JP6694240B2 - 細胞の品質を評価する方法、及び細胞の品質判定キット - Google Patents
細胞の品質を評価する方法、及び細胞の品質判定キット Download PDFInfo
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Landscapes
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Description
(2)前記miRNAが、配列番号1〜96の塩基配列からなるmiRNAの群より選択される少なくとも1種のmiRNAである、(1)記載の方法。
(3)前記miRNAが、配列番号1、4、6、12〜14、16、21、26、29、30、37、40、44〜49、67、68、80、81、86及び95の塩基配列からなるmiRNAの群より選択される少なくとも1種のmiRNAである、(2)記載の方法。
(4)前記miRNAが、前記培養上清中のエクソソームに含まれるmiRNAである、(1)から(3)のいずれか記載の方法。
(5)前記細胞が、脂肪由来間葉系幹細胞である、(1)から(4)のいずれか記載の方法。
(6)前記細胞の培養が、無血清培地による培養である、(1)から(5)のいずれか記載の方法。
(7)無血清培地中で細胞を培養する工程、
特定の時期に培養上清の一部をサンプリングする工程、
サンプリングした培養上清からエクソソームを回収する工程、
回収したエクソソームからmiRNAを抽出する工程、及び
miRNAの発現レベルを測定する工程
を含む、細胞の老化を評価する方法。
(8)前記miRNAの発現レベルを測定する工程において測定するmiRNAが、配列番号1〜96の塩基配列からなるmiRNAの群より選択される少なくとも1種である、(7)記載の方法。
(9)前記配列番号1〜13、16〜69の塩基配列からなるmiRNAの群より選択される少なくとも1種のmiRNAの発現レベルが所定の基準値よりも低い場合、及び/又は配列番号14若しくは15、70〜96の塩基配列からなるmiRNAの発現レベルが所定の基準値より高い場合に、前記細胞の老化の程度が高いと評価する、(8)記載の方法。
(10)配列番号1〜96の塩基配列からなるmiRNAの群より選択される少なくとも1種のmiRNAに特異的にハイブリダイズするプライマーを少なくとも1つ有する、細胞老化判定用キット。
本発明における細胞としては、インビトロ条件下で培養できる細胞であれば特に限定されないが、哺乳動物由来の細胞であることが好ましい。また、インビトロ条件下で培養できるのであれば、哺乳動物より摘出した組織を形成する細胞であっても、インビトロで株化された細胞であってもよい。
本発明における細胞の培養方法は、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、細胞の継代の時期及び方法もそれぞれの細胞に適していれば特に限定されず、細胞の様子を見ながら、従来と同様に行うことができる。
本発明の方法において、細胞の老化の指標として用いるmiRNAとしては、細胞の老化に応じて細胞から分泌される量が変化するものであれば特に限定されない。また、このようなmiRNAとしては、細胞の種類によってそれぞれ適切なものが選択され得る。例えば、ヒトの脂肪由来間葉系幹細胞の老化の指標としては、配列表の配列番号1〜96に示される塩基配列からなるmiRNAが好ましい。これらはいずれも、下記実施例において、細胞の老化に応じて培養上清中の存在量が変化することが具体的に確認されているものである。
(i)無血清培地中で細胞を培養する培養工程、
(ii)特定の時期に培養上清の一部をサンプリングする工程、
(iii)サンプリングした培養上清からエクソソームを回収する工程、
(iv)回収したエクソソームからmiRNAを抽出する工程、及び
(v)miRNAの発現レベルを測定する工程
(vi)老化細胞を検出する工程を含んでいてもよい。
本工程においては、無血清培地中で細胞を培養する。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、細胞の継代の時期及び方法もそれぞれの細胞に適していれば特に限定されず、細胞の様子を見ながら、従来と同様に行うことができる。なお、培養は、細胞の全培養期間に渡って無血清培地を用いて行われてもよいし、miRNAの測定のために回収する培養上清についてのみ無血清培地としてもよい。ここで、用いる無血清培地については、前記(培養)の項での説明を適用できる。
細胞の老化の程度を評価したい細胞について、継代1日後〜5日後、好ましくは1日後〜4日後、より好ましくは1日後〜3日後、さらに好ましくは2日後〜3日後に、培養上清の一部をサンプリングする。サンプリングする液量は、その後の分析に十分な量であれば特に制限されない。なお、細胞の老化の評価の際の基準値を算出するために、老化が起こる以前の細胞増殖能等を十分に保持している状態の細胞についても培養上清のサンプリングをすることができる。
エクソソームの回収は、当業者に公知の多くの方法を用いて行われ得る。一般には、超遠心分離法を用いた方法が広く用いられるが、市販のエクソソーム単離キット(Total exosome isolation from cell culture media,invitrogen等)を用いることもできる。
エクソソームからmiRNAを抽出するためには、当業者に公知の多くの方法を用いることができる。また、市販のmiRNA抽出用キット(miRNeasyMini Kit,Qiagen等)を用いることもできる。
抽出した全miRNA中のいくつかのmiRNAの発現レベルを測定するためには、当業者に公知の多くの方法を用いることができる。また、市販のmiRNA用のマイクロアレイ(Agilent DesignID 046064等)を用いることで、複数種のmiRNAの発現プロファイルを確認することができる。また、定量的リアルタイムPCR(TaqMan MicroRNA Assays、Applied Biosystems等)を用いることでもそれぞれのmiRNAの発現レベルを確認することができる。
