WO2013187194A1 - Composition pharmaceutique efficace pour le traitement de maladies osseuses - Google Patents

Composition pharmaceutique efficace pour le traitement de maladies osseuses Download PDF

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WO2013187194A1
WO2013187194A1 PCT/JP2013/064153 JP2013064153W WO2013187194A1 WO 2013187194 A1 WO2013187194 A1 WO 2013187194A1 JP 2013064153 W JP2013064153 W JP 2013064153W WO 2013187194 A1 WO2013187194 A1 WO 2013187194A1
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pharmaceutical composition
cells
bone
patient
culture supernatant
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PCT/JP2013/064153
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English (en)
Japanese (ja)
Inventor
晃弘 大山
石川　博
邦弘 栗原
美隆 渡邊
貴 中原
吉昭 井出
伊東　章
Original Assignee
医療法人社団 土合会
学校法人 日本歯科大学
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Priority to JP2014521229A priority Critical patent/JPWO2013187194A1/ja
Publication of WO2013187194A1 publication Critical patent/WO2013187194A1/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
    • C12N5/0654—Osteocytes, Osteoblasts, Odontocytes; Bones, Teeth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • 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
    • C12N2500/00—Specific components of cell culture medium
    • C12N2500/30—Organic components
    • C12N2500/38—Vitamins
    • 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
    • C12N2500/00—Specific components of cell culture medium
    • C12N2500/30—Organic components
    • C12N2500/42—Organic phosphate, e.g. beta glycerophosphate
    • 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
    • C12N2501/39—Steroid hormones
    • 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"
    • C12N2502/1352—Mesenchymal stem cells
    • C12N2502/1382—Adipose-derived stem cells [ADSC], adipose stromal stem cells

