WO2007058021A1 - Modele animal et procede de production de ce modele - Google Patents

Modele animal et procede de production de ce modele Download PDF

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Publication number
WO2007058021A1
WO2007058021A1 PCT/JP2006/319415 JP2006319415W WO2007058021A1 WO 2007058021 A1 WO2007058021 A1 WO 2007058021A1 JP 2006319415 W JP2006319415 W JP 2006319415W WO 2007058021 A1 WO2007058021 A1 WO 2007058021A1
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WIPO (PCT)
Prior art keywords
cells
observation
marker
animal model
transplanted
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PCT/JP2006/319415
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English (en)
Japanese (ja)
Inventor
Tetsuo Maruyama
Hirotaka Masuda
Yasunori Yoshimura
Hideyuki Okano
James Hirotaka Okano
Yumi Matsuzaki
Original Assignee
Keio University
Chugai Pharmaceutical Co., Ltd.
Central Institute For Experimental Animals
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Keio University, Chugai Pharmaceutical Co., Ltd., Central Institute For Experimental Animals filed Critical Keio University
Priority to JP2007545171A priority Critical patent/JP5288395B2/ja
Publication of WO2007058021A1 publication Critical patent/WO2007058021A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases

Definitions

  • the present invention relates to an animal model and a method for producing the same.
  • Endometriosis is an ectopic occurrence of endometrial cells in various organs other than the uterus, particularly in the peritoneum, ovary, and eclampsia, where it proliferates in response to normal female hormone secretion.
  • This disease is one of the most common diseases in which the number of patients is as high as 15% of women of reproductive age, and the incidence is increasing in recent years. And this disease is a typical disease that damages women's quality of life (QOL), and disability at the time of women's social advancement also contributes to the era of low birthrates, so it cannot be overlooked socially. It is one of the diseases.
  • Organic lesions of eclampsia include blueberry spots, ovarian chocolate cysts, gonococcal adenomyosis, and Douglas fistula endometriosis.
  • Treatments include pharmacotherapy and surgery depending on the situation. Treatment is selected.
  • GnRH gonococcal adenomyosis
  • Douglas fistula endometriosis Treatments include pharmacotherapy and surgery depending on the situation. Treatment is selected.
  • GnRH gonococcal adenomyosis
  • Douglas fistula endometriosis Treatments include pharmacotherapy and surgery depending on the situation. Treatment is selected.
  • GnRH gonococcal adenomyosis
  • Douglas fistula endometriosis Treatment is selected.
  • GnRH gonococcal adenomyosis
  • Douglas fistula endometriosis Treatments include pharmacotherapy and surgery depending on the situation. Treatment is selected.
  • the present invention provides an animal model that can more accurately reflect a lesion of human intimal disease, a method for producing the same, and an animal that enables noninvasive observation of transplanted cells. It is an object of the present invention to provide a model and a manufacturing method thereof.
  • the animal model according to the present invention is a non-human vertebrate model having transplanted cells under the kidney capsule, and using the transplanted cell force observation marker, It is characterized by being able to distinguish vertebrate cell forces by invasive observation.
  • the location and z or proliferation of the transplanted cells may then be determined in real time by non-invasively observing the vertebrates.
  • the transplanted cells may be dispersed cells.
  • the transplanted cell may have an observation marker that allows noninvasive observation.
  • the observation marker may be a fluorescent marker or a luminescent marker.
  • the vertebrate may be an immunodeficient mouse, for example NO
  • mice may also be used.
  • the transplanted cells may be derived from human eclampsia intima or may be derived from a lesion of human eclampsia.
  • the present invention also includes a screening method for a therapeutic agent for endometriosis, comprising an administration step of administering a candidate substance for the therapeutic agent for endometriosis to an animal model.
  • the transplanted cells may be derived from a diseased lesion other than human eclampsia.
  • the present invention also includes a therapeutic drug screening method characterized by including an administration step of administering a therapeutic drug candidate substance for the disease to an animal model.
  • a method for producing an animal model according to the present invention is a production method including a transplanting step of transplanting cells under the kidney coating of a vertebrate other than a human, and the cells are placed under the kidney capsule.
  • the vertebrate cells can be distinguished from the vertebrate cells by non-invasive observation. This cell location and Z or proliferation may be determined in real time by non-invasive observation of vertebrates after transplantation under the renal capsule.
  • the cells may also be dispersed when transplanted.
  • this production method may include an introduction step of introducing an observation marker capable of noninvasive observation into cells.
  • the observation marker may be a fluorescent marker or a luminescent marker.
  • this observation marker may be introduced into a cell by introducing an expression vector having a gene encoding the observation marker, and the expression vector may be a viral vector.
  • the production method of the present invention may further include a sorting step of sorting cells into which the observation marker has been introduced using the observation marker as an index before transplantation, or the cells are subjected to the cell before transplantation.
  • the method may further include a second introduction step for introducing the selection marker and a selection step for selecting the cell into which the observation marker is introduced, using the selection marker as an index.
  • the cells to be transplanted may be derived from human eclampsia. Alternatively, it may be derived from a diseased part of a human disease.
