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from Wikipedia
Thy-1 or CD90 (Cluster of Differentiation 90) is a 25–37 kDa heavily N-glycosylated, glycophosphatidylinositol (GPI) anchored conserved cell surface protein with a single V-like immunoglobulin domain, originally discovered as a thymocyte antigen. Thy-1 can be used as a marker for a variety of stem cells and for the axonal processes of mature neurons. Structural study of Thy-1 led to the foundation of the Immunoglobulin superfamily, of which it is the smallest member, and led to some of the initial biochemical description and characterization of a vertebrate GPI anchor and also the first demonstration of tissue specific differential glycosylation.
Discovery and nomenclature
[edit]The antigen Thy-1 was the first T cell marker to be identified. Thy-1 was discovered by Reif and Allen in 1964[5] during a search for heterologous antisera against mouse leukemia cells, and was demonstrated by them to be present on murine thymocytes, on T lymphocytes, and on neuronal cells. It was originally named theta (θ) antigen, then Thy-1 (THYmocyte differentiation antigen 1) due to its prior identification in thymocytes (precursors of T cells in the thymus). The human homolog was isolated in 1980 as a 25kDa protein (p25) of T-lymphoblastoid cell line MOLT-3 binding with anti-monkey-thymocyte antisera.[6] The discovery of Thy-1 in mice and humans led to the subsequent discovery of many other T cell markers, which is very significant to the field of immunology since T cells (along with B cells) are the major cellular components of the adaptive immune response.[6]
The conserved gene and its alleles
[edit]Thy-1 has been conserved throughout vertebrate evolution and even in some invertebrates, with homologs described in many species like squid, frogs, chickens, mice, rats, dogs, and humans.
The Thy-1 gene is located at human chromosome 11q22.3 (mouse chromosome 9qA5.1). In AceView, it covers 6.82 kb, from 119294854 to 119288036 (NCBI 37, August 2010), on the reverse strand. This locus is very close to CD3 & CD56/NCAM genes. Some believe that there may be a functional significance of both this gene and CD3 delta subunit (T3D) mapping to chromosome 11q in man and chromosome 9 in mouse, though there is no homology (in fact this speculation led to its localization in chromosome 11q - the human chromosome region syntenic to mouse chromosome 9 which harbored T3D). In mice, there are two alleles: Thy-1.1 (Thy-1a, CD90.1) and Thy-1.2 (Thy-1b, CD90.2). They differ by only one amino acid at position 108; an arginine in Thy-1.1 and a glutamine in Thy-1.2. Thy-1.2 is expressed by most strains of mice, whereas Thy-1.1 is expressed by others such as AKR/J and PL mouse strains.
The Protein
[edit]The 25-kDa core protein (excluding the heavy glycosylation) of rodent Thy-1 is 111 or 112 amino acids in length, and is N-glycosylated at three sites (In contrast to only two glycosylation sites for human Thy-1). The 162aa (murine, 161 for human) Thy1 precursor has 19 amino acid (aa 1–19) signal sequence and 31 amino acid (aa 132–162) C-terminal transmembrane domain that is present in pro form but removed when transferring the 112 amino acid (aa 20–131) mature peptide to GPI anchor which would attach through the aa 131.
Some of the common monoclonal antibodies used to detect this protein are clones OX7, 5E10, K117 and L127. There have been some reports of Thy1 monoclonal antibodies cross reacting with some cytoskeletal elements: anti Thy-1.2 with actin in marsupial, murine, and human cells and anti Thy-1.1 with vimentin, and were suggested to be due to sequence homology by studies done more than 20 years back.[7]
Thy-1, like many other GPI anchored proteins can be shed by special types of Phospholipase C e.g. PI-PLC (phosphatidyl-Inositol Phospholipase C, or PLC β). it can also be involved in cell to cell transfer of GPI anchored proteins like CD55 and CD59.
Glycosylation
[edit]Thy-1 is one of the most heavily glycosylated membrane proteins with a carbohydrate content up to 30% of its molecular mass.[8] Thy-1 in most species has 3 N-glycosylation sites (Asn 23, 74 and 98) but no O-glycosylation. The composition of Thy-1 carbohydrate moieties varies considerably between different tissues or even among cells of the same lineage at different stages of differentiation: e.g., galactosamine only in brain Thy-1, sialic acid in thymic Thy-1 in far excess than brain Thy-1, that too increasing in parallel with T cell maturation. In this regard it has yet another historic association: Thy-1 happens to be the first glycoprotein in which cell type specificity of variant glycosylation on an invariant protein was demonstrated. Analysis of Differencial glycosylation of Thy-1 from brain and thymus showed that all the complex N-linked structures differed between the two forms, superimposed upon a site specific common core. In case of Thy-1 this core pattern was constituted by Asn23 carrying mostly oligomannose structures, Asn74 carrying the most extended complex structures, and Asn98 carrying smaller complex structure. The structure of the sugar residues in the GPI anchor and their associated esterified structures (e.g. additional fatty acids and alcohols) also can be cell type and species specific.
Expression
[edit]Thy-1 expression varies between species. Amongst the cells reported to generally express Thy-1 are thymocytes (precursor of T cells in the thymus) & CD34(+) prothymocytes; neurons, mesenchymal stem cells, hematopoietic stem cells, NK cells, murine T-cells, endothelium (mainly in high endothelial venules or HEVs where diapedesis takes place), renal glomerular mesangial cells, circulating metastatic melanoma cells, follicular dendritic cells (FDC), a fraction of fibroblasts and myofibroblasts.
Detailed expression of Thy-1
[edit]- In mice, Thy-1 is also found on thymocytes, peripheral T cells, myoblasts, epidermal cells, and keratinocytes. It is one of the "pan T cell markers"(of mice) like CD2, CD5 and CD28.
- In humans, Thy-1 is also expressed by endothelial cells, smooth muscle cells, a subset of CD34+ bone marrow cells, and umbilical cord blood-, cardiac fibroblasts, and fetal liver-derived hemopoietic cells.
- Thy-1 is present on a fraction of brain cells and a fraction of fibroblasts of most vertebrate species studied.
- Nervous tissue: Thy-1 expression in the nervous system is predominantly neuronal, but some glial cells also express Thy-1 especially at later stages of their differentiation. One study compared Thy-1 expression in four human neuronal cell lines, two neuroglial cell lines, and fresh tumor cells of neuronal origin and found three of the four neuronal cell lines, all of the neuroglial cell lines, and 80% of the tumors to be strongly positive for Thy-1.[9] Brain part specific ELISA reports are available which show highest concentrations of Thy-1 protein in the striatum and hippocampus, followed by the neocortex, cerebellum, spinal cord, and the retina and optic nerve. Thy-1 promoter has often been assumed to be "brain specific". "Neuron specific" mouse Thy-1 promoter has been used to drive "brain specific" forced expression of proteins e.g. mutated Amyloid precursor protein(APP) as transgenic animal models of Alzheimer's disease.[10] Thy-1 expression in the brain is developmentally regulated. Thy-1 levels in the neonatal rat brain, as well as the developing human brain, are low compared to adult brain. During the first few weeks of postnatal development, Thy-1 levels increase exponentially as the brain matures.
