JP2021521895A - 哺乳動物細胞における組織再生の誘導及びセノリシスのための改良された方法 - Google Patents
哺乳動物細胞における組織再生の誘導及びセノリシスのための改良された方法 Download PDFInfo
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Abstract
Description
本出願は、2018年4月23日に出願された米国仮特許出願62/661,322号の優先権及び利益を主張し、この出願はその内容全体が本明細書に組み込まれるものとする。
本発明は、哺乳動物細胞の胚−胎児転換及び出生前/出生後転換の状況を変化させることによって再生及びセノリシス(senolysis)を制御する分子経路の調節を介し、老化、変性疾患及び癌を含む医学的状態を処置する新規な治療製剤をスクリーニングするための組成物及び方法に関する。
AC − 成体由来細胞
AMH − 抗ミュラー管ホルモン
ASC − 成体幹細胞
cGMP − 現行の適正製造プロセス
CM − 癌成熟
CSC − 癌幹細胞
CNS − 中枢神経系
DMEM − ダルベッコ改変イーグル培地
DMSO − ジメチルスルホキシド
DNAm − 細胞及び組織の加齢のマーカー又は「時計」を提供するDNAのメチル化における変化。
DNN − ディープニューラルネットワーク
DPBS − ダルベッコリン酸緩衝生理食塩水
ED細胞 − 胚由来細胞;hED細胞はヒトED細胞である
EDTA − エチレンジアミンテトラ酢酸
EFT − 胚−胎児転換
EG細胞 − 胚性生殖細胞;hEG細胞はヒトEG細胞である
EOP − 胚−腫瘍表現型
EP − 胚祖先
ES細胞 − 胚性幹細胞;hES細胞はヒトES細胞である
ESC − 胚性幹細胞
FACS − 蛍光活性化細胞ソーティング
FBS − ウシ胎仔血清
FPKM − RNAシークエンシングからの百万マップリードあたりの転写産物1キロベースあたりのフラグメント
GFER − 成長因子、肝臓再生のオーグメンター(ALR)
GFP − 緑色蛍光タンパク質
GMP − 適正製造基準
HAEC − ヒト大動脈内皮細胞
hED細胞 − ヒト胚由来細胞
hEG細胞 − 「ヒト胚性生殖細胞」は胎児組織の原始生殖細胞由来の幹細胞である。
HESC − ヒト胚性幹細胞
hiPS細胞 − 「ヒト人工多能性幹細胞」は、hES特異的転写因子、たとえばSOX2、KLF4、OCT4、MYC、又はNANOG、LIN28、OCT4、及びSOX2への曝露後に体細胞から得られたhES細胞と類似している特性を有する細胞である。
HSE − 「ヒト皮膚等価物」は、創傷修復の促進において試験目的のために又は治療用途のために製造される細胞と生物学的又は合成マトリックスとの混合物である。
iCM − 誘導性癌成熟。
iPS細胞 − 「人工多能性幹細胞」は、ES特異的転写因子、たとえばSOX2、KLF4、OCT4、MYC、若しくはNANOG、LIN28、OCT4、及びSOX2、SOX2、KLF4、OCT4、MYC、及び(LIN28A又はLIN28B)、又はOCT4、SOX2、KLF4、NANOG、ESRRB、NR5A2、CEBPA、MYC、LIN28A及びLIN28Bの他の組合せへの曝露後に体細胞から得られたhES細胞と類似している特性を有する細胞である。
iS−CSC − 「癌幹細胞の誘導性セノリシス」は、化学療法剤又は放射線療法による除去に対して難治性である悪性腫瘍における細胞の処置を指し、前記iS−CSC処置を行うと、前記難治性細胞は遺伝子発現の胎児前パターンに復帰し、化学療法剤又は放射線療法に対して感受性が高くなる。
iTM − 誘導性組織成熟
iTR − 誘導性組織再生
MEM − 最小必須培地
MSC − 間葉幹細胞
NT − 核移植
PBS − リン酸緩衝生理食塩水
PPT − 「出生前−出生後転換」は、出生時又は出生後1週間以内に胎盤哺乳動物の細胞において生じる分子変化を指す。
PS線維芽細胞 − 「瘢痕前線維芽細胞」は、妊娠初期皮膚の皮膚由来の、又はそれらが瘢痕形成することなく皮膚創傷が迅速に治癒することを促進するという点において遺伝子発現の出生前パターンを示すED細胞由来の線維芽細胞である。
RFU − 相対蛍光単位
RNA−seq − RNAシークエンシング
