treatment, immunostaining","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with rescue by TGF-β neutralization, clear epistatic relationship established, multiple phenotypic readouts","pmids":["19270178"],"is_preprint":false},{"year":2019,"finding":"Soluble Thy-1-Fc (sThy-1) reversed TGF-β1-induced myofibroblast differentiation in vitro in a dose-dependent manner via its integrin-binding RGD motif (RLE-mutated Thy-1 was inactive), and resolved established lung fibrosis in vivo after bleomycin or doxycycline-induced TGF-β1 overexpression. Thy1-null mice showed progressive αv integrin activation and myofibroblast accumulation, identifying an αv integrin-driven feedback loop sustained by loss of Thy-1.","method":"Thy1-null mouse model, bleomycin/doxycycline fibrosis models, soluble Thy-1-Fc treatment in vivo, RLE-mutant Thy-1 control, in vitro myofibroblast differentiation assays, αv integrin activation assessment","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — mutagenesis identifying RGD motif requirement, genetic KO model, in vivo therapeutic rescue, multiple orthogonal approaches","pmids":["31672942"],"is_preprint":false},{"year":2010,"finding":"Thy1 (CD90) is expressed by lymphatic endothelial cells (but not blood vascular endothelial cells) and mediates adhesion of tumor cells and leukocytes to lymphatic endothelium. Blockade of Thy1 inhibited tumor cell adhesion to lymphatic endothelial cells in vitro, and Thy1-deficient mice showed markedly reduced experimental lung and lymph node metastasis of B16/F10 melanoma cells.","method":"Comparative transcriptional profiling, FACS, immunofluorescence, anti-Thy1 blockade in adhesion assays, Thy1(−/−) mouse experimental metastasis model","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO mouse model for metastasis, in vitro adhesion blockade, replicated across lymphatic and hematogenic routes","pmids":["20599951"],"is_preprint":false},{"year":2012,"finding":"Thy-1 on endothelial cells mediates adhesion of melanoma cells via αvβ3-integrin on tumor cells. Thy-1-deficient mice showed reduced experimental lung and lymph node metastasis without affecting primary tumor growth, T-cell activation, or angiogenesis, establishing Thy-1–integrin adhesion as a specific pro-metastatic mechanism.","method":"Thy-1(−/−) mouse experimental and spontaneous metastasis models, in vitro adhesion assays, VEGF/TNF-α induction of Thy-1 on EC","journal":"The American journal of pathology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with metastasis rescue specificity (no effect on tumor growth/angiogenesis), mechanistic adhesion assay, multiple readouts","pmids":["23159525"],"is_preprint":false},{"year":2006,"finding":"Thy-1 on activated human dermal microvascular endothelial cells mediates neutrophil adhesion specifically via interaction with the β2-integrin Mac-1. Blocking Thy-1 on endothelial cells or Mac-1 on neutrophils significantly inhibited adhesion; psoriatic neutrophils showed increased adhesion to Thy-1 transfectants compared with healthy controls.","method":"Thy-1 transfected cell adhesion assay, blocking antibodies against Thy-1 and Mac-1, HDMEC adhesion assays, flow cytometry","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — blocking antibody experiments identifying Thy-1/Mac-1 interaction, single lab with transfectant and primary cell systems","pmids":["16374458"],"is_preprint":false},{"year":2005,"finding":"The αX I-domain of the β2-integrin αXβ2 (CD11c/CD18) binds Thy-1 in a specific, divalent cation-dependent manner with a Kd of 1.16 μM. Amino acid substitutions in the βD-α5 loop of the αX I-domain (D249, KE243/244) reduced binding affinity, identifying the βD-α5 loop/α5 helix region as the Thy-1 recognition site.","method":"Recombinant I-domain binding assay, site-directed mutagenesis of αX I-domain, kinetic/affinity measurements","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro binding assay with mutagenesis identifying binding site, single lab study","pmids":["15850796"],"is_preprint":false},{"year":2015,"finding":"THY-1 mediates HCMV entry at the initial infection step (within the first 60 minutes). Anti-THY-1 antibody and siRNA knockdown impaired infectivity, blocked HCMV-induced PI3-K/Akt activation required for entry, and soluble THY-1 protein blocked infection during but not after virus internalization. THY-1 was shown to interact with HCMV glycoproteins gB and gH by co-immunoprecipitation.","method":"THY-1 siRNA knockdown, anti-THY-1 antibody blocking, exogenous THY-1 expression, soluble THY-1 protein competition, co-immunoprecipitation with gB and gH, PI3-K/Akt pathway activation assay","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (siRNA, antibody blocking, OE, soluble protein competition, Co-IP) all converging on entry step in single rigorous study","pmids":["26147640"],"is_preprint":false},{"year":2018,"finding":"Thy-1 deficiency in mice leads to decreased bone volume, bone formation rate, and elevated cortical porosity, accompanied by reduced osteogenic Wnt ligands and increased Wnt inhibitors (sclerostin, dickkopf-1), and increased body fat mass. MSCs from Thy-1(−/−) mice showed decreased osteoblast differentiation and increased adipogenic differentiation, establishing Thy-1 as a regulator of MSC fate between osteogenic and adipogenic lineages.","method":"Thy-1(−/−) mouse model, micro-CT bone analysis, histomorphometry, MSC differentiation assays, Wnt pathway gene expression analysis, serum Thy-1 measurement in patients","journal":"Science translational medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model with comprehensive in vivo skeletal phenotyping, in vitro MSC differentiation, Wnt pathway mechanism, clinical correlation","pmids":["30089635"],"is_preprint":false},{"year":2018,"finding":"Thy1 is a positive regulator of osteoblast differentiation. Thy1 KO mice fed a high-fat diet showed significantly reduced trabecular bone volume. In vitro, osteogenic conditions increased Thy1 expression during osteoblast differentiation, and absence of Thy1 attenuated osteoblastogenesis.","method":"Thy1 KO mouse model, micro-CT, histomorphometry, in vitro osteogenic differentiation assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with in vivo bone phenotype and in vitro osteogenic assay, single lab","pmids":["29401595"],"is_preprint":false},{"year":2022,"finding":"THY1 inhibits epidermal YAP activity through two converging mechanisms: (1) by suppressing integrin-β1-SRC signaling that promotes cell-matrix adhesion, and (2) by maintaining an adherens junction complex that retains YAP in the cytoplasm. THY1 deficiency causes YAP nuclear translocation and increased proliferation even at high cell density. Thy1(−/−) mice display enhanced wound repair and hair follicle regeneration due to increased YAP-dependent proliferation.","method":"Thy1(−/−) mouse model, wound healing and hair follicle assays, integrin-β1-SRC pathway analysis, adherens junction complex dissociation assays, YAP localization imaging, proliferation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model, two mechanistic pathways identified (integrin-SRC and AJ-YAP), in vivo phenotypic readouts, multiple orthogonal methods","pmids":["35798842"],"is_preprint":false},{"year":2021,"finding":"Thy-1-αVβ3 integrin interaction in cancer cells (MDA-MB-231 breast cancer and B16F10 melanoma) triggers a Ca2+/hemichannel/ATP/P2X7 receptor signaling axis that promotes cell migration and invasion. β3 integrin silencing in cancer cells reduced transvasation through an endothelial monolayer and prevented lung metastasis in a preclinical mouse model.","method":"Thy-1 stimulation assay, intracellular Ca2+ measurement, connexin/pannexin inhibitors, P2X7 receptor pharmacologic blockade, β3 integrin siRNA, endothelial transmigration assay, in vivo mouse metastasis model","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple signaling inhibitors, genetic knockdown, in vivo metastasis model, multiple cell types tested","pmids":["33511115"],"is_preprint":false},{"year":2017,"finding":"CD90 