WO2006038462A1 - Cellule novatrice de production de stéroïde - Google Patents

Cellule novatrice de production de stéroïde Download PDF

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WO2006038462A1
WO2006038462A1 PCT/JP2005/017349 JP2005017349W WO2006038462A1 WO 2006038462 A1 WO2006038462 A1 WO 2006038462A1 JP 2005017349 W JP2005017349 W JP 2005017349W WO 2006038462 A1 WO2006038462 A1 WO 2006038462A1
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cell
steroid
steroidogenic
cells
producing
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PCT/JP2005/017349
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Japanese (ja)
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Shigeki Gondo
Toshihiko Yanase
Taijirou Okabe
Hajime Nawata
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Kyushu University, National University Corporation
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Publication of WO2006038462A1 publication Critical patent/WO2006038462A1/fr

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    • A61K31/566—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol having an oxo group in position 17, e.g. estrone
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    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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    • 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
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    • C12N2506/00—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells
    • C12N2506/13—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from connective tissue cells, from mesenchymal cells
    • C12N2506/1346—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from connective tissue cells, from mesenchymal cells from mesenchymal stem cells
    • C12N2506/1353—Differentiation of animal cells from one lineage to another; Differentiation of pluripotent cells from connective tissue cells, from mesenchymal cells from mesenchymal stem cells from bone marrow mesenchymal stem cells (BM-MSC)

Definitions

  • the present invention relates to the production of steroid-producing cells, and more specifically, to a novel steroid-producing cell produced thereby and a production method thereof.
  • the invention also relates to the use of the cells so produced.
  • steroid hormones are known as “steroidal agents” used in bronchial asthma and rheumatism in addition to external and internal use for atopic dermatitis.
  • This steroidal agent has a strong immunosuppressive action, and it should be used with caution from the viewpoint of the power and side effects used in the treatment of a wide range of diseases.
  • steroid hormones produced in vivo are hormones that play a very important role in living organism maintenance. Insufficient production of steroid hormones in vivo reduces maintenance of regulation of glucose, regulation of Na'K balance, promotion of protein synthesis, control of inflammatory response 'immune response, sexual development, reproductive function, etc. When this steroid hormone is missing or decreased for various reasons, a condition called “steroid hormone deficiency” is caused.
  • adrenal cortex dysfunction is caused by a lack of adrenal steroid hormones, and specific symptoms include generalized malaise due to lack of secretion of the stress-responsive hormone glucocorticoid cortisol. It may become stronger and medical findings may include hypotension, hypoglycemia, hyponatremia, hyperkemia, and pigmentation. In the worst case, acute adrenal insufficiency may result in death due to an absolute shortage of adrenal steroid hormones or a sudden increase in the amount required due to stress such as infection. Adrenal cortex dysfunction is often accompanied by poor secretion of the mineralocorticoid hormone aldosterone, further promoting hyponatremia and hyperkemia.
  • Gonadal dysfunction All have a decreased production of gonadal steroid hormones due to a variety of etiologies, such as genetic factors, tumors, inflammation, surgery, radiation, etc. Refers to the disease state. Basically it is not a life-threatening problem, but when it occurs in young people in their teens and twenties, secondary sexual characteristics are impaired and the lack of masculinity and femininity also causes complex problems. It can happen. At the same time, it can be a problem that affects future fertility. In addition, there is a problem that osteoporosis and arteriosclerosis are likely to occur due to a long-term absence of gonadal hormones that are caused only by the effects on the reproductive system.
  • Steroid hormone supplementation therapy has been established as a current treatment method for these steroid hormone deficiencies, and provides many benefits as described in Non-Patent Document 1, for example.
  • Glucocorticoids are generally supplemented, but mineral corticoids are also added if that alone does not correct the electrolyte dysfunction.
  • it may be a fixed-dose oral administration, and it may be difficult to respond when the steroid requirement is rapidly increased due to infection, etc. If steroid excess continues, various side effects may occur.
  • Non-patent document 1 Laureti, S., Falorni, A., and Santeusanio, F. Improveme nt of treatment of primary adrenal insufficiency by administration of cortisone acetate in three daily doses.