- Lymphoid tissue Thy-1 expression is highly variable between species. In humans, Thy-1 expression is restricted to only a small population of cortical thymocytes[11] and not expressed in mature human T cells.[12] It is probably the most abundant glycoprotein of murine thymocytes, with about One million copies per cell covering up to 10–20% of the cell surface.[13] Mouse cortical thymocytes express higher levels of Thy-1 than medullary thymocytes which in turn express more than lymph node cells (~200,000 copies/cell). A similar inverse developmental temporal expression profile is seen in rats T cells, although rat Thy-1 is lost at an earlier stage of T cell maturation.[14] Thy-1 is only expressed on thymocytes in rats (contrast to thymocytes and splenocytes in mice). The third intron of the mouse Thy-1 gene has a 36 base pair region that recruits nuclear transcription factors, such as Ets-1-like NF, expressed in thymocytes and splenocytes. The homologous region of the rat gene lacks the Ets-1-like NF binding site, but instead binds another NF expressed in rat thymocytes but not splenocytes.
Induction of Thy-1 expression
[edit]- Agents shown to induce Thy-1 expression include: Thymopoietin, thymosin, prostaglandins, nerve growth factor, IL-1, TNF, PMA, Ca2+ ionophore, and diacylglycerol (DAG).[15]
Localization
[edit]As a GPI-anchored protein, Thy-1 is present in the outer leaflet of lipid rafts in the cell membrane. In case of neurons it is known to be expressed strongly in the mature axon. The axon hillock can act as a barrier for its lateral spread even though it has no transmembrane segment. Thy-1 has been suggested to interact with G inhibitory proteins, the Src family kinase (SFK) member c-fyn, and tubulin within lipid rafts.[citation needed] In rats and mice, Thy-1 protein is present on the soma (cell body) and dendrites of neurons but is not expressed on axons until axonal growth is complete, and is again temporarily suppressed during axonal injury.[citation needed] HIV-1 Matrix co-localizes with Thy-1 in lipid rafts, the site of virus particle budding from cells, and Thy-1 is incorporated into virus particles as a result of this process.[citation needed]
Function
[edit]The function of Thy-1 has not yet been fully elucidated. It has speculated roles in cell-cell and cell-matrix interactions, with implication in neurite outgrowth, nerve regeneration, apoptosis, metastasis, inflammation, and fibrosis.
Role in cognition
[edit]The Thy-1 knockout (KO) mice are viable and appear grossly normal. They display normal social interactions and normal learning in a maze, but fail to learn from social cues (e.g. learning from other mice which foods are safe to eat as compared to wild-type mice). This failure can be rescued by the transgenic expression of Thy-1 or pharmacologic treatment with a GABA (A) receptor antagonists. This suggests that Thy-1 KO mice have excessive GABAergic inhibition in the dentate gyrus and regional inhibition of long-term potentiation.
Axon growth regulation
[edit]Crosslinking anti-Thy-1 Ab can promote neurite outgrowth which is dependent on G{alpha}i and L- and N-type calcium channel activation. The ligand for promotion of neurite outgrowth on astrocytes is not yet identified, but the inhibitory ligand has been suggested to be integrins.[16] Thy1 is one of the known ligands of beta 3 integrins.[17] Interaction of thy1 expressed on maturing axons with beta 3 integrins expressed on mature astrocytes is one of the causes of halting of axon growth.[18][19]
T-cell activation
[edit]Crosslinking Thy-1 molecules in the membrane raft, in the context of strong costimulatory signaling through CD28 in mouse T cells can act to some extent as a substitute activating signal for T-cell receptor signaling. Conversely it can substitute CD28 costimulation for activation through the TCR.[15]
Cell death
[edit]Cross linking antibody induced aggregation of Thy1 cause death of thymocytes and mesangial cells mainly by apoptosis despite Bcl2 upregulation. The death of mesangial cells seems to be apoptosis by TUNEL staining or annexin V staining, but electron microscopy suggest it is necrosis.
Antibody target for animal model of glomerulonephritis
[edit]Single tail vein intravenous injection of antibody (OX7 mouse monoclonal IgG) against Thy1.1 in rats is used as a standard animal model to produce experimental mesangioproliferative glomerulonephritis[20] which is popularly known in the field of nephrology as antiThy1 GN.
Tumor suppression
[edit]It has also been proven to be a tumor suppressor for some tumors.[21] It probably is aided by its action in upregulating thrombospondin, SPARC (osteonectin), and fibronectin. However it has also been speculated to aid in extravasation in circulating melanoma cells. In case of prostate cancer it has been shown to be expressed in cancer associated stroma but not in normal stroma and has been suggested to be of potential help for cancer specific drug targeting [1].
Role in cell adhesion, extravasation, migration
[edit]Acting through several integrins and probably a few yet unknown other receptors Thy-1 mediates adhesion of leukocytes and monocytes to endothelial cells and fibroblasts, melanoma cells to endothelium, and thymocytes to thymic epithelium.[22] Thy1 expression comes on when endothelial cells are activated. It has been shown to interact with the leukocyte integrin Mac1 (CD11b/CD18) and may play a role in leukocyte homing and recruitment.[23]
Modulating fibrosis
[edit]Role of Thy-1 in fibrosis and fibroblast differentiation may have some tissue variation. Thy1 knock out mice have increased fibrosis in the lung. Fibrosis induced by chemotherapeutic agent Bleomycin is also increased in these mice.
Other roles
[edit]Thy-1 knock out mice also show impaired cutaneous immune responses and abnormal retinal development: thinning of the inner nuclear, inner plexiform, ganglion cell, and outer segment layers of the retina.
Use in stem cell biology
[edit]Thy-1 can be considered as a surrogate marker for various kind of stem cells (e.g. hematopoietic stem cells or HSCs). It is one of the popular combinatorial surface markers for FACS for stem cells in combination with other markers like CD34. In humans, Thy-1 is expressed on neurons and HSCs among others. It is considered a major marker of HSC pluripotency in concordance with CD34. In human HSCs, Thy1 cells are all CD34 positive.[24][25][26][27] Thy 1 is also a marker of other kind of stem cells, for example: mesenchymal stem cells, hepatic stem cells ("oval cells"),[28] keratinocyte stem cells,[29] putative endometrial progenitor/(?)stem cells.[30]
References
[edit]- ^ a b c GRCh38: Ensembl release 89: ENSG00000154096 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000032011 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Reif AE, Allen JM (September 1964). "The Akr Thymic Antigen and ITS Distribution in Leukemias and Nervous Tissues". The Journal of Experimental Medicine. 120 (3): 413–433. doi:10.1084/jem.120.3.413. PMC 2137766. PMID 14207060.
