JP2023104644A - Pluripotent stem cell differentiation inhibitor - Google Patents
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Abstract
Description
本発明は、冬虫夏草を有効成分とする多能性幹細胞分化抑制剤に関する。 TECHNICAL FIELD The present invention relates to a pluripotent stem cell differentiation inhibitor containing Cordyceps sinensis as an active ingredient.
幹細胞とは自己増殖能と多分化能をもつ細胞であり、幹細胞の未分化状態の維持は生体内の恒常性維持に非常に重要である。単球やマクロファージが過度に増加することで生じるサイトカインストームや、造血幹細胞が過度に増加することにより生じる白血病の予防・治療など様々な分野における活用が期待される。
しかしながら、幹細胞の未分化状態を維持する技術は十分に整っておらず、早期実現に向けた研究開発が日々行われている。
Stem cells are cells with self-proliferation and multipotency, and maintenance of the undifferentiated state of stem cells is very important for maintenance of in vivo homeostasis. It is expected to be used in various fields such as cytokine storm caused by excessive increase of monocytes and macrophages, and prevention and treatment of leukemia caused by excessive increase of hematopoietic stem cells.
However, the technology for maintaining the undifferentiated state of stem cells is not sufficiently developed, and research and development are being conducted daily for early realization.
冬虫夏草においてはフィラグリン産生促進剤（特許文献１）、ＰＰＡＲ活性化剤（特許文献２）、脂肪細胞の分化抑制剤及び脂肪細胞の肥大化抑制剤（特許文献３）などが研究開発されている。 For cordyceps, a filaggrin production promoter (Patent Document 1), a PPAR activator (Patent Document 2), an adipocyte differentiation inhibitor and an adipocyte hypertrophy inhibitor (Patent Document 3), etc. have been researched and developed.
本発明は、冬虫夏草を有効成分とする多能性幹細胞分化抑制剤を提供することを課題とする。 An object of the present invention is to provide a pluripotent stem cell differentiation inhibitor containing cordyceps as an active ingredient.
本発明は、冬虫夏草を有効成分とする多能性幹細胞分化抑制剤を提供する。 The present invention provides a pluripotent stem cell differentiation inhibitor containing Cordyceps sinensis as an active ingredient.
冬虫夏草を有効成分とする本発明は、多能性幹細胞の未分化状態を維持し、分化を抑制する効果を発揮する。 The present invention containing cordyceps as an active ingredient exerts the effect of maintaining the undifferentiated state of pluripotent stem cells and suppressing their differentiation.
以下本発明を実施するための形態を説明する。 A mode for carrying out the present invention will be described below.
多能性幹細胞とは、複数種の細胞に分化可能である多能性を有し、かつ、自己増殖能を併せもつ幹細胞を指す。多能性幹細胞には、特に限定されないが、例えば人工多能性幹細胞（ｉｎｄｕｃｅｄ ｐｌｕｒｉｐｏｔｅｎｔ ｓｔｅｍ ｃｅｌｌ：ｉＰＳ細胞）、胚性幹細胞（ｅｍｂｒｙｏｎｉｃ ｓｔｅｍ ｃｅｌｌ：ＥＳ細胞）、精子幹細胞（ｇｅｒｍｌｉｎｅ ｓｔｅｍ ｃｅｌｌ：ＧＳ細胞）、胚性生殖細胞（ｅｍｂｒｙｏｎｉｃ ｇｅｒｍ ｃｅｌｌ：ＥＧ細胞）、核移植により得られるクローン胚由来の胚性幹細胞（ｎｕｃｌｅａｒ ｔｒａｎｓｆｅｒ ＥＳ ｃｅｌｌ：ｎｔＥＳ細胞）、融合幹細胞などが含まれる。本発明において好ましい多能性幹細胞はｉＰＳ細胞である。 A pluripotent stem cell refers to a stem cell that has pluripotency capable of differentiating into multiple types of cells and also self-proliferation ability. Examples of pluripotent stem cells include, but are not limited to, induced pluripotent stem cells (iPS cells), embryonic stem cells (ES cells), and germline stem cells (GS cells). , embryonic germ cells (EG cells), cloned embryo-derived embryonic stem cells (nuclear transfer ES cells) obtained by nuclear transfer, fusion stem cells, and the like. Preferred pluripotent stem cells in the present invention are iPS cells.
