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WO2005095588A1 - Écorce glutamatergique précurseur de neurone produisant une écorce glutamatergique précurseuse de neurone seule in vivo. - Google Patents

Écorce glutamatergique précurseur de neurone produisant une écorce glutamatergique précurseuse de neurone seule in vivo. Download PDF

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Publication number
WO2005095588A1
WO2005095588A1 PCT/JP2005/006821 JP2005006821W WO2005095588A1 WO 2005095588 A1 WO2005095588 A1 WO 2005095588A1 JP 2005006821 W JP2005006821 W JP 2005006821W WO 2005095588 A1 WO2005095588 A1 WO 2005095588A1
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cells
cerebral
cortex
cerebral cortical
cell
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PCT/JP2005/006821
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Japanese (ja)
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Nobuaki Tamamaki
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Kyoto 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
    • C12N5/0618—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
    • C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
    • C12N2506/02—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from embryonic 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
    • C12N2510/00—Genetically modified cells

Definitions

  • the invention of this application relates to a cerebral cortical glutamatergic neural progenitor that produces only cerebral cortical glutamatergic neurons and itself (cerebral cortical glutamate neural progenitor cells) in vivo. It is about cells. More specifically, the invention of this application makes it possible to restore the area of the cerebral cortical gluten-mate nervous cells lacking or reduced to normal by cell transplantation, thereby enabling a therapeutic action for treating cerebral dysfunction. It relates to cells as medical materials and the like.
  • Neurons in the central nervous system include excitatory neurons and inhibitory neurons. Both neurons are included in various ratios depending on the area of the central nervous system, and information processing is performed.
  • excitatory neurons use glucan mate as a neurotransmitter.
  • Excitatory neurons in the cerebral cortex are present in about 80% of the neurons, so that the neural circuit as a whole can maintain a moderate level of activity and perform smooth information processing.
  • traumatic disorders, cerebrovascular disorders, and disorders caused by genetic disorders result in loss of excitatory neurons in the cerebral cortex and, at the same time, loss of some brain functions.
  • Non-Patent Document 9 In the fetal cerebral neocortex, dal evening mate-operated neurons have been thought to be produced by division of neural stem cells in the ventricular zone (Non-Patent Documents 1, 3, 7, and 8). Recently, it has been suggested that some of these may be produced by Svetl-positive cells in the subventricular zone (Non-Patent Document 9). However, this Non-Patent Document 9 merely suggests the production of cerebral cortical glutamatergic neurons outside the ventricular zone, and that the subventricular zone Svetl-positive cells are cerebral cortical glutamatergic neurons. There is no evidence that they produced only neurons and cerebral cortical glutamatergic neural progenitors.
  • Molecules that are expressed in mammalian cerebral cortical cells and are considered to be involved in the differentiation of neurons include, in addition to the aforementioned Svet and Otxl, proneural basic helix-loop-helix (abbreviated bHLH) transcriptional factor Neurogenin l neruogenin2, and bHLH differentiation gene that promotes neural differentiation, NeuroD, NeuroD-related-factor, NEX (also known as Math2) are known. Tbr2 is also known.
  • Non-Patent Documents 2 NeuroD, NeuroD-related-factor, and Tbr2 have also been thought to be expressed in cells that do not undergo cell division, promoting neuronal differentiation.
  • Non-Patent Document 1 Angevine, JB & Sidman, RL Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse.Nature 192, 766-768 (1961).
  • Non-Patent Document 2 Bartholoma, A. & Nave, KA NEX-1: a novel brain-specific helix-loop-helix protein with autoregulation and sustained expression in mature cortical neurons.Mech. Dev. 48, 217-228 (1994)
  • Non-Patent Document 3 Noctor, SC, Flint, AC, Weissman, TA, Dammerman, RS & Kriegstein, AR Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 7 14-720 (200 1 ).
  • Non-Patent Document 4 Ross, S.E. and Greenberg, M.E.Basic helix-loop-helix factors in cortical development.Neuron 39, 12-25 (2003).
  • Non-Patent Document 5 Shimizu, C, Akazawa, C., Nakanishi, S. & Kageyama, R. MATH-2, a mammalian helix-loop-helix factor structurally related to the product of Drosophila proneural gene atonal, is specifically expressed in The nervous system. Eur. J. Biochem. 229, 239-248 (1995).
  • Non-Patent Document 6 Schwab, MH et al. Neuronal basic helix-loop-helix proteins (NEX, neuroD, NDRF): spatiotemporal expression and targeted disruption of the NEX gene in transgenic mice.J. Neurosci. 18, 1408-1418 ( 1998).
  • Non-patent literature Takahashi, T. et al. Sequence of neuron origin and neocortical laminar fate: relation to cell cycle of origin in the developing murine cerebral wall. J. Neurosci. 19, 10357-10371 (1999).
