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WO2007004635A1 - Procede de culture pour la differenciation d'un preadipocyte en adipocyte par co-culture avec un macrophage, et criblage d'une substance susceptible d'influer sur le processus de differenciation d'un preadipocyte en adipocyte - Google Patents

Procede de culture pour la differenciation d'un preadipocyte en adipocyte par co-culture avec un macrophage, et criblage d'une substance susceptible d'influer sur le processus de differenciation d'un preadipocyte en adipocyte Download PDF

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Publication number
WO2007004635A1
WO2007004635A1 PCT/JP2006/313285 JP2006313285W WO2007004635A1 WO 2007004635 A1 WO2007004635 A1 WO 2007004635A1 JP 2006313285 W JP2006313285 W JP 2006313285W WO 2007004635 A1 WO2007004635 A1 WO 2007004635A1
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differentiation
adipocytes
culture
preadipocytes
adipocyte
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PCT/JP2006/313285
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English (en)
Japanese (ja)
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Akifumi Matsuyama
Yoshiki Sawa
Yuzuru Kanakura
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Osaka University
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Publication of WO2007004635A1 publication Critical patent/WO2007004635A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • 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
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0653—Adipocytes; Adipose tissue
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/30—Hormones
    • C12N2501/38—Hormones with nuclear receptors
    • C12N2501/385—Hormones with nuclear receptors of the family of the retinoic acid recptor, e.g. RAR, RXR; Peroxisome proliferator-activated receptor [PPAR]
    • 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
    • C12N2502/00—Coculture with; Conditioned medium produced by
    • C12N2502/11—Coculture with; Conditioned medium produced by blood or immune system cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • the present invention relates to a culture method for differentiating preadipocytes into adipocytes, a screening method for substances that affect the differentiation process, and the like.
  • arteriosclerotic diseases such as coronary artery disease and cerebrovascular disorder secondary to metabolic syndrome has increased. This is associated with almost all arteriosclerotic conditions, including metabolic syndrome is obesity, impaired glucose tolerance associated with insulin resistance, dyslipidemia, hypertension, and thrombus formation and inflammation with elevated PAI-1 and CRP, respectively. Because. Therefore, in order to prevent and treat these diseases, there is an urgent need for elucidation of the onset physiology of metabolic syndrome and drugs to prevent and treat them.
  • Adipocytes which are the main constituent cells of adipose tissue, are derived from pre-adipocytes! /, A fibroblast-like mesenchymal cell, and prematurely mature into preadipocytes and then adipocytes.
  • adipocytes produce many secretory factors (adipocyte power-in), and these secretory factors are involved in the development of metabolic syndrome. Therefore, by using a culture system that differentiates preadipocytes into adipocytes, we elucidate the pathogenesis of metabolic syndrome, screen for drugs that control the amount of metabolic processes, and use them for metabolism. Attempts have been made to control the onset of the syndrome.
  • the conventional differentiation culture method of human preadipocytes into adipocytes uses a medium supplemented with PPAR- ⁇ agost and isobutylmethylxanthine ( ⁇ ) that are not present in the living body as essential components.
  • PPAR- ⁇ agoist and PPAR- ⁇ agogo are particularly useful when screening drugs using a forceful system that interacts with candidate drugs.
  • -Candidate drugs due to the strong action of strikes Identification becomes difficult. Therefore, it is appropriate to perform drug screening using the conventional conventional culture method.
  • Non-patent literature l Hemmrich K et al., Differentiation 73: 28-35 (2005)
  • Non-Patent Document 2 Bruun JM et al, J Clin. Endocrinol Metab. 90: 2282-2289 (2005) Disclosure of the Invention
  • the problem to be solved by the present invention is that it is closer to the situation in the living body without using PPAR- ⁇ agost and sputum! It is to provide a method for screening substances that affect the sorting process.
  • the present inventors obtained adipocytes without using PPAR-yagost and IBMX by co-culturing adipose precursor cells with macrophages. As a result, the present invention has been completed.
  • the present invention provides:
  • a culture method for differentiating adipose precursor cells into adipocytes characterized by co-culturing adipose precursor cells with macrophages in a medium that does not contain PPAR—yagost and IBMX;
  • the cell is derived from a human, (1) or (2),
  • a fat cell obtainable by the method according to any one of (1) to (3),
  • a candidate substance is added to the medium, and the fat precursor
  • Adipocytes that can be obtained by the method a method for effectively screening for substances that influence the process of dividing fat precursor cells into fat cells using the culture method, and fat precursor cells that can be obtained thereby Substances that influence the process of differentiation into adipocytes, and kits for powerful screening are provided.
  • FIG. 1 is a microscopic image of oil red O-stained adipocytes obtained by co-culturing adipose precursor cells with macrophages for 7 days.