本発明において使用可能な冬虫夏草は特に制限はなく、一般に知られている蝶蛾類鱗翅目および鞘翅目の昆虫又はその幼虫に寄生してその体内に菌核を形成し、夏季に宿主である昆虫又はその幼虫の体表面に子実体を形成するものであればよい。本発明においては特に好ましく使用可能な冬虫夏草として、コウモリ蛾科の幼虫（Ｈｅｐｉａｌｕｓ ａｒｍｏｒｉｃａｎｕｓ Ｏｂｅｒ.）に寄生してその体内に菌核を形成し、夏季に頭部から根棒状の子実体を形成するコルダイセプシネンシス（Ｃｏｒｄｙｃｅｐｓ ｓｉｎｅｎｓｉｓ）が挙げられる。また、コルダイセプシネンシス以外の冬虫夏草としてはセミタケ（Ｏｏｒｄｙｃｅｐｓ ｓｏｂｏｌｉｆｅｒａ Ｂ.）やサナギタケ（Ｃｏｒｄｙｃｅｐｓ ｍｉｌｉｔａｒｉｓ Ｌｉｎｋ）、ミミカキタケ（Ｃｏｒｄｙｃｅｐｓ ｎｕｔａｎｓ Ｐａｔ.）などが知られており、これらも本発明において好ましく使用できるものである。本発明の多能性幹細胞分化抑制剤に用いる冬虫夏草は子実体又は菌糸体の区別なく使用可能である。 Cordyceps sinensis that can be used in the present invention is not particularly limited, and generally known insects of the order Lepidoptera and Coleoptera of the butterfly moth family, or insects that form sclerotia in their bodies by parasitizing their larvae and are hosts in the summer season. Alternatively, any substance that forms a fruiting body on the body surface of the larva may be used. Cordyceps that can be particularly preferably used in the present invention is Corda, which parasitizes larvae of the bat moth family (Hepialus armoricanus Ober.), forms sclerotia in its body, and forms a rod-shaped fruiting body from the head in summer. and Cordyceps sinensis. In addition, Cordyceps sinensis other than Cordyceps sinensis is known, such as Oordyceps sobolifera B., Cordyceps militaris Link, and Cordyceps nutans Pat., and these can also be preferably used in the present invention. be. Cordyceps sinensis used for the pluripotent stem cell differentiation inhibitor of the present invention can be used regardless of whether it is a fruiting body or a mycelium.
本発明において、冬虫夏草は生のまま抽出に供してもよいが、抽出効率を考えると、細切，乾燥，粉砕等の処理を行った後に抽出を行うことが好ましい。抽出は、抽出溶媒に浸漬して行う。抽出効率を上げるため撹拌を行ったり、抽出溶媒中でホモジナイズしたりしてもよい。抽出温度としては、５℃程度から抽出溶媒の沸点以下の温度とするのが適切である。抽出時間は抽出溶媒の種類や抽出温度によっても異なるが、４時間～１４日間程度とするのが適切である。 In the present invention, Cordyceps sinensis may be used for extraction as it is, but it is preferable to perform extraction after processing such as chopping, drying, and pulverizing in consideration of extraction efficiency. Extraction is performed by immersion in an extraction solvent. Stirring may be performed or homogenization may be performed in the extraction solvent in order to increase the extraction efficiency. A suitable extraction temperature is from about 5° C. to a temperature below the boiling point of the extraction solvent. Although the extraction time varies depending on the type of extraction solvent and the extraction temperature, it is suitable to be about 4 hours to 14 days.