  • Non-Patent Document 8 Tamamaki, N., Nakamura, K., Okamoto, K. & Kaneko, T. Radial glia is a progenitor of neocortical neurons in the developing cerebral cortex. Neurosci. Res. 41, 51-60 (2001) .
  • Non-Patent Document 9 Tarabykin, V., Stoykova, A., Usman, N., & Gruss, P. Cortical upper layer neurons derive from the subventricular zone as indicated by Svetl gene expression. Development 128, 1983-1993 (2001).
  • Non-Patent Document 10 Wu, S. et al., Pyramidal neurons of the neocortex generated from progenitor cells in the mantle layer, (submitted).
  • the present application relates to cerebral cortical cells for transplantation used for treating dysfunction caused by cerebral cortical damage and the like.
  • the task is to provide cells that produce only sexual neural progenitor cells.
  • Another object of the present invention is to provide a method for separating and obtaining the cells.
  • This application provides the following inventions (1) to (20) to solve the above problems.
  • (c) expressing one or more molecules selected from the group consisting of NEX (Math2), NeuroD, NeuroD-related-factor, Neurogeninl, Neurogenin2, Svetl, Otxl, Tbr2,
  • the cell of the above invention (1) which is derived from a human.
  • the cell of the invention (2) which is derived from a human embryonic stem cell.
  • the cell of the invention (1) which is derived from a mammal closely related to human.
  • the cell of the above-mentioned invention (4) which is derived from an embryonic stem cell of a human closely related mammal.
  • a method for separating cerebral cortical glumate-operating neural progenitor cells that specifically produces cerebral cortical glumate-operating neurons and cerebral cortex gulatmate-operating neural progenitors in vivo The following steps:
  • a method comprising:
  • a method for separating cerebral cortex gluten-mate-operating neural progenitor cells that specifically produces cerebral cortical gluten-mate-operating neural cells and cerebral cortical gluten-mate-operating neural progenitor cells in vivo. The following steps:
  • a method comprising:
  • NEX Math2
  • NeuroD NeuroD-related-factor
  • Neurogenin l Neurogenin2, Svetl, Otxl or Tbr2
  • Any gene promoter linked to the downstream of the gene promoter and forced expression A step of introducing, into each cell of the cell population, an expression vector linked downstream of the promoter with a drug resistance gene imparting drug resistance properties after genetic recombination; (c) isolating cerebral cortical glumate-operating neurons and cerebral cortical glumate-operating neural progenitor cells from other cells depending on the presence or absence of drug resistance.
  • the cell population prepared in step (a) is a cell population prepared by dispersing tissue containing cerebral cortical glumate-operating neural cells and cerebral cortex glumate-operating neural progenitor cells of the donor animal.
  • the cells provided by the invention of this application proliferate when cultured under appropriate conditions, and when transplanted into the human cerebral neocortex, continue to produce gluten-mate-operating neurons, and produce the dalnymate-operated neurons.
  • Nerve cells are incorporated into neural circuits of the cerebral cortex and can restore dysfunction due to a lack of glutamatergic neurons.
  • “cerebral cortical glutamate-operating neural progenitor cells” are referred to as “cerebral cortical glutamate-active neural progenitors” and “cerebral cortical glutamate-operating neural progenitor cells” in vivo. Are cells produced by cell proliferation.
  • Non-Patent Document 10 the daughter cells resulting from the division differentiate into “cerebral cortical glutamatergic neurons” or stay in “cerebral cortical glutamatergic neural progenitor cells” in vivo.
  • Cell division of cerebral cortex gluten-mate neural progenitor cells is constantly regulated by growth factors secreted by surrounding cells. Therefore, when cerebral cortical gluten-mate-operating neural progenitor cells are taken out and grown in vitro, an appropriate culture solution is required (Non-Patent Document 10).
  • FIG. 1 shows that a recombinant adenovirus (CApromoter-loxP-CAT-loxP-GGFP) is infected into the E14 fetal ventricle of a NEX-Cre knock-in mouse and stained at 3 weeks of age Cerebral cortex gluten mate-operated neurons. In a study of 1000 GFP-positive cells, all cells exhibited the characteristics of cerebral cortical gluten-mate neurons.
  • Fig. 2a shows NEX-GFP positive and phosphorylated histone H3 positive cells in the E15 fetal cerebral cortex.
  • Figure 2b shows NEX-GFP positive and phosphorylated histone H3 positive cells.
  • Figure 2c shows isolated NEX-GFP positive and Ki-67 positive cells.
  • Figure 3 shows that NEX-GFP-positive cells were taken from the cerebral cortex tissue of the half of the cortical plate immediately after BrdU labeling, dispersed, transplanted into the cerebral cortex of a wild-type mouse immediately after birth, and GFP found one week later. Cerebral cortical pyramidal cells where label and BrdU label overlap.
  • Figure 4a shows NEX-Cre-positive and tva800-positive cells that became GFP-positive by infection with recombinant ASLV.
  • FIG. 4b is an explanatory diagram in which up to four or one pyramidal cell is stained in three days.
  • Figure 4c is an illustration of the cell lineage.
