41 results about "Tgfβ signalling" patented technology

The present invention includes the selection and isolation of thioaptamers that target the signaling protein TGF-β1, compositions of such thioaptamers and the use of such thioaptamers to either block or enhance signal transduction of the TGF-β1 protein and thus function as, e.g., immunomodulatory agents. Thioaptamers may also be targeted alone or in combination with other thioaptamers against the ligand, the receptors, the ligand trap protein(s) and / or the co-receptors to modulate TGF-β signaling pathway.

Various human monoclonal antibodies that bind to human TGF-β type II receptor to inhibit the signal transduction of human TGF-β signal into cells are produced by immunizing human antibody-producing transgenic mice generated by genetic engineering techniques with the soluble human TGF-β type II receptor. Further, these human monoclonal antibodies were demonstrated to be effective for preventing and treating various diseases induced by human TGF-β in various organs (for example, tissue fibrosis).

Disclosed herein is a method for developing human endothelial cells (ECs) from human embryonic stem cells (ESCs). The method is based on inhibition of TGF signaling following mesoderm induction and during vascular differentiation of hESC-derived cells. Also disclosed herein is a substantially pure and stable population of ECs that maintains a high degree of proliferation and phenotypic homogeneity for extended culture periods. Related pharmaceutical compositions and therapeutic methods are also disclosed. A reporter hESC line useful for tracking the development of ECs is also provided.

The combined use of a TGF-β signaling inhibitor and an antitumor active substance or an imaging agent modified by a drug-encapsulating macromolecular micelle, or the like, is provided. The selective delivery capability of the antitumor active substance or the imaging agent to the target is improved, increasing the antitumoral activity in the target.

The present invention relates to a composition for inhibiting fibrosis and more specifically, to a composition for inhibiting fibrosis, wherein the composition is effective in inhibiting fibrosis of tissue cells by containing a peptide derived from telomerase. The peptide according to the present invention exhibits an effect of inhibiting the progression of various kinds of fibrosis, including fibrosis due to occurrence of cancer, fibrosis due to the administration of chemotherapy anticancer drugs, fibrosis due to the exposure to radiation, or progressive fibrosis of tissues, including a TGF-β signaling procedure, and thus can provide a composition for anti-fibrosis or inhibiting fibrosis and a method for treating diseases due to fibrosis.

The present invention provides a method of producing more mature telencephalon or a progenitor tissue thereof, in vitro, from mammalian pluripotent stem cells, comprising obtaining a telencephalon marker-positive aggregate by culturing an aggregate of pluripotent stem cells in suspension in the presence of a Wnt signal inhibitor and a TGFβ signal inhibitor, and further culturing the telencephalon marker-positive aggregate in suspension under a high oxygen partial pressure condition. In one embodiment, the suspension culture under a high oxygen partial pressure condition is performed in the presence of a Wnt signal enhancer and a bone morphogenetic factor signal transduction pathway activating substance.

This disclosure demonstrates that blockade of TGFβ signaling after a hematopoietic stress (e.g., chemotherapy, transplantation, and infection) accelerates hematopoietic reconstitution and delays the return of cycling hematopoietic stem and progenitor cells (HSPCs) to quiescence. TGFβ blockade in these settings promotes multilineage hematopoietic regeneration by prolonging HSPC cycling and by promoting HSC self-renewal, and is useful for treating hematologic deficiencies caused various hematopoietic stresses.

This invention relates to peptide molecules and compounds which are negative regulators of TGFβ signaling, particularly of TβR-I kinase activity. The invention further relates to methods of using such peptides and compounds in the treatment of disease.

The methods and compositions described herein relate to producing, expanding, enriching, and / or maintaining hematopoietic stem cells ex vivo by treating the cells with an agent(s) that exhibits two or more activities selected from modulation of histone methylation; inhibition of TGFβ signaling; inhibition of p38 signaling; activation of canonical Wnt signaling; and modulation of histone acetylation. In some embodiments, the technology described herein relates to transplantation of hematopoietic stem cells.

