JP6928555B2 - 高機能間葉系幹細胞、その調製方法、および調製用培地 - Google Patents
高機能間葉系幹細胞、その調製方法、および調製用培地 Download PDFInfo
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- JP6928555B2 JP6928555B2 JP2017528653A JP2017528653A JP6928555B2 JP 6928555 B2 JP6928555 B2 JP 6928555B2 JP 2017528653 A JP2017528653 A JP 2017528653A JP 2017528653 A JP2017528653 A JP 2017528653A JP 6928555 B2 JP6928555 B2 JP 6928555B2
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Description
(1)少なくとも一種の抗炎症剤により間葉系幹細胞を処理する工程を含む、高機能間葉系幹細胞の調製方法。
(2)高機能間葉系幹細胞において、抗炎症機能、免疫調節機能、抗腫瘍機能、組織修復機能、上皮系細胞のタイトジャンクション形成によるバリア増強機能からなる群より選択される少なくとも一種の機能が、無処理の間葉系幹細胞と比較して亢進している、(1)に記載の方法。
(3)抗炎症剤が、非ステロイド性抗炎症剤である、(1)または(2)に記載の方法。
(4)非ステロイド性抗炎症剤が、プロピオン酸系抗炎症剤である、(3)に記載の方法。
(5)非ステロイド性抗炎症剤が、抗アレルギー剤である、(3)に記載の方法。
(6)間葉系幹細胞が、臍帯由来である、(1)〜(5)いずれか一に記載の方法。
(7)(1)〜(6)のいずれか一に記載の方法によって調製された、高機能間葉系幹細胞。
(8)(7)に記載の高機能間葉系幹細胞を含有する医薬組成物。
(9)少なくとも一種の抗炎症剤を含む、高機能間葉系幹細胞調製用培地。
本発明の高機能間葉系幹細胞の調製方法は、少なくとも一種の抗炎症剤により間葉系幹細胞を処理する工程を含む。
(1)間葉系幹細胞を培養する工程
(2)上記(1)で得られた間葉系幹細胞を抗炎症剤で処理する工程
(3)高機能間葉系幹細胞を回収する工程
本工程においては、各組織から得られた間葉系幹細胞を培養する。組織から単離した間葉系幹細胞の培養方法は、それぞれの細胞に適した方法であれば特に限定されず、従来と同様の方法が用いられる。通常、30℃〜37℃の温度、2%〜7%CO2環境下、5%〜21%O2環境下で行われる。また、間葉系幹細胞の継代の時期及び方法も間葉系幹細胞に適していれば特に限定されず、間葉系幹細胞の形態を観察しながら、従来と同様に行うことができる。
本工程は、間葉系幹細胞含有溶液に抗炎症剤を添加して、一定の時間インキュベートする工程である。間葉系幹細胞含有溶液は培地であってよく、また、培地ではない処理用溶液であってもよい。
(2)において抗炎症剤により処理された間葉系幹細胞について、細胞の状態を勘案して適切な時間に、トリプシン、コラゲナーゼ等の酵素で処理して細胞を剥離させ、またはトリプシン、コラゲナーゼ等の酵素処理なしで、遠心分離して高機能間葉系幹細胞を回収する。
回収した高機能間葉系幹細胞はそのまま、またはリン酸緩衝液等で洗浄した後、治療用高機能間葉系幹細胞として治療に使用することができる。保存する場合は、保存用の溶液を用いて保存用容器中に保存する。
本発明の高機能間葉系幹細胞調製用培地は、少なくとも一種の抗炎症剤を含む培地である。本発明の培地は、間葉系幹細胞培養用培地に少なくとも一種の抗炎症剤が添加された培地である。間葉系幹細胞培養用培地は、間葉系幹細胞の培養に適する培地であれば特に制限されず、当業者に従来公知の培地を用いることができる。間葉系幹細胞培養用培地としては、例えば、Promo Cell社、Life Line社、Lonza社等の間葉系幹細胞培養用培地等が挙げられる。培地は、生物由来原料(例えば、動物血清)を含有してもよい。必要に応じて、アルブミン、FCS等の生物由来原料を添加することもできる。例えば、DMEM/F−12培地等、またはこれらの基本培地にFCSを、0.1%〜10%の範囲で含む培地等が挙げられる。得られる細胞を動物(ヒトを含む)の疾患の治療に用いることを考慮すると、できるだけ生物由来原料を含まない培地(例えば、無血清培地)であることが好ましい。
本発明は、上述の本発明の調製方法により得られた高機能間葉系幹細胞も含む。本発明の高機能間葉系幹細胞は、サイトカイン等の分泌タンパク質、細胞内発現タンパク質の種類と量が変化しており、優れた治療効果を有する幹細胞である。本発明の高機能間葉系幹細胞は、抗炎症剤で処理をしない間葉系幹細胞に比較して、治療のための機能の少なくとも一つの機能が亢進している細胞である。該治療のための機能としては、例えば抗炎症機能、免疫調節機能、抗腫瘍機能または組織修復機能、上皮系細胞のタイトジャンクション形成によるバリア増強機能が挙げられる。本発明の高機能間葉系幹細胞の具体的な特徴については、本発明の調製方法における説明を適用できる。
本発明の医薬組成物は、本発明の調製方法により得られた上記高機能間葉系幹細胞を含む。さらに、高機能間葉系幹細胞以外の成分を、本発明の効果を損なわない範囲で含んでいてもよい。その他の成分としては、一般的な医薬品、医薬部外品等が含むことができる有効成分以外の成分が挙げられる。