  • the scale bar is 49.9 ⁇ m.
  • FIG. 2 is a graph showing the lipid content of adipocytes obtained by co-culturing adipose precursor cells with macrophages.
  • FIG. 3 is a graph showing the effect of ECGC on the differentiation process from preadipocytes to adipocytes by oil red O staining.
  • Fig. 4 shows the effects of ECGC on the differentiation process from preadipocytes to adipocytes, adiponectin, AP-2, glucose transporter, IRS-1, leptin, LPL, PAI-1, TGF- ⁇ , It is a graph shown by expression of TNF-a and resistin.
  • White is without EC GC, black is co-cultured with adipocytes in the presence of ECGC Is.
  • the present invention is characterized in that adipose precursor cells are co-cultured with macrophages in a medium that does not contain PPAR-yagost and IBMX.
  • the present invention relates to a culture method. Since PPAR- ⁇ agonist and I ⁇ are artificial substances that are not produced in vivo, the culture method of the present invention using a medium that does not include both PPAR-y agonist and IB MX uses these substances.
  • Conventional differentiation culture methods for example, PPAR-yagost and IBMX are considered essential in the differentiation culture method of human adipose precursor cells into adipocytes.
  • the preadipocytes used in the present invention can be obtained by means and methods known to those skilled in the art. For example, it is induced from a stem cell such as a mesenchymal stem cell or an ES cell that is isolated from an animal, in particular, a visceral adipose tissue or a subcutaneous adipose tissue force. However, it is not limited to these.
  • the animal species from which the preadipocytes are derived is not particularly limited, and is preferably a mammal including, for example, a mouse, a rat, a rabbit, a dog, a cat, a rabbit, a horse, a monkey, and the like, more preferably a human It comes from.
  • a mammal including, for example, a mouse, a rat, a rabbit, a dog, a cat, a rabbit, a horse, a monkey, and the like, more preferably a human It comes from.
  • human preadipocytes it becomes possible to study the pathogenesis of metabolic syndrome and the like.
  • the animal species from which the macrophages co-cultured with the preadipocytes in the method of the present invention are not particularly limited, and may be the same or different from the animal species from which the preadipocytes are derived. Good.
  • cells are derived from the same animal species, more preferably from the same individual.
  • adipose precursor cells and macrophages derived from humans preferably from the same person, adipose cells that have been proliferated in vitro according to the present invention in reconstruction after mastectomy of breast cancer patients are used. It can also be used.
  • co-culture means that preadipocytes and macrophages can interact with each other. Thus, culturing these cells.
  • fat precursor cells and macrophages may be mixed and cultured in the same container.
  • fat precursor cells and macrophages may be isolated and cultivated with a permeable material.
  • Cells and macrophages can be placed in separate containers, and these containers can be connected by permeable means and cultured.
  • permeability means a property that allows cells to pass through substances such as medium force-in produced and secreted from medium components and cells.
  • the preferred co-culture mode is economical, or the convenience such as subsequent assembly and operation is considered.
  • the preadipocytes and macrophages are isolated from each other by a permeable material.
  • a strong culture form can be realized by using an incubator such as Coaster / Corning or Millipore. Isolation means that the preadipocytes are not in direct contact with the macrophage.
  • Those skilled in the art can select and use various incubators and isolation means according to the purpose and desired conditions.
  • the medium used in the present invention a medium well known in the art can be used, and can be appropriately selected and used according to the cells to be used, the culture conditions, and the purpose.
  • DMEMZF-12 medium containing 10% FCS, 66 nM insulin, 0.033 mM piotin, 0.017 mM pantothenic acid may be used.
  • the adipose precursor cells may adhere to the base material in a strong medium, or may be suspended in a low-adhesion culture dish.
  • the object of the present invention can also be achieved by adding the culture supernatant of macrophages to the medium of preadipocytes. Therefore, such a culture form is also included in the co-culture of the present invention.
  • the present invention provides a fat cell obtainable by the above-described method for culturing fertilizer.
  • Powerful adipocytes which do not contain artificial substances and are cultured under conditions similar to those in vivo, have properties similar to those in vivo. Therefore, it becomes possible to conduct in vitro experiments under conditions close to in vivo using the fat cells obtained by the present invention.
  • the present invention is characterized in that a fat cell obtainable by a culture method for differentiating the aforementioned preadipocytes into a fat cell is administered to a subject.
  • the present invention relates to a method for treating or preventing diseases such as ataxia, leprosy, and lipodystrophy.
  • treatment can be performed by performing the above method using adipose precursor cells derived from a subject with lipodystrophy and transplanting the obtained adipocytes into the subject.