- ^ a b Ades EW, Zwerner RK, Acton RT, Balch CM (February 1980). "Isolation and partial characterization of the human homologue of Thy-1". The Journal of Experimental Medicine. 151 (2): 400–406. doi:10.1084/jem.151.2.400. PMC 2185777. PMID 6153212.
- ^ Dales S, Fujinami RS, Oldstone MB (September 1983). "Serologic relatedness between Thy-1.2 and actin revealed by monoclonal antibody". Journal of Immunology. 131 (3): 1332–1338. doi:10.4049/jimmunol.131.3.1332. PMID 6136544. S2CID 27990060.
- ^ Pont S (April 1987). "Thy-1: a lymphoid cell subset marker capable of delivering an activation signal to mouse T lymphocytes". Biochimie. 69 (4): 315–320. doi:10.1016/0300-9084(87)90022-8. PMID 2888493.
- ^ Kemshead JT, Ritter MA, Cotmore SF, Greaves MF (March 1982). "Human Thy-1: expression on the cell surface of neuronal and glial cells". Brain Research. 236 (2): 451–461. doi:10.1016/0006-8993(82)90727-2. PMID 6121610. S2CID 25024190.
- ^ Moechars D, Dewachter I, Lorent K, Reversé D, Baekelandt V, Naidu A, et al. (March 1999). "Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain". The Journal of Biological Chemistry. 274 (10): 6483–6492. doi:10.1074/jbc.274.10.6483. PMID 10037741.
- ^ McKenzie JL, Fabre JW (March 1981). "Human thy-1: unusual localization and possible functional significance in lymphoid tissues". Journal of Immunology. 126 (3): 843–850. doi:10.4049/jimmunol.126.3.843. PMID 7462633. S2CID 45789481.
- ^ Saalbach A, Kraft R, Herrmann K, Haustein UF, Anderegg U (July 1998). "The monoclonal antibody AS02 recognizes a protein on human fibroblasts being highly homologous to Thy-1". Archives of Dermatological Research. 290 (7): 360–366. doi:10.1007/s004030050318. PMID 9749990. S2CID 21090989.
- ^ Killeen N (December 1997). "T-cell regulation: Thy-1 - hiding in full view". Current Biology. 7 (12): R774 – R777. Bibcode:1997CBio....7R.774K. doi:10.1016/S0960-9822(06)00402-7. PMID 9382830. S2CID 18093637.
- ^ Crawford JM, Barton RW (February 1986). "Thy-1 glycoprotein: structure, distribution, and ontogeny". Laboratory Investigation; A Journal of Technical Methods and Pathology. 54 (2): 122–135. PMID 2868157.
- ^ a b Haeryfar SM, Hoskin DW (September 2004). "Thy-1: more than a mouse pan-T cell marker". Journal of Immunology. 173 (6): 3581–3588. doi:10.4049/jimmunol.173.6.3581. PMID 15356100.
- ^ Leyton L, Schneider P, Labra CV, Rüegg C, Hetz CA, Quest AF, et al. (July 2001). "Thy-1 binds to integrin beta(3) on astrocytes and triggers formation of focal contact sites". Current Biology. 11 (13): 1028–1038. doi:10.1016/S0960-9822(01)00262-7. hdl:10533/172542. PMID 11470407.
- ^ Hermosilla T, Muñoz D, Herrera-Molina R, Valdivia A, Muñoz N, Nham SU, et al. (June 2008). "Direct Thy-1/alphaVbeta3 integrin interaction mediates neuron to astrocyte communication". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1783 (6): 1111–1120. doi:10.1016/j.bbamcr.2008.01.034. PMC 2587321. PMID 18346467.
- ^ Herrera-Molina R, Frischknecht R, Maldonado H, Seidenbecher CI, Gundelfinger ED, Hetz C, et al. (30 March 2012). "Astrocytic αVβ3 integrin inhibits neurite outgrowth and promotes retraction of neuronal processes by clustering Thy-1". PLOS ONE. 7 (3) e34295. Bibcode:2012PLoSO...734295H. doi:10.1371/journal.pone.0034295. PMC 3316703. PMID 22479590.
- ^ Maldonado H, Calderon C, Burgos-Bravo F, Kobler O, Zuschratter W, Ramirez O, et al. (February 2017). "Astrocyte-to-neuron communication through integrin-engaged Thy-1/CBP/Csk/Src complex triggers neurite retraction via the RhoA/ROCK pathway". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1864 (2): 243–254. doi:10.1016/j.bbamcr.2016.11.006. PMID 27842221.
- ^ Yamamoto T, Wilson CB (October 1987). "Quantitative and qualitative studies of antibody-induced mesangial cell damage in the rat". Kidney International. 32 (4): 514–525. doi:10.1038/ki.1987.240. PMID 2892961.
- ^ Abeysinghe HR, Cao Q, Xu J, Pollock S, Veyberman Y, Guckert NL, et al. (June 2003). "THY1 expression is associated with tumor suppression of human ovarian cancer". Cancer Genetics and Cytogenetics. 143 (2): 125–132. doi:10.1016/S0165-4608(02)00855-5. PMID 12781446.
- ^ Rege TA, Hagood JS (June 2006). "Thy-1 as a regulator of cell-cell and cell-matrix interactions in axon regeneration, apoptosis, adhesion, migration, cancer, and fibrosis". FASEB Journal. 20 (8): 1045–1054. doi:10.1096/fj.05-5460rev. PMID 16770003. S2CID 16467655.
- ^ Wetzel A, Chavakis T, Preissner KT, Sticherling M, Haustein UF, Anderegg U, et al. (March 2004). "Human Thy-1 (CD90) on activated endothelial cells is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18)". Journal of Immunology. 172 (6): 3850–3859. doi:10.4049/jimmunol.172.6.3850. PMID 15004192.
- ^ Boitano AE, Wang J, Romeo R, Bouchez LC, Parker AE, Sutton SE, et al. (September 2010). "Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells". Science. 329 (5997): 1345–1348. Bibcode:2010Sci...329.1345B. doi:10.1126/science.1191536. PMC 3033342. PMID 20688981.
- ^ Craig W, Kay R, Cutler RL, Lansdorp PM (May 1993). "Expression of Thy-1 on human hematopoietic progenitor cells". The Journal of Experimental Medicine. 177 (5): 1331–1342. doi:10.1084/jem.177.5.1331. PMC 2191025. PMID 7683034.
- ^ Majeti R, Park CY, Weissman IL (December 2007). "Identification of a hierarchy of multipotent hematopoietic progenitors in human cord blood". Cell Stem Cell. 1 (6): 635–645. doi:10.1016/j.stem.2007.10.001. PMC 2292126. PMID 18371405.
