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WO2016060520A1 - Composition pour la différenciation de cellules souches en cellules précurseurs neurales et procédé d'utilisation associé - Google Patents

Composition pour la différenciation de cellules souches en cellules précurseurs neurales et procédé d'utilisation associé Download PDF

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WO2016060520A1
WO2016060520A1 PCT/KR2015/010983 KR2015010983W WO2016060520A1 WO 2016060520 A1 WO2016060520 A1 WO 2016060520A1 KR 2015010983 W KR2015010983 W KR 2015010983W WO 2016060520 A1 WO2016060520 A1 WO 2016060520A1
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cells
composition
hdac
stem cells
inhibitor
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Korean (ko)
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황동연
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Industry Academic Cooperation Foundation of College of Medicine Pochon CHA University
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Industry Academic Cooperation Foundation of College of Medicine Pochon CHA University
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0603—Embryonic cells ; Embryoid bodies
    • C12N5/0606—Pluripotent embryonic cells, e.g. embryonic stem cells [ES]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/115—Aptamers, i.e. nucleic acids binding a target molecule specifically and with high affinity without hybridising therewith ; Nucleic acids binding to non-nucleic acids, e.g. aptamers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0618—Cells of the nervous system
    • C12N5/0619—Neurons
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0618—Cells of the nervous system
    • C12N5/0623—Stem cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/16—Aptamers