  • the pathological animal model of eclampsia associated with the present invention is a vertebrate model other than human, and a lesion derived from cells isolated from the human endometrium is placed under the renal capsule. It has.
  • the vertebrate may be derived from an immunodeficient mouse, for example, a NOG mouse.
  • the present invention also provides a screening method for a therapeutic agent for endometriosis, comprising an administration step of administering a candidate substance for the treatment of endometriosis to such an animal model of endometriosis. Including.
  • the present invention provides a human endometrium with respect to any of the animal models of endometriosis in which cells derived from a human endometrium or a lesion of endometriosis are transplanted. Including a method of reproducing the environment, the method comprising the step of administering an exogenous steroid hormone.
  • FIG. 1 is a diagram showing the results of gross and histological observations of NOG mice transplanted with endometrial dispersed cells in an example of the present invention. Force of transplanted mouse Photo of the isolated uterus (first row) and kidney (second row, the transplant site is indicated by the arrowhead), and H-E staining (third row) and immunostaining of the tissue section of the transplant site An optical micrograph of (fourth column) is shown.
  • FIG. 2 is a diagram showing the results of immunohistological observation of the transplanted site in the examples of the present invention.
  • the immunostained images (first and second rows) and the nuclear stained images (third row) using the antibodies listed in Table 1 are shown as a superimposed image (fourth row).
  • FIG. 3 is a diagram showing a method and results of cyclic hormone treatment applied to endometrial cell transplanted mice in the examples of the present invention.
  • (A) is a schematic diagram showing the process of hormone treatment, which is a combination of constant administration of E and cyclic administration of P to mice after cell transplantation.
  • FIG. 4 is a schematic diagram showing a gene map of a marker gene expression vector introduced into a cell to be transplanted in an example of the present invention.
  • FIG. 5 is a diagram showing the results of observing endometrial cells cultured by introducing a marker gene in Examples of the present invention.
  • (a) shows a fluorescence microscope image of stromal cells (upper) or glandular epithelial cells (lower) on the culture plate.
  • (b) shows an observation image of the whole culture plate, and the intensity of luminescence by luciferase at the concentration of the scale bar on the right side of the figure.
  • FIG. 6 In the example of the present invention, the transplantation site of the abdomen (a, the position of the kidney in the circle) viewed from the outside of the endometrial cell transplanted mouse, the kidney exposed by the laparotomy of the same site (b), FIG. 3 is a diagram showing the results of BLI observation of bioluminescence emitted by the left and right kidneys (c) that were removed.
  • the image power of the luminescence intensity indicated by the density of the scale bar on the right side of each figure is superimposed on the photographic image, and the dark part near the center of the luminescent part has a particularly strong luminescence intensity (about 30000 for a).
  • b shows about 3.5 X 10 5 or more
  • c shows about 12000 or more).
  • FIG. 7 is a BLI observation image (a) of the abdomen of an endometrial cell transplanted mouse subjected to steady hormone treatment in the example of the present invention (a) and a graph showing the result of quantifying the luminescence intensity by analyzing the image (b ).
  • the dark portion near the center of the light-emitting part of the image a shows that the light emission intensity is particularly strong.
  • FIG. 8 A BLI observation image (a) of the abdomen of a mouse and hormonal and antihormone-treated mouse treated with hormones and antihormones (a) and a dra ).
  • the dark part near the center of the light emitting part of the image a shows that the light emission intensity is particularly strong.
  • FIG. 9 Schematic diagram of cyclic hormone treatment applied to endometrial cell transplanted mice in Example of the present invention (a), image of observation results by BLI of transplanted mouse abdomen (b), and results of quantification thereof. It is a graph (c) showing. The dark and colored portions near the center of the light emitting part of the image b indicate that the light emission intensity is particularly strong.
  • the vertebrate model according to the present invention is a vertebrate model having transplanted cells under the kidney capsule, and the transplanted cells can be easily obtained by noninvasive observation of the vertebrate using an observation marker. Can be distinguished from other cells. In this way, if the transplanted cells can be distinguished from the vertebrate recipient animals by non-invasive observation of the vertebrates, the state of the transplanted cells can be observed while the vertebrates remain alive. Will be able to.
  • the cells to be transplanted may be derived from any source, but a disease model animal can be prepared by using cells derived from human lesions.
  • cell morphology is cell clumps, tissue pieces, individually dispersed cells, cells that have been isolated and cultured, cells that have been transplanted into other animals, and cells that have been isolated from animal power through a process. Any cell can be used, but dispersed cells are preferred. This is because the number of cells at the time of transplantation can be made uniform, and the reproducibility of the cell state after transplantation is improved.
  • the number of cells to be transplanted may be a small number of 10 6 or less! However, it is possible to transplant more cells!
  • the site for cell transplantation according to the present invention is under the capsule of the kidney.
  • (3) Reasonable factors such as abundant growth factors are suitable.
  • the use of organs such as kidneys that have a pair of animals on the left and right side means that different grafts can be transplanted and compared to the transplant sites on the left and right organs of the same individual. It is also preferable in that the difference between the resulting transplantation results and the effect on the therapeutic agent can be accurately evaluated.