- ^ Mestas J, Hughes CC (March 2004). "Of mice and not men: differences between mouse and human immunology". Journal of Immunology. 172 (5): 2731–2738. doi:10.4049/jimmunol.172.5.2731. PMID 14978070.
- ^ Masson NM, Currie IS, Terrace JD, Garden OJ, Parks RW, Ross JA (July 2006). "Hepatic progenitor cells in human fetal liver express the oval cell marker Thy-1". American Journal of Physiology. Gastrointestinal and Liver Physiology. 291 (1): G45 – G54. doi:10.1152/ajpgi.00465.2005. PMID 16769813.
- ^ Nakamura Y, Muguruma Y, Yahata T, Miyatake H, Sakai D, Mochida J, et al. (June 2006). "Expression of CD90 on keratinocyte stem/progenitor cells". The British Journal of Dermatology. 154 (6): 1062–1070. doi:10.1111/j.1365-2133.2006.07209.x. PMID 16704635. S2CID 28647667.
- ^ Gargett CE (June 2006). "Identification and characterisation of human endometrial stem/progenitor cells". The Australian & New Zealand Journal of Obstetrics & Gynaecology. 46 (3): 250–253. doi:10.1111/j.1479-828X.2006.00582.x. PMID 16704483. S2CID 46030653.
External links
[edit]- Human THY1 genome location and THY1 gene details page in the UCSC Genome Browser.
from Grokipedia
CD90, also known as Thy-1, is a glycophosphatidylinositol (GPI)-anchored glycoprotein that belongs to the immunoglobulin superfamily and serves as a cell surface antigen involved in cell adhesion, signaling, and modulation of cellular phenotypes across various tissues.[1] Encoded by the THY1 gene, which is highly conserved among vertebrates, CD90 consists of a single immunoglobulin-like domain with a molecular weight of 25–37 kDa due to extensive N-glycosylation, and it lacks a transmembrane or intracellular domain, relying instead on lipid rafts for signal transduction.[2] First identified as a marker on thymocytes in mice, CD90 is expressed on a wide range of cells, including neurons (where it constitutes up to 7.5% of axonal membrane protein), subsets of fibroblasts, endothelial cells, hematopoietic stem cells, and T cells, with expression patterns varying by species—such as abundance on mature mouse T cells but absence on human counterparts.[1][2]
In physiological contexts, CD90 plays critical roles in neural development by regulating axon outgrowth and synapse formation, in immune responses through T cell activation and thymocyte differentiation, and in stromal interactions by influencing fibroblast behavior in tissue remodeling and fibrosis.[1] Its functions are context-dependent, often acting as a sensor of the microenvironment to modulate cell proliferation, migration, and differentiation; for instance, it inhibits neurite extension in mature neurons while promoting myogenic potential in certain stem cell populations.[1][3]
In pathology, CD90 has garnered attention as a biomarker and functional regulator in cancer and fibrotic diseases, where it can exhibit dual roles: serving as a tumor suppressor by impeding ovarian cancer progression or as a promoter of metastasis in hepatocellular carcinoma and glioblastoma through enhancement of cancer stem cell properties and invasion.[2] Similarly, elevated CD90 expression on fibroblasts contributes to excessive extracellular matrix deposition in skin and organ fibrosis, positioning it as a potential therapeutic target.[4] Ongoing research highlights its involvement in stem cell biology, including the enrichment of osteogenic progenitors when selected via CD90-positive isolation.[5]
Discovery and Nomenclature
Initial Identification
The theta (θ) antigen, the first identified marker for T-lymphocytes, was discovered in 1964 by Arnold E. Reif and Joan M. V. Allen during experiments to detect leukemia-specific antigens in mice. They immunized strain A mice with thymocytes from AKR strain mice, generating an antiserum that specifically recognized an antigen on thymocytes and certain leukemias, which they initially termed the AKR thymic antigen. This antigen was found to be abundant in the thymus and nervous tissues of AKR and RF mice but absent from thymocytes of 16 other strains tested, including C57BL.[6] Subsequent studies revealed strain-specific expression patterns, with high levels in AKR/J mice (θAKR allele) and low or undetectable levels in C57BL mice, while C3H mice expressed a distinct but related allele (θC3H). These differences were confirmed through antisera raised by cross-immunization between strains, establishing θ as an allelic system controlled by a single autosomal locus and recognizing it as a reliable surface marker on thymocytes and T-lymphocytes.[7] Early experiments further demonstrated θ's utility in distinguishing T-lymphocytes from B-lymphocytes in lymphoid tissues. In 1969, Martin C. Raff used θ-specific antisera to show that nearly all thymocytes and a subset of peripheral lymphocytes (thymus-derived T cells) expressed θ, whereas bone marrow-derived cells and plasma cells did not, providing the first clear separation of these lymphocyte populations based on surface antigens. This work solidified θ as a foundational tool for T-cell identification in mouse immunology.[8] A human homolog of the θ antigen, termed human Thy-1, was first isolated and partially characterized in 1980 by McKenzie and Fabre from human thymus and brain tissues.[9]Standardization and Synonyms
The theta antigen, first identified on mouse thymocytes in 1964, was renamed Thy-1 in 1971 to denote its thymic origin and the first such differentiation antigen recognized on T lymphocytes, highlighting its evolutionary conservation across mammalian species. This nomenclature emphasized the protein's role as a key surface marker for distinguishing T cells from B cells in early immunological studies. The Thy-1 designation facilitated comparative research, particularly in rodents and humans, where homologous forms of the antigen were subsequently characterized for their shared structural and functional properties in immune cell identification. In 1993, during the Fifth International Workshop on Human Leukocyte Differentiation Antigens (HLDA), the human ortholog was formally assigned the cluster of differentiation number CD90, establishing it as a standardized marker for leukocyte subsets and promoting uniformity in antibody-based assays across global research efforts. This assignment built on prior provisional naming as CDw90 and integrated Thy-1 into the CD system, enabling precise cross-species comparisons in immunology, such as between rat Thy-1.1/Thy-1.2 alleles and human CD90. Common synonyms for the antigen include Thy-1 and the early provisional CDw90, reflecting its dual usage in molecular and immunological contexts.[10]Genetics
Gene Location and Structure
The THY1 gene, encoding the CD90 antigen, is located on the long arm of human chromosome 11 at cytogenetic band 11q23.3. In the GRCh38.p14 assembly, it spans approximately 9.5 kb on the reverse strand, from genomic coordinates 119,415,476 to 119,424,985.[11][12] The orthologous Thy1 gene in mice is situated on chromosome 9 at band A5.1. In the GRCm39 assembly, the mouse gene extends over roughly 5 kb on the forward strand, from positions 43,954,681 to 43,959,876.[13] The human THY1 gene comprises 4 exons separated by 3 introns. Exon 1 encodes the signal (leader) peptide, exons 2 and 3 together form the immunoglobulin-like domain of the mature protein, and exon 4 contains the signal sequence for glycosylphosphatidylinositol (GPI) anchor attachment.[14] The promoter region of THY1 is G+C-rich and lacks a canonical TATA box, characteristic of housekeeping-like promoters within CpG islands. It features multiple Sp1 binding sites and an inverted CCAAT box as key regulatory elements that support basal and tissue-specific transcription. This promoter architecture is highly conserved across mammalian species, with the overall gene organization showing structural similarity between human and mouse, including comparable exon-intron boundaries.[15]Allelic Variants