Definitions

  • the present invention relates to a pharmaceutical composition useful for the treatment of a bone disease and a method for treating a bone disease using the pharmaceutical composition.
  • the present invention provides a pharmaceutical composition for treating a patient suffering from a bone disease, comprising the following steps: (1) culturing cells containing stem cells in a medium under conditions for inducing bone differentiation; (2) obtaining a culture supernatant by removing the cells from the medium; and (3) preparing a pharmaceutical composition comprising components contained in the culture supernatant.
  • a pharmaceutical composition that can be obtained (or actually obtained).
  • the present invention provides a method for treating a patient suffering from a bone disease, (1) culturing cells containing stem cells in a medium under conditions for inducing bone differentiation; (2) obtaining a culture supernatant by removing the cells from the medium; (3) preparing a pharmaceutical composition containing components contained in the culture supernatant; and (4) administering to the patient a therapeutically effective amount of the pharmaceutical composition;
  • a therapeutic method comprising:
  • Osteoporosis is a disease in which the fine structure of bone is broken due to a decrease in bone mass or bone mineral content, and bone strength is lowered to easily cause fracture.
  • osteoporosis there are about 11 million osteoporosis patients in Japan, 80% of which are women. In the United States, it is estimated that symptoms appear in more than 30 million people. Furthermore, since osteoporosis is a common disease after middle age, it is estimated that the number of patients will increase with the aging of developed countries in recent years.
  • osteoporosis The symptoms of osteoporosis are thought to be caused by the deterioration of bone quality caused by the imbalance between bone formation and bone resorption in bone metabolism. In particular, after menopause, the effect of female hormone on bone resorption decreases with the decrease in female hormone secretion, and thus osteoporosis tends to occur.
  • Drugs for improving bone metabolism such as bone resorption inhibitors such as bisphosphonates, estrogens and calcitonin, bone formation promoters such as vitamin K2, and bone metabolism regulators such as calcium agents for the treatment of osteoporosis Is used.
  • bone resorption inhibitors such as bisphosphonates, estrogens and calcitonin
  • bone formation promoters such as vitamin K2
  • bone metabolism regulators such as calcium agents for the treatment of osteoporosis Is used.
  • osteoporosis not only osteoporosis but also other bone diseases such as osteogenesis imperfecta, rickets, osteodysplasia, or fractures are similarly untreated medical treatments for effective osteoporosis treatment.
  • osteogenesis imperfecta a bone disease that causes osteogenesis imperfecta, rickets, osteodysplasia, or fractures.
  • fractures are similarly untreated medical treatments for effective osteoporosis treatment.
  • An object of the present invention is to provide a pharmaceutical composition useful for the treatment of bone diseases, which is a type different from the conventional treatment of bone diseases.
  • the present invention has the following features.
  • the pharmaceutical composition of the present invention is a pharmaceutical composition for treating a patient suffering from a bone disease, comprising the following steps: (1) culturing cells containing stem cells in a medium under conditions for inducing bone differentiation; (2) obtaining a culture supernatant by removing the cells from the medium; and (3) preparing a pharmaceutical composition containing the components contained in the culture supernatant; Is a pharmaceutical composition that can be obtained.
  • the pharmaceutical composition of the present invention is a pharmaceutical composition for treating a bone disease, comprising the following steps: (1) culturing cells containing stem cells in a medium under conditions for inducing bone differentiation; (2) obtaining a culture supernatant by removing the cells from the medium; and (3) preparing a pharmaceutical composition containing the components contained in the culture supernatant; By (actually) obtained pharmaceutical composition.
  • the preparation method of the present invention is a preparation method of a pharmaceutical composition for treating a patient suffering from a bone disease, (1) culturing cells containing stem cells in a medium under conditions for inducing bone differentiation; (2) obtaining a culture supernatant by removing the cells from the medium; and (3) preparing a pharmaceutical composition containing the components contained in the culture supernatant; It is a preparation method containing.
  • the treatment method of the present invention is a treatment method for a patient suffering from a bone disease, (1) culturing cells containing stem cells in a medium under conditions for inducing bone differentiation; (2) obtaining a culture supernatant by removing the cells from the medium; (3) preparing a pharmaceutical composition containing components contained in the culture supernatant; and (4) administering to the patient a therapeutically effective amount of the pharmaceutical composition; Is a treatment method.
  • the bone disease in the present invention broadly means bone-related diseases.
  • the bone disease in the present invention includes osteoporosis, osteogenesis imperfecta, rickets, osteodysplasia, or fracture.
  • the bone differentiation-inducing condition in the present invention may be any bone differentiation-inducing condition generally understood by those skilled in the art when bone differentiation is induced.
  • bone differentiation-inducing conditions using ascorbic acid, ⁇ -glycerophosphate, and dexamethasone are well known.
  • cells containing stem cells may or may not be derived from patients.
  • the “cells containing stem cells” in the present invention are derived from a patient, for example, they may be derived from a patient's adipose tissue, but are not limited thereto.
  • the patient's adipose tissue can be obtained from, for example, subcutaneous fat, cheek fat, visceral fat and the like.
  • the culture medium for culturing the “cells containing stem cells” in the present invention may contain blood serum collected from the patient.
  • blood serum collected from the patient infection problems can be significantly reduced when the pharmaceutical composition of the present invention is administered to the patient.
  • the “cells containing stem cells” in the present invention are not derived from a patient, for example, even if they are derived from a human body other than the patient or derived from an animal other than the human body, they were established. It may be derived from a cell line, but is not limited thereto.