  • the present invention has been made in view of such problems, and an object of the present invention is to provide a novel steroid-producing cell that can be used for the treatment of abnormal steroid hormone secretion such as steroid hormone deficiency.
  • steroid-producing cells that can secrete physiologically diverse steroid hormones, their production methods, uses, pharmaceutical compositions using the secreted hormones, and various diseases using the cells A cure for the disease For that purpose.
  • bone marrow cell transplantation may contribute to the regeneration of hematopoietic / mesenchymal cell groups in various organs.
  • bone marrow cells contain pluripotent progenitor cells that can be divided into various organs.
  • Bone marrow stem cells are known to grow into hematopoietic and mesenchymal cell groups, but before the present invention, they were not known to be separated into steroidogenic cells.
  • bone marrow cells can be separated into muscles and fats derived from the mesenchymal system as well as the adrenal cortex 'gonadal gland, and when steroidogenic cells are separated from bone marrow cells, Based on this new knowledge, and based on this and sincere examination and experimentation, we have succeeded in producing steroid-producing cells with several properties as described below.
  • a steroid-producing cell characterized by introducing a factor involved in steroid hormone synthesis into bone marrow cells and allowing the bone marrow cells to differentiate. Provided.
  • a novel steroid hormone-producing cell that can be used for treatment of abnormal steroid hormone secretion such as steroid hormone deficiency can be obtained by transplantation or the like.
  • the bone marrow cells include, but are not limited to, bone marrow stem cells, bone marrow mesenchymal stem cells, hematopoietic stem cells, and pluripotent progenitor cells.
  • a steroid characterized by introducing a factor involved in steroid hormone synthesis into a pluripotent stem cell and allowing the pluripotent stem cell to differentiate.
  • a production cell is provided.
  • the pluripotent stem cells are preferably somatic pluripotent stem cells including mesenchymal stem cells and hematopoietic stem cells.
  • the pluripotent stem cells are preferably derived from bone marrow cells.
  • the pluripotent stem cells of the present invention are not limited to those derived from bone marrow, but may be those derived from yarn and tissue where pluripotent stem cells are present.
  • the factor involved in the steroid synthesis is not limited to this, but is a transcriptional regulator of steroid hormone synthase. Transcription of this steroid hormone synthase
  • the factor is preferably Steroidogenic factor 1 (SF—l).
  • the steroid hormones produced in the steroidogenic cells are predanenolone, progesterone, oxycorticosterone, conoleticosterone. emissions (corticoste rone), 18-hydroxy-Kono retinyl corticosterone (18- hydroxycorticosterone), Anoredosute Ron, aldosterone Roh, 1 ⁇ Hitoro 3 r shea pregnenolone, 17 a- hyaroxypregnelone)
  • 17-Hydroxyprogesterone (17 0; -11 (1): 0): 0865 6]: 0116), 11 deoxyconoreth, 11-deoxycortisol, Cortisol, DHEA (dehydroepia ndrosterone, Andros anion ( one or more of the steroid hormones consisting of androstenedione), estrone, androstenediol, testosterone, and estradiol.
  • the steroid-producing cells secrete steroid hormones over a predetermined period.
  • the predetermined period is preferably at least 2 weeks. This can reduce the frequency of treatment and reduce the burden on the patient.
  • the steroidogenic cells are adrenocorticotropic hormone (ACTH) responsive.
  • ACTH responsiveness is dose dependent.
  • a steroidogenic bone marrow cell obtained in the present invention is transplanted to a patient with adrenal insufficiency, if the steroid in the adrenal cortex in the living body is insufficient, ACTH is secreted, and the adrenal gland is secreted from the cell.
  • Cortical steroids are secreted and, conversely, if excessive, ACTH can be suppressed and, as a result, corticosteroid secretion can also be suppressed.
  • the steroid-producing cells are cultured in a retinoic acid-containing medium or a medium containing retinoic acid and hCG (human chorionic stimulating hormone) to obtain a gonadal steroid hormone.
