WO2007001016A1 - Matériau destiné à améliorer le tissu dermique et utilisation de celui-ci - Google Patents

Matériau destiné à améliorer le tissu dermique et utilisation de celui-ci Download PDF

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Publication number
WO2007001016A1
WO2007001016A1 PCT/JP2006/312871 JP2006312871W WO2007001016A1 WO 2007001016 A1 WO2007001016 A1 WO 2007001016A1 JP 2006312871 W JP2006312871 W JP 2006312871W WO 2007001016 A1 WO2007001016 A1 WO 2007001016A1
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Prior art keywords
fibroblasts
skin tissue
improving material
cells
human
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PCT/JP2006/312871
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English (en)
Japanese (ja)
Inventor
Katsumi Ebisawa
Minoru Ueda
Hideaki Kagami
Kunihiko Okada
Ryuji Kato
Mazlyzam Abdul Latif
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National University Corporation Nagoya University
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Application filed by National University Corporation Nagoya University filed Critical National University Corporation Nagoya University
Priority to JP2007523972A priority Critical patent/JP4982865B2/ja
Publication of WO2007001016A1 publication Critical patent/WO2007001016A1/fr

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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
    • C12N5/0652—Cells of skeletal and connective tissues; Mesenchyme
    • C12N5/0656—Adult fibroblasts
    • 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
    • C12N5/0697—Artificial constructs associating cells of different lineages, e.g. tissue equivalents
    • C12N5/0698—Skin equivalents
    • 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
    • C12N2502/09—Coculture with; Conditioned medium produced by epidermal cells, skin cells, oral mucosa cells
    • C12N2502/094—Coculture with; Conditioned medium produced by epidermal cells, skin cells, oral mucosa cells keratinocytes
    • 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
    • C12N2502/13—Coculture with; Conditioned medium produced by connective tissue cells; generic mesenchyme cells, e.g. so-called "embryonic fibroblasts"
    • C12N2502/1323—Adult fibroblasts