expression in glioblastoma cells promotes adhesion and migration through enhanced SRC and FAK signaling. Modulation of CD90 expression in GBM cells dramatically affected their adhesion and migration in vitro, and CD90 expression induced invasive phenotypes in orthotopic xenografts in vivo. Pharmacologic inhibition of SRC/FAK blunted adhesion/migration in CD90-positive cells.","method":"CD90 siRNA knockdown in GBM cells, CD90 complementation in CD90-negative U87 cells, orthotopic xenograft models, SRC/FAK inhibitor treatment, GBM patient transcriptome analysis","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with in vivo xenograft, pharmacologic pathway validation, single lab","pmids":["28939749"],"is_preprint":false},{"year":2015,"finding":"CD90 promotes liver cancer stem cell properties via a signal axis involving its RLD integrin-binding domain, β3 integrin, and AMPK/mTOR pathway, leading to upregulation of CD133. Mutation of the integrin-binding RLD domain of CD90 and silencing of β3 integrin both attenuated CD133 induction and anchorage-independent growth. Ectopic CD90 expression induced mTOR phosphorylation and AMPK dephosphorylation.","method":"CD90 ectopic expression and shRNA knockdown, RLD-domain mutant CD90, β3 integrin shRNA, mTOR/AMPK phosphorylation Western blot, anchorage-independent growth assay, xenograft tumorigenicity assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis and genetic knockdown of downstream integrin, signaling pathway analysis, single lab","pmids":["26556861"],"is_preprint":false},{"year":2016,"finding":"CD90 inhibits ovarian cancer anchorage-independent growth and tumor formation in vivo via β3 integrin-dependent suppression of CD133 and the AMPK/mTOR axis. Mutation of CD90's RLE (integrin-binding) domain to RLD abolished tumor-suppressive effects, and β3 integrin shRNA restored anchorage-independent growth and CD133 expression in CD90-overexpressing cells.","method":"CD90 overexpression in SKOV3 cells, RLE-to-RLD domain mutation, β3 integrin shRNA, anchorage-independent growth assay, xenograft tumor formation, ALDH activity, Western blot for mTOR/AMPK","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis, genetic knockdown of mediator (β3 integrin), in vivo tumor assay, single lab","pmids":["27633757"],"is_preprint":false},{"year":2016,"finding":"Reduction of CD90 expression in mesenchymal stromal cells using shRNA lentiviral vectors enhanced osteogenic and adipogenic differentiation in vitro and caused a decrease in CD44 and CD166 expression, demonstrating that CD90 controls MSC differentiation commitment.","method":"CD90-targeted shRNA lentiviral knockdown, osteogenic/adipogenic differentiation assays, flow cytometry for surface markers","journal":"Stem cell research & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct genetic knockdown with defined differentiation readouts, single lab study","pmids":["27465541"],"is_preprint":false},{"year":2017,"finding":"Environmental chemical TBBPA reduces Thy1 expression in human and mouse (pre)adipocyte cells by inducing miR-103 (and miR-107), which directly targets the Thy1 mRNA 3'UTR. Reduced Thy1 levels promoted adipogenesis; miR-103 induction by TBBPA was confirmed and luciferase reporter assays validated miR-103 targeting of Thy1 mRNA.","method":"Flow cytometry, Western blotting, qPCR for Thy1 expression, miRNA qPCR, luciferase reporter assay with Thy1 3'UTR, miR-103/107 prediction and validation","journal":"Toxicological sciences","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — luciferase reporter assay validates miR-103 targeting of Thy1 3'UTR, multiple assays, single lab","pmids":["28329833"],"is_preprint":false},{"year":2007,"finding":"FcεRI-enriched membrane domains and Thy-1-enriched membrane domains have distinct lipid compositions: FcεRI domains contain approximately 2-fold more sphingomyelin and higher cholesterol-to-fatty acid ratios than Thy-1 microdomains, and plasmenyl-glycerophosphoethanolamine (plasmalogen GPE) is 2.5–3 times more abundant in FcεRI domains. Thy-1 domains are devoid of FcεRI subunits.","method":"Magnetic bead isolation of receptor/Thy-1 enriched membrane vesicles (detergent-free), lipidomics by positive and negative ion electrospray mass spectrometry, protein analyses","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct biochemical isolation and lipidomic characterization of Thy-1 membrane domains, single rigorous study","pmids":["17387221"],"is_preprint":false},{"year":2012,"finding":"Thy-1 siRNA knockdown in skin wound regions retarded wound repair in mice, reduced re-epithelialization quality, and caused continuously increased TGF-β1 levels at wound sites. In fibroblasts, Thy-1 affects cell migration into wounds, cell proliferation, and cytoskeletal structure.","method":"Thy-1 siRNA injection at wound sites in mice, wound healing rate measurement, TGF-β1 measurement, fibroblast scratch assay, proliferation and cytoskeletal imaging","journal":"Journal of dermatological science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo siRNA knockdown with wound healing phenotype and TGF-β1 quantification, single lab","pmids":["23312577"],"is_preprint":false},{"year":2019,"finding":"CD90+ fibroblasts in the colon crypt express class 3 semaphorins (Sema3) that are required for their supportive effect on intestinal organoid growth, in addition to expressing stem cell niche factors Grem1, Wnt2b, and R-spondin3.","method":"Stromal cell phenotyping, organoid co-culture assays, gene expression analysis (Sema3, Grem1, Wnt2b, R-spondin3), functional blockade experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional co-culture system identifying Sema3 requirement, CD90 used as cell identifier rather than direct functional target, single lab","pmids":["30917322"],"is_preprint":false},{"year":2022,"finding":"USF1 transcription factor directly regulates CD90 expression in glioblastoma stem cells (confirmed by luciferase assay and ChIP-qPCR). CD90 of GSCs functions as a physical anchor for monocyte/macrophage adhesion, supporting immunosuppressive TAM features that in turn enhance GSC stemness. CD90 overexpression rescued stemness properties in USF1-knockdown GSCs.","method":"USF1 siRNA knockdown, luciferase reporter assay, ChIP-qPCR for USF1 binding to CD90 promoter, CD90 overexpression rescue, co-culture of GSCs with macrophages, in vivo GBM models","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — ChIP-qPCR and luciferase assay establish direct USF1 regulation of CD90 promoter, functional rescue with CD90 OE, single lab","pmids":["35287174"],"is_preprint":false},{"year":2018,"finding":"Breast cancer cells undergoing epithelial-mesenchymal transition enhance neutrophil TIMP-1 secretion via CD90 in a cell-contact manner. In vivo, CD90 blockade significantly reduced metastasis in tumor-bearing mice, supporting CD90 as a juxtacrine signal in the CD90-TIMP-1 pro-metastatic loop.","method":"Transwell and 3D Matrigel co-culture of neutrophils and cancer cells, antibody microarray cytokine screening, CD90 blockade in vivo, TIMP-1 neutralization in vivo","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-contact mechanism with antibody blockade and in vivo validation, single lab","pmids":["30482778"],"is_preprint":false},{"year":2004,"finding":"Thy-1 expression in neuronal cells is regulated by iron availability: iron chelation significantly decreased Thy-1 expression in PC12 cells in a dose- and time-dependent manner. Brain homogenates from iron-deficient rats showed decreased Thy-1 levels, and Thy-1 concentration in the substantia nigra of Restless Legs Syndrome patients (with lower iron) was less than half that of controls.","method":"Iron chelation in PC12 cells, Western blot for Thy-1 and transferrin receptor, rat iron-deficiency model, brain tissue homogenate analysis from RLS patients","journal":"Journal of the neurological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dose-dependent in vitro effect with transferrin receptor control, supported by in vivo