  • tissue stem cells or iPS cells can be used as stem cells in “cells containing stem cells” in the present invention, but are not limited thereto. Although it is technically possible to use ES cells, ES cells can be excluded from the “cells containing stem cells” in the present invention when such use of ES cells is not preferred.
  • “cells containing stem cells” are cultured in a medium under conditions for inducing bone differentiation.
  • the “cells containing stem cells” are components useful for the treatment of bone diseases (such as physiologically active substances) in the medium. Release.
  • a culture supernatant can be obtained by removing cells from the medium.
  • the culture supernatant contains components useful for the treatment of bone diseases.
  • the present invention provides a pharmaceutical composition for use in the treatment of bone diseases, containing the useful component thus obtained.
  • the bone disease in the present invention broadly means bone-related diseases.
  • the bone disease in the present invention includes osteoporosis, osteogenesis imperfecta, rickets, osteodysplasia, or fracture.
  • “cells containing stem cells” may or may not be derived from patients. From the viewpoint of the problem of infection, it can be said that it is preferable to use those derived from patients as the “cells containing stem cells” in the present invention.
  • the “cells containing stem cells” in the present invention are derived from a patient, for example, they may be derived from a patient's adipose tissue, but are not limited thereto.
  • the adipose tissue of the patient can be collected from, for example, subcutaneous fat, cheek fat, visceral fat and the like.
  • the cell group constituting the adipose tissue includes stem cells, fibroblasts, endothelial cells constituting blood vessels, and the like in addition to adipocytes. .
  • Examples of a method for collecting tissue from a patient include an incision method and a suction method.
  • the collected tissue can be separated into discrete cells by using an enzyme.
  • Many known enzymes are already known. Examples of such enzymes include lipase, trypsin, collagenase, dispase and the like. These enzymes can be used as appropriate as a single solution or as a mixed solution of two or more.
  • the medium for culturing the “cells containing stem cells” in the present invention is blood serum collected from the patient (in the present invention, “autologous serum”). May be included).
  • autologous serum blood serum collected from the patient
  • infection problems can be significantly reduced when the pharmaceutical composition of the present invention is administered to the patient.
  • the “cells containing stem cells” in the present invention are not derived from a patient, for example, even if they are derived from a human body other than the patient or derived from an animal other than the human body, they were established. It may be derived from a cell line, but is not limited thereto.
  • tissue stem cells or iPS cells can be used as stem cells in “cells containing stem cells” in the present invention, but are not limited thereto. Although it is technically possible to use ES cells, ES cells can be excluded from the “cells containing stem cells” in the present invention when such use of ES cells is not preferred.
  • the bone differentiation-inducing condition in the present invention may be any bone differentiation-inducing condition that is generally understood by those skilled in the art to induce bone differentiation.
  • bone differentiation-inducing conditions using at least ascorbic acid, ⁇ -glycerophosphate, and dexamethasone are well known. It is also known to use vitamin D, BMP-2, BMP-4, and / or FGF-2 in addition to these three types.
  • cells containing stem cells can be cultured in a medium to which these predetermined substances are added, but are not limited thereto.
  • a medium supplemented with these substances can be used at the following final concentrations.
  • Ascorbic acid (100 ⁇ M), ⁇ -glycerophosphate (10 mM), dexamethasone (10 nM) Ascorbic acid (50 ⁇ M), ⁇ -glycerophosphate (10 mM), dexamethasone (100 nM) (3) Ascorbic acid (200 ⁇ M), ⁇ -glycerophosphate (10 mM), dexamethasone (100 nM) (4) Ascorbic acid (200 ⁇ M), ⁇ -glycerophosphate (10 mM), dexamethasone (100 nM), vitamin D (10 nM)
  • a medium for culturing (also referred to as a culture solution in the examples), a known medium can be widely used as long as it is suitable.
  • ⁇ -MEM, Ham F10, Ham F12, RPMI 1640, DMEM, DMEM / F12 and the like can be mentioned, but not limited thereto.
  • the medium contains a substance that satisfies the condition for inducing bone differentiation.
  • autologous serum may be included in the culture medium as necessary.
  • the “cells containing stem cells” When “cells containing stem cells” are cultured in a medium under conditions for inducing bone differentiation, the “cells containing stem cells” contain components (such as physiologically active substances) useful for the treatment of bone diseases in the medium. discharge.
  • the culture supernatant can be obtained by removing cells from the medium.
  • the culture supernatant contains components useful for the treatment of bone diseases.
  • the present invention provides a pharmaceutical composition for use in the treatment of bone diseases, containing the useful component thus obtained.
  • the said culture supernatant can also be used as it is as a pharmaceutical composition of this invention, it can also be used after passing through predetermined processes, such as refinement
  • the solution containing the useful component can be intravenously administered to a patient by drip infusion after being diluted with physiological saline or lactek Ringer's solution. It can also be administered to a patient without such dilution.
  • the surprising and remarkable effect of the pharmaceutical composition of the present invention is that when “cells containing stem cells” are cultured in a medium under conditions for inducing bone differentiation, the “cells containing stem cells” are released into the medium. It is presumed that the component (such as a physiologically active substance) that works is useful for the treatment of bone diseases.
  • stem cells and released into the medium are produced by stem cells and released into the medium, but at the same time, they may be produced by cells other than stem cells and released into the medium. There will be.
  • first, second, etc. may be used to represent various elements, it is understood that these elements should not be limited by those terms. These terms are only used to distinguish one element from another, for example, the first element is referred to as the second element, and similarly, the second element is the first element. Can be made without departing from the scope of the present invention.