Definitions

  • the present invention relates to the use of cells derived from oral tissues, and more specifically to a skin tissue improving material (composition for improving skin tissue) mainly composed of the cells.
  • the present invention also relates to a method for improving skin tissue using cells derived from oral tissues.
  • Various biomaterials are used as a skin tissue repair material to repair abnormalities or defects in skin tissue due to wounds or the like, or congenital or acquired (aged) wrinkles or depressions. ing.
  • WO1997Z004720 corresponding to JP 11-510069 A
  • dermal fibroblasts isolated from the patient's own skin tissue are cultured outside the body, and the culture is then applied to the skin tissue (affected area). The method of injecting is described.
  • the C-terminal and N-terminal peptide parts are removed and the antigen is removed.
  • biochemical materials such as those described in each of the above journals are not hydrolyzed in vivo, and the effect of the administration site disappears at an early stage, so the effect does not continue. There is a drawback. Also, it is difficult to completely eliminate immunological effects when using this type of material.
  • the present invention creates a biocompatible material having a content different from that of a conventional skin tissue repair material (that is, an affected area filling material), and the purpose thereof is skin tissue (affected area) in which an abnormality or defect has occurred.
  • a material for improving skin tissue (composition containing living cells) having a function capable of improving the physiological state of the affected tissue and the surrounding skin tissue to a healthier one with the repair (filling) of It is.
  • Another object of the present invention is to provide a method for improving the physiological state of the affected area by using such a material for improving skin tissue, that is, applying it to the affected area (skin tissue).
  • the skin improving material that is, a composition for improving skin tissue
  • a composition for improving skin tissue is mainly composed of fibroblasts derived from human or other oral tissues of mammals.
  • the skin improvement material (composition for improving skin tissue) disclosed herein comprises a pharmaceutically acceptable medium (including a carrier).
  • skin tissue is a term that should be interpreted broadly unless otherwise specified, and includes epidermis, dermis and subcutaneous tissue.
  • oral tissue is a term that should be broadly interpreted unless otherwise specified, and includes periodontal tissue (including gingiva, periodontal ligament, alveolar bone, and cementum). )) And vaginal mucosa.
  • the present inventors administered fibroblasts collected from the oral mucosa (for example, gingiva or vaginal mucosa) completely different from the skin tissue to be repaired, to the skin tissue to be repaired. Not only the filling effect on the skin tissue, but also the physiological state of the administration site and its surrounding sites (for example, promoting cell division in the epidermis and the color of the skin based on the skin, galling, texture, etc. Improvement of the physical state of the skin and improvement of the nutritional state of Z or skin), and the present invention has been completed.
  • the oral mucosa for example, gingiva or vaginal mucosa
  • oral tissue-derived fibroblasts which are the main constituents of the material, are highly efficient with various cell growth factors ( As a result of continuous production (ie, supply to the affected area) of VEGF, KGF, etc.) at the administration site, the skin tissue (typically subcutaneous tissue) deformation site similar to conventional skin tissue repair materials may be obtained.
  • the physiological state of the site and the surrounding skin tissue can be improved.
  • a preferred embodiment of the skin tissue improving material disclosed herein is a culture obtained by proliferating fibroblasts derived from human or other mammalian oral tissues in vitro as the fibroblasts. It is characterized by being composed mainly of cultured cells.
  • Fibroblasts derived from intraoral tissues have a relatively high growth rate in in vitro culture (eg, compared to dermal dermal cells) and a desired amount of intraoral tissue-derived fibers. Blast cells can be produced efficiently in a short period of time. For this reason, according to the skin tissue improving material of this embodiment, the cost for producing fibroblasts can be reduced, and the skin tissue (affected part) can be quickly repaired and improved.
  • a preferred embodiment of the skin tissue improving material disclosed herein is characterized in that the fibroblasts are human gingival fibroblasts and Z or periodontal ligament fibroblasts. These fibroblasts are particularly active in producing a group of cell growth factors, and can obtain a high skin tissue improvement effect in addition to a skin tissue repair (filling) effect.
  • a preferable skin tissue improving material is prepared in the form of a suspension containing cultured cells obtained by growing the fibroblasts in vitro, and a particularly preferable skin tissue improving material (living cells).