  • a retinoic acid-containing medium or a medium containing retinoic acid and hCG human chorionic stimulating hormone
  • a step of preparing bone marrow cells (a) a step of preparing bone marrow cells, and (b) introducing a factor involved in steroid hormone synthesis in the bone marrow cells,
  • a method for producing steroid-producing cells comprising the step of separating the cells into steroid-producing cells. This makes it possible to produce a variety of effective steroid hormones It becomes possible to produce steroidogenic cells that can be secreted.
  • the method further comprises a step of culturing in a retinoic acid-containing medium, or a retinoic acid and hCG (human chorionic stimulating hormone) -containing medium.
  • a method for producing a steroidogenic cell characterized by inducing differentiation.
  • a pharmaceutical composition comprising the physiologically diverse steroid hormone secreted by the steroidogenic cell force and a pharmaceutically acceptable carrier. According to the pharmaceutical composition thus obtained, it becomes possible to effectively treat steroid hormone secretion abnormalities such as steroid hormone deficiency and various self-exemptions.
  • a steroidogenic cell obtained by introducing a factor involved in a steroid synthase into bone marrow cells or pluripotent stem cells and allowing the cells to differentiate.
  • bone marrow cell transplantation may contribute to the regeneration of hematopoietic and mesenchymal cells in various organs.
  • bone marrow cells contain pluripotent progenitor cells that can be divided into various organs.
  • Bone marrow stem cells are known to grow into hematopoietic and mesenchymal cells, but before the present invention, they were known to be separated into steroidogenic cells.
  • bone marrow cells can be divided into muscles and fats derived from the mesenchymal system as well as the adrenal cortex 'gonadal gland, and when steroidogenic cells are separated from bone marrow cells, As a result of obtaining new knowledge and conducting repeated sincerity studies and experiments based on this knowledge, we succeeded in generating steroid-producing cells having several desirable properties described below.
  • bone marrow cells and pluripotent stem cells can be separated into steroidogenic cells. It is not limited to a good person or a mammal such as a mouse.
  • the cell collection method may be a known method.
  • SF-1 a tissue-specific transcription factor of steroid hormone synthase, also known as ad renal 4 binding protein (Ad4BP), belongs to the nuclear receptor superfamily and is reported to be involved in many steroidogenic genes. (1). SF-1 is thought to be particularly important for steroidogenesis and steroidogenic tissue growth, as a complete absence of adrenal glands and gonadal glands was observed in this SF-1 knockout mouse.
  • Ad4BP a tissue-specific transcription factor of steroid hormone synthase
  • Ad4BP ad renal 4 binding protein
  • the transcriptional regulatory factor is not limited to Steroidogenic factor 1 (SF-1), but may be a factor necessary for synthesizing steroid hormones in the cell.
  • SF-1 Steroidogenic factor 1
  • an adenovirus vector for example, an adenovirus vector, an adeno-associated virus vector, a retrovirus vector, a lenti Virus vectors, HIV vectors, etc. This is done using a kuta. However, it can be carried out by using known techniques such as electoral positioning and protein direct introduction using only such methods using vectors derived from viruses.
  • the method of separating bone marrow cells and the like into steroid-producing cells is considered to be a method in which an exogenous factor that acts only by introduction of an endogenous factor involved in steroid hormone synthesis is also possible. That is, by culturing the bone marrow cells in a culture solution and medium containing exogenous factors, it is possible to separate them into target steroid-producing cells.
  • the production of steroid hormones by steroid-producing cells according to the present invention increases the amount of steroid hormone synthase in bone marrow cells by introducing a synthase transcription regulatory factor. It seems to be the cause. That is, in the steroidogenic cells according to the present invention, it was found from experiments using RT-PCR that the mRNA expression of the steroid hormone synthase is enhanced by forcibly expressing the transcriptional regulatory factor. Furthermore, immunostaining experiments using anti-cytochrome P450 SCC antibodies showed that the expression of the steroid hormone synthase is enhanced at the protein level.
  • the steroidogenic bone marrow cells obtained in the present invention are required to produce stable steroid hormones for a certain period or longer (at least 2 weeks, preferably 3 weeks or more).
  • steroid hormone production continued for at least 112 days.