  • tissue-constituting cell group usually contains stem cells because well-known techniques (for example, methods of transplanting to immunodeficient animals to produce teratomas or PCR-specific genes expressed in stem cells). It can be confirmed by a method of analysis, etc.).
  • the solution containing the adipose tissue constituent cells obtained by the treatment with the enzyme in this manner is placed in a centrifuge tube, centrifuged (1500 rpm, 10 minutes), and the adipose tissue constituent cells floating in the upper layer, the fat content, and Then, by removing the supernatant, a precipitate of the precipitated adipose tissue constituting cells was obtained (in this example, the adipose tissue constituting cell group suspended in the upper layer was removed, but was suspended in the upper layer.
  • a “cell containing a stem cell” can also be obtained from a group of adipose tissue constituent cells, and this is also within the scope of the present invention.
  • normal culture solution means “autologous serum” (in this example, blood supernatant obtained by centrifuging blood collected from the patient (3000 rpm, 10 minutes). Is a culture solution (DMEM / F12) to which 10% is added.
  • the suspension was transferred to two 75 cm 2 flasks for cell culture (Corning 430641) and cultured in a culture apparatus (37 ° C., 5% carbon dioxide gas, 100% humidity).
  • induction culture medium means “ordinary culture medium” and bone differentiation-inducing reagents (ascorbic acid (100 ⁇ M), ⁇ -glycerophosphate (10 mM), dexamethasone (10 nM), The concentration means the final concentration in the culture solution) and refers to the culture solution obtained by adding.
  • the induced cells were removed while washing the cultured cells with Hanks' solution (Note that this washing is not limited to Hanks solution, but is suitable. As long as it is, any solution may be used, for example, a salt buffer solution containing glucose may be suitable.) Furthermore, the cells were cultured for 4 days in the “normal culture solution”. Subsequently, the cells were removed from the culture solution to obtain a supernatant (culture supernatant) of the culture solution.
  • Hanks' solution any solution may be used, for example, a salt buffer solution containing glucose may be suitable.
  • the cells are removed from the culture solution by (1) obtaining an upper culture solution from the culture solution so that cells (existing below the culture solution) are not included as much as possible ( 2)
  • the upper culture solution thus obtained was centrifuged (3000 rpm, 10 minutes), and (3) the supernatant after centrifugation was further filtered using a 0.45 ⁇ m filter.
  • the culture supernatant thus obtained is referred to as “with cell culture supernatant with differentiation induction” in this example.
  • the cells were removed from the culture solution to obtain a supernatant (culture supernatant) of the culture solution.
  • the cells are removed from the culture solution by (1) obtaining an upper culture solution from the culture solution so that cells (existing below the culture solution) are not included as much as possible ( 2)
  • the upper culture solution thus obtained was centrifuged (3000 rpm, 10 minutes), and (3) the supernatant after centrifugation was further filtered using a 0.45 ⁇ m filter.
  • the culture supernatant thus obtained is referred to as “cell culture supernatant without differentiation induction” in this example.
  • osteoporosis model rat An osteoporosis model rat was created by removing bilateral ovaries of a 9-week-old female rat.
  • the osteoporosis model rat is a disease model characterized in that estrogen is deficient by ovariectomy and bone turnover is increased, and the epiphysis of the long bone and the cancellous bone of the vertebral body are markedly reduced. It is a rat.
  • Results ⁇ Image of femur cross section >> The longitudinal and transverse sections of the femur of each rat were analyzed using ELE-SCAN, and the results are shown in FIG.
  • the upper part is a longitudinal sectional view
  • the lower part is a transverse sectional view.
  • cross-sectional views A, B, and C show cross-sectional views of the femur at the sites indicated by dotted lines A, B, and C in the vertical cross section.
  • “Con.” Does not remove the ovary, and administration of any culture supernatant (“cell culture supernatant with differentiation induction” and “cell culture supernatant without differentiation induction”) is administered.
  • FIG. 1 A longitudinal section and a transverse section are shown for a normal rat that has not been performed.
  • OVX shows a longitudinal sectional view and a transverse sectional view of an osteoporosis model rat (as described above, the ovary has been removed) to which neither culture supernatant has been administered.
  • CM (SC) shows a longitudinal sectional view and a transverse sectional view of an osteoporosis model rat administered with “cell culture supernatant without induction of differentiation”.
  • CM (OS) shows a longitudinal sectional view and a transverse sectional view of an osteoporosis model rat administered with “cell culture supernatant with differentiation induction”.
  • the femur of an osteoporosis model rat that has not been administered any culture supernatant compared to the femur of a normal rat (Con.) From which the ovaries have not been removed is It was found that the bone crest was significantly reduced and osteoporosis was developed. Further, in the femur of an osteoporosis model rat (CM (SC)) to which “cell culture supernatant without differentiation induction” was administered, the femur of an osteoporosis model rat (OVX) to which no culture supernatant was administered. It was found that bone crest decreased to the same extent as osteoporosis.
  • CM osteoporosis model rat
  • CM osteoporosis model rat
  • SC osteoporosis model rat
  • Bone density etc. was analyzed using Latheta LCT-200.
  • Table 1 shows the values of bone density and volume in cortical bone and cancellous bone, and the values of bone mineral density calculated from these values.
  • bone mineral content bone density ⁇ bone volume”.
  • CM osteoporosis model rat
  • OVX osteoporosis model rat
  • the cortical bone density is slightly lower in the osteoporosis model rat (OVX) in which none of the culture supernatant is administered, compared to the normal rat (Con.) From which the ovaries have not been removed. It turns out that the numerical value has not fallen.
  • the cancellous bone density in the osteoporosis model rat (OVX) in which none of the culture supernatants was administered, the value was remarkably reduced as compared with the normal rat (Con.) In which the ovaries were not removed. You can see that From this result, it can be seen that in osteoporosis model rats (OVX), the density of cancellous bone is significantly reduced compared to cortical bone. This phenomenon is similar to the symptoms seen in human osteoporosis.
  • the pharmaceutical composition of the present invention can be advantageously used for the treatment of bone diseases.