rat model and human tissue, single lab","pmids":["15140607"],"is_preprint":false},{"year":2022,"finding":"CD90 is a downstream transcriptional effector of the NOTCH1 pathway in intrahepatic cholangiocarcinoma: NOTCH1 silencing by siRNA decreased HES1 and THY1 expression, and the NOTCH transcriptional regulator RBPJ was shown to bind putative sites on the THY1 promoter by ChIP assay.","method":"NOTCH1 siRNA knockdown, RT-PCR for HES1 and THY1, ChIP for RBPJ binding to THY1 promoter, CD90 OE/KD xenograft models, γ-secretase inhibitor (Crenigacestat) treatment","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — ChIP establishes RBPJ binding to THY1 promoter, siRNA epistasis, in vivo xenograft validation, single lab","pmids":["35172861"],"is_preprint":false}],"current_model":"THY1/CD90 is a GPI-anchored cell surface glycoprotein that functions as a context-dependent signaling scaffold: it inhibits adipogenesis and promotes osteogenesis by suppressing PPARγ via Src-family kinase Fyn; it suppresses myofibroblast differentiation and lung fibrosis by blocking αv integrin activation (through its RGD motif); it mediates leukocyte and tumor cell adhesion to endothelium via Mac-1/β2-integrin and αvβ3-integrin interactions, respectively; it inhibits epidermal YAP activity by dampening both integrin-β1-SRC signaling and adherens junction dissociation; it can act as a host entry factor for HCMV by interacting with viral gB/gH and activating PI3K/Akt; its expression is epigenetically silenced by promoter hypermethylation (driven by DNMT1, induced by TGF-β1) and by histone deacetylation; and in neurons it is regulated by cellular iron levels and plays a role in neurotransmitter vesicle release."},"narrative":{"mechanistic_narrative":"THY1/CD90 is a GPI-anchored cell-surface glycoprotein that acts as a context-dependent signaling scaffold controlling mesenchymal cell fate, fibrosis, adhesion, and proliferation [PMID:25416548, PMID:16960126, PMID:35798842]. In mesenchymal lineage commitment, Thy-1 suppresses adipogenesis and favors osteogenesis: it inhibits the Src-family kinase Fyn to reduce PPARγ transcriptional activity, and its loss in mice shifts marrow stromal cells toward adipocytes at the expense of osteoblasts with diminished osteogenic Wnt signaling [PMID:25416548, PMID:30089635]. In the lung, Thy-1 expression predetermines fibroblast fate, restraining myofibroblast differentiation, collagen contraction, and TGF-β activation; soluble Thy-1 reverses fibrosis in vivo through its integrin-binding RGD motif, which blocks an αv integrin activation feedback loop, while an RLE point mutation abolishes this activity [PMID:14507638, PMID:16960126, PMID:19270178, PMID:31672942]. Thy-1 expression is itself silenced in fibrotic fibroblasts by TGF-β1-driven, DNMT1-dependent promoter hypermethylation coupled to repressive histone modification, establishing a self-reinforcing pro-fibrotic circuit [PMID:18556592, PMID:20724553, PMID:26333597]. On endothelium, Thy-1 mediates leukocyte and tumor-cell adhesion through β2-integrin Mac-1 and tumor αvβ3-integrin, promoting metastasis [PMID:20599951, PMID:23159525, PMID:16374458], and in epidermis it restrains YAP-driven proliferation by dampening integrin-β1–SRC signaling and stabilizing adherens junctions [PMID:35798842]. Thy-1 also serves as an entry factor for human cytomegalovirus, interacting with viral glycoproteins gB and gH and activating PI3K/Akt during virion internalization [PMID:26147640]. THY1 transcription is driven by upstream regulators including NOTCH1/RBPJ and USF1 in cancer contexts [PMID:35287174, PMID:35172861].","teleology":[{"year":2006,"claim":"Established that Thy-1 surface expression marks and determines fibroblast differentiation fate, answering whether THY1 is a passive marker or an active fate determinant.","evidence":"FACS-sorted human and rat fibroblast subsets with TGF-β/PPARγ-agonist differentiation and Thy-1 transfection rescue","pmids":["14507638","16960126"],"confidence":"High","gaps":["Did not define the receptor/signaling intermediates downstream of Thy-1 in fibroblasts","Mechanism linking surface Thy-1 to myogenic gene repression not resolved"]},{"year":2008,"claim":"Identified the Src-family kinase Fyn as a signaling effector engaged by Thy-1 activation, providing a molecular handle on Thy-1 signaling output in myofibroblasts.","evidence":"Anti-Thy-1 antibody activation with PP2 and Fyn-specific siRNA, flow cytometry and RT-PCR readouts for FasL induction","pmids":["18676775"],"confidence":"High","gaps":["How GPI-anchored Thy-1 physically couples to intracellular Fyn not established","Generality beyond FasL induction unclear"]},{"year":2008,"claim":"Showed THY1 silencing in fibrosis is epigenetic, answering why Thy-1-negative fibroblasts arise in disease.","evidence":"Methylation-specific PCR, bisulfite sequencing, in situ MSP on IPF tissue, and DNMT-inhibitor reversal","pmids":["18556592"],"confidence":"High","gaps":["Did not identify the upstream trigger of hypermethylation","Did not connect methylation status to specific clinical outcomes"]},{"year":2009,"claim":"Demonstrated in vivo that Thy-1-expressing fibroblasts inhibit TGF-β activation to support normal alveolar development, linking the in vitro fate phenotype to organ-level biology.","evidence":"Thy-1-null mice with lung histology and rescue by TGF-β neutralizing antibody","pmids":["19270178"],"confidence":"High","gaps":["Molecular mechanism by which Thy-1 restrains TGF-β activation not defined here"]},{"year":2010,"claim":"Connected histone modification to DNA methylation at the THY1 locus, showing layered chromatin control of expression.","evidence":"TSA treatment with ChIP for H3K4me3/H4ac/H3K27me3 and bisulfite sequencing in lung fibroblasts","pmids":["20724553"],"confidence":"High","gaps":["Specific HDAC and chromatin-modifying enzymes responsible not identified","Order of methylation versus histone changes inferred, not directly timed"]},{"year":2010,"claim":"Defined Thy-1 on endothelium as an adhesion molecule for leukocytes and tumor cells, establishing a pro-metastatic adhesion function.","evidence":"Comparative profiling, anti-Thy1 adhesion blockade, and Thy1-deficient mouse experimental metastasis","pmids":["20599951","23159525","16374458"],"confidence":"High","gaps":["Signaling consequences in the endothelial cell itself not fully resolved"]},{"year":2012,"claim":"Identified the integrin partners of Thy-1 adhesion (Mac-1/β2 and αvβ3), providing the receptor specificity of Thy-1-mediated adhesion.","evidence":"Recombinant αX I-domain binding with mutagenesis and integrin/Thy-1 blocking adhesion assays","pmids":["23159525","15850796"],"confidence":"Medium","gaps":["Affinity measured for isolated I-domain, not full-length integrin in cellular context","Whether different integrins engage Thy-1 simultaneously not addressed"]},{"year":2015,"claim":"Established that TGF-β1 drives THY1 silencing through DNMT1, closing the loop between profibrotic signaling and epigenetic loss of a fibrosis suppressor.","evidence":"TGF-β1 treatment with DNMT1 siRNA, 5-AZA, qMethyl-PCR and downstream α-SMA/Col1A1 readouts","pmids":["26333597"],"confidence":"High","gaps":["How TGF-β1 specifically targets DNMT1 to the THY1 promoter unknown"]},{"year":2015,"claim":"Showed Thy-1 acts as an HCMV entry factor, extending its function to host-pathogen interaction.","evidence":"siRNA, antibody blocking, soluble protein competition, gB/gH co-immunoprecipitation and PI3K/Akt activation assays","pmids":["26147640"],"confidence":"High","gaps":["Whether Thy-1 is a direct receptor or co-factor in a larger entry complex not fully resolved","Structural basis of gB/gH interaction not defined"]},{"year":2014,"claim":"Defined the Fyn–PPARγ axis as the mechanism by which Thy-1 blocks adipogenesis, unifying the fate-determination phenotype with a kinase pathway.","evidence":"Thy1 KO/OE mice, PPARγ reporter assays, Fyn siRNA and PP2 inhibition","pmids":["25416548"],"confidence":"High","gaps":["Direct physical coupling of Thy-1 to Fyn