The present disclosure provides methods and kits for the differentiation of stem cells into relevant liver cell lineages, as well as methods of using the relevant liver cell lineages in screening for a cellular response, a phenotype and in the treatment of a condition. In one embodiment, stem cells are first differentiated into cells of the definitive endoderm lineage, which are differentiated into posterior foregut (PFG) lineage cells by one or more of retinoic acid activators and / or one or more inhibitors of transforming growth factor-β (TGFβ). An additional embodiment provides a method for the differentiation of posterior foregut lineage cells into liver bud progenitors (LB) by one or more activators of TGFβ signalling, and / or one or more modulators of Wnt signalling, and / or one or more activators of cyclic AMP / PKA signaling; and a further embodiment provides a method for the differentiation of liver bud progenitors into hepatic progenitors by one or more inhibitors of TGFβ signalling and / or fibroblast growth factor (FGF) inhibitors and / or one or more Notch inhibitors. Another embodiment discloses the differentiation of hepatic progenitors into hepatocyte-like cells or perivenous hepatocyte-like cells by one or more of Notch inhibitors and / or activators of glucocorticoid signalling and / or one or more activators of insulin signalling and / or one or more of ascorbic acid signalling activators and / or additional factors. Methods and kits for maintaining LB in self renewal state, hepatocyte-like cells in perivenous or periportal state, as well as surface markers for LB and mid / hindgut (MHG) cells are also disclosed.

The present invention provides a treatment drug or prophylactic drug for diseases, disorders, or conditions related to endoplasmic reticulum (ER) stress. Specifically, the present invention provides a treatment drug or prophylactic drug for diseases, disorders, or conditions related to endoplasmic reticulum (ER) stress in the corneal epithelium, the drug containing a TGFβ-signal inhibitor. As a preferred TGFβ-signal inhibitor, the drug contains 4-[4-(1,3-benzodioxole-5-yl)-5-(2-pyridinyl)-1H-imidazole-2-yl]benzamide.

The present invention relates to a composition for inhibiting fibrosis and more specifically, to a composition for inhibiting fibrosis, wherein the composition is effective in inhibiting fibrosis of tissue cells by containing a peptide derived from telomerase. The peptide according to the present invention exhibits an effect of inhibiting the progression of various kinds of fibrosis, including fibrosis due to occurrence of cancer, fibrosis due to the administration of chemotherapy anticancer drugs, fibrosis due to the exposure to radiation, or progressive fibrosis of tissues, including a TGF-β signaling procedure, and thus can provide a composition for anti-fibrosis or inhibiting fibrosis and a method for treating diseases due to fibrosis.

Methods of inhibiting metastasis in cancer patients are provided, wherein the methods comprise reducing TGFβ signaling, for example, by reducing TGF receptor II expression in myeloid cells. Vectors comprising a TGFβ receptor II RNAi nucleic acid sequence operably linked to a myeloid specific promoter also are provided. A method of diagnosing cancer in an individual by determining TGFβ receptor II expression in myeloid cells in the individual is provided. Additionally, a method of modulating TGFβ activity in myeloid cells in a cancer patient comprising administering a regulator of at least one of the GSK3 and PI3K pathways to the patient is provided.

The present invention provides a method for producing iPS cells, comprising reacting cells with at least one connexin inhibitor and at least one TGFβ signaling inhibitor; iPS cells comprising at least one connexin inhibitor; an iPS cell inducer comprising at least one inhibitor selected from the group consisting of connexin inhibitors and TGFβ signaling inhibitors; a medium for inducing iPS cells, comprising at least one inhibitor selected from the group consisting of connexin inhibitors and TGFβ signaling inhibitors; and a kit for inducing iPS cells, comprising at least one inhibitor selected from the group consisting of connexin inhibitors and TGFβ signaling inhibitors.

Described herein are compositions and methods for enhancing peripheral macrophage Aβ phagocytosis activity. The methods include inhibiting the TGF-β signaling pathway and activating the BMP signaling pathway in peripheral macrophages to promote central nervous system infiltration and enhance macrophage Aβ phagocytosis activity. Inhibition of TGF-β signaling and activation of BMP signaling in peripheral macrophages represents an advantageous anti-amyloid therapeutic approach for Alzheimer's disease.