  • this long-lasting ability to produce steroids is due to the introduced adenovirus-derived urine SF-1 rather than by induction of endogenous mouse SF-1. It was confirmed. That is, even if the expression level of ushi SF-1 by adenovirus is low, the bone marrow cells are sufficient for long-term and diverse steroid production, or SF-1 is necessary for the initiation of steroid production. However, it is not important to maintain it.
  • the novel steroidogenic cells can control steroid secretion in response to corticotropin (ACTH).
  • This ACTH response is dose-dependent.
  • the steroidogenic cells obtained in the present invention are considered to be beneficial.
  • ACTH corticotropin
  • the steroidogenic cells obtained in the present invention are considered to be beneficial.
  • ACTH corticotropin
  • the steroidogenic cells obtained in the present invention are transplanted to a patient with adrenal insufficiency
  • ACTH is secreted if the steroid in the adrenal cortex in the living body is insufficient, and the corticosteroid is secreted from the cells.
  • a CTH is suppressed, and as a result, corticosteroid secretion can also be suppressed.
  • the present inventors further examined how the novel steroidogenic cells are affected by the culture conditions.
  • the novel steroid-producing cells can produce gonadal steroid hormones by culturing them in a medium containing retinoic acid or a medium containing retinoic acid and hCG (human chorionic stimulating hormone).
  • retinoic acid induces the production of a potent gland hormone that is known to induce the production of adrenal hormone (corticosterone).
  • steroids can be secreted at a high local concentration in transplantation in vivo. In other words, steroids are secreted at the necessary site as much as necessary, and the systemic steroids do not become excessive, so no serious side effects are expected.
  • the steroidogenic bone marrow cells obtained in the present invention were transferred to autologous cells.
  • steroid hormone secretion abnormalities such as steroid hormone deficiency, allergy / autoimmune disease treatment, rejection of transplanted organ rejection, etc.! U, thought to provide a cure.
  • steroid hormone secretion abnormalities such as steroid hormone deficiency, allergy / autoimmune disease treatment, rejection of transplanted organ rejection, etc. by transplanting the novel steroid-producing cells to a target site in the living body.
  • a method of treatment is provided.
  • a pharmaceutical composition comprising the steroid hormone secreted from the novel steroidogenic cell obtained above and a pharmaceutically acceptable carrier. Is done.
  • the pharmaceutical composition may be used as a “steroid” for the treatment of bronchial asthma, rheumatism and the like, as well as external use for oral atopic dermatitis. It can also be used for the treatment of steroid deficiency, allergies, autoimmune diseases and the like.
  • the pluripotency of bone marrow cells obtained in the present invention into adrenal or gonadal steroid-producing cells is an important model for elucidating the tissue, site, and cell-specific mechanism of adrenal gonadal cell differentiation. It is speculated that it can be.
  • the steroidogenic cells obtained in one embodiment of the present invention are differentiated from pluripotent stem cells such as bone marrow stem cells, mesenchymal stem cells, hematopoietic stem cells in bone marrow cells. Presumed to be. As is known, mesenchymal stem cells are also present in fat and muscle. Therefore, it is considered that mesenchymal stem cells and hematopoietic stem cells can be separated from the steroid-producing cells of the present invention even if they are not derived from bone marrow cells. If it can be collected from sources other than bone marrow, it has the advantages of wide options and high convenience and safety.
  • pluripotent stem cells such as bone marrow stem cells, mesenchymal stem cells, hematopoietic stem cells in bone marrow cells. Presumed to be.
  • mesenchymal stem cells are also present in fat and muscle. Therefore, it is considered that mesenchymal stem cells and hematopoietic stem cells can be separated from the
  • a recombinant (recombinant) vector derived from a human type 5-adenovirus vector was prepared.
  • Usci SF—lZAd4BP cDNA (distributed by Prof. Kenichiro Morohashi, National Institute for Basic Biology, Okazaki National Research Institute) was digested with BamHI and EcoRI, and the recombinant cosmid vector pAxCAwt (Takara) containing the CAG promoter Inserted into Swal site.
  • the recombinant bovine SF-1 adenoviral vector (Adx-bSF-1) is reported by Miyake et al. (See Proc. Natl. Acad. Sci. USA 93: 132, 1996) I made it.