  • the present invention uses an adipocyte obtainable by the above-described culture method for differentiating the preadipocyte into an adipocyte. It relates to a treatment method. This method can be applied to, for example, breast reconstruction and various cosmetic operations. Preferably, problems such as side effects can be avoided by using adipocytes differentiated from autologous adipose precursor cells.
  • the present invention relates to a method for screening for a substance that affects the differentiation process from preadipocytes to adipocytes using the culture method described above. Since the differentiation culture method of the present invention is a method for separating adipose precursor cells under conditions close to those in a living body without containing an artificial substance, a screening method performed using this method was obtained. This has the advantage of increasing the possibility that the substance will show the same effect in vivo.
  • To influence the separation process means to suppress, stop or promote the differentiation of preadipocytes into adipocytes. Specifically, reducing the differentiation rate from preadipocytes to adipocytes, delaying the differentiation, incompletely or completely stopping the differentiation, reducing the number of adipocytes, or On the contrary, increasing the differentiation rate, increasing the number of adipocytes, and further allowing the differentiated adipocytes to become younger.
  • the screening method of the present invention is carried out by adding a candidate substance to the differentiation culture system and examining differentiation from adipose precursor cells to adipocytes.
  • a candidate substance for example, ECGC (epigalocatechin gallate) analogs, derivatives or mutants, or macrophages, which are known to suppress the differentiation of preadipocytes into adipocytes
  • ECGC epigalocatechin gallate
  • macrophages which are known to suppress the differentiation of preadipocytes into adipocytes
  • the number of fat cells is calculated by microscopic observation. Observe the size, number, fat content, etc. of lipid droplets by staining with oil red o Substances whose expression decreases or increases with differentiation from adipocyte precursor cells to adipocytes, such as a P2, CD36, adiponectin , Resistin, GLUT4, TNF-a, PAI-1 etc. are measured by quantitative PCR or immunoplot.
  • differentiation from adipose precursor cells to adipocytes in the above differentiation culture system when no candidate substance is added is also examined, and compared with differentiation when a candidate substance is added. If the differentiation is suppressed in the candidate substance-added culture system, the candidate substance is considered to be a substance that suppresses the differentiation, and conversely, if the differentiation is promoted! It is considered to be a substance that promotes the differentiation.
  • a substance that suppresses differentiation into adipocytes using a human-derived adipose precursor cell may be obesity, diabetes, hypertension. It is considered to be a substance useful for the treatment or prevention of diseases such as hyperlipidemia, metabolic syndrome, arteriosclerotic disease, and ischemic heart disease. In addition, if a substance that promotes differentiation is found, it is considered to be a substance useful for the treatment or prevention of diseases such as malnutrition, itchiness, and lipodystrophy.
  • the screening method of the present invention is carried out in the absence of PPA- ⁇ agonist and ⁇ , it is possible to find useful substances that are close to in vivo conditions and that can eliminate the effects of these substances and that are useful. It can be said to be an easy, efficient and economical method. Furthermore, by using the patient-derived cells and the screening method of the present invention, it becomes possible to create drugs and cells for tailor-made treatment. In addition, for example, it is possible to screen for substances that are useful for producing meat that meets the needs of consumers by using fat precursor cells derived from sea bream and inducing adipocytes efficiently at desired sites. .
  • the present invention relates to a substance that can be obtained by the above-described screening method and that influences the process of dividing preadipocytes into adipocytes.
  • a substance that promotes differentiation from preadipocytes into adipocytes may be used in the culture method of the present invention to increase the number of adipocytes obtained.
  • the present invention screens a substance that affects the differentiation process from preadipocytes to adipocytes, characterized by using the culture method described above.
  • Providing a kit for The kit of the present invention may include a container, a device, a culture medium and the like for performing the co-culture of the present invention. Usually, an instruction manual is attached to the kit.
  • means for facilitating screening and promoting efficiency such as an oil red O staining solution for confirming differentiation into adipocytes, quantitative PCR.
  • Human adipose tissue-derived adipose precursor cells were suspended in a basic medium (DMEMZF-12 medium containing 10% FCS) to a concentration of 100,000 ZmL, and 1.5 mL of this suspension was seeded in a 6-well culture dish. . The basal medium was changed the next day, and every 3 days thereafter, and adipose precursor cells were grown until confluent.
  • a basic medium (DMEMZF-12 medium containing 10% FCS)
  • Palin was collected from the periphery to 30 mL. After separating lymphocytes at a specific gravity of 1.066, 15 mL of the separated solution was transferred to a 50 mL tube. Next, 30 mL of blood was layered and centrifuged at 500 g, 16 ° C. for 40 minutes, and separated from the bottom into approximately three layers of red blood cells, lymphocyte separation liquid (colorless and transparent), and plasma (yellow and transparent). A white cell layer located between the lymphocyte separation solution and plasma was collected and suspended in a medium. After washing by centrifugation (3 times), the resulting cell pellet was suspended in DMEM / F-12 medium containing 10% human serum.