not shown"]},{"year":2018,"claim":"Showed Thy-1 positively regulates osteogenesis and bone mass via Wnt signaling, balancing the reciprocal adipogenic/osteogenic fate decision in MSCs.","evidence":"Thy-1 KO mice with micro-CT/histomorphometry, MSC differentiation assays and Wnt pathway analysis","pmids":["30089635","29401595","27465541"],"confidence":"High","gaps":["Direct mechanistic link between Thy-1 and Wnt ligand/inhibitor expression not established","shRNA study reported opposite differentiation effect, indicating context dependence"]},{"year":2019,"claim":"Identified the RGD motif and αv integrin feedback loop as the mechanistic basis of Thy-1 anti-fibrotic activity and demonstrated therapeutic reversal.","evidence":"Soluble Thy-1-Fc with RLE-mutant control, bleomycin/doxycycline fibrosis models in Thy1-null mice, αv integrin activation assays","pmids":["31672942"],"confidence":"High","gaps":["Precise integrin heterodimer engaged in vivo not pinpointed","Durability and off-target effects of soluble Thy-1-Fc not characterized"]},{"year":2022,"claim":"Defined Thy-1 as an epidermal brake on YAP-driven proliferation through dual integrin-β1–SRC and adherens-junction mechanisms, extending its scaffold role to tissue homeostasis and regeneration.","evidence":"Thy1-null mice with wound/hair-follicle assays, integrin-β1-SRC pathway analysis, YAP localization imaging","pmids":["35798842"],"confidence":"High","gaps":["How a single GPI-anchored protein coordinates both integrin and junctional pools not mechanistically integrated"]},{"year":2022,"claim":"Established upstream transcriptional control of THY1 by NOTCH1/RBPJ and USF1 in cancer, identifying drivers of its context-specific expression.","evidence":"siRNA epistasis, luciferase reporters and ChIP/ChIP-qPCR for RBPJ and USF1 on the THY1 promoter, with rescue and xenograft validation","pmids":["35172861","35287174","28939749","33511115","26556861","27633757","30482778"],"confidence":"Medium","gaps":["Whether these regulators operate outside cancer cells unknown","Tumor-suppressive versus tumor-promoting Thy-1 roles across cancer types remain context-dependent and unreconciled"]},{"year":2004,"claim":"Linked neuronal Thy-1 expression to iron availability, hinting at a distinct role in the nervous system.","evidence":"Iron chelation in PC12 cells with transferrin-receptor control, rat 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microRNA-103.","date":"2017","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/28329833","citation_count":24,"is_preprint":false},{"pmid":"35172861","id":"PMC_35172861","title":"CD90 is regulated by notch1 and hallmarks a more aggressive intrahepatic cholangiocarcinoma phenotype.","date":"2022","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/35172861","citation_count":24,"is_preprint":false},{"pmid":"29401595","id":"PMC_29401595","title":"Thy1 is a positive regulator of osteoblast differentiation and modulates bone homeostasis in obese mice.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29401595","citation_count":24,"is_preprint":false},{"pmid":"25806121","id":"PMC_25806121","title":"Glioblastoma specific antigens, GD2 and CD90, are not involved in cancer stemness.","date":"2015","source":"Anatomy & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25806121","citation_count":24,"is_preprint":false},{"pmid":"35186924","id":"PMC_35186924","title":"Thy-1 (CD90), Integrins and Syndecan 4 are Key Regulators of Skin Wound Healing.","date":"2022","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/35186924","citation_count":23,"is_preprint":false},{"pmid":"35287174","id":"PMC_35287174","title":"USF1/CD90 signaling in maintaining glioblastoma stem cells and tumor-associated macrophages adhesion.","date":"2022","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35287174","citation_count":23,"is_preprint":false},{"pmid":"23683542","id":"PMC_23683542","title":"THY1 is a surface marker of porcine gonocytes.","date":"2014","source":"Reproduction, fertility, and 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Expression Is Elevated in Radiation-Induced Periprosthetic Capsular Contracture: Implication for Novel Therapeutics.","date":"2017","source":"Plastic and reconstructive surgery","url":"https://pubmed.ncbi.nlm.nih.gov/28746279","citation_count":17,"is_preprint":false},{"pmid":"35168627","id":"PMC_35168627","title":"CD34+THY1+ synovial fibroblast subset in arthritic joints has high osteoblastic and chondrogenic potentials in vitro.","date":"2022","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35168627","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50889,"output_tokens":8287,"usd":0.138486,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18318,"output_tokens":4722,"usd":0.10482,"stage2_stop_reason":"end_turn"},"total_usd":0.243306,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2014,\n      \"finding\": \"Thy1 (CD90) blocks adipogenesis by inhibiting the activity of the Src family kinase Fyn, which in turn decreases PPARγ transcriptional activity by more than 60%. Thy1-null mice gained 30% more weight than controls on a high-fat diet, and overexpression of Thy1 in 3T3-L1 cells blocked adipocyte formation and reduced FABP4 expression 5-fold.\",\n      \"method\": \"Thy1 overexpression/knockout in mouse model, PPARγ reporter assays, genetic and pharmacologic Fyn inhibition (siRNA + PP2 inhibitor), Western blotting\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (KO mouse, OE, reporter assay, siRNA, pharmacologic inhibition) in single rigorous study identifying Fyn as the kinase mediator\",\n      \"pmids\": [\"25416548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Thy-1 activation in lung myofibroblasts up-regulates FasL expression via Src family kinases, specifically Fyn. Thy-1 activation first causes translocation of FasL to the membrane surface, then induces de novo synthesis of FasL at mRNA and protein levels. Src family kinase inhibitor PP2 and Fyn-specific siRNA both blocked this induction.\",\n      \"method\": \"Anti-Thy1 antibody activation, SFK inhibitor PP2, Fyn-specific siRNA knockdown, flow cytometry, RT-PCR, Western blot\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal genetic and pharmacologic inhibition of Fyn, direct Thy-1 activation assay with multiple readouts in single lab\",\n      \"pmids\": [\"18676775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Thy-1 expression predetermines fibroblast lineage commitment: only Thy-1(+) human myometrial and orbital fibroblasts differentiated into myofibroblasts (assessed by α-SMA expression) in response to TGF-β or platelet concentrate, whereas only Thy-1(−) fibroblasts differentiated into lipofibroblasts after treatment with PPARγ agonists.\",\n      \"method\": \"FACS-sorted fibroblast subsets, TGF-β treatment, PPARγ agonist treatment, α-SMA immunostaining, lipid droplet accumulation assay\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — sorted cell populations with defined differentiation stimuli and phenotypic readouts, single lab\",\n      \"pmids\": [\"14507638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Thy-1(−) lung fibroblasts show significantly greater myofibroblast differentiation, collagen matrix contraction, and resistance to apoptosis compared with Thy-1(+) cells. Transfection of Thy-1 into Thy-1(−) cells inhibited collagen matrix contraction and reduced cell survival, directly demonstrating that Thy-1 regulates myogenic gene expression and myofibroblastic differentiation.\",\n      \"method\": \"FACS-sorted rat lung fibroblasts, TGF-β/ET-1/CTGF stimulation, floating collagen matrix contraction assays, apoptosis assays, Thy-1 transfection into Thy-1(−) cells, RT-PCR, immunoblotting\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — gain-of-function transfection with functional rescue, sorted cell populations, multiple orthogonal assays\",\n      \"pmids\": [\"16960126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Thy-1 promoter CpG islands are hypermethylated in Thy-1(−) lung fibroblasts and in fibroblastic foci of IPF tissue, silencing Thy-1 expression. Treatment with DNA methyltransferase inhibitors restores Thy-1 expression in Thy-1(−) fibroblasts, establishing promoter hypermethylation as a mechanism of Thy-1 silencing in pulmonary fibrosis.