  • Figure 5 shows that the isolated E15 fetal cerebral cortex NEX-GFP positive was run on a cell sorter. Isolate only GFP-positive cells, add EGF, bFGF, and BrdU to a conditioned medium in which the fetal brain was cultured overnight with NeuroBasal, culture for 2 days, extract DNA from the cells, attach them to the membrane, and add BrdU. Detected by immunochemical method. Also shown is the case where DNA synthesis was inhibited with AraC using 293 cells as a control group.
  • the cerebral cortical glutamate-operating nerve of the present invention which produces only cerebral cortical glutamate-operated neurons and itself (cerebral cortical glutamate-operated neural progenitor cells) in vivo.
  • Neural progenitor cells are characterized by having the following characteristics.
  • the characteristic ( ⁇ ) is a cell population having proliferative ability or a stimulus in the cell population of ( ⁇ ⁇ ). Are identified as proliferating cells. “Stimulation” in this case refers to the administration of unknown and known growth factors, and the degree of stimulation differs depending on the combination, concentration, timing, and the like of the growth factors. Furthermore, the characteristic ( ⁇ ) is selected from the group consisting of NEX (Math2), NeuroD, NeuroD-related-factor, Neurogeninl, Neurogemn2, Svetl, Otxl, and Tbr2 among the cells having the proliferative ability of the above ( ⁇ ). Identified as cells expressing one or more selected molecules.
  • Whether or not these molecules are expressed can be determined, for example, by examining the presence of the transcript (mRNA) of the gene encoding these molecules, for example, by hybridization using a probe DNA prepared based on the nucleotide sequence. It can be confirmed by measurement and quantification by the PCR method, the PCR method using primer DNA, the RT-PCR method, or the method using a DNA microarray. Expression can also be confirmed by using an antibody that recognizes each molecule. The information such as the amino acid sequence of each molecule and the gene sequence encoding it is stored in an existing database (eg, GenBank: http://www.ncbi.nlm.nih.gov/Genbank). /index.html) You can know exactly what you are doing.
  • the cells identified by the above characteristics (1), (D), and (m) are cerebral cortical glutamate-operating neurons and cerebral cortex that produce in vivo the Dalmes-mate-operating neural progenitor cells themselves. It is a glutamatergic neural progenitor cell.
  • the cells as described above (cerebral cortex glumate-operated neural progenitor cells that produce cerebral cortex glumate-operated neural progenitors and cerebral cortex glutamate-operated neural progenitors in vivo) are the invention of this application. (6) It can be isolated by the method of (9). That is, the methods of the inventions (6) to (9) are characterized by including the following steps. (a) a step of preparing a cell population containing cerebral cortex dalmatergic neurons and cerebral cortex glumate nervous neural progenitor cells;
  • step (c) a step of isolating cerebral cortical glutamatergic neurons and cerebral cortical glutamatergic neural progenitors from other cells by expressing the function of the expression vector.
  • the cell population of step (a) can be prepared as described above, for example, by deriving from embryonic stem cells or neural stem cells of mammals including humans, or at a specific time in mammals including humans. It can be prepared as a cell population isolated from cerebral tissue.
  • the “expression vector designed to identify any expression of a specific expression molecule” in step (b) can be detected in vivo, for example, downstream of the gene promoter encoding each molecule. This is an expression vector linked to a signal gene for a repo that emits a signal.
  • the repo overnight protein gene a gene (cDNA or the like) encoding a green fluorescent protein (GFP or EGFP) can be used.
  • the above-mentioned expression vector is an expression vector in which a drug resistance protein gene is linked downstream of a gene promoter encoding each molecule.
  • a drug resistance protein gene for example, a known gene such as a neomycin resistance gene can be used.
  • the following expression vector can be used. That is, an expression vector is constructed in which a DNA recombinase (eg, ere recombinase) gene is ligated to DNA containing the promoter region of the specific expression molecule gene.
  • a DNA containing a stop codon sequence is placed downstream of the forced expression promoter between two DNA sequences recognized by DNA recombinase (for example, ⁇ ) in the forward direction. Then, an expression vector in which a repo overnight DNA (for example, GFP) or a drug resistance gene DNA (for example, neo mycin resistance gene) is placed downstream of the DNA sequence recognized by the second DNA recombinase. I do. These two expression vectors are introduced into each cell of the cell population prepared in the step (a).
  • a repo overnight DNA for example, GFP
  • a drug resistance gene DNA for example, neo mycin resistance gene
  • the expression vector-transduced cells are cerebral cortical glumate-operating neural progenitors that produce cerebral cortical glutamate-active neural progenitors and cerebral cortical glutamate-active neural progenitors in vivo.