SFM − 無血清培地
St. Dev. − 標準偏差
TR − 組織再生
「分析的再プログラミング技術」という用語は、体細胞の遺伝子発現のパターンを、より多能性の状況のもの、たとえばiPS、ES、ED、EC又はEG細胞のものに再プログラミングするためのさまざまな方法を指し、再プログラミングは、複数の個別の工程で生じ、体細胞の卵母細胞への移植及びその卵母細胞の活性化に単に依存するものではない(米国特許出願60/332,510号(2001年11月26日出願)、同10/304,020号(2002年11月26日出願)、国際特許出願PCT/US02/37899号(2003年11月26日出願)、米国特許出願60/705625号(2005年8月3日出願)、同60/729173号(2005年8月20日出願)、同60/818813号(2006年7月5日出願)及び国際特許出願PCT/US06/30632号(2006年8月3日出願)を参照。これらの開示は参照により本明細書に組み込まれる)。
以下に記載する方法に加えて、瘢痕のない再生潜在力に対応する遺伝子発現の胚パターンを有する細胞の生成及び使用において使用が認められる方法は、以下に見出すことができる:たとえば、発明の名称が「Novel Uses of Cells With Prenatal Patterns of Gene Expression」である国際特許出願PCT/US2006/013519号(2006年4月11日出願);発明の名称が「Methods to Accelerate the Isolation of Novel Cell Strains from Pluripotent Stem Cells and Cells Obtained Thereby」である米国特許出願11/604,047号(2006年11月21日出願);発明の名称が「Methods to Accelerate the Isolation of Novel Cell Strains from Pluripotent Stem Cells and Cells Obtained Thereby」である米国特許出願12/504,630号(2009年7月16日出願)、米国特許仮出願61/831,421号(2013年6月5日出願)、国際特許出願PCT/US2014/040601号(2014年6月3日出願)、米国特許出願14/896,664号(2015年12月7日出願)、発明の名称が「Compositions and Methods for Induced Tissue Regeneration in Mammalian Species」(国際公開第2014/197421号)、及び、発明の名称が「Improved Methods for Detecting and Modulating the Embryonic-Fetal Transition in Mammalian Species」の出願(国際公開第2017/214342号)、これらは、その内容全体が参照によりそれぞれ本明細書に組み込まれる。
非限定的な例として、dsRNAを、フランキングT7プロモーターを含むPCR生成テンプレートを使用してin vitro転写反応(Promega)から調製し、フェノール抽出及びエタノール沈殿によって精製し、水中で再懸濁後にアニールする。外科手術から2時間後に第1の注入を用いて誘導性組織傷害を開始する前に、無傷の実験用動物に4×30nL dsRNAを3日間連続して注入する。
本開示は、新規なiTRモジュレーター及びその使用方法を提供する。いくつかの側面において、本発明は、再生を強化する新規な方法であって、前記iTRモジュレーターの濃度を変更する薬剤を、それを必要とする多細胞生物に投与することを含む方法を提供する。