Definitions

  • a composition for differentiating stem cells into neural progenitor cells and a method using the same is provided.
  • hESCs human embyonic stem cells
  • hiPSCs human induced pluripotent stem cells
  • hESCs differentiate into specific cells or tissues
  • the hESCs aggregate together to form an embryoid body (EB) and then differentiate into cells or tissues.
  • EB embryoid body
  • NPCs neural precursor cells
  • EBs rounded cell embryos
  • the embryos are attached to the bottom of the culture vessel and adhered to the neural progenitor cells while adherent culture.
  • compositions for differentiation of stem cells into neural progenitor cells are provided.
  • One aspect provides a composition for differentiation of stem cells into neural precursor cells (NPCs) comprising inhibitors of histone deacetylases (HDACs).
  • NPCs neural precursor cells
  • HDACs histone deacetylases
  • the HDAC can be, for example, HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, HDAC11, Sirtuin, Sir2, or a combination thereof.
  • the inhibitor may be an HDAC protein activity inhibitor or an HDAC gene expression inhibitor.
  • HDAC protein activity inhibitors are also called histone deacetylase inhibitors (HDAC inhibitors; HDIs) and can be, for example, small molecule compounds, anti-HDAC antibodies or antigen binding fragments thereof.
  • the small molecule compounds are for example 4- (dimethylamino) -N- [6- (hydroxyamino) -6-oxohexyl] -benzamide, FK228, MS275, RG2833, CI994, ITF2357, Droxinostat, MC1568, SB939, ACY1215, PCI34051, SB939, JNJ-26481585, JNJ-26481585, or a combination thereof.
  • the HDAC gene expression inhibitor may be, for example, a chemical compound, an antisense oligonucleotide specific for HDAC, a small interfering RNA (siRNA), an aptamer, or a combination
  • stem cell refers to a totipotent cell, a pluripotent cell, or a multipotent cell, which can differentiate into any kind of cell.
  • Stem cells can be differentiated into cells of a specific tissue as undifferentiated cells.
  • Stem cells may be embryonic stem cells (ESCs), adult stem cells, or induced pluripotent stem cells (iPSCs).
  • the embryonic stem cells are cultured in vitro by extracting the inner cell mass from the blastocyst embryo just before the fertilized egg implants in the mother's uterus.
  • the adult stem cells are undifferentiated cells in which only a very small amount is present in each tissue of the body and refers to cells that replace dead cells or damaged tissues.
  • the induced pluripotent stem cell refers to a cell which induces pluripotency, such as an embryonic stem cell, by injecting a cell differentiation-related gene into a differentiated somatic cell and returning it to a cell stage before differentiation.
  • the induced pluripotent stem cells may be, for example, human feeder free-iPSCs (hFF-iPSCs) or urine-iPSCs.
  • the neural progenitor cell refers to a cell having a marker factor of neural progenitor cells and capable of producing various neuronal cells after differentiation.
  • pluripotent stem cells can be differentiated into certain types of progenitor cells (e.g., neural progenitor cells), and then to specific cells (e.g., neurons, glial cells, etc.). Can be.
  • progenitor cells e.g., neural progenitor cells
  • specific cells e.g., neurons, glial cells, etc.
  • the composition may further include insulin, transferrin, sodium selenite, or a combination thereof.
  • Insulin is a peptide hormone secreted from ⁇ cells on the islet of Langerhans.
  • Transferrin is a type of ⁇ globulin that binds to two molecules of trivalent iron ions absorbed in the serum, and is an iron transporting protein that supplies iron necessary for cell proliferation or hemoglobin production to cells through transferrin receptors.
  • Sodium selenite is an inorganic compound having the formula Na 2 SeO 3 .
  • the composition may be a medium.
  • the composition may further include, for example, Dulbecco's Modified Eagle Medium (DMEM) medium, Ham's F12 medium, glutamine, or a combination thereof.
  • DMEM Dulbecco's Modified Eagle Medium
  • Another aspect provides the step of culturing stem cells in the presence of HDAC inhibitors to differentiate stem cells into neural progenitor cells.
  • the stem cells, HDACs, HDAC inhibitors, neural progenitor cells, and differentiation are as described above.
  • the stem cells can be cultured in the presence of an inhibitor at a final concentration of 0.01 nM to 3 ⁇ M, 0.1 nM to 2 ⁇ M, or 0.2 to 1 ⁇ M.
  • the method can be cultured in an attachment culture in which the stem cells are attached to the bottom of the culture dish and cultured.
  • stem cells may form an embryoid body, which is a cell mass formed by agglomerating balls in the early stage of cell division. Therefore, it may not form an embryo.
  • the method may culture stem cells in a culture dish in which polypeptide is immobilized to attach and culture the stem cells to the culture dish.
  • the polypeptide may be a single protein or protein complex.
  • the single protein can be, for example, vitronectin.
  • the protein complex may be MATRIGEL TM (BD Biosciences).
  • the method may culture the stem cells in the presence of additional insulin, transferrin, sodium selenite, or a combination thereof.
  • additional insulin transferrin, sodium selenite, or a combination thereof.
  • insulin, transferrin, sodium selenite, or a combination thereof may be included in the stem cell culture medium.
  • the incubation time of stem cells may vary depending on the culture conditions.
  • stem cells can be cultured for example for 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days.
  • the method may further comprise differentiating differentiated neural progenitor cells into nervous system cells.
  • Differentiating neural progenitor cells into neural cells may be performed by methods known in the art.