The present invention discloses a neural induction medium comprising Wnt-signal agonist, TGFβ-signal inhibitor and FGF-signal agonist for inducing neural differentiation. The neural induction medium used in a culture system is capable for inducing the neural differentiation of stem cells into neuroepithelial cells which are useful for the clinical applications. Therein, the neuroepithelial cells can further differentiate into mature neurons for the practical applications including regeneration medicine and drug discovery for neural disorders.

The methods and compositions described herein relate to producing, expanding, enriching, and / or maintaining hematopoietic stem cells ex vivo by treating the cells with an agent(s) that exhibits two or more activities selected from modulation of histone methylation; inhibition of TGFβ signaling; inhibition of p38 signaling; activation of canonical Wnt signaling; and modulation of histone acetylation. In some embodiments, the technology described herein relates to transplantation of hematopoietic stem cells.

The present invention discloses cell permeable RUNX3 recombinant proteins where a Macromolecule Transduction Domain (MTD) is fused to a tumor and metastasis suppressor RUNX3. Also disclosed are polynucleotides encoding the cell permeable RUNX3 recombinant proteins, an expression vector containing the cell permeable RUNX3 recombinant protein, and a pharmaceutical composition for preventing metastasis which contains the cell permeable RUNX3 recombinant protein as an effective ingredient. The cell permeable RUNX3 recombinant proteins of the present invention can induce the reactivation of TGF-β signal transduction pathway which causes cell cycle arrest by efficiently introducing a tumor and metastasis suppressor RUNX3 into a cell. Therefore, the cell permeable RUNX3 recombinant proteins of the present invention can be effectively used as an anticancer agent capable of preventing cancer growth and metastasis by suppressing the proliferation, differentiation, and migration of cancer cells.

Provided is a drug or method for treating or preventing a condition, disorder, or disease of the corneal endothelium caused by transforming growth factor-β (TGF-β) signals, mitochondrial abnormalities, and / or endoplasmic reticulum (ER) associated stress in corneal endothelial cells, using p38 MAP kinase inhibitors. The present invention provides a drug which includes p38 MAP kinase inhibitors, and which is for treating or preventing a condition, disorder, or disease of the corneal endothelium caused by TGF-β signals and / or mitochondrial abnormalities in corneal endothelial cells. In the preferred embodiment, the condition, disorder, or disease of the corneal endothelium is Fuchs' corneal endothelial dystrophy.

The present invention provides a method for producing a human cell aggregate containing a midbrain-hindbrain boundary neural progenitor tissue, including subjecting an aggregate of human pluripotent stem cells to suspension culturing in a serum-free medium containing insulin, and treating, in the suspension culturing, the aggregate of human pluripotent stem cells or a human cell aggregate derived therefrom with a ROCK inhibitor, a TGFβ signal inhibitor, and a first fibroblast growth factor. Furthermore, the human cell aggregate containing the midbrain-hindbrain boundary neural progenitor tissue is subjected to suspension culturing in a serum-free medium to induce formation of a neuroepithelial structure by neural progenitor in the neural progenitor tissue, whereby the human cell aggregate containing the cerebellar plate tissue can be obtained.

Disclosed herein are methods for generating dopaminergic neurons in vitro by inhibiting a pathway component of a TGF-β signaling pathway and overexpressing one or more cell fate-inducing polypeptides in pluripotent cells, causing differentiation of the pluripotent cells into dopaminergic neurons. Also disclosed are methods for treating a neurodegenerative disease in a patient by generating dopaminergic neurons in vitro, and transplanting them into the brain of the patient, such that the dopaminergic neurons are sufficient to reduce or eliminate the symptoms of the neurodegenerative disease.

Described herein are methods and compositions relating to expanding, enriching, and / or maintaining a population of hematopoietic stem cells ex vivo. In some embodiments, the methods and compositions can relate to a combination of two or more agents, e.g., an agent that increases the expression of a Notch target gene; an agent that activates a ubiquitin ligase complex comprising cereblon; a compound that inhibits BMP signaling; a modulator of histone methylation; an inhibitor of TGFβ signaling; an inhibitor of p38 signaling; an activator of canonical Wnt signaling; a modulator of histone acetylation; a compound represented by formula (1); an aryl hydrocarbon receptor inhibitor; a histone demethylase inhibitor; a TGFβ receptor inhibitor; a compound that inhibits a protein that propagates p38 signaling; a compound that inhibits a protein that promotes β-catenin degradation; a histone deacetylase inhibitor; Prostaglandin; an agonist of Notch signaling; an inhibitor of SIRT1; UM171; and / or a compound listed in Table 1.