  • Expression molecule The DNA recombinase is expressed by the promoter activity of the gene, recombination occurs between the DNA sequences recognized by the two DNA recombinases, and the DNA containing the stop codon sequence between them is removed, Yuichi Protein genes (eg, GFP gene) and drug resistance genes (eg, neomycin resistance gene) are placed downstream of the forced expression promoter and are expressed.
  • the expression vector may be introduced by transformation via a viral vector such as adenovirus or retrovirus, or a physical method such as electroporation, ultrasound, or microinjection.
  • a known method such as a method for introducing an expression vector by a method such as a method for introducing an expression vector by a transformation via a lipid such as ribosome, and the like can be employed.
  • the expression of the function of the expression vector introduced in the step (b) (for example, the expression of a repo protein or a drug resistance trait) is used as an index, and the cerebral cortical glutagenic activity is determined. Separate neurons and cerebral cortical gluten-mate neural progenitors from other cells.
  • fluorescent protein (GFP) -positive cells can be separated on a cell saw.
  • Neomycin-resistant dividing cells can be selected by culturing by adding Geneticin (G418) to the culture solution.
  • the invention (19) of the present application further comprises isolating cells having a proliferative ability from the cerebral cortical gluten-mate-operating neurons and the cerebral cortex Dalmat-mate-operating neural progenitor cells isolated in the above invention. In this method, only Dalmat mate neural progenitor cells of the cerebral cortex are separated. Further, in a preferred embodiment, the isolated cells are transplanted into a recipient animal.
  • proliferating cells specifically refer to somatic cells that completely replicate genome DNA and divide, and the two daughter cells after division maintain both cell functions.
  • invention (20) is a kit of reagents and cells used in the method of the invention, which is used for obtaining cells that produce only cerebral cortical glutamate-nergic neurons and cerebral cortical glutamate-nergic neural progenitors in vivo. It is.
  • a kit can be composed of, for example, cerebral cortical gluten-mate-operating neural progenitor cells and a growth factor mix thereof.
  • Examination of 1000 GFP-positive cells revealed that all cells had a dense spine on the dendritic surface, a characteristic of cerebral cortical gluten-mate neurons, and 95% of cells had The apical dendrites were confirmed, confirming that they were pyramidal cells (Fig. 1).
  • the fate of NEX-positive cells was examined by extracting 1000 cells at the third week after birth. It means that the fruits were 100% cerebral cortical glutamate-operated neurons.
  • the separated cells were spread on a slide glass, dried, and then subjected to immunocytochemical staining for GFP and phosphorylated histone H3.
  • NEX-positive cells phosphorylated histone H3.
  • Fig. 2b Double labeling of Ki-67, which is often used as a marker molecule for the cell growth phase, by immunocytochemistry revealed that 14% of GFP-positive cells were in the cell growth cycle (Fig. 2c). ).
  • Cerebral cortex HEX-positive cells prove that there are cells with the ability to reproduce 3
  • ASLV avian sarcoma- leukosis virus receptor
  • tva800 avian sarcoma- leukosis virus receptor
  • Kuta pCA-loxP-CAT-loxP-tva800
  • the solution was mixed with recombinant ASLV (RCAS-CMV-GGFP) at the same time.
  • tva800 began only in the subventricular zone, and GFP-positive cells also appeared in the subventricular zone.
  • the stained cells On day 3 post-transfection, the stained cells also contained juvenile pyramidal cells with apical and basal dendrites, extending the axons toward the intermediate zone.
  • Figure 4a The known cell division cycle of the subventricular zone is 15 hours, and the cell cycle of the ventricular zone is 17 hours and, due to the nature of the retrovirus, it starts from one cell, assuming that cell division continues without stopping.
  • the estimated number of cells was 2 at 2 days and 4-8 at 3 days. In actual experiments, the number of cells found in labeled cell clones was up to 2 on day 2 and up to 4 on day 3, so the predictions and experiments were consistent and some cerebral cortex It was found that mate-operated neural progenitors continued to divide at the highest frequency (Fig. 4b, c).
  • NEX-positive cells in the cerebral cortex can be cultured in vitro Multiply NEX-Cre knock-in mouse with GFP reporter mouse for Cre detection
  • all Cre-positive cells were extracted from the mouse cerebral cortex tissue labeled with GFP, and separated into individual cells using protease. The separated cells were subjected to celso overnight using GFP fluorescence as an index, and only GFP-positive cells were collected and cultured in vitro for 2 days.
  • the culture medium used was a conditioned medium obtained by culturing the fetal brain with NeuroBasal plus EGF, bFGF, and BrdU. Two days later, DNA was extracted from the cultured cells, attached to the membrane, and BrdU was detected by immunochemistry (FIG. 5).
  • the figure also shows the case where DNA synthesis was inhibited with AraC using 293 cells as a control group.
  • This example showed that only NEX-GFP-positive cells were taken out and that cerebral cortical gluten-mate-operating neural progenitor cells could be cultured and grown in vitro without feeder cells.