In mice, the Thy1 gene exhibits two major allelic variants, Thy1^a and Thy1^b, encoding the Thy-1.1 and Thy-1.2 isoforms, respectively. The Thy1^a allele is characteristic of strains such as AKR/J, while the Thy1^b allele predominates in strains like C57BL/6. These alleles differ by a single amino acid substitution at position 89 of the mature protein, with arginine in Thy-1.1 and glutamine in Thy-1.2.[16] Strains carrying the Thy1^a allele generally display higher Thy-1 surface expression on peripheral T cells compared to those with Thy1^b, contributing to differences in detectable Thy-1-positive populations; for instance, AKR/J mice show approximately 78% Thy-1-positive peripheral T cells, reflecting elevated expression levels relative to Thy1^b strains where expression is notably lower on mature T lymphocytes.[17][1] This allelic variation primarily impacts antibody recognition, as the amino acid difference creates distinct epitopes that allow for allele-specific monoclonal antibodies, such as those targeting Thy-1.1 versus Thy-1.2, without evidence of altered core protein functions like cell adhesion or signaling.[18][19] Surface density variations between alleles may influence detection sensitivity in immunological assays but do not appear to modify the fundamental biological roles of Thy-1.[17] In humans, the THY1 gene lacks major polymorphic alleles analogous to those in mice, with only rare single nucleotide polymorphisms (SNPs) identified that may subtly modulate expression levels in specific tissues, though no widespread functional impacts have been established.[20][11]Molecular Structure
Core Protein Features
CD90, also known as Thy-1, is a compact cell surface glycoprotein whose core polypeptide chain consists of 112 amino acids in its mature form following signal peptide cleavage. This yields an unglycosylated core with a theoretical molecular mass of approximately 13 kDa, though the protein is often characterized with an apparent mass of 25 kDa when considering the full unmodified structure including the GPI anchor.[21][22] The defining structural feature is a single immunoglobulin V-set (IgV) domain spanning residues 20 to 126, which adopts a beta-sandwich fold typical of the immunoglobulin superfamily and serves as the primary site for ligand binding and intermolecular interactions.[10] Membrane association of the core protein occurs via a glycosylphosphatidylinositol (GPI) anchor covalently linked to the C-terminal glycine residue (position 112) during post-translational processing in the endoplasmic reticulum. This GPI attachment is mediated by a transamidase complex that recognizes a specific cleavage site in the C-terminal hydrophobic signal peptide (typically after a small spacer sequence rich in hydrophobic and charged residues), excising the peptide and transferring the preassembled GPI moiety from phosphatidylinositol, thereby enabling lipid raft localization without requiring a transmembrane or cytoplasmic domain.[23][24] The IgV domain is stabilized by an intramolecular disulfide bond between cysteine residues 38 and 104, which is essential for maintaining the compact beta-sheet architecture characteristic of V-set domains; an additional disulfide (Cys28-Cys130) may form in precursor forms but is not retained in the mature protein.[10] Sequence conservation is high across species, with the human CD90 sharing 66% overall amino acid identity with the mouse ortholog, rising to greater similarity within the conserved IgV domain framework that preserves the structural fold and functional motifs.[23] Glycosylation at multiple asparagine residues substantially increases the molecular mass to 25-37 kDa in the native form.[23]Glycosylation and Modifications
CD90, also known as Thy-1, is a glycoprotein subject to N-linked glycosylation at three asparagine residues in mice (Asn23, Asn74, and Asn98 of the mature protein) and at two sites in humans (Asn23 and Asn74), as the third site is not conserved due to substitution with serine.[25] These modifications account for approximately 30% of the protein's mass, adding 10-15 kDa to the core polypeptide and resulting in an apparent molecular weight of 25-37 kDa observed on SDS-PAGE.[23] The N-glycans are complex-type structures, with variations in processing that influence the protein's electrophoretic mobility and stability. Tissue-specific glycoforms of CD90 exhibit distinct oligosaccharide patterns, particularly between neural (brain) and lymphoid (thymus) sources, despite identical core protein sequences. In brain-derived CD90, the N-glycans at all three sites feature more branched, sialylated structures compared to thymus forms, which show simpler antennae and lower sialylation levels; these differences arise from site-specific variations, such as at Asn74, and contribute to enhanced protein stability and unique antigenicity in neural contexts. For instance, neural glycoforms can carry epitopes like HNK-1, a sulfated glucuronyl motif associated with cell adhesion in the nervous system, which is absent or minimal in thymic variants.[26] Beyond glycosylation, CD90 is anchored to the membrane via a glycosylphosphatidylinositol (GPI) moiety attached at the C-terminus, rendering it sensitive to cleavage by phosphatidylinositol-specific phospholipase C (PI-PLC), which releases the intact protein from the cell surface.[24] No O-linked glycosylation has been reported for CD90 across species.[25] Soluble forms of CD90 are detected in biological fluids, often retaining the GPI anchor and potentially arising from membrane vesicle release or proteolytic shedding mediated by ADAM family metalloproteases, which cleave near the GPI attachment site in various cell types.[1]Expression Patterns
Cellular and Tissue Distribution
CD90, also known as Thy-1, exhibits high expression on thymocytes in mice, though expression is notably lower on human thymocytes and peripheral T cells.[27] It is also highly expressed on mature neurons, particularly along axons, as well as on fibroblasts, mesenchymal stem cells (MSCs), and hematopoietic stem cells, where it serves as a marker for subsets involved in tissue repair and differentiation.[1] In contrast, CD90 expression is low or absent on B cells and hepatocytes across species.[2] In terms of tissue distribution, CD90 is prominently found in the brain, where it is expressed on neurons, particularly in contexts of neural remodeling.[28] It is also detected in the thymus (predominantly in mice), skin (on fibroblasts and during wound healing), and kidney (on interstitial cells).[14][29] Expression patterns of CD90 show significant species variation: in mice, it is more ubiquitous, appearing on thymocytes, peripheral T cells, and many endothelial cells, whereas in humans, distribution is more restricted, with minimal presence on T cells and variable but generally lower expression on most endothelial cells.[23][27] Quantitatively, on thymocytes it approaches 10^6 molecules per cell in rodents, contributing to dense coverage on axonal membranes.[30] Detection of CD90 expression is commonly achieved through flow cytometry using monoclonal antibodies such as F15-42-1, which specifically binds the human CD90 antigen on the cell surface.[31]Regulation of Expression