<抗炎症剤処理高機能間葉系幹細胞の取得>
臍帯由来間葉系幹細胞(UC−MSC;Umbilical Cord derived Mesenchymal Stem Cells Wharton’s Jelly(HMSC−WJ)、FC−0020、LifeLine社)を、37℃、5%CO2の条件下、推奨培地にて馴化し、2〜3日おきに継代しながら培養を行った。
<抗炎症剤処理高機能間葉系幹細胞の取得>
プラノプロフェン処理、またはトラニラスト処理を4日に延長した以外は、実施例1と同様にして、抗炎症剤処理高機能UC−MSCを得た。
UC−MSCを5×104cells/well〜2×105cells/wellとなるよう6well plate(2ml、LifeLine社推奨培地)に播種し、翌日細胞を回収した。
マウスマクロファージ細胞株Raw264.7を24または48well plate(1mlまたは0.5ml、10%FCS含有DMEM/F−12培地)に播種し、コンフルエント状態になるまで、培養した。細胞数は2×104cells/ml〜5×105cells/mlであった。Raw264.7の細胞数に対し、1/10、1/100、1/1000、1/10000の細胞数の上記UC−MSCを添加し共培養を行った。共培養開始から4時間後にLPS(100ng/ml)添加し、18時間後に上清を回収し、IL−6量をELISA法により測定した(図3)。なお、陽性対照としてデキサメタゾン(和光純薬製:DEXと表記)を使用した。Raw264.7の細胞数に対し、1/10〜1/1000の細胞数のUC−MSCを添加した場合は、UC−MSC細胞比率に対応して抗炎症効果が認められた
<抗炎症機能評価1>
継代6−12回目のUC−MSCを5×104cells/well〜2×105cells/wellとなるよう6well plate(2ml、LifeLine社推奨培地)に播種した。1日後、プラノプロフェン(CAS No.52549−17−4、培地中0.005%および0.025%)を添加した。添加4日後にリン酸緩衝液で2回洗浄し、抗炎症剤処理高機能UC−MSCを得た。この抗炎症剤処理UC−MSCについて、上記抗炎症機能の評価系を用いて評価した。Raw264.7の細胞数に対し、抗炎症剤処理UC−MSCの細胞数を1/500とした。プラノプロフェン0.025%で処理されたUC−MSCは、無処理のUC−MSCと比較して、IL−6産生抑制効果がより高まっていたことから、抗炎症機能が高い細胞となっていることがわかった(図4)。なお、抗炎症剤処理したUC−MSCは共培養前に十分に洗浄しているため、残存する抗炎症剤そのものの効果ではなく、事前処理によってUC−MSCを改質し、抗炎症機能を増強したことが示唆された。
<抗炎症機能評価2>
継代6−12回目のUC−MSCを5×104cells/well〜2×105cells/wellとなるよう6well plate(2ml、LifeLine社推奨培地)に播種した。1日後、プラノプロフェン(CAS No.52549−17−4、培地中0.004%)、イブプロフェン(CAS No.15687−27−1、培地中0.001%)又はグリチルリチン酸(CAS No.1405−86−3、培地中0.004%)を添加した。添加5日後にリン酸緩衝液で2回洗浄し、抗炎症剤処理高機能UC−MSCを得た。この抗炎症剤処理UC−MSCについて、上記抗炎症機能の評価系を用いて評価した。Raw264.7の細胞数に対し、抗炎症剤処理UC−MSCの細胞数を1/250とした。
<抗炎症機能評価3>
継代6−12回目のUC−MSCを2×104cells/wellとなるよう6well plate(2ml、LifeLine社推奨培地)に播種した。1日後、プラノプロフェン(CAS No. 52549−17−4、培地中0.004%)、イブプロフェン(CAS No. 15687−27−1、培地中0.001%)又はグリチルリチン酸(CAS No. 1405−86−3、培地中0.004%)を添加した。添加5日後にリン酸緩衝液で2回洗浄し、抗炎症剤処理高機能UC−MSCを得た。得られた抗炎症剤処理高機能UC−MSCにおける各種遺伝子発現(IL−4、IL−10、IL−11、IL−1RA、IL−6、IL−8)をマイクロアレイ又はqPCRにより確認した。結果を下記表1に示す。「n.d.」は、実験を行っていないことを示す。「Fold change」は、抗炎症剤処理をしなかったUC−MSCでの各遺伝子発現強度を1としたときの各細胞における発現強度を示す。
Claims (5)
- プラノプロフェン、トラニラスト、イブプロフェン及びグリチルリチン酸から成る群より選択される少なくとも一種の抗炎症剤により間葉系幹細胞を処理する工程を含む、無処理の間葉系幹細胞と比較して抗炎症機能が亢進している高機能間葉系幹細胞の調製方法。
- 間葉系幹細胞が、臍帯由来である、請求項1に記載の方法。
- 請求項1又は2に記載の方法によって調製された、高機能間葉系幹細胞。
- 請求項3に記載の高機能間葉系幹細胞を含有する医薬組成物。
- プラノプロフェン、トラニラスト、イブプロフェン及びグリチルリチン酸から成る群より選択される少なくとも一種の抗炎症剤を含む、無処理の間葉系幹細胞と比較して抗炎症機能が亢進している高機能間葉系幹細胞調製用培地。
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