本発明は、(a)容易に検出可能なマーカー、たとえばその発現が、本明細書で記載するTR活性化因子遺伝子のうちの1つのプロモーターによって駆動されるGFP又はβガラクトシダーゼを含むレポーター分子、たとえばCOX7A1に関するものを使用して、iTR因子を同定するための方法を提供する。本発明は、被検化合物が、TR活性化因子遺伝子の発現に影響を与えるかどうか及び/又はTR阻害性遺伝子の発現を阻害するかどうかの判定に関与するスクリーニングアッセイを提供する。本発明は、方法を実施するのに有用なレポーター分子及び組成物をさらに提供する。一般的に、本発明の方法を使用して同定された化合物は、TR活性化因子又は阻害剤遺伝子を増加させる又は減少させる機序のうちのいずれかによってそれぞれ作用し得る。COX7A1プロモーターの場合、ヒト遺伝子のプロモーター配列フランキング5’末端は、ATG翻訳開始コドンに対して−756塩基の位置で特徴付けられている(Yu,M.,et al. Biochimica and Biophysica Acta 1574(2002)345-353)。大部分のcDNAの転写開始部位は、翻訳開始コドンの−55塩基で観察された。COX7A1の発現は組織特異的であるが、プロモーター並びに残りの遺伝子配列は、多くのハウスキーピング遺伝子のプロモーターと同様にCpGアイランドにある。CpGアイランドは、少なくとも200塩基のスパンに対して、平均的なゲノムに関して予測される含有量のものを上回るCGジヌクレオチドの存在量によって特徴付けられる。プロモーターは、いくつかの調節性結合部位配列:位置−524においてMEF2、並びに位置−58、−279及び−585においてそれぞれ3つのEボックス(E1、E2、及びE3として特徴付けられる)を含み;Eボックスは、調節性タンパク質の筋原性ファミリーのメンバーに結合するDNA結合部位(CAACTG)である。さらに、およそ−95から−68塩基の領域において、転写因子Sp1によって認識されるものと類似している複数のCGリッチセグメントが存在する。
一般的に、本発明のレポーター分子において有用である検出可能な部分としては、検出可能な蛍光、化学発光又は生物発光シグナルを生成するか又は消光する発光又は光吸収化合物がある。いくつかの態様において、TR活性化因子遺伝子が活性化されるか又はTR阻害性遺伝子が阻害されると、検出可能な部分が液体培地へ放出され、培地(又はその試料)に存在する放出された検出可能な部分によって生成されるか又は消光されるシグナルが検出される。いくつかの態様において、得られたシグナルは検出可能な部分の特性に変化をもたらし、そのような変化は、たとえば、光学シグナルとして検出することができる。たとえば、シグナルは、検出可能な部分による電磁放射線(たとえば、スペクトルの赤外、可視又はUV部分の範囲内の波長を有する放射線)の放出又は吸収が変化する場合がある。いくつかの態様において、レポーター分子は、蛍光又は発光部分を含み、第2の分子は、蛍光又は発光部分を消光する消光剤としての役割を果たす。そのような変化は、当技術分野において既知の装置及び方法を使用して検出してもよい。
TR活性化因子及びTR阻害剤遺伝子を図8の「胚マーカー」及び「胎児/成体マーカー」の見出しの下にそれぞれ挙げる。本発明の方法において有用なTR活性化因子及びTR阻害剤ポリペプチドは、さまざまな方法によって得ることができる。いくつかの態様において、ポリペプチドは、組換えDNA技術を使用して生成する。組換えタンパク質発現に関する標準的な方法を使用してもよい。TR活性化因子又はTR阻害剤をコードする核酸遺伝子は、たとえば、遺伝子を発現する細胞から(たとえば、PCR又は他の増幅方法によって又はクローニングによって)又は化学的合成又はcDNA配列ポリペプチド配列に基づいてin vitro転写によって容易に得ることができる。当業者であれば、遺伝コードの縮重に起因して、遺伝子が多くの異なる核酸配列によってコードされていてもよいことは既知であろう。任意に、配列は、選択した宿主細胞において発現するためにコドン最適化される。遺伝子は、細菌、真菌、動物、若しくは植物細胞又は生物において発現する場合がある。遺伝子は、それを自然に発現する細胞から、又はタンパク質をコードする核酸が一時的に又は安定に導入された細胞、たとえば遺伝子をコードする発現ベクターを含む細胞から単離してもよい。いくつかの態様において、遺伝子は、培養物中の細胞によって分泌され、培養培地から単離される。