  • Adx-LacZ an adenovirus vector into which only the j8-galactosidase gene was transferred was constructed. This vector was called Adx-LacZ.
  • a 3-month-old male B6-GFP (green fluorescence protein) mouse (C57BLZ6Tgl 4 (act-EGFP) osbY01) was donated by Yamada (Kyoto University).
  • 4-month-old male 129SVJ mice were also used.
  • the bone marrow cells were cultured using conventional techniques with some adjustments. Briefly, fresh complete bone marrow cells were recovered by pouring the bone marrow cells from the mice into the culture medium.
  • Culture medium A consists of 2 mM ML-daltamine, lOOUZml penicillin, 100 gZml sprepmycin, 0.0125 / z gZml amphotericin (Sigma—aldrich, Irvine ⁇ UK) ⁇ 10-7 M hydrocortisone (Nikkenk ayaku, Japan) and Contains a-MEM containing 20% donor horse serum (Lot6603F and 7307F, ICN Biochemicals, Aurora, Ohio). The collected cells were seeded in a 75 cm 2 tissue culture flask (Nalge Nunc, Rochester, NY) and incubated with the culture medium A at 37 ° C. and 5% C02.
  • Adherent cells were cultured for several weeks, treated with trypsin, and stored at ⁇ 80 ° C. with a cell banker until use.
  • the stored BMCs were cultured in culture medium A for 120-180 days (passage 12-18) with the goal of growing a relatively purified cell population as needed in the experiment. From this cell population, 5 ⁇ 10 5 BMCs were again seeded in a 60 mm Petri dish (Nunc) with the culture medium A. When the BMCs grow to subconfluent The cells were infected with adenovirus with about 10 plaque forming unit Z cells. As a control for all experiments, the BMCs expressed
  • Progesterone P4
  • Deoxycorticosterone DOC
  • Corticosterone ⁇
  • 17 ⁇ Hydroxyprogesterone 17 ⁇ —OH P4
  • 11 Deoxycortisol S
  • dehydroepandrosterone DHEA
  • ⁇ 4-A ⁇ 4 -androstenedione
  • T testosterone
  • the amount of P4 and DOC secreted into the culture medium was also confirmed in the presence of synthetic 124ACTH (Shionogi Co., Osaka, Japan) in the absence of Z.
  • the detection limits for P4, DOC, ⁇ , 17 ⁇ —OH ⁇ 4, S, DHEA, ⁇ 4— A, and T are 0.1 ng / ml, 0.02 ⁇ g / ml, 20. Ong / ml, 0 lng / ml, 0.04 ng / ml, 0.2 ng / ml, 0.1 ng / ml, and 0.05 ngZml or less.
  • LightCycler for quantitative analysis of various steroidogenic enzymes, including StAR, ACTH receptor (ACTH—R), and P450scc, P450cl7, P450C11, P450501, P450ald, 3 j8— HSD, and 17 j8—HSD type 3 GmbH, Mannheim, Germany).
  • the cultured BMCs and Y-1 Total RNA was isolated from cells using RNasy mini kit (Qiagen) and from mouse testis and adrenal gland using Isogen (Wako Pure Chemical Industries, Osaka Japan).
  • First-strand complementary DNA was synthesized using 5 ⁇ g of total RNA as a template, and PCR was performed in the LightCycler according to the manufacturer's instructions.
  • the sense Z antisense primer used was reported by Mukai et al. (Conditionally immortalized adrenocortical cell lines at undifferentiated states exhibit inducible Expression of glucocorticoid—synthesizing g enes; Eur. J. Biochem. 269, 69-81, 2002 ). PCR conditions are available upon request. The threshold was measured when the fluorescence intensity determined in LightCycler Software Ver. 3.5 was in the geometric phase of amplification. The product was subjected to a 2% agarose gel. The nucleotide sequence of each PCR product was confirmed by direct sequencing using appropriate primers. The relative expression levels of the mRNA were calibrated against their ⁇ -actin and its ratio to mouse adrenal cortex ⁇ -1 cells, or mouse testis or adrenal gland, which were the controls.