  • differentiated neural progenitor cells can be cultured in the presence of basic fibroblast growth factor (bFGF) to differentiate neural progenitor cells into neuronal cells.
  • the nervous system cell may be a nerve cell or a glioma cell.
  • Neurons, also called neurons are cells that transmit stimulation and excitement of the nervous system.
  • Glial cells refer to cells that supply substances necessary for nerve cells and create a chemical environment suitable for the activity of nerve cells.
  • the glial cells may be, for example, astrocytes, oligoendrocytes, microglia, ependymal cells, or Schwann cells.
  • a composition for differentiating stem cells into neural progenitor cells and a method of using the same may be used as a composition for treating brain or neurological diseases.
  • the composition may be a cell therapy.
  • the brain or nervous system diseases include Parkinson's disease, neuralgia, arthritis, headache, schizophrenia, epilepsy, stroke, insomnia, dementia, depression, dyskinesia, Alzheimer's disease, lewy body dementia, Lou Gehrig's disease, multiple sclerosis ), Multiple system atrophy, Huntington's disease, Tourette's syndrome, anxiety, learning and memory impairment, various neurodegenerative disorders, bipolar disorder, autism, attention deficit hyperactivity disorder And diseases that appear in the brain or nervous system due to reduced or abnormal function of the nervous system such as ADHD).
  • composition for differentiation of stem cells into neural progenitor cells comprising an HDAC inhibitor according to one aspect and a method of using the same, it is possible to efficiently differentiate into neural progenitor cells in a short time without forming embryoid bodies from the stem cells.
  • FIG. 1 is a schematic diagram of induction of differentiation into neural progenitor cells by attaching and cultured hPSC in the presence of HDAC isotype inhibitors.
  • FIG. 2 is a graph showing the results of flow cytometry showing the percentage (%) of cells expressing Sox1, which is a neural precursor cell when hESCs were differentiated in the presence of HDAC isotype inhibitors.
  • Figure 3 is a schematic diagram of induction of differentiation into neural progenitor cells by attaching and cultured hPSC in the presence of HDAC isotype-specific siRNA
  • Figure 4 is the HDAC mRNA for siRNA when hESC is cultured in the presence of siRNA specific to HDAC This graph shows the relative amounts.
  • FIG. 5 is a graph showing the results of flow cytometry showing the percentage (%) of cells expressing Sox1 in hPSCs cultured in the presence of siRNA that inhibits the expression of HDAC1 or HDAC4. A random sequence siRNA was used as a negative control.
  • HDAC histone deacetylase
  • HDAC isotype-specific inhibitors (Selleck Chemicals, Huston, TX, USA) of Table 1 dissolved in DMSO (Sigma-Aldrich) were added to the cell culture, and hESC was added at 5 ° C. and 5% CO 2 . Incubated for days. The dose was administered at least an IC 50 value or more within the range where no cytotoxicity was observed for each HDAC isotype to be inhibited. For example, CI994 was administered at 1 ⁇ M with 1 ⁇ M of HDAC1 and 2, while the IC 50 was 1.2 ⁇ M of HDAC3 with minimal effect. In addition, Droxinostat was treated with 2 ⁇ M to suppress HDAC8 but less effect on HDAC6, so that Droxinostat was treated with 2 ⁇ M.
  • DMSO Sigma-Aldrich
  • HDAC Isotype HDAC Inhibitors IC 50 Dosage HDAC 1,2,3 CI994 HDAC1: 0.57 ⁇ M HDAC2: 0.9 ⁇ M HDAC3: 1.2 ⁇ M 1 ⁇ M HDAC 6 and 8 Droxinostat HDAC6: 2.47 ⁇ M HDAC8: 1.46 ⁇ M 2 ⁇ M HDAC 4,5,7,9 MC1568 220 nM 300 nM HDAC 6 Rocilinostat (ACY1215) (selective inhibitor) 5 nM 20 nM HDAC 8 PCI34051 (Selective Inhibitor) 10 nM 20 nM
  • Example 1.1 flow cytometry was performed to confirm whether the cells cultured in the presence of HDAC isotype inhibitors were neural progenitor cells.
  • differentiated cells in the presence of HDAC isotype specific inhibitors in Example 1.1 were added to one well of a 12 well plate and accutase (Life Technologies) was added. Incubate for 5 minutes to make the cells single cells, then centrifuge (200xg, 5 minutes) to obtain the cells, add 2% (v / v) paraformaldehyde (Sigma-Aldrich) to the cells and at room temperature Cells were fixed by incubation for minutes.
  • HDAC1 inhibitors As a result of the flow cytometry, the percentage (%) of cells expressing Sox1 in cells cultured in the presence of HDAC isotype inhibitors is shown in FIG. 2. As shown in FIG. 2, it was confirmed that HDAC1 inhibitors, HDAC2 inhibitors, HDAC6 inhibitors, and HDAC11 inhibitors induce differentiation into Sox1 + cells (HDAC1 inhibitors: 71.7%, HDAC2 inhibitors: 85.2%, HDAC6 inhibitors: 43% , HDAC11 inhibitor: 58.3%).
  • Example 2 Histone Deacetylase About siRNA Human pluripotency when administered Stem cells Confirmation of whether induction of differentiation into neural progenitor cells under adherent culture conditions
  • siRNA small interfering RNA
  • siRNA was administered to hESCs to inhibit the expression of HDAC1 or HDAC4. Random polynucleotide sequences were used as negative controls.
  • Negative control sense strand 5'-agcguguagcuagcagaggtt-3 '(SEQ ID NO: 1)
  • HDAC1 siRNA sense strand 5'-gcuucaaucuaacuaucaatt-3 '(SEQ ID NO: 3)
  • HDAC4 siRNA sense strand 5'-agcguguagcuagcagaggtt-3 '(SEQ ID NO: 5)
  • siRNA and Visufect samples for delivering them into cells were prepared by Serin Bioscience, Inc. (Seolin Bioscience, seongnam, Korea).
  • hESCs were prepared as described in Example 1.1, and hESCs were incubated for 5 days at 37 ° C. and 5% CO 2 . As shown in FIG. 3, the prepared siRNA was added to the culture medium once every 24 hours while hESC was incubated (arrow; siRNA addition).
  • the amount of target mRNA was confirmed by quantitative RT-PCR (qRT-PCR) method.