  • vertebrates other than humans can be used as recipient animals as long as they have a kidney that enables transplantation as described above.
  • Observation markers that can be non-invasively observed may have cells to be transplanted or The transplanted vertebrate cell may have an observation marker.
  • a genetically modified animal in which a gene for an observation marker is integrated into a body cell such as a recombinant mouse into which a luminescent gene has been introduced, a so-called “shining mouse” is used as a recipient animal.
  • a so-called “shining mouse” is used as a recipient animal.
  • it is more preferable to introduce a non-invasive observation marker for the cells to be transplanted because it is possible to select an appropriate observation marker and an observation method corresponding to it in transplantation.
  • a fluorescent marker such as GFP
  • the site where the cells are transplanted can be easily and non-invasively optically observed.
  • a luminescent marker such as luciferase
  • BBI bioluminescence imaging
  • proliferation can be determined in real time by non-invasive observation of the transplanted vertebrate.
  • observation methods such as X-ray computed tomography (computerized tomography), such as radioisotopes used as contrast agents, can be used as observation markers to make the transplanted site observable. tomography, CT) 'Magnetic resonance imaging ⁇ MRI ⁇ % ⁇
  • PET positron emission tomography
  • an expression vector having a gene encoding the observation marker is used in the cell.
  • a method for infecting a virus is mentioned.
  • the expression vector for example, a virus vector is suitable in terms of high infection efficiency, but other commonly used expression vectors such as a plasmid vector and a cosmid vector can also be used.
  • the observation marker is a protein as well as other substances, general introduction methods for introducing foreign substances into living cells, such as the lipofusion method and the electoral position method, can also be used to introduce observation markers. Can be used for
  • the transplanted cells remain in the state where donor organisms and patient force are collected, or although it may be used in the state after the introduction of the observation marker as described above, an operation for selecting cells having the observation marker can be added at the time of transplantation.
  • the marker for selection may be the same as the aforementioned marker for observation, or a different marker may be used.
  • a selection marker it is preferable to use a visualization marker such as a luminescent marker or a fluorescent marker for the same reason as in the case of the marker for observation described above.
  • a fluorescent marker is used, flow cytometry can be used for sorting.
  • other substances that can be used as selection markers such as surface antigens and magnetic beads, can also be used as a suitable selection method, such as cell panning and magnetic separation methods. Can be used in combination
  • the method for introducing the selection marker into the cell can be the same method as the method for introducing the observation marker described above.
  • the step of introducing the selection marker may be performed simultaneously by the same method as the introduction of the observation marker, or may be performed separately by the same or different method.
  • the marker is a protein
  • the ability to separately infect cells with two types of expression vectors having the genes of each marker separately Co-infection of both at the same time This is preferable because both markers are more likely to coexist in the same cell.
  • the introduction is performed simultaneously, for example, a single expression vector having both marker genes can be constructed and cells can be infected with it. This method is more preferable because the introduction process is simpler and the cells selected using the selection marker have an observation marker.
  • an animal model of the disease can be prepared according to the present invention. Then, by continuously breeding the created animal model and observing the transplantation site, it is possible to noninvasively follow the changes in lesions derived from the disease. For example, the details to be transplanted
  • an animal model of eclampsia can be produced, and by using cells derived from other diseases such as tumors, tumor animal models can be produced. Therefore, it is possible to easily observe a lesion derived from such a disease non-invasively.
  • the vertebrate cell force can be distinguished by non-invasive observation of the transplanted cell force vertebrate using the observation marker. The condition can be observed continuously and quantitatively in a non-invasive manner. Furthermore, if the lesion or the entire animal is treated, and changes in the transplantation site are traced to the treatment, analysis of the effectiveness of the treatment and basic research for investigating the cause of the disease will be conducted. Yes.
  • a cyclic hormone that mimics the change in hormone concentration according to the menstrual cycle by adjusting the dose and timing.
  • the menstrual cycle-like hormonal environment can be continuously reproduced, and as a result, changes in the lesion similar to changes in the menstrual cycle in the endometrium can be analyzed.
  • an animal model of endometriosis drug candidates is administered to such animal models and screening is performed for candidate substances that can improve lesions, development of endometriosis drugs Can be useful.
  • the animal model of the present invention has the advantage of being able to observe a lesion in real time in a non-invasive manner, and thus a disease state that requires continuous tracking over a long period of time.
  • a model for example, a tumor cell derived from a tumor patient is transplanted, it is extremely useful as a model of a disease state of a tumor.
  • a method for producing such an animal model is also included in the scope of the present invention. It can be provided for the elucidation of the cause of the corresponding disease and the development of therapeutic methods and drugs. For example, if a tumor therapeutic drug candidate substance is administered to an animal model of a tumor prepared as described above, and screening is performed for a substance that can improve the lesion, It can be used to develop therapeutic drugs.