CD90 (Thy-1) expression is tightly regulated during cellular development, particularly in the immune and nervous systems. In T-cell maturation, Thy-1 levels peak on immature thymocytes, comprising up to 20% of the cell surface area in mice, and are prominently expressed at the CD4+/CD8+ double-positive stage before being downregulated in mature peripheral T cells following activation.[1] This developmental pattern supports Thy-1's role in early thymic selection, with expression inversely correlating with T-cell maturity. Similarly, in neuronal differentiation, Thy-1 mRNA precedes protein upregulation during maturation of rat dorsal root ganglion neurons and mouse Purkinje cells, reaching 2.5-7.5% of axonal protein content in mature neurons to stabilize axonal processes.[1] Transcriptional control of Thy-1 expression involves multiple signaling pathways responsive to environmental cues. In cancer contexts, Notch1 signaling drives Thy-1 expression via the transcription factor HES1, as demonstrated in intrahepatic cholangiocarcinoma where NOTCH1 knockdown reduces HES1 and THY1 levels, correlating with aggressive phenotypes.[32] Cytokines like TGF-β regulate Thy-1 in fibroblasts; TGF-β1 induces promoter hypermethylation, leading to epigenetic silencing and loss of Thy-1 expression, which promotes myofibroblast differentiation in lung fibroblasts.[33] Recent studies (2022-2024) highlight epigenetic mechanisms in fibrotic diseases. In pulmonary fibrosis, Thy-1 promoter hypermethylation silences expression in fibroblastic foci, exacerbating myofibroblast activation, as confirmed in idiopathic pulmonary fibrosis patient samples.[34] In skin fibrosis models, such as scleroderma, Thy-1 expression is upregulated and contributes pathogenically to inflammation and extracellular matrix deposition, with knockout attenuating bleomycin-induced fibrosis.[4] Additionally, miR-29a downregulation in fibrotic models, including corneal scarring, correlates with elevated CD90 levels that enhance fibrotic gene expression.[35]Localization
Subcellular Compartmentalization
CD90, also known as Thy-1, is initially synthesized as a precursor protein in the endoplasmic reticulum (ER), where it undergoes N-linked glycosylation and covalent attachment of a glycosylphosphatidylinositol (GPI) anchor to its C-terminal residue.[36] This GPI anchoring occurs in the ER lumen via a transamidase complex, ensuring the protein's orientation on the outer leaflet of the plasma membrane. Following ER processing, CD90 is transported to the Golgi apparatus, where it receives additional complex glycosylation modifications, including the addition of sialic acid and other sugars, before being sorted to the cell surface via the secretory pathway.[36] Once at the plasma membrane, CD90 exhibits polarized distribution depending on the cell type. In polarized epithelial cells, such as Madin-Darby canine kidney (MDCK) cells, CD90 localizes preferentially to the apical domain, a process directed by dual targeting signals: an intrinsic sequence within the protein moiety and the GPI anchor itself. In neurons, particularly mature hippocampal neurons, CD90 is predominantly axonal, with 80-95% of surface-localized protein confined to axons rather than dendrites, facilitating its role in neuronal polarity. This polarized positioning is maintained through dynamic trafficking, including recycling via endosomal compartments that allow retrieval and redistribution of the protein.[36] CD90 can also be released from the cell surface as a soluble form through enzymatic cleavage of the GPI anchor by phospholipases, such as GPI-specific phospholipase D.[36] This shedding generates circulating soluble CD90 detectable in serum at low nanogram-per-milliliter concentrations. Recent studies have shown elevated serum levels of soluble CD90 in patients with advanced fibrosis in conditions like primary biliary cholangitis (median levels correlating with fibrosis grade, odds ratio 3.762) and metabolic dysfunction-associated steatotic liver disease (odds ratio 10.661), suggesting its potential as a biomarker for fibrotic severity.[37] Additionally, CD90 associates with lipid rafts, cholesterol- and sphingolipid-enriched membrane domains that influence its lateral mobility and compartmentalization.[36]Association with Cellular Structures
CD90, also known as Thy-1, is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein that preferentially localizes to lipid raft microdomains in the plasma membrane due to the lipid nature of its GPI anchor.[38] This enrichment in caveolae-like domains facilitates its association with signaling molecules such as Src family kinases (SFKs), where the GPI anchor is essential for modulating SFK phosphorylation and subcellular localization in response to extracellular cues like thrombospondin-1.[38] Additionally, CD90 co-localizes with integrins, including αvβ3, through conformational coupling that regulates Fyn priming and integrin activation, thereby influencing cell rigidity sensing and adhesion dynamics.[39] CD90 forms complexes with the actin cytoskeleton indirectly through adaptor proteins, linking to ezrin via the Na+/H+ exchanger regulatory factor 1 (EBP50/NHERF1), which connects the CD90/C-terminal Src kinase-binding protein (CBP) complex to ERM (ezrin-radixin-moesin) proteins for cytoskeletal anchoring and signal propagation.[40] In the context of viral infection, CD90 associates with the HIV-1 matrix protein (part of the Gag polyprotein) within lipid rafts at sites of virus budding, where confocal microscopy has shown co-localization of HIV-1 structural proteins with CD90, contributing to virion incorporation of host membrane components.[41] Dynamically, CD90 clusters in cholesterol-rich lipid rafts upon ligand binding, such as to integrins or other extracellular matrix components, which is required to initiate Src-dependent downstream signaling pathways that regulate cellular responses.[42] Recent evidence from 2023 highlights the role of this raft-dependent clustering in promoting cancer cell migration, where CD90 engagement with adhesome components in lipid microdomains facilitates focal adhesion turnover and directional motility in tumor microenvironments.[43]Functions
Nervous System Roles