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Abstract

L'invention concerne une composition contenant un inhibiteur d'histone désacétylase, pour différencier des cellules souches en des cellules associé. Ainsi, la différenciation en cellules précurseurs neurales peut être efficacement réalisée en peu de temps, sans formation d'un corps embryoïde à partir des cellules souches.
PCT/KR2015/010983 2014-10-16 2015-10-16 Composition pour la différenciation de cellules souches en cellules précurseurs neurales et procédé d'utilisation associé Ceased WO2016060520A1 (fr)

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KR1020140140159A KR101660450B1 (ko) 2014-10-16 2014-10-16 줄기 세포의 신경 전구 세포로의 분화용 조성물 및 이를 이용한 방법

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018184267A1 (fr) * 2017-04-07 2018-10-11 东南大学 Nanocorps codé par arnm et son application
CN110734924A (zh) * 2019-10-25 2020-01-31 山东大学第二医院 一种抑郁症检测、治疗和预后靶点及应用
WO2024113351A1 (fr) * 2022-12-02 2024-06-06 Nuwacell Biotechnologies Co., Ltd. Milieu de culture, matrice de revêtement et procédé de maturation de cellules progénitrices dopaminergiques du mésencéphale

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KR20130085767A (ko) * 2012-01-20 2013-07-30 고려대학교 산학협력단 유전자 도입 없이 직접적 역분화를 통해 체세포로부터 신경상피세포 및 신경줄기세포를 유도하는 방법

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KR20130085767A (ko) * 2012-01-20 2013-07-30 고려대학교 산학협력단 유전자 도입 없이 직접적 역분화를 통해 체세포로부터 신경상피세포 및 신경줄기세포를 유도하는 방법

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SCHWECHTER, BRANDON R. ET AL.: "Histone deacetylase inhibition-mediated differentiation of RGC-5 cells and interaction with survival", INVESTIGATIVE OPHTHALMOLOGY AND VISUAL SCIENCE, vol. 48, no. 6, 2007, pages 2945 - 2857 *
SIEBZEHNRUBL, FLORIAN A. ET AL.: "Histone deacetylase inhibitors increase neuronal differentiation in adult forebrain precursor cells", SPRINGER, vol. 176, no. 4, 2007, pages 672 - 678, XP019472176, DOI: doi:10.1007/s00221-006-0831-x *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018184267A1 (fr) * 2017-04-07 2018-10-11 东南大学 Nanocorps codé par arnm et son application
CN110734924A (zh) * 2019-10-25 2020-01-31 山东大学第二医院 一种抑郁症检测、治疗和预后靶点及应用
CN110734924B (zh) * 2019-10-25 2020-10-23 山东大学第二医院 一种抑郁症检测、治疗和预后靶点及应用
WO2024113351A1 (fr) * 2022-12-02 2024-06-06 Nuwacell Biotechnologies Co., Ltd. Milieu de culture, matrice de revêtement et procédé de maturation de cellules progénitrices dopaminergiques du mésencéphale
US12391919B2 (en) 2022-12-02 2025-08-19 Nuwacell Biotechnologies Co., Ltd. Culture medium, coating matrix and method for maturing midbrain dopaminergic progenitor cells

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