  • the present inventors used the above-described method to adenovirus with ushi SF-1 (Adx — BSF— Created 1). As a result of experiments, the present inventors have clarified that various steroids are produced when long-term cultured bone marrow cells are infected with Adx-bSF-1.
  • Adx—bSF 1 infected bone marrow cells contain significant amounts of progesterone (P4), deoxycorticosterone (DOC), corticosterone ( ⁇ ), 17 ⁇ hydroxyprogesterone (17 ⁇ -OH).
  • Adx—LacZ infected cells did not produce. In Adx-LacZ-infected control cell cultures, all steroids except S were not detected. The trace amount of S detected in the control medium is probably a cross-reaction (9.5%) of S antibody to hydrocortisone, and no steroid precursors are likely to be produced.
  • FIG. 2 (a) to (f) are graphs showing the results of real-time PCR for StAR, P450scc, 3 j8- HSD, P450cl1, P450cl7, 17 j8- HSD type 3 and ACTH-R, respectively.
  • the actual specific PCR band in the agarose gel amplified above 40 centimeters and stained with ethidium bromide is shown below the figure.
  • the relative mRNA expression level is j8— Calibrated with actin.
  • S and L indicate BM Cs transfected with Adx-bSF-1 and BMCs transfected with Adx-LacZ, respectively.
  • Adx LacZ-infected target Itoda force, etc.
  • the steroid hormone synthetase ster oidogenic acute regulatory protein (StAR), P450scc, 3 j8—hydroxysteroid dehydrogenase (3 j8—USD;), P450cl l, P450cl7, and 17 j8—USD type 3 MRNA expression was observed in bone marrow cells at 11 days after Adx-bSF-1 infection. On the other hand, it was not observed in Adx-LacZ-infected cells. P450ald mRNA could not be verified.
  • Adrenocorticotropic hormone receptor (ACTH-R) was also expressed in Adx-LacZ-infected cells but the expression level was very low (2Z1000 of adrenal expression) and was further decreased in Adx bSF-1 infected cells .
  • the relative ratio to the expression of control Y-1 cells is expressed in the case of StAR, P450scc, and 3 ⁇ HSD; for the expression of the mouse adrenal gland, it is expressed in the case of P450cl l and ACTH-R. It is expressed in the case of P450cl7 and 17
  • FIG. Fig. 3 reveals the expression of P450scc, a steroid hormone synthase. Green fluorescent cells are positive for P450scc. As a negative control, preimmune serum and cells did not react (data not shown). That is, it was found that the expression level of steroid hormone synthase protein is enhanced by expressing bSF-1 in the bone marrow cells.
  • the steroidogenic cells simultaneously produce a mixture of adrenal and gonadal steroids, that is, DOC, B, DHEA, ⁇ 4-A, and T.
  • P450cl7 which is a steroid hormone synthase, is expressed in human adrenal gland but not in mouse adrenal gland, the prominent expression of P450cl 7 in the bone marrow cells in the present invention is due to the mixed production of steroids. It suggests that it will occur beyond.
  • the bone marrow cells are pluripotent in steroid-producing cells, and there is a common source of steroid-producing tissue; that is, the bone marrow cell-derived steroid obtained in the present invention. It was suggested that the producer cells may be stem cells. Then, this assumption was examined using flow cytometry.
  • FIG. 4 (a) to (f) show cell surface markers c-kit, CDl lb, CD34, CD44, CD45, and Sea-1. From the experimental results, CD45 specific for hematopoietic cells and CD34 specific for hematopoietic progenitor cells were negative. CD1 lb, a marker for monocytes and macrophages, was also negative. Although the mouse mesenchymal stem cell marker is not completely clear and controversial, the potential marker CD44 was negative in the bone marrow cells. On the other hand, hematopoietic and mesenchymal stem / progenitor cell markers c kit and Sea-1 were positive.
  • the bone marrow cells obtained in the present invention are heterogeneous, steroidogenic cells were probably pluripotent and originated from immature stem cells.
  • Long-term cultured bone marrow cells were treated with 0.05 mM ascorbic acia, 10 mM ⁇ -glycerophosphate ⁇ and 0.1 ⁇ dexameth asone, so that they were separated like osteoblasts stained with alkaline phosphatase (data shown). ) This proves that long-term cultured bone marrow cells have mesenchymal properties!