  • the endometriosis or pathological animal model of endometriosis which has a diseased part derived from cells from which human endometriosis or endometriotic lesion force has been isolated, under the kidney capsule, has no marker introduced. However, it can be used effectively.
  • This pathologic model shows that by administering periodic exogenous steroid hormones, the isolated endometrial cell force reconstructed tissue shows changes similar to the endometrial menstrual cycle change, i.e. This is the first model animal to reproduce the human endometrial environment.
  • exogenous steroid hormones such as estrogen and progesterone should be administered by various methods such as subcutaneous and intraperitoneal injection, dietary administration, and sustained release subcutaneous transplantation. Can do.
  • an analysis such as a histological observation is performed on the transplantation site of an animal model that reproduces the menstrual cycle-like hormonal environment as described above by adjusting the hormone administration, it is possible to analyze eclampsia.
  • a substance that can improve the lesion by administering a candidate drug for treating endometriosis to the model animal for endometriosis, a substance that causes regression of the lesion, or a periodic
  • a substance that becomes resistant to mon administration and does not respond to hormones it can be used to develop endometriosis drugs.
  • NOG NOD / SCID / y nuU mice (Laboratory Animal Central Laboratory, Kaoru Kawasaki) 10% bent
  • the excised kidney was embedded in Tissue-Tek OCT compound (Sakura Finetech, Califol, U.S., USA), frozen, and 6 ⁇ m thick using a cryostat (Leica Microsystems, Germany's Wetzlar). Sliced continuously. A portion of the obtained frozen section was subjected to tissue observation with a hematoxylin 'eosin (HE) staining solution (Sigma-Aldrich), and the remaining sections obtained on the slide glass were summarized in Table 1.
  • HE hematoxylin 'eosin
  • Table 1 The primary antibodies shown in the above were used in combination, followed by immunostaining according to the most appropriate method shown below.
  • the stained sections were washed and secondary fluorescently stained with Alexa Fluor 488 (for green fluorescence) or Alexa Fluor 568 (for red fluorescence) labeled secondary antibody (Molecular Probes, Inc., Oregon, USA). Furthermore, the sections were counterstained with the nuclear stain Hoechst 33258 (Sigma) for 5 minutes.
  • the sections after each staining were encapsulated with VECTAS HIELD (Vector Laboratories, California, USA) and examined with a DMIRE2 inverted fluorescence microscope (Leica Microsystems). Images were captured with a VB-700 CCD camera (Keyence Corp., Osaka City). I took it in.
  • Endometrial dispersed cells prepared by the same method as described above were cultured, and SDEC on a culture plate grown to a confluency of about 60% was compared with a multiplicity of infection of 1: 1.
  • the marker gene expression vector solution was added so as to maintain the ratio, and the culture was further continued.
  • stromal cells and glandular epithelial cells on the culture plate were examined with an inverted fluorescence microscope, Nikon ECLIPSE TS100 (Nikon, Tokyo), both of them were observed to emit fluorescence and bioluminescence (Fig. 5). ).
  • the cells on the plate are collected and transferred to HBSS + medium containing 2 ⁇ g Zml of Probidium Iodine (PI). After staining only dead cells, the MoFlo cell sorter (Cytomation , Colorado, USA). Sorted cells that were negative for PI staining and positive for Venus fluorescence were used as live cells in which the marker gene had been introduced into SDEC in the following transplantation experiments.
  • PI Probidium Iodine
  • the sorted gene-transferred cells were transplanted under the kidney capsule of ovariectomized NOG mice in the same manner as described above, and the mice were bred.
  • a bioluminescent substrate D-luciferin (Sumisho Bioscience, Tokyo) was intraperitoneally administered to the transplanted mice under anesthesia by administration of 2% isoflurane (Merck's Whey, Osaka) at a dose of 150mgZkg body weight.
  • isoflurane Merck's Whey, Osaka
  • the abdomen of the transplanted mouse in the living state was observed using a BLI viewing image (Xenogen-IVIS 100 cooled and CD optical macroscopic imaging system) (Sumisho Bioscience), and bioluminescence was imaged. .
  • BLI viewing image Xenogen-IVIS 100 cooled and CD optical macroscopic imaging system
  • a constant hormonal treatment was performed by subcutaneous transplantation.
  • an anti-hormone was administered to some of these by daily subcutaneous injection of estrogen receptor antagonist ICI 182,780 (Tocris Cookson Inc., Missouri, USA) at a dose of 100 ⁇ g / ml. Processed.
  • ICI 182,780 Tocris Cookson Inc., Missouri, USA
  • Constant hormone treatment was performed by subtransplantation. In addition, a part of them was subjected to periodic hormonal treatment by subcutaneous injection of 1 mg dose of P preparation in the same manner as described above ( Figure 9a).
  • the animal model of the present invention is particularly suitable for continuously observing the kinetics of transplanted cells over a long period of time. For example, if cell transplantation derived from the eclampsia is performed, the pathology of endometriosis It was possible to create an animal model that reproduced the above. Furthermore, it is possible to observe such an animal model non-invasively, continuously and quantitatively with the method of the present invention, elucidating the etiology of a disease from which transplanted cells are derived, and therapeutic agents. For example, in the case of an animal model of eclampsia, it is clear that it is possible to provide an animal model that can track changes in the pathology according to the administration of hormones and antihormonal agents. became.
  • an animal model that can more accurately reflect a lesion of human endometriosis, a method for producing the same, an animal model that enables noninvasive observation of transplanted cells, and a method for producing the animal model. Can be provided.