  • VEGF vascular endothelial growth factor
  • It is a skin tissue improving material substantially composed of a liquid.
  • it is substantially a suspension containing the cells, wherein the suspension has a keratinocyte growth factor (KGF) content of at least 0.5 ng per mg of protein in the supernatant of the suspension.
  • KGF keratinocyte growth factor
  • gingival fibroblasts and Z or periodontal ligament fibroblasts are administered to the affected area.
  • Methods for supplying VEGF and Z or KGF are provided.
  • the present invention also provides a suitable method for producing the skin tissue improving material (composition for improving skin tissue) disclosed herein. That is, the production method of the present invention comprises preparing fibroblasts derived from oral tissues (preferably periodontal tissues) of humans or other mammals, culturing the fibroblasts in vitro, and And collecting the cultured cells. Typically, the cultured cells are suspended in a suitable liquid medium. Preferably, a suspension containing the cultured cells is prepared so that a subject (patient) to which the skin tissue improving material is applied does not contain a substance that can be an immunogen.
  • fibroblasts derived from oral tissues (preferably periodontal tissues) prepared for culture are collected from a subject (patient) to be applied or a person related to the person. According to the method disclosed here, fibroblasts derived from the oral tissue (preferably periodontal tissue) procured are cultured (proliferated), and a skin tissue improving material having the above-mentioned effects is efficiently produced. Can do.
  • a preferred embodiment of the method for producing a skin tissue improving material disclosed herein is characterized in that the prepared fibroblasts are human gingival fibroblasts and Z or periodontal ligament fibroblasts.
  • the cells are cultured under conditions capable of producing VEGF and Z or KGF.
  • the present invention provides a method for repairing (or improving) the skin tissue of the affected area by injecting the skin tissue improving material disclosed herein into the affected area of the subject.
  • This method typically involves a suspension comprising fibroblasts derived from any of the skin tissue improvers disclosed herein (eg, human or other mammalian oral tissues, preferably periodontal tissues). ) And administering (preparing cells) the prepared skin tissue improving material (for example, the above-mentioned fibroblast suspension) to the affected area (skin tissue, for example, subcutaneous tissue) of the subject.
  • the prepared skin tissue improving material for example, the above-mentioned fibroblast suspension
  • the present invention provides a method for using fibroblasts for skin tissue improvement, comprising administering (transplanting) fibroblasts derived from oral tissues of humans or other mammals to affected areas. To do.
  • human gingival fibroblasts and Z or periodontal ligament fibroblasts are administered to the affected area ( Transplant).
  • gingival fibroblasts and Z or periodontal ligament fibroblasts collected from a subject in advance are cultured in vitro, and the resulting self-cultured cells (typically pharmaceutically acceptable with the cultured cells).
  • a cell suspension containing a medium (a suitable solvent) is administered (injected) to the affected area (skin tissue, eg, subcutaneous tissue) of the subject. It is particularly preferred to administer cells cultured under conditions capable of producing VEGF and Z or KGF.
  • the present invention provides a method for improving skin tissue characterized by administering (transplanting) human gingival fibroblasts and Z or periodontal ligament fibroblasts (preferably cells obtained from the patient itself) to the affected area. The method of using the fibroblast is provided.
  • FIG. 1 is a graph showing the amount of VEGF produced in the culture medium by human gingival fibroblasts (cultured cells) according to Examples and human skin fibroblasts (cultured cells) according to Comparative Examples.
  • the horizontal axis is the culture time (h)
  • the vertical axis is the VEGF concentration (pgZmg protein).
  • the left side of the figure is the result of human gingival fibroblasts (GF), and the right side of the figure is the result of human dermal fibroblasts (DF).
  • Fig. 2 is a graph showing the amount of KGF produced in the culture solution by human gingival fibroblasts (cultured cells) according to the examples and human skin fibroblasts (cultured cells) according to the comparative examples.
  • the horizontal axis is the culture time (h)
  • the vertical axis is the KGF concentration (ngZmg protein).
  • the left side of the figure is the result of human gingival fibroblasts (GF), and the right side of the figure is the result of human skin fibroblasts (DF).
  • FIG. 3 is a photomicrograph of the tissue after fluorescent immunostaining showing the state of the injection site after 2 months have passed since the human gingival fibroblasts according to the example were injected into the dorsal dermis of nude mice. (Rate 40 times).