さまざまな被検化合物を、iTR因子及びiTRの広範囲のモジュレーターを同定するための本発明の方法において使用することができる。たとえば、被検化合物は、低分子、ポリペプチド、ペプチド、核酸、オリゴヌクレオチド、脂質、炭水化物、抗体、又はこれらに限定されないが、遺伝子OCT4、SOX2、KLF4、NANOG、ESRRB、NR5A2、CEBPA、MYC、LIN28A及びLIN28Bに関するmRNAを単独で及び多様な組合せで含む本明細書で記載するものであって、低分子化合物の多様な組合せ、たとえば以下の化合物の組合せのもの:これらに限定されないが、CHIR99021を含むグリコーゲンシンターゼ3(GSK3)阻害剤;これらに限定されないが、SB431542、A−83−01、及びE616452を含むTGF−βシグナル伝達阻害剤;これらに限定されないが、バルプロ酸、フェニルブチレート、及びn-ブチレートを含む、これらに限定されないが、脂肪族酸化合物を含むHDAC阻害剤;トラポキシンB及びデプシペプチドを含む環式テトラペプチド;ヒドロキサム酸、たとえばトリコスタチンA、ボリノスタット(SAHA)、ベリノスタット(PXD101)、LAQ824、パノビノスタット(LBH589)、及びベンズアミドエンチノスタット(MS−275)、CI994、モセチノスタット(MGCD0103);サーチュイン阻害剤ニコチノアミド(nicotinomide)、NAD、ジヒドロクマリン、ナフトピラノン、及び2-ヒドロキシナフトアルデヒドの多様な誘導体、又はIV(HDAC11)デアセチラーゼを含む、クラスI(HDAC1、HDAC2、HDAC3、及びHDAC8)、IIA(HDAC4、HDAC5、HDAC7、及びHDAC9)、IIB(HDAC6及びHDAC10)、III(SIRT1、SIRT2、SIRT3、SIRT4、SIRT5、SIRT6、又はSIRT7)を具体的に標的とするもの;これらに限定されないが、パルネートを含むH3K4/9ヒストンメチル基分解酵素LSD1阻害剤;これらに限定されないが、EPZ004777を含むDot1L阻害剤;これらに限定されないが、Bix01294を含むG9a阻害剤;これらに限定されないが、DZNepを含むEZH2阻害剤、これらに限定されないが、RG108を含むDNAメチルトランスフェラーゼ阻害剤;5-アザ-2’デオキシシチジン(商標名Vidaza及びAzadine);DNAメチル化を阻害し、脱メチル化の第1の工程である5hmCを増加させることができるTet1を増加させるビタミンC;これらに限定されないが、PS48を含む3’ホスホイノシチド依存性キナーゼ1の活性化因子;これらに限定されないが、ケルセチン及びフルクトース2,6-ビスホスフェート(ホスホフルクトキナーゼ1の活性化因子)を含む解糖系プロモーター;これらに限定されないが、ケルセチンを含むHIF1転写複合体の活性を促進する薬剤;これらに限定されないが、AM580、CD437、及びTTNPBを含むRARアゴニスト;これらに限定されないが、レスベラトロールを含む低酸素症を模倣する薬剤;これらに限定されないが、テロメラーゼ(TERT)の触媒構成成分の外因性発現を含むテロメラーゼ活性を増加させる薬剤、LSD1の下方制御を介したエピジェネティック改変を促進する薬剤、これらに限定されないが、リチウムを含むH3K4特異的ヒストンメチル基分解酵素;又はこれらに限定されないが、PD032590を含むMAPK/ERK経路の阻害剤を含むハイブリッド分子であってもよい。追加の化合物としては、ヒストン脱アセチル化酵素阻害剤MS−275、ヒストンメチルトランスフェラーゼ阻害剤BIX01294、DNAメチルトランスフェラーゼ阻害剤RG108、レチノイン酸類似体AM580又はCD437(レチノイン酸受容体アゴニスト)、及びヒストンメチルトランスフェラーゼ阻害剤EPZ004777(DOT1Lの阻害剤、並びにテロメアサイレンシング1様の撹乱物質)、並びにDNAメチルトランスフェラーゼ及びHDAC RSC133の阻害剤がある。そのような化合物は、多様な組合せ、濃度、及び異なる期間で投与して、たとえば、COX7A1、ADIRF、TNFRSF11B、若しくは本明細書に記載するiTRの他の阻害剤の発現の減少に関してアッセイすることによって、及び/又はAMH若しくは他の活性化因子若しくは本明細書に記載するiTRの発現の増加に関してアッセイすることによって、広範囲のiTRマーカーを使用して培養された細胞に対してin vitroで、又は損傷した若しくは罹患した組織においてin vivoで、又は動物の寿命の調節においてin vivoでiTRの効果を最適化してもよい。