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Abstract

La présente invention s'attaque au problème consistant à fournir une composition pharmaceutique utile pour le traitement de maladies osseuses, qui est d'un type différent des compositions pharmaceutiques classiques utilisées pour le traitement de maladies osseuses. A cet effet, la présente invention concerne une composition utile pour le traitement de maladies osseuses ; et un procédé de traitement de maladies osseuses utilisant la composition. De manière plus spécifique, la présente invention concerne une composition pharmaceutique qui peut être utilisée pour traiter un patient souffrant d'une maladie osseuse, et qui peut être produite par l'intermédiaire des étapes consistant à : (1) cultiver des cellules contenant des cellules souches dans un milieu de culture dans des conditions induisant une différentiation osseuse ; (2) éliminer les cellules du milieu de culture pour obtenir un surnageant de culture ; et (3) préparer une composition pharmaceutique qui contient un composant contenu dans le surnageant de culture.
PCT/JP2013/064153 2012-06-12 2013-05-22 Composition pharmaceutique efficace pour le traitement de maladies osseuses WO2013187194A1 (fr)

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Cited By (3)

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WO2015166845A1 (fr) * 2014-05-01 2015-11-05 株式会社島津製作所 Procédé pour l'évaluation de l'état de différenciation de cellules
WO2019022451A3 (fr) * 2017-07-24 2019-04-11 한양대학교 에리카산학협력단 Composition pour prévenir ou traiter l'ostéoporose contenant des exosomes extraits de cellules souches à titre de principe actif
KR20190090369A (ko) * 2017-07-24 2019-08-01 한양대학교 에리카산학협력단 줄기세포로부터 추출된 엑소좀을 유효성분으로 포함하는 골다공증 예방 또는 치료용 조성물

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WO2015166845A1 (fr) * 2014-05-01 2015-11-05 株式会社島津製作所 Procédé pour l'évaluation de l'état de différenciation de cellules
WO2019022451A3 (fr) * 2017-07-24 2019-04-11 한양대학교 에리카산학협력단 Composition pour prévenir ou traiter l'ostéoporose contenant des exosomes extraits de cellules souches à titre de principe actif
KR20190090369A (ko) * 2017-07-24 2019-08-01 한양대학교 에리카산학협력단 줄기세포로부터 추출된 엑소좀을 유효성분으로 포함하는 골다공증 예방 또는 치료용 조성물
KR102035273B1 (ko) 2017-07-24 2019-10-22 한양대학교 에리카산학협력단 줄기세포로부터 추출된 엑소좀을 유효성분으로 포함하는 골다공증 예방 또는 치료용 조성물

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