  • FIG. 5 is a graph showing the results.
  • mRNA induction of steroidogenic enzymes P450scc, 3 ⁇ -HSD, P450c21, P450cl1, and 17j8-HSD by 2.4 M ACTH was also confirmed by real-time PCR.
  • mRNA induction of ACTH-R was not confirmed (Fig. 6).
  • Cells used in the experiment were treated with 2.4 ⁇ ACTH on days 0, 4, and 7 after infection with Adx-bSF-1 (DayO) and cultured for 4 days. On day 11, the total RNA of the cells was extracted and subjected to real-time PCR.
  • Figures 6 (a) to (f) are respectively P450scc, 3
  • 8— HSD, P450c21, P450cl l in the presence of 2.4 M ACTH (lower right oblique column) and absence (white column). , 17 j8-HSD type 3 and ACTH-R mRNA expression. The values in the figure are indicated by the average value person SD (n 3). Relative mRNA expression levels were calibrated with ⁇ 8-actin.
  • control Y-1 cells The relative ratio to the expression of control Y-1 cells is expressed in the case of P4 50scc and 3 j8- HSD; P450c21, P45 for mouse adrenal glands It is expressed in the case of Ocl l and ACTH-R; it is expressed in the case of 17 j8-HSD type 3 for mouse testis.
  • Figs. 7 (a) and 7 (b) show the results of progesterone (P4) and deoxycorticosterone (DOC) in the culture medium of long-term cultured BMCs from GFP mice, respectively. Shows the time course of basal secretions (time course). The value in the figure shows the average value of duplicate (duplicate) dishes.
  • the black column shows the steroid secreted by the cell force infected with Adx-bSF-1. Secretion of P4 and DOC was not detectable in cultures from BMCs infected with Adx-LacZ (data not shown). From Figure 7, it is clear that P4 and DOC production lasted at least 112 days. Considering the half-life of adenovirus (2-3 weeks), this long-term steroid production is unexpected.
  • bSF-1 RT-PCR was performed using RNA extracted from cell forces obtained on days 0, 14, 21, and 49 in FIG. Electrophoresis was performed on a 1.5% agarose gel, and ethidium bromide was used for staining.
  • Fig. 8 shows the results.
  • Y1, V, (1), S and L are Y-1 cells (negative control), Adx-bSF1 (positive control), BMCs before infection, Adx-bSF, respectively.
  • the present inventors further examined how the steroidogenic cells of the present invention are affected by the culture conditions. Similar to the method described above, long-term cultured bone marrow cells (LTBMCs) Infection with urine SF-1-expressing virus or control virus, and retinoic acid (A TRA), retinoic acid and hCG (human chorionic stimulating hormone) during viral infection and medium exchange. day 0, 4, 7, 11, 14), dayl 4-18 [Honolemon in the cultured medium was measured. The results are shown in FIGS. 9A and 9B (when ATRA is added to the medium) and FIGS. 10A and 1 OB (when ATRA and hCG are added to the medium).
  • LTBMCs long-term cultured bone marrow cells
  • a TRA retinoic acid
  • hCG human chorionic stimulating hormone
  • the production of testosterone was markedly promoted (from Fig. 9B)
  • the steroid-producing cells of the present invention were induced to differentiate into gonadal hormone-producing cells when cultured in a medium containing retinoic acid. It was suggested.
  • Fig. 1 (a) to (h) are long-term cultures from GFP mice, pgestesterone (P4), deoxycorticosterone (DOC), corticostero (B), 17 ⁇ hydroxyprogesterone (17 ⁇ — ⁇ 4), 11 deoxycortisol (S), dehydroepandrosterone (DHEA), ⁇ 4—androstenedine ( ⁇ 4—A), And a graph showing the basal secretion amount of testosterone (T).
  • FIG. 2 (a) to (f) are graphs showing the results of real-time PCR of StAR, P450scc, 3 j8- HSD, P450cl 1, P450cl 7, 17 j8-HSD type 3 and ACTH-R, respectively.