  • FIG. 4 is a photomicrograph of the tissue after fluorescent immunostaining showing the state of the injection site after 2 months have passed since the human gingival fibroblasts according to the example were injected into the dorsal dermis of nude mice. (Large rate 400 times).
  • the skin tissue improving material disclosed herein may be a skin tissue improving material (pharmaceutical composition) for humans and other mammals, and oral tissues (preferably periodontium) of humans and other mammals. It is a skin tissue improving material composed mainly of fibroblasts derived from tissue or sputum mucosa. Usually, fibroblasts collected from a subject (subject) that is preferentially used as a component of oral tissues of mammals of the same species as the subject (subject) due to immunological problems Or it is preferable to adopt the cultured cells (autologous cells).
  • the cell type is particularly selected.
  • gingival fibroblasts of humans preferably the subject
  • Z or skin tissue improving materials mainly composed of periodontal fibroblasts are preferable.
  • These fibroblasts are preferred as cell materials because they have the ability to efficiently produce various cell growth factors (typically VEGF or KGF) that grow rapidly in vitro (in vitro). ,.
  • the cultured cells at the stage of actual use are derived from the fibroblasts and the purpose of the present invention (that is, repair and improvement of skin tissue). If the cell growth factor (VEGF, KGF, etc.) required to achieve () is produced, the cell appearance and other factors will be increased by repeated subculture. Even if the nature of the is different from the primary fibroblasts collected.
  • the “fibroblast derived from intraoral tissue” according to the present invention includes cells after such subculture.
  • fibroblasts derived from oral tissues is similar to the conventional method for collecting cells of this type and does not require any special treatment.
  • fibroblasts derived from periodontal tissue typically gingiva or periodontal ligament
  • the cells to be used should be collected from the submucosa (for example, the mucous membrane) in the oral cavity! This is an advantage for the target person).
  • the collected fibroblasts can be cultured and propagated in the same manner as the conventional cell culturing method to establish a cell line (subculture system).
  • a general a MEM medium, Eagle medium, Dulbecco's modified Eagle medium (DMEM medium) or the like to which an appropriate serum material, antibiotics or the like are added can be suitably used as the medium.
  • Cultured cells are confluent at about 37 ° C (preferably in a CO incubator) in a suitable culture vessel.
  • the number of passages is not particularly limited, but is typically 10 or less (for example, 3 to 6).
  • the target cells are recovered from the culture vessel.
  • the recovery method is the same as that of the conventional fibroblast, and no special operation / treatment is required for carrying out the present invention.
  • cells attached to the inner wall surface of the culture vessel are treated with an appropriate enzyme (eg, trypsin) to be released and collected together with the culture solution.
  • the collected cells are cultured in an appropriate serum-free medium for 12 hours or longer, preferably 24 hours or longer.
  • immunogenic substances typically serum components contained in the medium can be substantially removed.
  • the cultured cells can be cryopreserved by a conventionally known method.
  • a cell suspension from which the immunogenic substance has been substantially removed ie, a composition based on cultured cells and an appropriate serum-free medium, buffer or other appropriate solvent
  • a composition based on cultured cells and an appropriate serum-free medium, buffer or other appropriate solvent is suitable for skin tissue.
  • the skin tissue-improving material includes fibroblasts as a main component and a pharmaceutically acceptable medium.
  • a pharmaceutically acceptable medium typically a medium such as a serum-free medium or a solvent such as a buffer
  • various auxiliary components may be included.
  • auxiliary components typically include a medium such as a serum-free medium or a solvent such as a buffer.
  • auxiliary components typically include a medium such as a serum-free medium or a solvent such as a buffer.
  • the prepared skin tissue improving material is a conventional skin tissue repair material (see, for example, the above-mentioned patent document (International Publication No. WO97 / 04720) or journal (DeLustro F et al., Duranti F et al.)). Can be administered to the affected area in the same manner.
  • the entire contents of these references are incorporated herein by reference.
  • a skin tissue improving material in the form of a cell suspension can be injected into the subdermal tissue using an appropriate syringe or the like.
  • a cell agglomerate composed of a target fibroblast cell may be used as a skin tissue improving material.
  • it can typically be administered as a complex of fibroblasts and a matrix.