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Abstract

Une méthode comprenant:l’étape de préparation d’une zone cellulaire produite à partir d’une écorce de tissu, de souches de cellules embryonnaires ou de souches de cellules nerveuses ; l’étape de transfère un vecteur d'expression, qui à un prometteur sélectionné à partir de NEX(Math2) NeuroD, lié-à-un-facteur, Neurogin 1, Neurogen 2, Svet 1, Otx1 et Tbr2 et un gène pour constater l’expression de cette molécule attachée en aval du prometteur en cellules individuelles dans la souche cellulaire ; l’étape d’isolement des écorces de neurones glutamatergiques et des écorces glutamatergiques précurseuses en utilisant la fonction de l’expression de la fonction du vecteur d'expression comme indicateur; et ; l’étape d’isolement des écorces précurseuses de neurones glutamatergiques en utilisant la capacité de prolifération comme indicateur. Selon cette méthode, il est possible d’obtenir une écorce précurseuse de neurones glutamatergiques pour le traitement de dysfonctionnement causé par une blessure d’écorce, Etc.
PCT/JP2005/006821 2004-03-31 2005-03-31 Écorce glutamatergique précurseur de neurone produisant une écorce glutamatergique précurseuse de neurone seule in vivo. WO2005095588A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002064748A2 (fr) * 2001-02-14 2002-08-22 Furcht Leo T Cellules souches adultes totipotentes, sources de ces cellules, procedes d'obtention et de maintien de ces dernieres, procedes de differentiation de ces cellules, procedes d'utilisation correspondants et cellules derivees des cellules susmentionnees

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002064748A2 (fr) * 2001-02-14 2002-08-22 Furcht Leo T Cellules souches adultes totipotentes, sources de ces cellules, procedes d'obtention et de maintien de ces dernieres, procedes de differentiation de ces cellules, procedes d'utilisation correspondants et cellules derivees des cellules susmentionnees

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BARTHOLOMA A. ET AL: "NEX-1: a novel brain specific helix-loop-helix protein with autoregulation and sustained expression in mature cortical neurons.", MECHANISM OF DEVELOPMENT., vol. 48, no. 3, 1994, pages 217 - 228, XP002992002 *
SCHWAB M.H. ET AL: "Neuronal basic helix-loop-helix proteins (NEX and BETA2/Neuro D) regulate terminal granule cell differentiation in the hippocampus.", THE JOURNAL OF NEUROSCIENCE., vol. 20, 2000, pages 3714 - 3724, XP002991783 *
SCHWAB M.H. ET AL: "Neuronal basic helix-loop-helix proteins (NEX, neuroD, NDRF): Spatiotemporal expression and targeted disruption of the NEX gene in transgenic mice.", THE JOURNAL OF NEUROSCIENCE., vol. 18, 1998, pages 1408 - 1418, XP002992032 *
WU S.X. ET AL: "Pyramidal neuron production in the extraventricular zone of the mouse neocortex.", SOCIETY FOR NEUROSCIENCE ABSTRACT VIEWER AND ITINERARY PLANNER., vol. 243, no. 6, 2003 *

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