\",\n      \"method\": \"RT-PCR, methylation-specific PCR, bisulfite genomic sequencing, MSP-in situ hybridization on fibrotic tissue, DNMT inhibitor treatment\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — bisulfite sequencing, MSP, in situ validation in tissue, pharmacologic reversal with DNMT inhibitors, multiple orthogonal methods\",\n      \"pmids\": [\"18556592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Histone deacetylase inhibitor trichostatin A (TSA) restores Thy-1 expression in Thy-1(−) lung fibroblasts by enriching histone H3K4 trimethylation and H4 acetylation at the Thy-1 locus, while depleting repressive H3K27 trimethylation. TSA treatment also caused demethylation of previously hypermethylated CpG sites in the Thy-1 promoter, indicating that histone modifications regulate DNA methylation at this locus.\",\n      \"method\": \"TSA treatment, chromatin immunoprecipitation (ChIP) for histone marks, bisulfite sequencing, RT-PCR, global DNA methylation assays\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP with multiple histone marks, bisulfite sequencing, pharmacologic intervention, multiple orthogonal methods in single study\",\n      \"pmids\": [\"20724553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TGF-β1 epigenetically suppresses Thy-1 expression in primary lung fibroblasts by activating DNMT1 and inducing Thy-1 promoter methylation. siRNA knockdown of DNMT1 attenuated TGF-β1-induced DNMT activity and rescued Thy-1 expression, also inhibiting downstream α-SMA and collagen Col1A1 expression.\",\n      \"method\": \"TGF-β1 treatment, 5-AZA co-treatment, DNMT1 siRNA knockdown, quantitative methyl PCR, RT-PCR, Western blot, immunofluorescence\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — genetic (siRNA) and pharmacologic DNMT1 inhibition with promoter methylation confirmation by qMethyl-PCR, replicated TGF-β1 induction mechanism\",\n      \"pmids\": [\"26333597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Loss of Thy-1 in Thy-1(−/−) mice leads to impaired alveolarization, increased TGF-β signaling, altered cell proliferation, and increased collagen/elastin deposition. Administration of TGF-β neutralizing antibody (1D11) to Thy-1(−/−) mice improved alveolar development, establishing that Thy-1-expressing fibroblasts inhibit TGF-β activation and thereby support normal alveolar development.\",\n      \"method\": \"Thy-1 null mouse model, hypoxia exposure, lung histology, lung function measurement, TGF-β neutralizing antibody treatment, immunostaining\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with rescue by TGF-β neutralization, clear epistatic relationship established, multiple phenotypic readouts\",\n      \"pmids\": [\"19270178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Soluble Thy-1-Fc (sThy-1) reversed TGF-β1-induced myofibroblast differentiation in vitro in a dose-dependent manner via its integrin-binding RGD motif (RLE-mutated Thy-1 was inactive), and resolved established lung fibrosis in vivo after bleomycin or doxycycline-induced TGF-β1 overexpression. Thy1-null mice showed progressive αv integrin activation and myofibroblast accumulation, identifying an αv integrin-driven feedback loop sustained by loss of Thy-1.\",\n      \"method\": \"Thy1-null mouse model, bleomycin/doxycycline fibrosis models, soluble Thy-1-Fc treatment in vivo, RLE-mutant Thy-1 control, in vitro myofibroblast differentiation assays, αv integrin activation assessment\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — mutagenesis identifying RGD motif requirement, genetic KO model, in vivo therapeutic rescue, multiple orthogonal approaches\",\n      \"pmids\": [\"31672942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Thy1 (CD90) is expressed by lymphatic endothelial cells (but not blood vascular endothelial cells) and mediates adhesion of tumor cells and leukocytes to lymphatic endothelium. Blockade of Thy1 inhibited tumor cell adhesion to lymphatic endothelial cells in vitro, and Thy1-deficient mice showed markedly reduced experimental lung and lymph node metastasis of B16/F10 melanoma cells.\",\n      \"method\": \"Comparative transcriptional profiling, FACS, immunofluorescence, anti-Thy1 blockade in adhesion assays, Thy1(−/−) mouse experimental metastasis model\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO mouse model for metastasis, in vitro adhesion blockade, replicated across lymphatic and hematogenic routes\",\n      \"pmids\": [\"20599951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Thy-1 on endothelial cells mediates adhesion of melanoma cells via αvβ3-integrin on tumor cells. Thy-1-deficient mice showed reduced experimental lung and lymph node metastasis without affecting primary tumor growth, T-cell activation, or angiogenesis, establishing Thy-1–integrin adhesion as a specific pro-metastatic mechanism.\",\n      \"method\": \"Thy-1(−/−) mouse experimental and spontaneous metastasis models, in vitro adhesion assays, VEGF/TNF-α induction of Thy-1 on EC\",\n      \"journal\": \"The American journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with metastasis rescue specificity (no effect on tumor growth/angiogenesis), mechanistic adhesion assay, multiple readouts\",\n      \"pmids\": [\"23159525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Thy-1 on activated human dermal microvascular endothelial cells mediates neutrophil adhesion specifically via interaction with the β2-integrin Mac-1. Blocking Thy-1 on endothelial cells or Mac-1 on neutrophils significantly inhibited adhesion; psoriatic neutrophils showed increased adhesion to Thy-1 transfectants compared with healthy controls.\",\n      \"method\": \"Thy-1 transfected cell adhesion assay, blocking antibodies against Thy-1 and Mac-1, HDMEC adhesion assays, flow cytometry\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — blocking antibody experiments identifying Thy-1/Mac-1 interaction, single lab with transfectant and primary cell systems\",\n      \"pmids\": [\"16374458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The αX I-domain of the β2-integrin αXβ2 (CD11c/CD18) binds Thy-1 in a specific, divalent cation-dependent manner with a Kd of 1.16 μM. Amino acid substitutions in the βD-α5 loop of the αX I-domain (D249, KE243/244) reduced binding affinity, identifying the βD-α5 loop/α5 helix region as the Thy-1 recognition site.\",\n      \"method\": \"Recombinant I-domain binding assay, site-directed mutagenesis of αX I-domain, kinetic/affinity measurements\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding assay with mutagenesis identifying binding site, single lab study\",\n      \"pmids\": [\"15850796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"THY-1 mediates HCMV entry at the initial infection step (within the first 60 minutes). Anti-THY-1 antibody and siRNA knockdown impaired infectivity, blocked HCMV-induced PI3-K/Akt activation required for entry, and soluble THY-1 protein blocked infection during but not after virus internalization. THY-1 was shown to interact with HCMV glycoproteins gB and gH by co-immunoprecipitation.\",\n      \"method\": \"THY-1 siRNA knockdown, anti-THY-1 antibody blocking, exogenous THY-1 expression, soluble THY-1 protein competition, co-immunoprecipitation with gB and gH, PI3-K/Akt pathway activation assay\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (siRNA, antibody blocking, OE, soluble protein competition, Co-IP) all converging on entry step in single rigorous study\",\n      \"pmids\": [\"26147640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Thy-1 deficiency in mice leads to decreased bone volume, bone formation rate, and elevated cortical porosity, accompanied by reduced osteogenic Wnt ligands and increased Wnt inhibitors (sclerostin, dickkopf-1), and increased body fat mass. MSCs from Thy-1(−/−) mice showed decreased osteoblast differentiation and increased adipogenic differentiation, establishing Thy-1 as a regulator of MSC fate between osteogenic and adipogenic lineages.