  • FIG. 3 is a view showing an immunostained image obtained by using an anti-cytochrome P450scc antibody of BMCs collected from a 129VJ mouse.
  • FIGS. 5 (a) and 5 (b) are graphs showing the effect of ACTH on the secretion of progesterone (P4) and DOC from cultured BMCs in which GFP mouse power was also collected.
  • Figures 6 (a) to (f) are respectively 2.
  • Figures 7 (a) and (b) show the time courses of the basal secretions of progesterone (P4) and deoxycorticosterone (DOC) in the culture medium of long-term cultured BMCs from GFP mice, respectively.
  • FIG. 8 shows the expression of AdSF-bSF-1 derived bSF-1 on agarose gel.
  • FIG. 9 129VJ mouse Adx-BSF-l infection BMCs obtained from retinoic acid (concentration 0 ⁇ : L0 _4 M) corticosterone production amount when cultured in medium containing the (a), Tesutosu The figure which shows teron production amount (b).
  • Fig. 10 shows Adx-bSF-l-infected BMCs collected from 129VJ mice when cultured under various culture conditions (containing cortisol, retinoic acid, and hCG (human chorionic gonadotropin)) The figure which shows corticosterone production amount (a) and testosterone production amount (b).

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Abstract

L’invention concerne une cellule novatrice de production de stéroïde utilisable dans le traitement de sécrétion d’hormone stéroïde anormale telle qu'une déficience hormonale stéroïde par transplantation ou équivalent. La cellule de production de stéroïde est caractérisée en ce qu'elle a été différenciée d’une cellule de moelle épinière ou d’une cellule souche multipotente par transfert d’un facteur participant à la synthèse d’hormone stéroïde. De plus, l’invention concerne un procédé de production de cette cellule de production de stéroïde, l'utilisation de celle-ci, une composition médicinale utilisant une hormone sécrétée par la cellule et un procédé de traitement de diverses maladies en utilisant la cellule.
PCT/JP2005/017349 2004-10-01 2005-09-21 Cellule novatrice de production de stéroïde WO2006038462A1 (fr)

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WO2007136044A1 (fr) * 2006-05-19 2007-11-29 Kyushu University, National University Corporation Cellule produisant une hormone stéroïenne
WO2011051406A1 (fr) 2009-10-29 2011-05-05 Ascendis Pharma As Stérilisation d'hydrogels biodégradables
US9133276B2 (en) 2010-09-17 2015-09-15 Sanofi-Aventis Deutschland Gmbh Prodrugs comprising an exendin linker conjugate
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US9265723B2 (en) 2009-07-31 2016-02-23 Sanofi-Aventis Deutschland Gmbh Long acting insulin composition
WO2023083839A1 (fr) 2021-11-09 2023-05-19 Technische Universität Dresden Procédé de production de cellules stéroïdogènes induites et leur utilisation dans la thérapie cellulaire

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007136044A1 (fr) * 2006-05-19 2007-11-29 Kyushu University, National University Corporation Cellule produisant une hormone stéroïenne
US9138462B2 (en) 2009-07-31 2015-09-22 Sanofi-Aventis Deutschland Gmbh Prodrugs comprising an insulin linker conjugate
US9265723B2 (en) 2009-07-31 2016-02-23 Sanofi-Aventis Deutschland Gmbh Long acting insulin composition
US9457066B2 (en) 2009-07-31 2016-10-04 Sanofi-Aventis Deutschland Gmbh Prodrugs comprising an insulin linker conjugate
WO2011051406A1 (fr) 2009-10-29 2011-05-05 Ascendis Pharma As Stérilisation d'hydrogels biodégradables
US8986609B2 (en) 2009-10-29 2015-03-24 Ascendis Pharma A/S Sterilization of biodegradable hydrogels
US9133276B2 (en) 2010-09-17 2015-09-15 Sanofi-Aventis Deutschland Gmbh Prodrugs comprising an exendin linker conjugate
WO2023083839A1 (fr) 2021-11-09 2023-05-19 Technische Universität Dresden Procédé de production de cellules stéroïdogènes induites et leur utilisation dans la thérapie cellulaire

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