  • suitable biocompatible materials polysaccharides, proteins and other high-molecular organic materials, inorganic materials, etc.
  • PRP platelet-rich plasma
  • the dose and the number of doses can vary depending on the symptoms, there are no particular limitations. Generally, the dose and the number of doses are determined by doctors and other users, and thus do not limit the present invention.
  • the skin tissue improving material disclosed here can be applied to the improvement of gingival tissue. That is, the present invention provides, as another aspect, fibroblasts derived from oral tissues of humans or other mammals (typically fibroblasts derived from oral tissues of humans or other mammals in vitro). A gingival tissue improving material mainly composed of cultured cells obtained by proliferation in step 1) is provided.
  • Fibroblasts from human gingival tissue were collected. That is, Nagoya University Hospital ⁇ Oral Surgery Adult patient power Gingival tissue was collected from the extracted tooth (approved by the Ethics Committee of Nagoya University School of Medicine and obtained the consent of the patient.) O The obtained gingival tissue was 37 ° C for 2 hours. Collagenase treatment (Wako Pure Chemical Industries, Ltd. product: concentration 5 mgZmL) was applied. The treated gingival tissue is transplanted to a culture dish containing a 3.5 cm diameter DMEM medium and cultured under conditions of 37 ° C and 5% CO to obtain fibroblasts (Examples) attached to the dish. It was.
  • DMEM medium (Sigma-) containing 10% ushi fetal serum (Invitrogen product; No. 10099-141) and 1% antibiotic antifungal agent (Invitrogen product; No. 15240-062).
  • Aid rich No. D6429
  • the fibroblasts adhering to the culture flask were recovered by treatment with an agent (Invitrogen product; TrypLE Select (trade name)). The number of collected cells was measured using a commercially available cell counting analyzer (product of Schar fe system; CASY (registered trademark)). The results are shown in Table 1.
  • the nutrient solution was aspirated and washed twice with PBS, and then DMEM medium without serum was added to continue the cultivation. After 24 hours, 48 hours, and 72 hours, 1 mL of the culture solution was collected, and 1 mL of fresh DMEM medium was added to the well. The culture solution collected at each time was centrifuged for 5 minutes at 4 ° C and lOOOOrpm, and the supernatant was collected. The collected supernatant was stored at -70 ° C as necessary.
  • VEGF vascular endothelial growth factor
  • KGF human KGF Immunoassay kit
  • Fig. 1 For VEGF and in Fig. 2 for KGF.
  • the left column graph shows the results for GF (gingival fibroblast), that is, gingival fibroblasts
  • DF skin fibroblast
  • gingival fibroblasts were significantly more capable of producing (secreting) both VEGF and KGF.
  • the amount of VEGF produced by gingival fibroblasts was 30 pg or more per mg of supernatant protein after 24 hours of culture in serum-free DMEM medium. In addition, it was confirmed that about 45 pg and about 60 pg or more of VEGF was produced (secreted) per mg of supernatant protein after 48 hours and 72 hours of culture, respectively.
  • the amount of KGF produced by gingival fibroblasts was 0.5 ng or more (more specifically, 0.8 ng or more) after 1 hour of culture in serum-free DMEM medium. In addition, it was confirmed that about 1.5 ng and about 2 ng or more of KGF was produced (secreted) per mg of supernatant protein after 48 hours and 72 hours of culture, respectively.
  • Gingival fibroblasts cultured under the same conditions as in Test Example 1 were treated with the cell dissociator and collected from the culture flask. The number of collected cells is determined using the above cell counting analyzer. Measured.
  • the product was stained (fluorescent rabenole) using a PKH26 Red Fluorescent Cell Linker Mini Kit.
  • the fluorescently labeled cells were suspended using PBS, and the cell concentration was adjusted to about IX 10 7 cells ZmL, and then injected into the dermis on the back of nude mice.
  • tissue-Tek O.C.T. Compound (Sakura Finetechnical Co.)” to prepare a section of about 6 ⁇ m.
  • the blue and fluorescent parts of the photographs shown in Fig. 3 (magnification 40x) and Fig. 4 (magnification 400x) are nuclei stained with the fluorescent dye “DAPI”, and the red! ⁇ fluorescent part is the fluorescent dye “PKH26”.
  • Transplanted cells (gingival fibroblasts) stained with “ The green fluorescent site is a fluorescently labeled anti-human collagen type I monoclonal antibody.
  • the gingival fibroblasts (skin tissue-improving material) transplanted to nude mice remain in the dermis after 2 months, as in the transplantation (ie, (Surviving) was confirmed (Fig. 3). It is also observed that human type I collagen exists in the cytoplasm of the transplanted gingival fibroblasts and the surrounding area. This confirms that gingival fibroblasts still produce type I collagen after transplantation.
  • the skin tissue improving material disclosed herein is used to repair skin tissue and improve physiological conditions. It can be performed. For this reason, it is useful as a material used for dermatological (including plastic and cosmetic surgery) treatment.