In some aspects, the invention provides a method of treating atherosclerosis in a subject. The method comprises administering to the subject an agent that increases the activity or level of a let-7 miRNA or an agent that decreases activity or level of a TGFβ signaling polypeptide in an endothelial cell in the subject. In some embodiments, the subject is administered an additional agent comprising a therapeutically effective amount of rapamycin or any derivative thereof. In some embodiments, the agent is a let-7 miRNA. In some other aspects, the invention provides a pharmaceutical composition comprising a let-7 miRNA. In some embodiments, the let-7 miRNA is encapsulated in a nanoparticle formulated for selective delivery to an endothelial cell.

The present invention provides a method of producing more mature telencephalon or a progenitor tissue thereof, in vitro, from mammalian pluripotent stem cells, comprising obtaining a telencephalon marker-positive aggregate by culturing an aggregate of pluripotent stem cells in suspension in the presence of a Wnt signal inhibitor and a TGFβ signal inhibitor, and further culturing the telencephalon marker-positive aggregate in suspension under a high oxygen partial pressure condition. In one embodiment, the suspension culture under a high oxygen partial pressure condition is performed in the presence of a Wnt signal enhancer and a bone morphogenetic factor signal transduction pathway activating substance.

Provided is a cocktail of factors for converting / reprogramming non-naïve pluripotent stem cells into TGFβ signaling-independent (TSI) naïve induced pluripotent stem cells (iPSCs). Also provided are methods for reprograming a non-naïve PSC into a TSI naïve iPSC by contacting the cell to be reprogrammed with effective amounts of compounds for a sufficient period of time to reprogram the cell into a TSI naïve iPSC.

In some aspects, the invention provides a method of treating atherosclerosis in a subject. The method comprises administering to the subject an agent that increases the activity or level of a let-7 miRNA or an agent that decreases activity or level of a TGFβ signaling polypeptide in an endothelial cell in the subject. In some embodiments, the subject is administered an additional agent comprising a therapeutically effective amount of rapamycin or any derivative thereof. In some embodiments, the agent is a let-7 miRNA. In some other aspects, the invention provides a pharmaceutical composition comprising a let-7 miRNA. In some embodiments, the let-7 miRNA is encapsulated in a nanoparticle formulated for selective delivery to an endothelial cell.

The present invention provides a method for producing iPS cells, comprising reacting cells with at least one connexin inhibitor and at least one TGFβ signaling inhibitor; iPS cells comprising at least one connexin inhibitor; an iPS cell inducer comprising at least one inhibitor selected from the group consisting of connexin inhibitors and TGFβ signaling inhibitors; a medium for inducing iPS cells, comprising at least one inhibitor selected from the group consisting of connexin inhibitors and TGFβ signaling inhibitors; and a kit for inducing iPS cells, comprising at least one inhibitor selected from the group consisting of connexin inhibitors and TGFβ signaling inhibitors.

The present invention relates to a pharmaceutical composition for the prevention or treatment of CFC (cardiofaciocutaneous) syndrome comprising a TGF-β signaling pathway inhibitor or a BMP signaling pathway activator. The treatment of SB-431542 or BMP4 protein was confirmed to increase the ALP activity and bone mineral deposition in the osteoblasts originated from the induced pluripotent stem cells derived from CFC syndrome patients. Thus, the TGF-β signaling pathway inhibitor containing SB-431542 or the BMP signaling pathway activator containing BMP4 protein can be effectively used for the prevention or treatment of CFC syndrome.

Methods of inhibiting metastasis in cancer patients are provided, wherein the methods comprise reducing TGFβ signaling, for example, by reducing TGFβ receptor II expression in myeloid cells. Vectors comprising a TGFβ receptor II RNAi nucleic acid sequence operably linked to a myeloid specific promoter also are provided. A method of diagnosing cancer in an individual by determining TGFβ receptor II expression in myeloid cells in the individual is provided. Additionally, a method of modulating TGFβ activity in myeloid cells in a cancer patient comprising administering a regulator of at least one of the GSK3 and PI3K pathways to the patient is provided.