本工程は、本発明の方法による老化の評価を確認するために、老化細胞を検出する工程である。老化細胞を検出するためには、当業者に公知の多くの方法を用いることができる。また、市販のSenescence−associated β−galactosidase発現検出キット(Senescence Detection Kit,Bio Vision)を用いることもできる。
本発明の細胞老化判定用キットは、測定対象又は測定原理等に応じた種々の構成をとることができる。本発明のキットの構成要素として、例えば、細胞の老化に伴って培養上清中の発現が増減するmiRNA(cDNA)の増幅用プライマー、及びDNAチップ等で使用するハイブリダイゼーション用のプローブを含むことができる。このような細胞の老化に伴って培養上清中の発現が増減するmiRNAとしては、本発明の細胞の老化を評価する方法において指標として採用するmiRNAが好ましい。具体的には、配列番号1〜96の塩基配列からなるmiRNAである。
3人の提供者からの脂肪由来間葉系幹細胞(Adipose derived Stem Cells,PT−5006、Lonza社)を、無血清培地にて馴化した後、2〜5日おきに継代しながら培養を行った。
(マイクロアレイ)
前記脂肪由来間葉系幹細胞について、4回継代後、6回継代後、11回継代後のそれぞれ3日目に、培養上清を各フラスコから100mLずつサンプリングした。前記各継代ステージ(4回継代、6回継代、11回継代)でサンプリングした培養上清から市販の試薬(Total exosome isolation from cell culture media,invitrogen)を用いてエクソソームを回収した。その後エクソソーム中のmiRNAを、市販の試薬(miRNeasyMini Kit,Qiagen)のプロトコールに従い抽出後、miRNAのマイクロアレイ(Agilent DesignID 046064)を実施した。結果のまとめを下記表1に示した。各数値は、各継代数における、miRNAの発現レベルの比を表している。
P6/P4:6回継代後(P6)の培養上清中のmiRNAの発現レベルを、4回継代後(P4)の培養上清中のmiRNAの発現レベルで除した値のLog値
P11/P6:11回継代後(P11)の培養上清中のmiRNAの発現レベルを、6回継代後(P6)の培養上清中のmiRNAの発現レベルで除した値のLog値
P11/P4:11回継代後(P11)の培養上清中のmiRNAの発現レベルを、4回継代後(P4)の培養上清中のmiRNAの発現レベルで除した値のLog値
up:継代回数が増えるに従って(細胞の老化の度合いが増すに従って)、培養上清中に含まれる量が増加するmiRNAであることを示す。
down:継代回数が増えるに従って(細胞の老化の度合いが増すに従って)、培養上清中に含まれる量が減少するmiRNAであることを示す。
前記マイクロアレイの結果、細胞の老化に伴って発現が顕著に減少する結果が得られたhsa−miR−1260a(配列番号12)、hsa−miR−1260b(配列番号13)、及びhsa−miR−1290(配列番号1)について、定量的リアルタイムPCR(TaqMan MicroRNA Assays、Applied Biosystems)を用いて、さらに詳細に発現レベルを確認した。結果を図1〜3にそれぞれ示すように、hsa−miR−1260a、hsa−miR−1260b、及びhsa−miR−1290の発現は、脂肪由来間葉系幹細胞の継代回数が増えるに従って(老化に伴って)、顕著に減少することが確認できた。
Claims (7)
- 細胞の培養上清中のmiRNAを指標として、前記細胞の老化を評価する方法であって、前記miRNAが、配列番号1、4、6、12〜14、16、21、26、29、30、37、40、44〜49、67、68、80、81、86、及び95の塩基配列からなるmiRNAの群より選択される少なくとも1種のmiRNAである、細胞の老化を評価する方法。
- 前記miRNAが、前記培養上清中のエクソソームに含まれるmiRNAである、請求項1記載の方法。
- 前記細胞が、脂肪由来間葉系幹細胞である、請求項1又は2記載の方法。
- 前記細胞の培養が、無血清培地による培養である、請求項1から3のいずれか1項記載の方法。
- 無血清培地中で細胞を培養する工程、
特定の時期に培養上清の一部をサンプリングする工程、
サンプリングした培養上清からエクソソームを回収する工程、
回収したエクソソームからmiRNAを抽出する工程、及び
miRNAの発現レベルを測定する工程
を含み、
前記miRNAが、配列番号1、4、6、12〜14、16、21、26、29、30、37、40、44〜49、67、68、80、81、86、及び95の塩基配列からなるmiRNAの群より選択される少なくとも1種である、
細胞の老化を評価する方法。 - 前記配列番号1、4、6、12、13、16、21、26、29、30、37、40、44〜49、67、及び68の塩基配列からなるmiRNAの群より選択される少なくとも1種のmiRNAの発現レベルが所定の基準値よりも低い場合、及び/又は配列番号14、80、81、86、又は95の塩基配列からなるmiRNAの群より選択される少なくとも1種のmiRNAの発現レベルが所定の基準値より高い場合に、前記細胞の老化の程度が高いと評価する、請求項5記載の方法。
- 配列番号1、4、6、12〜14、16、21、26、29、30、37、40、44〜49、67、68、80、81、86、及び95の塩基配列からなるmiRNAの群より選択される少なくとも1種のmiRNAに特異的にハイブリダイズするプライマーを少なくとも1つ有する、細胞老化判定用キット。
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