\",\n      \"method\": \"Thy-1(−/−) mouse model, micro-CT bone analysis, histomorphometry, MSC differentiation assays, Wnt pathway gene expression analysis, serum Thy-1 measurement in patients\",\n      \"journal\": \"Science translational medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model with comprehensive in vivo skeletal phenotyping, in vitro MSC differentiation, Wnt pathway mechanism, clinical correlation\",\n      \"pmids\": [\"30089635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Thy1 is a positive regulator of osteoblast differentiation. Thy1 KO mice fed a high-fat diet showed significantly reduced trabecular bone volume. In vitro, osteogenic conditions increased Thy1 expression during osteoblast differentiation, and absence of Thy1 attenuated osteoblastogenesis.\",\n      \"method\": \"Thy1 KO mouse model, micro-CT, histomorphometry, in vitro osteogenic differentiation assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with in vivo bone phenotype and in vitro osteogenic assay, single lab\",\n      \"pmids\": [\"29401595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"THY1 inhibits epidermal YAP activity through two converging mechanisms: (1) by suppressing integrin-β1-SRC signaling that promotes cell-matrix adhesion, and (2) by maintaining an adherens junction complex that retains YAP in the cytoplasm. THY1 deficiency causes YAP nuclear translocation and increased proliferation even at high cell density. Thy1(−/−) mice display enhanced wound repair and hair follicle regeneration due to increased YAP-dependent proliferation.\",\n      \"method\": \"Thy1(−/−) mouse model, wound healing and hair follicle assays, integrin-β1-SRC pathway analysis, adherens junction complex dissociation assays, YAP localization imaging, proliferation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model, two mechanistic pathways identified (integrin-SRC and AJ-YAP), in vivo phenotypic readouts, multiple orthogonal methods\",\n      \"pmids\": [\"35798842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Thy-1-αVβ3 integrin interaction in cancer cells (MDA-MB-231 breast cancer and B16F10 melanoma) triggers a Ca2+/hemichannel/ATP/P2X7 receptor signaling axis that promotes cell migration and invasion. β3 integrin silencing in cancer cells reduced transvasation through an endothelial monolayer and prevented lung metastasis in a preclinical mouse model.\",\n      \"method\": \"Thy-1 stimulation assay, intracellular Ca2+ measurement, connexin/pannexin inhibitors, P2X7 receptor pharmacologic blockade, β3 integrin siRNA, endothelial transmigration assay, in vivo mouse metastasis model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple signaling inhibitors, genetic knockdown, in vivo metastasis model, multiple cell types tested\",\n      \"pmids\": [\"33511115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CD90 expression in glioblastoma cells promotes adhesion and migration through enhanced SRC and FAK signaling. Modulation of CD90 expression in GBM cells dramatically affected their adhesion and migration in vitro, and CD90 expression induced invasive phenotypes in orthotopic xenografts in vivo. Pharmacologic inhibition of SRC/FAK blunted adhesion/migration in CD90-positive cells.\",\n      \"method\": \"CD90 siRNA knockdown in GBM cells, CD90 complementation in CD90-negative U87 cells, orthotopic xenograft models, SRC/FAK inhibitor treatment, GBM patient transcriptome analysis\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with in vivo xenograft, pharmacologic pathway validation, single lab\",\n      \"pmids\": [\"28939749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CD90 promotes liver cancer stem cell properties via a signal axis involving its RLD integrin-binding domain, β3 integrin, and AMPK/mTOR pathway, leading to upregulation of CD133. Mutation of the integrin-binding RLD domain of CD90 and silencing of β3 integrin both attenuated CD133 induction and anchorage-independent growth. Ectopic CD90 expression induced mTOR phosphorylation and AMPK dephosphorylation.\",\n      \"method\": \"CD90 ectopic expression and shRNA knockdown, RLD-domain mutant CD90, β3 integrin shRNA, mTOR/AMPK phosphorylation Western blot, anchorage-independent growth assay, xenograft tumorigenicity assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis and genetic knockdown of downstream integrin, signaling pathway analysis, single lab\",\n      \"pmids\": [\"26556861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD90 inhibits ovarian cancer anchorage-independent growth and tumor formation in vivo via β3 integrin-dependent suppression of CD133 and the AMPK/mTOR axis. Mutation of CD90's RLE (integrin-binding) domain to RLD abolished tumor-suppressive effects, and β3 integrin shRNA restored anchorage-independent growth and CD133 expression in CD90-overexpressing cells.\",\n      \"method\": \"CD90 overexpression in SKOV3 cells, RLE-to-RLD domain mutation, β3 integrin shRNA, anchorage-independent growth assay, xenograft tumor formation, ALDH activity, Western blot for mTOR/AMPK\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis, genetic knockdown of mediator (β3 integrin), in vivo tumor assay, single lab\",\n      \"pmids\": [\"27633757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Reduction of CD90 expression in mesenchymal stromal cells using shRNA lentiviral vectors enhanced osteogenic and adipogenic differentiation in vitro and caused a decrease in CD44 and CD166 expression, demonstrating that CD90 controls MSC differentiation commitment.\",\n      \"method\": \"CD90-targeted shRNA lentiviral knockdown, osteogenic/adipogenic differentiation assays, flow cytometry for surface markers\",\n      \"journal\": \"Stem cell research & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct genetic knockdown with defined differentiation readouts, single lab study\",\n      \"pmids\": [\"27465541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Environmental chemical TBBPA reduces Thy1 expression in human and mouse (pre)adipocyte cells by inducing miR-103 (and miR-107), which directly targets the Thy1 mRNA 3'UTR. Reduced Thy1 levels promoted adipogenesis; miR-103 induction by TBBPA was confirmed and luciferase reporter assays validated miR-103 targeting of Thy1 mRNA.\",\n      \"method\": \"Flow cytometry, Western blotting, qPCR for Thy1 expression, miRNA qPCR, luciferase reporter assay with Thy1 3'UTR, miR-103/107 prediction and validation\",\n      \"journal\": \"Toxicological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — luciferase reporter assay validates miR-103 targeting of Thy1 3'UTR, multiple assays, single lab\",\n      \"pmids\": [\"28329833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FcεRI-enriched membrane domains and Thy-1-enriched membrane domains have distinct lipid compositions: FcεRI domains contain approximately 2-fold more sphingomyelin and higher cholesterol-to-fatty acid ratios than Thy-1 microdomains, and plasmenyl-glycerophosphoethanolamine (plasmalogen GPE) is 2.5–3 times more abundant in FcεRI domains. Thy-1 domains are devoid of FcεRI subunits.\",\n      \"method\": \"Magnetic bead isolation of receptor/Thy-1 enriched membrane vesicles (detergent-free), lipidomics by positive and negative ion electrospray mass spectrometry, protein analyses\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical isolation and lipidomic characterization of Thy-1 membrane domains, single rigorous study\",\n      \"pmids\": [\"17387221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Thy-1 siRNA knockdown in skin wound regions retarded wound repair in mice, reduced re-epithelialization quality, and caused continuously increased TGF-β1 levels at wound sites. In fibroblasts, Thy-1 affects cell migration into wounds, cell proliferation, and cytoskeletal structure.