抽出溶媒としては、水の他、メタノール，エタノール，プロパノール，イソプロパノール等の低級アルコール、１，３－ブチレングリコール，プロピレングリコール，ジプロピレングリコール，グリセリン等の多価アルコール、エチルエーテル，プロピルエーテル等のエーテル類、酢酸エチル，酢酸ブチル等のエステル類、アセトン，エチルメチルケトン等のケトン類などの極性有機溶媒を用いることができ、これらより１種又は２種以上を選択して用いる。また、生理食塩水，リン酸緩衝液，リン酸緩衝生理食塩水等を用いてもよい。 Examples of extracting solvents include water, lower alcohols such as methanol, ethanol, propanol and isopropanol, polyhydric alcohols such as 1,3-butylene glycol, propylene glycol, dipropylene glycol and glycerin, and ethers such as ethyl ether and propyl ether. , esters such as ethyl acetate and butyl acetate, and ketones such as acetone and ethyl methyl ketone. Physiological saline, phosphate buffer, phosphate buffered saline, etc. may also be used.
また、前述の抽出工程において発生する残渣をそのまま、あるいは酵素処理後濾過したもののうち濾液をそのまま、又は乾燥させたもの、あるいは酵素処理後濾過したもののうちの残渣を細切，乾燥，粉砕等の処理を行ったものを用いてもよい。 In addition, the residue generated in the above-mentioned extraction step may be used as it is, or the filtrate obtained by filtration after enzyme treatment may be used as it is, or the residue obtained by filtration after enzyme treatment may be finely chopped, dried, pulverized, or the like. You may use the thing which processed.
前述の工程により得られたものをそのまま用いることもできるが、その効果を失わない範囲で、脱臭、脱色、濃縮などの精製操作を加えたり、カラムクロマトグラフィーなどを用いて分画物として用いたりしてもよい。これらの精製物や分画物はこれらから溶媒を除去することによって乾固物とすることもでき、さらにはアルコールなどの溶媒に可溶化した形態、あるいは乳剤の形態など、用時に溶媒に溶解して用いることもできる。また、リポソーム等のベシクルやマイクロカプセル等に内包させて用いることもできる。 The product obtained by the above steps can be used as it is, but it may be subjected to purification operations such as deodorization, decolorization, concentration, etc., or may be used as a fractionated product using column chromatography or the like, as long as the effect is not lost. You may These purified products and fractionated products can be dried by removing the solvent from them. can also be used. It can also be used by encapsulating it in vesicles such as liposomes or microcapsules.
さらに公知の安定剤、賦形剤、結合剤等の添加物質をともに含有し、本発明の多能性幹細胞分化抑制剤とすることができる。添加物質としては本発明の効果を損なわないものであれば特に限定されないが、デンプン、デキストリン、粉末セルロース、結晶セルロース、セルロース誘導体、ショ糖脂肪酸エステル、乳糖、アラビアガム、マンニトール、トレハロース、グルコース、ゼラチン、二酸化ケイ素等を単独で又は組み合わせて利用することが可能である。中でもデキストリンを用いることが好ましい。 Furthermore, it can be used as the pluripotent stem cell differentiation inhibitor of the present invention by containing additives such as known stabilizers, excipients, and binders. Additives are not particularly limited as long as they do not impair the effects of the present invention, but starch, dextrin, powdered cellulose, crystalline cellulose, cellulose derivatives, sucrose fatty acid esters, lactose, gum arabic, mannitol, trehalose, glucose, gelatin. , silicon dioxide, etc. may be utilized alone or in combination. Among them, it is preferable to use dextrin.
本発明の多能性幹細胞分化抑制剤の剤型については、特に限定されず、固体状、半固体状、又は液体状のいずれであってもよい。 The dosage form of the pluripotent stem cell differentiation inhibitor of the present invention is not particularly limited, and may be solid, semi-solid, or liquid.
以下、実施例により本発明を具体的に説明するが、これにより本発明の範囲が限定されるものではない。なお、配合量は特に断りのない限り質量％である。 EXAMPLES The present invention will be specifically described below with reference to examples, but the scope of the present invention is not limited by these examples. In addition, the compounding quantity is mass % unless otherwise specified.
まず、実施例等に用いる冬虫夏草の調製方法を示す。 First, the preparation method of Cordyceps sinensis used in Examples and the like will be described.