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Abstract

Cette invention concerne un matériau destiné à améliorer un tissu dermique comprenant principalement un fibroblaste dérivé d’un tissu buccal d’un humain ou d’un autre mammifère. Le fibroblaste sera de préférence un fibroblaste gingival humain et/ou un fibroblaste parodontal humain qui possède d’excellentes capacités pour produire un facteur de croissance de l’endothélium vasculaire (VEGF) et/ou un facteur de croissance des kératinocytes (KGF).
PCT/JP2006/312871 2005-06-29 2006-06-28 Matériau destiné à améliorer le tissu dermique et utilisation de celui-ci WO2007001016A1 (fr)

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Cited By (8)

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WO2008081818A1 (fr) * 2006-12-28 2008-07-10 National University Corporation Nagoya University Matière pour améliorer un tissu cutané et son procédé de fabrication
JP2010213892A (ja) * 2009-03-17 2010-09-30 Univ Of Tokyo 粘膜組織由来の線維芽細胞、これを含有する組織改善材及びこれらの製造方法並びに利用方法
WO2011014883A2 (fr) * 2009-07-31 2011-02-03 Chironcell Inc. Traitement de rajeunissement de la peau et des rides par fibroblastes gingivaux et son facteur de croissance : activation de l'effet par l'acide hyaluronique
WO2011024550A1 (fr) * 2009-08-31 2011-03-03 国立大学法人大阪大学 Méthode de production efficace de cellules souches pluripotentes induites au moyen de cellules dérivées de la muqueuse buccale
JP2011519358A (ja) * 2008-04-11 2011-07-07 ケアジェン カンパニー，リミテッド 成長因子−模倣（ｍｉｍｉｃｋｉｎｇ）ペプチド及びその用途
JP2015057419A (ja) * 2008-03-31 2015-03-26 スカルセル テラピュティク 皮膚の老化の美容的処置法
JP2016523948A (ja) * 2013-07-09 2016-08-12 アシスタンス パブリク−オピトー ドゥ パリ 脱毛症の治療における歯肉線維芽細胞の使用
WO2018091698A1 (fr) * 2016-11-18 2018-05-24 Scarcell Therapeutics Compositions utiles pour le traitement de maladies liées à l'immunité

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JP7333272B2 (ja) * 2017-01-11 2023-08-24 スパイナルサイト， エルエルシー 線維芽細胞治療活性を増強する方法

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8338174B2 (en) 2006-12-28 2012-12-25 National University Corporation Nagoya University Material for ameliorating skin tissue and method for producing the same
WO2008081818A1 (fr) * 2006-12-28 2008-07-10 National University Corporation Nagoya University Matière pour améliorer un tissu cutané et son procédé de fabrication
JP2015057419A (ja) * 2008-03-31 2015-03-26 スカルセル テラピュティク 皮膚の老化の美容的処置法
JP2017014277A (ja) * 2008-03-31 2017-01-19 スカルセル テラピュティク 皮膚の老化の美容的処置法
JP2011519358A (ja) * 2008-04-11 2011-07-07 ケアジェン カンパニー，リミテッド 成長因子−模倣（ｍｉｍｉｃｋｉｎｇ）ペプチド及びその用途
JP2010213892A (ja) * 2009-03-17 2010-09-30 Univ Of Tokyo 粘膜組織由来の線維芽細胞、これを含有する組織改善材及びこれらの製造方法並びに利用方法
WO2011014883A3 (fr) * 2009-07-31 2011-07-14 Chironcell Inc. Traitement de rajeunissement de la peau et des rides par fibroblastes gingivaux et son facteur de croissance : activation de l'effet par l'acide hyaluronique
WO2011014883A2 (fr) * 2009-07-31 2011-02-03 Chironcell Inc. Traitement de rajeunissement de la peau et des rides par fibroblastes gingivaux et son facteur de croissance : activation de l'effet par l'acide hyaluronique
WO2011024550A1 (fr) * 2009-08-31 2011-03-03 国立大学法人大阪大学 Méthode de production efficace de cellules souches pluripotentes induites au moyen de cellules dérivées de la muqueuse buccale
JP5514215B2 (ja) * 2009-08-31 2014-06-04 国立大学法人大阪大学 口腔粘膜由来細胞を利用した誘導多能性幹細胞の効率的な製造方法
US8748179B2 (en) 2009-08-31 2014-06-10 Osaka University Method for efficient production of induced pluripotent stem cells utilizing cells derived from oral mucosa
JP2016523948A (ja) * 2013-07-09 2016-08-12 アシスタンス パブリク−オピトー ドゥ パリ 脱毛症の治療における歯肉線維芽細胞の使用
WO2018091698A1 (fr) * 2016-11-18 2018-05-24 Scarcell Therapeutics Compositions utiles pour le traitement de maladies liées à l'immunité
US11229670B2 (en) 2016-11-18 2022-01-25 Scarcell Therapeutics Compositions useful for the treatment of immune-related diseases

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