CD90, also known as Thy-1, plays a critical role in modulating cognitive processes within the nervous system, particularly through its influence on synaptic plasticity in the hippocampus. Studies using Thy-1 knockout mice have demonstrated a selective impairment in long-term potentiation (LTP) in the dentate gyrus, a form of synaptic strengthening essential for memory formation, while LTP in the CA1 region remains unaffected. This regional specificity highlights Thy-1's involvement in regulating excitatory neurotransmission and dendritic spine stability, which are foundational to cognitive functions such as learning and memory consolidation. Although basal spatial learning in water maze tasks appears normal in young Thy-1 knockout mice, the LTP deficit suggests potential vulnerabilities in more complex or aged cognitive paradigms, underscoring Thy-1's modulatory role in hippocampal-dependent cognition. In axon growth and regeneration, Thy-1 acts primarily as an inhibitory signal in the central nervous system (CNS) by binding to β3-containing integrins on astrocytes, thereby restricting neurite outgrowth. This interaction, mediated through Thy-1's RLD motif, triggers the formation of focal adhesions and cytoskeletal rearrangements in astrocytes, which in turn suppress axonal extension via downstream signaling pathways involving RhoA activation and reduced ciliary neurotrophic factor expression. In the context of CNS injury, Thy-1 contributes to the inhibitory environment akin to myelin-associated inhibitors, limiting regenerative potential by promoting a non-permissive glial scar. Conversely, in the peripheral nervous system (PNS), Thy-1 does not elicit similar inhibition on Schwann cells, facilitating axon sprouting and regeneration post-injury, as evidenced by enhanced outgrowth in Thy-1-deficient models or upon antibody blockade.[44] Recent insights from a 2020 review emphasize Thy-1's involvement in mechanotransduction during neuronal differentiation, where it integrates mechanical cues from the extracellular matrix to influence neurite outgrowth and cell fate decisions. Through cis and trans interactions with integrins, Thy-1 facilitates force-dependent signaling that promotes neuronal maturation, highlighting its broader role in adapting neural development to biomechanical contexts. A 2025 study further reveals that neuronal Thy-1 signaling maintains astrocytes in a quiescent state, suppressing reactive gliosis and contributing to neural homeostasis, as evidenced by astrocyte activation in Thy-1 knockout mice.[45][46]Immune System Roles
CD90, also known as Thy-1, plays a significant role in modulating T-cell signaling and activation within the immune system. Crosslinking of CD90 on T cells enhances T-cell receptor (TCR) signaling by associating with Src family kinases such as Lck, Fyn, and Lyn, which initiate downstream tyrosine kinase-dependent pathways.[47] This costimulatory effect promotes T-cell proliferation and cytokine production, particularly interleukin-2 (IL-2), when CD90 is engaged alongside TCR or CD28 stimulation.[48] For instance, antibody-mediated crosslinking of CD90 in the context of CD28 costimulation induces IL-2 synthesis and expression of the high-affinity IL-2 receptor alpha chain (CD25), facilitating T-cell expansion during immune responses.[49] In addition to its pro-activation functions, CD90 ligation can trigger T-cell death, contributing to immune homeostasis. Antibody crosslinking of CD90 on activated T cells, such as in hybridoma models like A1.1, upregulates Fas ligand (FasL) expression, leading to activation-induced cell death (AICD) through the Fas-FasL pathway.[50] This process involves caspase-8 activation at the death-inducing signaling complex (DISC), initiating the caspase cascade that executes apoptosis and prevents excessive T-cell accumulation post-activation.[50] Studies in malignant T-lymphoma cell lines further demonstrate that anti-CD90 antibodies induce apoptosis independently of Bcl-2 upregulation, via sustained elevation of intracellular calcium levels, underscoring CD90's dual role in T-cell survival and demise. CD90 also influences immune pathology in models of glomerulonephritis, where it is expressed on mesangial cells. In rat models of anti-Thy-1 nephritis from the 1990s and 2000s, injection of anti-Thy-1 antibodies (e.g., ER4 monoclonal IgG2a) binds CD90 on glomerular mesangial cells, inducing apoptosis through mechanisms involving phosphatidylserine externalization, DNA fragmentation, and terminal deoxynucleotidyl transferase-mediated labeling.[52] This antibody-dependent cell death mimics aspects of proliferative glomerulonephritis, highlighting CD90's involvement in complement-independent mesangial injury and renal inflammation resolution.[52]Cancer and Fibrosis Roles
CD90, also known as Thy-1, exhibits context-dependent roles in cancer, acting as both a tumor suppressor and promoter. In certain malignancies, CD90 inhibits tumor progression; for instance, in melanoma, blockade of the CD90-αvβ3 integrin interaction on endothelial cells disrupts melanoma cell adhesion and metastasis formation, thereby suppressing tumor spread. Similarly, in nasopharyngeal carcinoma (NPC), CD90 maintains adherens junctions by inhibiting SRC activation, reducing cell invasion and acting as a tumor suppressor, with its downregulation linked to increased metastatic potential. In ovarian cancer, CD90 expression suppresses tumor formation by interacting with β3 integrin, promoting anoikis and inhibiting tumorigenicity. Conversely, high CD90 expression promotes cancer in stem-like cells across various tumors; in hepatocellular carcinoma (HCC), CD90 marks liver cancer stem cells that drive tumor initiation and metastasis through enhanced self-renewal and invasiveness. In glioma, CD90-high glioma-associated mesenchymal stem cells accelerate tumor proliferation, migration, and adhesion, contributing to aggressive progression.[53] A 2022 study on intrahepatic cholangiocarcinoma (iCCA) further links high CD90 expression, regulated by the NOTCH1/HES1 pathway, to poor prognosis and increased tumor aggressiveness.[54] CD90 serves as a key marker for cancer-associated fibroblasts (CAFs), which remodel the tumor microenvironment to support malignancy. In lung adenocarcinoma, Thy-1+ CAFs promote tumor invasion by enhancing extracellular matrix (ECM) deposition and stromal remodeling. Similarly, in prostate and pancreatic cancers, elevated CD90 on CAFs correlates with tumor-stroma interactions that foster progression and metastasis. In fibrotic diseases, CD90 plays a complex role, often with loss of expression driving pathogenesis. In lung fibrosis, Thy-1+ fibroblasts typically exhibit anti-fibrotic properties, but their depletion or transition to Thy-1- states exacerbates ECM accumulation via heightened TGF-β signaling and myofibroblast differentiation. However, in skin fibrosis associated with scleroderma, Thy-1 expression on fibroblasts contributes pathogenically, serving as a biomarker for disease severity and promoting fibrotic remodeling. Soluble Thy-1 reverses established lung fibrosis in preclinical models by binding integrins and inhibiting TGF-β-induced myofibroblast activation, reducing collagen deposition. In advanced fibrosis, a Thy-1- immunofibroblast subpopulation emerges as a dominant pro-fibrotic driver, displaying elevated contractility, ECM production, and immune modulation that perpetuate tissue scarring, as demonstrated in 2024 biomaterial and organ fibrosis studies.Adhesion and Migration Roles