［冬虫夏草］
本発明の実施例で使用した冬虫夏草は、下記の手順で調製したものを使用した。
１．冬虫夏草（Ｃｏｒｄｙｃｅｐｓ ｓｉｎｅｎｓｉｓ）１０ｇを乾燥後粉砕する。
２．熱水で９０分間抽出後ろ過し、濾液を乾燥させることでエキスＡとする。
３．２のろ過工程における残渣を酵素処理し、ろ過したもののうち濾液を酵素処理末、残渣を微粉砕化したものをエキスＢとする。
４．エキスＡにデキストリンを混合し、６gとなるように質量調整を行ったものをエキス末とする。
５．エキスＢに倍量のデキストリンを加え製剤性を高めたものを加工粉末とする。
６．上記工程により製造されたエキス末・酵素処理末・加工粉末を混合し、冬虫夏草として使用する。
[Cordyceps]
Cordyceps sinensis used in the examples of the present invention was prepared by the following procedure.
1. 10 g of Cordyceps sinensis are dried and ground.
2. After being extracted with hot water for 90 minutes, the extract is filtered, and the filtrate is dried to obtain an extract A.
The residue in the filtration step of 3.2 is treated with an enzyme, filtered, and the filtrate is an enzyme-treated powder, and the residue is pulverized to obtain an extract B.
4. Dextrin was mixed with the extract A, and the mass was adjusted to 6 g to obtain the extract powder.
5. A processed powder is obtained by adding twice the amount of dextrin to the extract B to improve formulation properties.
6. The extract powder, the enzyme-treated powder, and the processed powder produced by the above steps are mixed and used as Cordyceps sinensis.
［多能性幹細胞分化抑制作用］
ヒトｉＰＳ細胞を、増殖培地を用いてマトリゲルコートした６０ｍｍｄｉｓｈに起眠し、ＣＯ２インキュベーター（３７℃、５%ＣＯ２、湿潤、以下同様）で培養した。１２ｗｅｌｌ ｐｌａｔｅをマトリゲルでコートし、その上に５０～２００μｍのヒトｉＰＳ細胞塊が１０～２０個／ｃｍ２となるように増殖培地を用いて播種した。市販のキット（ＳＴＥＭｄｉｆｆ Ｈｅｍａｔｏｐｏｉｅｔｉｃ ｋｉｔ）を用いて、ヒトｉＰＳ細胞を中胚葉へ、中胚葉を未熟な造血幹細胞へ、未熟な造血幹細胞を造血幹細胞へ、造血幹細胞を単球へと分化させた。具体的には、播種翌日（Ｄａｙ １）、Ｍｅｄｉｕｍ Ａで培地を全量交換し、中胚葉分化を開始させた。中胚葉分化開始翌日（Ｄａｙ ２）、Ｍｅｄｉｕｍ Ａで培地を半量交換した。中胚葉分化３日後（Ｄａｙ ３） に、冬虫夏草を添加したＭｅｄｉｕｍ Ｂで培地を全量交換し、造血幹細胞分化を誘導した。造血幹細胞分化２日目（Ｄａｙ ５）、前述の冬虫夏草添加Ｍｅｄｉｕｍ Ｂで培地交換した。造血幹細胞分化４日後（Ｄａｙ ７）に、冬虫夏草を添加したＭｅｄｉｕｍ Ｃで培地を全量交換し、単球分化を誘導した。単球分化３日目（Ｄａｙ １０）、６日目（Ｄａｙ １３）、９日目（Ｄａｙ １６）、１２日目（Ｄａｙ １９）、１５日目（Ｄａｙ ２２）にそれぞれ前述の冬虫夏草添加Ｍｅｄｉｕｍ Ｃで培地を全量交換すると共に、細胞上清を回収した。回収した細胞上清に含まれている浮遊細胞について、ＦＣＭ解析を行った。細胞はＣＤ３４抗体（造血幹細胞のマーカー）、ＣＤ１４抗体（単球のマーカー）及び死細胞染色試薬で処理後、２％ＦＢＳ添加ＰＢＳで洗浄・懸濁して、フローサイトメーターで解析を行った。結果を表１および表２に示す。
冬虫夏草非添加群と陽性対照/冬虫夏草添加群の差を、冬虫夏草非添加群をコントロールとしたＳｔｕｄｅｎｔ’ｓ ｔ－ｔｅｓｔにより検定した。有意水準は両側５％とした。
[Pluripotent stem cell differentiation inhibitory action]
Human iPS cells were awakened in a matrigel-coated 60 mm dish using a growth medium and cultured in a CO 2 incubator (37° C., 5% CO 2 , humid, hereinafter the same). A 12-well plate was coated with matrigel, and human iPS cell aggregates of 50-200 μm were seeded thereon at 10-20 cells/cm 2 using a growth medium. Using a commercially available kit (STEMdiff Hematopoietic kit), human iPS cells were differentiated into mesoderm, mesoderm into immature hematopoietic stem cells, immature hematopoietic stem cells into hematopoietic stem cells, and hematopoietic stem cells into monocytes. Specifically, the day after seeding (Day 1), the medium was entirely replaced with Medium A to initiate mesoderm differentiation. Half of the medium was replaced with Medium