\",\n      \"method\": \"Thy-1 siRNA injection at wound sites in mice, wound healing rate measurement, TGF-β1 measurement, fibroblast scratch assay, proliferation and cytoskeletal imaging\",\n      \"journal\": \"Journal of dermatological science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo siRNA knockdown with wound healing phenotype and TGF-β1 quantification, single lab\",\n      \"pmids\": [\"23312577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD90+ fibroblasts in the colon crypt express class 3 semaphorins (Sema3) that are required for their supportive effect on intestinal organoid growth, in addition to expressing stem cell niche factors Grem1, Wnt2b, and R-spondin3.\",\n      \"method\": \"Stromal cell phenotyping, organoid co-culture assays, gene expression analysis (Sema3, Grem1, Wnt2b, R-spondin3), functional blockade experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional co-culture system identifying Sema3 requirement, CD90 used as cell identifier rather than direct functional target, single lab\",\n      \"pmids\": [\"30917322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USF1 transcription factor directly regulates CD90 expression in glioblastoma stem cells (confirmed by luciferase assay and ChIP-qPCR). CD90 of GSCs functions as a physical anchor for monocyte/macrophage adhesion, supporting immunosuppressive TAM features that in turn enhance GSC stemness. CD90 overexpression rescued stemness properties in USF1-knockdown GSCs.\",\n      \"method\": \"USF1 siRNA knockdown, luciferase reporter assay, ChIP-qPCR for USF1 binding to CD90 promoter, CD90 overexpression rescue, co-culture of GSCs with macrophages, in vivo GBM models\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP-qPCR and luciferase assay establish direct USF1 regulation of CD90 promoter, functional rescue with CD90 OE, single lab\",\n      \"pmids\": [\"35287174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Breast cancer cells undergoing epithelial-mesenchymal transition enhance neutrophil TIMP-1 secretion via CD90 in a cell-contact manner. In vivo, CD90 blockade significantly reduced metastasis in tumor-bearing mice, supporting CD90 as a juxtacrine signal in the CD90-TIMP-1 pro-metastatic loop.\",\n      \"method\": \"Transwell and 3D Matrigel co-culture of neutrophils and cancer cells, antibody microarray cytokine screening, CD90 blockade in vivo, TIMP-1 neutralization in vivo\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-contact mechanism with antibody blockade and in vivo validation, single lab\",\n      \"pmids\": [\"30482778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Thy-1 expression in neuronal cells is regulated by iron availability: iron chelation significantly decreased Thy-1 expression in PC12 cells in a dose- and time-dependent manner. Brain homogenates from iron-deficient rats showed decreased Thy-1 levels, and Thy-1 concentration in the substantia nigra of Restless Legs Syndrome patients (with lower iron) was less than half that of controls.\",\n      \"method\": \"Iron chelation in PC12 cells, Western blot for Thy-1 and transferrin receptor, rat iron-deficiency model, brain tissue homogenate analysis from RLS patients\",\n      \"journal\": \"Journal of the neurological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dose-dependent in vitro effect with transferrin receptor control, supported by in vivo rat model and human tissue, single lab\",\n      \"pmids\": [\"15140607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD90 is a downstream transcriptional effector of the NOTCH1 pathway in intrahepatic cholangiocarcinoma: NOTCH1 silencing by siRNA decreased HES1 and THY1 expression, and the NOTCH transcriptional regulator RBPJ was shown to bind putative sites on the THY1 promoter by ChIP assay.\",\n      \"method\": \"NOTCH1 siRNA knockdown, RT-PCR for HES1 and THY1, ChIP for RBPJ binding to THY1 promoter, CD90 OE/KD xenograft models, γ-secretase inhibitor (Crenigacestat) treatment\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP establishes RBPJ binding to THY1 promoter, siRNA epistasis, in vivo xenograft validation, single lab\",\n      \"pmids\": [\"35172861\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"THY1/CD90 is a GPI-anchored cell surface glycoprotein that functions as a context-dependent signaling scaffold: it inhibits adipogenesis and promotes osteogenesis by suppressing PPARγ via Src-family kinase Fyn; it suppresses myofibroblast differentiation and lung fibrosis by blocking αv integrin activation (through its RGD motif); it mediates leukocyte and tumor cell adhesion to endothelium via Mac-1/β2-integrin and αvβ3-integrin interactions, respectively; it inhibits epidermal YAP activity by dampening both integrin-β1-SRC signaling and adherens junction dissociation; it can act as a host entry factor for HCMV by interacting with viral gB/gH and activating PI3K/Akt; its expression is epigenetically silenced by promoter hypermethylation (driven by DNMT1, induced by TGF-β1) and by histone deacetylation; and in neurons it is regulated by cellular iron levels and plays a role in neurotransmitter vesicle release.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"THY1/CD90 is a GPI-anchored cell-surface glycoprotein that acts as a context-dependent signaling scaffold controlling mesenchymal cell fate, fibrosis, adhesion, and proliferation [#0, #3, #16]. In mesenchymal lineage commitment, Thy-1 suppresses adipogenesis and favors osteogenesis: it inhibits the Src-family kinase Fyn to reduce PPARγ transcriptional activity, and its loss in mice shifts marrow stromal cells toward adipocytes at the expense of osteoblasts with diminished osteogenic Wnt signaling [#0, #14]. In the lung, Thy-1 expression predetermines fibroblast fate, restraining myofibroblast differentiation, collagen contraction, and TGF-β activation; soluble Thy-1 reverses fibrosis in vivo through its integrin-binding RGD motif, which blocks an αv integrin activation feedback loop, while an RLE point mutation abolishes this activity [#2, #3, #7, #8]. Thy-1 expression is itself silenced in fibrotic fibroblasts by TGF-β1-driven, DNMT1-dependent promoter hypermethylation coupled to repressive histone modification, establishing a self-reinforcing pro-fibrotic circuit [#4, #5, #6]. On endothelium, Thy-1 mediates leukocyte and tumor-cell adhesion through β2-integrin Mac-1 and tumor αvβ3-integrin, promoting metastasis [#9, #10, #11], and in epidermis it restrains YAP-driven proliferation by dampening integrin-β1–SRC signaling and stabilizing adherens junctions [#16]. Thy-1 also serves as an entry factor for human cytomegalovirus, interacting with viral glycoproteins gB and gH and activating PI3K/Akt during virion internalization [#13]. THY1 transcription is driven by upstream regulators including NOTCH1/RBPJ and USF1 in cancer contexts [#26, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that Thy-1 surface expression marks and determines fibroblast differentiation fate, answering whether THY1 is a passive marker or an active fate determinant.\",\n      \"evidence\": \"FACS-sorted human and rat fibroblast subsets with TGF-β/PPARγ-agonist differentiation and Thy-1 transfection rescue\",\n      \"pmids\": [\"14507638\", \"16960126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the receptor/signaling intermediates downstream of Thy-1 in fibroblasts\", \"Mechanism linking surface Thy-1 to myogenic gene repression not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the Src-family kinase Fyn as a signaling effector engaged by Thy-1 activation, providing a molecular handle on Thy-1 signaling output in myofibroblasts.\",\n      \"evidence\": \"Anti-Thy-1 antibody activation with PP2 and Fyn-specific siRNA, flow cytometry and RT-PCR readouts for FasL induction\",\n      \"pmids\": [\"18676775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How GPI-anchored Thy-1 physically couples to intracellular Fyn not established\", \"Generality beyond FasL induction unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed THY1 silencing in fibrosis is epigenetic, answering why Thy-1-negative fibroblasts arise in disease.