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  • Life Sciences & Earth Sciences (AREA)
  • Environmental Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • General Health & Medical Sciences (AREA)
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Abstract

L'invention concerne un modèle animal qui peut refléter de manière plus fidèle le site atteint par l'endométriose humaine, un procédé de production de ce modèle, un modèle animal qui permet une observation non invasive d'une cellule transplantée et un procédé de production de ce modèle. Le modèle animal qui présente une lésion uniforme d'endométriose peut être produit en introduisant un vecteur d'expression qui contient un gène qui code pour un marqueur d'observation, par exemple la luciférase, dans une cellule isolée d'un être humain, en transplantant une cellule qui a été amenée à exprimer le marqueur d'observation en dessous de la capsule rénale d'une souris immunodéficiente, par exemple une souris NOG, et en isolant de l'endomètre ou d'un site focal de l'endométriose la cellule à transplanter.
PCT/JP2006/319415 2005-11-16 2006-09-29 Modele animal et procede de production de ce modele WO2007058021A1 (fr)

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JP2007545171A JP5288395B2 (ja) 2005-11-16 2006-09-29 動物モデルとその作製方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014033626A (ja) * 2012-08-08 2014-02-24 Juntendo ヒト癌上皮細胞の遠隔転移のモデルマウス作出方法
WO2017141987A1 (fr) * 2016-02-19 2017-08-24 コニカミノルタ株式会社 Procédé d'essai non clinique caractérisé par l'évaluation quantitative d'échantillon d'animal de laboratoire

Citations (1)

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WO1998042185A1 (fr) * 1997-03-26 1998-10-01 Reprogen, Inc. Souris utilisees comme modele pour l'etude de l'endometriose

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WO1998042185A1 (fr) * 1997-03-26 1998-10-01 Reprogen, Inc. Souris utilisees comme modele pour l'etude de l'endometriose

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014033626A (ja) * 2012-08-08 2014-02-24 Juntendo ヒト癌上皮細胞の遠隔転移のモデルマウス作出方法
WO2017141987A1 (fr) * 2016-02-19 2017-08-24 コニカミノルタ株式会社 Procédé d'essai non clinique caractérisé par l'évaluation quantitative d'échantillon d'animal de laboratoire

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