A on the day following the initiation of mesoderm differentiation (Day 2). Three days after mesoderm differentiation (Day 3), the whole amount of the medium was replaced with Medium B supplemented with cordyceps to induce hematopoietic stem cell differentiation. On day 2 of hematopoietic stem cell differentiation (Day 5), the medium was replaced with the aforementioned Medium B containing Cordyceps sinensis. Four days after hematopoietic stem cell differentiation (Day 7), the medium was entirely exchanged with Medium C supplemented with cordyceps to induce monocyte differentiation. On the 3rd day (Day 10), 6th day (Day 13), 9th day (Day 16), 12th day (Day 19), and 15th day (Day 22) of monocyte differentiation, the aforementioned Cordyceps sinensis-added Medium C The entire amount of the medium was exchanged at , and the cell supernatant was collected. Floating cells contained in the recovered cell supernatant were subjected to FCM analysis. The cells were treated with CD34 antibody (hematopoietic stem cell marker), CD14 antibody (monocyte marker) and dead cell staining reagent, washed and suspended in 2% FBS-added PBS, and analyzed with a flow cytometer. Results are shown in Tables 1 and 2.
The difference between the cordyceps non-addition group and the positive control/cordyceps addition group was tested by Student's t-test using the cordyceps non-addition group as a control. The significance level was 5% on both sides.
表１及び表２に示した通り、冬虫夏草を添加した場合、中胚葉から未成熟な造血幹細胞へ、未成熟な造血幹細胞から造血幹細胞へ、造血幹細胞から単球へと分化する過程の中でＣＤ３４陽性細胞（造血幹細胞）率およびＣＤ１４陽性細胞（単球）率がいずれも減少した。以上のことより、冬虫夏草は未成熟な造血幹細胞にて分化を抑制し、未分化状態を維持することが分かった。未成熟な造血幹細胞は様々な細胞に分化し得る多能性をもつことが知られている。従って、冬虫夏草は多能性幹細胞の未分化状態を維持し、分化を抑制する効果を発揮することが分かった。以上のことより、本発明の多能性幹細胞分化抑制剤は多能性幹細胞の未分化状態を維持し、分化を抑制する効果を発揮する。 As shown in Tables 1 and 2, when Cordyceps was added, during the process of differentiation from mesoderm to immature hematopoietic stem cells, from immature hematopoietic stem cells to hematopoietic stem cells, and from hematopoietic stem cells to monocytes, CD34 Both the positive cell (hematopoietic stem cell) rate and the CD14 positive cell (monocyte) rate decreased. From the above, it was found that cordyceps suppresses the differentiation of immature hematopoietic stem cells and maintains an undifferentiated state. Immature hematopoietic stem cells are known to have pluripotency capable of differentiating into various cells. Therefore, it was found that Cordyceps maintains the undifferentiated state of pluripotent stem cells and exerts an effect of suppressing differentiation. As described above, the pluripotent stem cell differentiation inhibitor of the present invention maintains the undifferentiated state of pluripotent stem cells and exhibits the effect of suppressing differentiation.
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