CD90, also known as Thy-1, plays a critical role in cell adhesion through its interactions with integrins such as αvβ3 and α5β1, facilitated by its RLD motif, which mimics the RGD sequence found in extracellular matrix (ECM) proteins. These interactions enable CD90 to bind fibronectin and other ECM components, promoting the formation of focal adhesions in mesenchymal cells like fibroblasts. As a glycosylphosphatidylinositol (GPI)-anchored protein, CD90 exhibits high lateral mobility within lipid rafts of the plasma membrane, allowing dynamic clustering with integrins and enhancing adhesion strength under mechanical stress.[43][55] In cell migration, CD90 regulates the motility of fibroblasts and endothelial cells by modulating focal adhesion kinase (FAK) signaling, which activates downstream pathways like Src/RhoA/ROCK to drive cytoskeletal remodeling and stress fiber assembly. For instance, CD90 engagement with integrins triggers FAK phosphorylation, facilitating force-dependent migration on stiff substrates in non-cancerous mesenchymal contexts. Conversely, CD90 on endothelial cells inhibits leukocyte transmigration during inflammation by serving as a counter-receptor for the αMβ2 integrin (Mac-1), thereby limiting excessive extravasation and maintaining vascular barrier integrity.[43][56][39] CD90 contributes to adhesome complex formation, integrating integrins, syndecan-4, and adaptor proteins like vinculin and paxillin to sense and respond to mechanical forces, thereby modulating force-dependent motility in non-cancer cells such as fibroblasts. This trimolecular complex exhibits catch-slip bond behavior, where applied force prolongs adhesion lifetimes, optimizing migration efficiency. Additionally, CD90 influences lineage commitment in mesenchymal stem cells, promoting osteogenic differentiation while suppressing adipogenic pathways; for example, Thy-1-positive cells favor bone formation over fat accumulation, as evidenced by enhanced mineralization and reduced lipid droplet formation in differentiation assays.[43][57]Applications
Stem Cell Marker
CD90, also known as Thy-1, serves as a key cell surface marker for identifying and isolating various stem cell populations, including mesenchymal stem cells (MSCs), hematopoietic progenitors, and neural stem cells. In MSCs derived from bone marrow, adipose tissue, or other sources, CD90 is consistently expressed alongside markers like CD73 and CD105, facilitating their characterization and enrichment via fluorescence-activated cell sorting (FACS). For hematopoietic stem cells, CD90 is particularly useful in combination with CD34 to identify primitive progenitors, such as the CD34+CD90+ subset, which exhibits long-term repopulating potential in transplantation assays. Similarly, CD90 marks neural stem cells isolated from post-mortem human brain tissue, where it correlates with high expression of other progenitor markers like CD133 and CD29. FACS-based sorting of CD90-high (CD90hi) subpopulations has been shown to enrich for multipotent stem cell subsets with enhanced differentiation capacity. In murine adipose-derived stem cells (ADSCs), CD90hi cells demonstrate superior osteogenic potential compared to CD90-low counterparts, supporting their use in tissue engineering applications. Functionally, CD90 regulates stem cell differentiation by promoting osteogenic lineage commitment while inhibiting adipogenesis. Studies using Thy-1-deficient mouse models revealed that loss of CD90 leads to reduced osteoblast differentiation and increased adipocyte formation in MSCs, highlighting its role in balancing bone and fat tissue homeostasis. These findings, from experiments conducted in 2018, were corroborated in a 2019 review emphasizing CD90's inhibitory effect on adipogenic pathways through modulation of signaling cascades like Wnt/β-catenin. Additionally, CD90 enhances the reprogramming efficiency of ADSCs into induced pluripotent stem cells (iPSCs); selection of CD90hi ADSCs in 2013 increased iPSC colony formation rates by up to twofold compared to unsorted populations, an observation reaffirmed in subsequent citations through the 2020s. Recent research has identified CD90 low glioma-associated MSCs as potent promoters of tumor progression, where low CD90 expression drives glioma cell proliferation, migration, and adhesion via paracrine signaling such as IL-6 secretion.[58] In iPSCs, Thy-1 expression influences lineage bias, with elevated levels favoring mesenchymal or osteogenic differentiation pathways during directed differentiation protocols. CD90 is also expressed on stem-like cancer cells across multiple tumor types, contributing to their self-renewal and therapeutic resistance.Therapeutic Targeting
CD90, also known as Thy-1, has emerged as a promising therapeutic target in fibrotic diseases due to its expression on activated fibroblasts and myofibroblasts that drive excessive extracellular matrix deposition. In experimental models of glomerulonephritis, anti-CD90 monoclonal antibodies (mAbs) have been employed to deplete Thy-1-positive fibroblasts and mesangial cells, reducing glomerular inflammation and fibrosis; for instance, the OX-7 clone induces targeted apoptosis in these cells, attenuating disease progression in rat models that mimic human mesangioproliferative glomerulonephritis. This approach highlights the potential of CD90-directed antibodies for selective fibroblast elimination in renal fibrotic conditions, though clinical translation requires addressing off-target effects on immune and neuronal cells.[59][60] Beyond depletion strategies, CD90 modulation offers anti-fibrotic benefits through soluble Thy-1 delivery, which competes with membrane-bound forms to inhibit integrin-mediated fibroblast activation. In preclinical lung fibrosis models, intratracheal administration of recombinant soluble Thy-1 reversed established fibrosis by binding αvβ3/αvβ5 integrins, suppressing TGF-β signaling, and promoting myofibroblast apoptosis without toxicity; this effect was integrin-dependent, as mutants lacking the binding motif failed to resolve fibrosis. Recent studies referencing this mechanism in 2024 underscore its relevance for idiopathic pulmonary fibrosis therapies, positioning soluble Thy-1 as a non-immunogenic alternative to mAbs for systemic anti-fibrotic delivery.[61][62] In oncology, CD90 serves as a marker for cancer stem-like cells (CSCs), enabling targeted immunotherapies against aggressive tumors. For hepatocellular carcinoma (HCC), CD90-targeted antibody-drug conjugates (ADCs) and nanoparticle-delivered cytotoxins have demonstrated selective elimination of CD90+ CSCs, reducing tumor initiation and metastasis in xenograft models. Similarly, in intrahepatic cholangiocarcinoma (iCCA), inhibition of the NOTCH1-HES1-CD90 axis using gamma-secretase inhibitors suppresses CD90 expression on tumor cells, impairing stemness and aggressiveness; high NOTCH-CD90 levels correlate with poor prognosis, suggesting combined NOTCH blockade and CD90 targeting for improved outcomes.[63][64][65] As of 2025, CD90 is gaining traction as a prognostic biomarker in fibrotic diseases, particularly for skin and lung conditions, where elevated soluble or membrane-bound levels predict progression and response to antifibrotics. In systemic sclerosis models, CD90+ fibroblast subsets indicate severe skin fibrosis and worse survival, while in idiopathic pulmonary fibrosis, low Thy-1 expression on lung fibroblasts forecasts rapid decline; circulating soluble Thy-1 inversely correlates with fibrosis severity in chronic kidney disease, offering a non-invasive monitoring tool. Therapeutic challenges include CD90 shedding, which reduces mAb efficacy by creating decoy targets, and isoform variability (e.g., glycosylated vs. non-glycosylated forms), complicating binding specificity and necessitating isoform-selective agents for optimal targeting.[66][67][68]References
- https://doi.org/10.1002/(SICI)1097-0215(19960516)66:4<544::AID-IJC20>3.0.CO;2-6