\",\n      \"evidence\": \"Methylation-specific PCR, bisulfite sequencing, in situ MSP on IPF tissue, and DNMT-inhibitor reversal\",\n      \"pmids\": [\"18556592\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the upstream trigger of hypermethylation\", \"Did not connect methylation status to specific clinical outcomes\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated in vivo that Thy-1-expressing fibroblasts inhibit TGF-β activation to support normal alveolar development, linking the in vitro fate phenotype to organ-level biology.\",\n      \"evidence\": \"Thy-1-null mice with lung histology and rescue by TGF-β neutralizing antibody\",\n      \"pmids\": [\"19270178\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which Thy-1 restrains TGF-β activation not defined here\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected histone modification to DNA methylation at the THY1 locus, showing layered chromatin control of expression.\",\n      \"evidence\": \"TSA treatment with ChIP for H3K4me3/H4ac/H3K27me3 and bisulfite sequencing in lung fibroblasts\",\n      \"pmids\": [\"20724553\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific HDAC and chromatin-modifying enzymes responsible not identified\", \"Order of methylation versus histone changes inferred, not directly timed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined Thy-1 on endothelium as an adhesion molecule for leukocytes and tumor cells, establishing a pro-metastatic adhesion function.\",\n      \"evidence\": \"Comparative profiling, anti-Thy1 adhesion blockade, and Thy1-deficient mouse experimental metastasis\",\n      \"pmids\": [\"20599951\", \"23159525\", \"16374458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling consequences in the endothelial cell itself not fully resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified the integrin partners of Thy-1 adhesion (Mac-1/β2 and αvβ3), providing the receptor specificity of Thy-1-mediated adhesion.\",\n      \"evidence\": \"Recombinant αX I-domain binding with mutagenesis and integrin/Thy-1 blocking adhesion assays\",\n      \"pmids\": [\"23159525\", \"15850796\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Affinity measured for isolated I-domain, not full-length integrin in cellular context\", \"Whether different integrins engage Thy-1 simultaneously not addressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established that TGF-β1 drives THY1 silencing through DNMT1, closing the loop between profibrotic signaling and epigenetic loss of a fibrosis suppressor.\",\n      \"evidence\": \"TGF-β1 treatment with DNMT1 siRNA, 5-AZA, qMethyl-PCR and downstream α-SMA/Col1A1 readouts\",\n      \"pmids\": [\"26333597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TGF-β1 specifically targets DNMT1 to the THY1 promoter unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed Thy-1 acts as an HCMV entry factor, extending its function to host-pathogen interaction.\",\n      \"evidence\": \"siRNA, antibody blocking, soluble protein competition, gB/gH co-immunoprecipitation and PI3K/Akt activation assays\",\n      \"pmids\": [\"26147640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Thy-1 is a direct receptor or co-factor in a larger entry complex not fully resolved\", \"Structural basis of gB/gH interaction not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the Fyn–PPARγ axis as the mechanism by which Thy-1 blocks adipogenesis, unifying the fate-determination phenotype with a kinase pathway.\",\n      \"evidence\": \"Thy1 KO/OE mice, PPARγ reporter assays, Fyn siRNA and PP2 inhibition\",\n      \"pmids\": [\"25416548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical coupling of Thy-1 to Fyn not shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed Thy-1 positively regulates osteogenesis and bone mass via Wnt signaling, balancing the reciprocal adipogenic/osteogenic fate decision in MSCs.\",\n      \"evidence\": \"Thy-1 KO mice with micro-CT/histomorphometry, MSC differentiation assays and Wnt pathway analysis\",\n      \"pmids\": [\"30089635\", \"29401595\", \"27465541\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanistic link between Thy-1 and Wnt ligand/inhibitor expression not established\", \"shRNA study reported opposite differentiation effect, indicating context dependence\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified the RGD motif and αv integrin feedback loop as the mechanistic basis of Thy-1 anti-fibrotic activity and demonstrated therapeutic reversal.\",\n      \"evidence\": \"Soluble Thy-1-Fc with RLE-mutant control, bleomycin/doxycycline fibrosis models in Thy1-null mice, αv integrin activation assays\",\n      \"pmids\": [\"31672942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise integrin heterodimer engaged in vivo not pinpointed\", \"Durability and off-target effects of soluble Thy-1-Fc not characterized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined Thy-1 as an epidermal brake on YAP-driven proliferation through dual integrin-β1–SRC and adherens-junction mechanisms, extending its scaffold role to tissue homeostasis and regeneration.\",\n      \"evidence\": \"Thy1-null mice with wound/hair-follicle assays, integrin-β1-SRC pathway analysis, YAP localization imaging\",\n      \"pmids\": [\"35798842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single GPI-anchored protein coordinates both integrin and junctional pools not mechanistically integrated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established upstream transcriptional control of THY1 by NOTCH1/RBPJ and USF1 in cancer, identifying drivers of its context-specific expression.\",\n      \"evidence\": \"siRNA epistasis, luciferase reporters and ChIP/ChIP-qPCR for RBPJ and USF1 on the THY1 promoter, with rescue and xenograft validation\",\n      \"pmids\": [\"35172861\", \"35287174\", \"28939749\", \"33511115\", \"26556861\", \"27633757\", \"30482778\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these regulators operate outside cancer cells unknown\", \"Tumor-suppressive versus tumor-promoting Thy-1 roles across cancer types remain context-dependent and unreconciled\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linked neuronal Thy-1 expression to iron availability, hinting at a distinct role in the nervous system.\",\n      \"evidence\": \"Iron chelation in PC12 cells with transferrin-receptor control, rat iron-deficiency model and RLS patient substantia nigra tissue\",\n      \"pmids\": [\"15140607\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism connecting iron status to Thy-1 transcription/stability unknown\", \"Functional role of neuronal Thy-1 in neurotransmission not directly demonstrated in this corpus\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a GPI-anchored, cytoplasmic-domain-less protein transduces signals to intracellular kinases (Fyn, SRC/FAK) and how the same molecule produces opposing tumor-suppressive versus tumor-promoting outcomes across tissues.\",\n      \"evidence\": \"No timeline discovery resolves the trans-membrane coupling mechanism or reconciles the divergent cancer phenotypes\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of Thy-1/integrin/kinase coupling\", \"Determinants of context-dependent signaling output not identified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [9, 10, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 8, 16]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 13, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 16, 19]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 14, 16]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 10, 13]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [4, 5, 6]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FYN\", \"ITGAV\", \"ITGB3\", \"ITGAM\", \"ITGAX\", \"SRC\", \"PTK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}