  • the medium of the 6-well culture dish obtained in A was replaced with 2.7 mL of DMEM / F12 medium containing 10% human serum, 66 nM insulin, 0.033 mM piotin, 0.017 mM pantothenic acid.
  • the lipid content was measured.
  • a control one cultured with preadipocytes alone was used.
  • the macrophage and adipose precursor cells were co-cultured, the lipid content of the cells was confirmed to be differentiated into adipocytes, which was larger than the lipid content of the cells when cultured alone with the adipose precursor cells (Fig. 1). And Figure 2).
  • adipose precursor cells were co-cultured with macrophages in a medium containing 100 M ECGC.
  • RNA was extracted from the adipocytes induced to differentiate.
  • PCR internal standard: GAPDH
  • adiponectin, AP-2, glucose transporter, IRS-1, leptin, LPL, PAI-1, TGF- ⁇ , TNF-a, and resistin were quantified.
  • adiponectin, glucose transporter, leptin, and TGF- ⁇ which are known to decrease during adipocyte differentiation, is greater in the presence of ECGC compared to those cultured in the absence of ECGC. It was confirmed that the number of cells was increased compared to the cultured cells (see Fig. 4).
  • the expression of AP-2, IRS-1, LPL, PAI-1, TNF- ⁇ , and resistin which are known to increase with adipocyte differentiation, was cultured in the absence of ECGC. It was confirmed that it was reduced in cells cultured in the presence of ECGC compared to those (see Fig. 4). From these results, the co-culture of the present invention In the system, it was found that substances that affect the differentiation of preadipocytes into adipocytes can be screened.
  • the present invention provides a culture method for differentiating adipocytes from preadipocytes without using PPAR-yagost and IBMX that do not exist in the body, and a screening method for substances that affect such a differentiation process. Therefore, in the field of pharmaceuticals, for example, in the field of development, manufacturing, health food, etc. of preventive, therapeutic or diagnostic agents for diseases such as metastatic syndrome, research on adipocytes and related cells It can be used in fields.

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Abstract

La présente invention concerne un procédé de culture pour induire la différenciation d'un préadipocyte en un adipocyte, le procédé comprenant la co-culture du préadipocyte avec un macrophage dans un milieu de culture exempt d'agoniste de PPAR-Ϝ et d'IBMX ; un adipocyte produit grâce au procédé de culture ; un procédé de criblage pour une substance susceptible d'influer sur le processus de différenciation d'un préadipocyte en un adipocyte, caractérisé par l'utilisation du procédé de culture ; une substance susceptible d'influer sur le processus de différenciation d'un préadipocyte en un adipocyte, la substance étant obtenue grâce au procédé de criblage ; un kit pour le criblage ; et autres.
PCT/JP2006/313285 2005-07-04 2006-07-04 Procede de culture pour la differenciation d'un preadipocyte en adipocyte par co-culture avec un macrophage, et criblage d'une substance susceptible d'influer sur le processus de differenciation d'un preadipocyte en adipocyte WO2007004635A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7758784B2 (en) 2006-09-14 2010-07-20 Iap Research, Inc. Method of producing uniform blends of nano and micron powders
US8889065B2 (en) 2006-09-14 2014-11-18 Iap Research, Inc. Micron size powders having nano size reinforcement
CN106834411A (zh) * 2017-03-24 2017-06-13 中国农业科学院北京畜牧兽医研究所 使用同一脂肪细胞联合分析细胞增殖和沉脂能力的方法
JP2018522556A (ja) * 2015-07-23 2018-08-16 コリア リサーチ インスティチュート オブ ケミカル テクノロジーＫｏｒｅａ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｃｈｅｍｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ 脂肪細胞とマクロファージの三次元共培養方法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7758784B2 (en) 2006-09-14 2010-07-20 Iap Research, Inc. Method of producing uniform blends of nano and micron powders
US8889065B2 (en) 2006-09-14 2014-11-18 Iap Research, Inc. Micron size powders having nano size reinforcement
JP2018522556A (ja) * 2015-07-23 2018-08-16 コリア リサーチ インスティチュート オブ ケミカル テクノロジーＫｏｒｅａ Ｒｅｓｅａｒｃｈ Ｉｎｓｔｉｔｕｔｅ Ｏｆ Ｃｈｅｍｉｃａｌ Ｔｅｃｈｎｏｌｏｇｙ 脂肪細胞とマクロファージの三次元共培養方法
CN106834411A (zh) * 2017-03-24 2017-06-13 中国农业科学院北京畜牧兽医研究所 使用同一脂肪细胞联合分析细胞增殖和沉脂能力的方法

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