胎児又は成体哺乳動物細胞におけるiTR効果の生成において有用である化合物又は化合物の組合せに関するスクリーニングは、in vitro又はin vivo(たとえば動物モデル)で行ってもよい。好ましくは、前記スクリーニングは、通常のスループット又はハイスループットでin vitroで行う。胚又は胎児/成体マーカーの増加又は減少に関するスクリーニングアッセイをそれぞれ行う。前記スクリーニングは、抗体の使用、RNA、代謝マーカー、又は、本明細書に記載する、若しくは「Compositions and Methods for Induced Tissue Regeneration in Mammalian Species」(国際公開第2014/197421号、その内容全体が、参照により本明細書に組み込まれる)、及び「Improved Methods for Detecting and Modulating the Embryonic-Fetal Transition in Mammalian Species」(国際公開第2017/214342号、その内容全体が参照により本明細書に組み込まれる)に記載されている、他のマーカーのアッセイを用いてもよい。好ましくは、前記スクリーニングは、mRNAマーカーのレベルを、最も好ましくはiTRの指標としてCOX7A1の発現における減少をアッセイする。最も好ましくは、前記スクリーニングは、マルチウェルフォーマットで行い、発現は、ゲノムのCOX7A1遺伝子座にノックインされたeGFPのようなレポーター遺伝子を使用する。
アッセイの実施の側面及び対照
上述のさまざまな本発明のスクリーニングアッセイは、被検化合物が活性TR阻害剤のレベルを阻害するか又は活性TR活性化因子のレベルを増加させるかどうかの判定に関与する。レポーター分子の発現に好適な細胞は上述している。本発明のアッセイを行う際に、アッセイ構成成分(たとえば、細胞、TR活性化因子又はTR阻害剤ポリペプチド、及び被検化合物)を、複数の容器又は他の容器へ典型的には分注する。細胞を含むことが可能な任意のタイプの容器又は物品を使用してもよい。本発明の多くの態様において、容器は、マルチウェルプレート(「マイクロウェルプレート」、「マイクロタイタープレート」などとも称する)のウェルである。説明の目的で「ウェル」という用語は、本発明のスクリーニングを行うために使用することができる任意のタイプの容器又は物品、たとえば、アッセイ構成成分を含むことができる任意の容器又は物品を指すために使用することになる。本発明はウェルを使用すること又はマルチウェルプレートを使用することに限定されないことは理解されるべきである。いくつかの態様において、複数の物理的に分離された空洞(又は他の封じ込める特徴)が基質に又はその上に存在する任意の製造品を使用することができる。たとえば、アッセイ構成成分は、流体中に封じ込めることができ、これは、表面上に任意に配列させてもよく、マイクロ流体デバイスなどのチャネル中の個別の場所に液滴を封じ込める耐水性物質によって任意に分離してもよい。
医薬組成物
iTR、iTM、老化細胞除去、iS−CSC及びiCM因子は、さまざまな異なる用途を有する。そのような用途の非限定的な例をここで論じる。いくつかの態様において、iTR因子は、器官又は組織の再生を強化するために使用する。いくつかの態様において、iTR因子は、四肢、指、軟骨、心臓、血管、骨、食道、胃、肝臓、胆嚢、膵臓、腸、直腸、肛門、内分泌腺(たとえば、甲状腺、副甲状腺、副腎、膵臓の内分泌部分)、皮膚、毛包、胸腺、脾臓、骨格筋、心筋の局所損傷、平滑筋、脳、脊髄、末梢神経、卵巣、卵管、子宮、膣、乳腺、精巣、精管、精嚢、前立腺、陰茎、咽頭、喉頭、気管、気管支、肺、腎臓、尿管、膀胱、尿道、眼(たとえば、網膜、角膜)、又は耳(たとえば、コルチ器官)の再生を強化するために使用する。いくつかの態様において、iTR因子は、間質層、たとえば、組織の実質を支える結合組織の再生を強化するために使用する。いくつかの態様において、iTR因子は、外科手術、たとえば、罹患したか又は損傷した、組織、器官、又は他の構造、たとえば四肢、指などの少なくとも一部の除去を伴う外科手術の後の再生を強化するために使用する。たとえば、そのような外科手術は、肝臓、肺、腎臓、胃、膵臓、腸、乳腺、卵巣、睾丸、骨、四肢、指、筋肉、皮膚などの少なくとも一部を除去する場合がある。いくつかの態様において、外科手術は腫瘍を除去するためのものである。いくつかの態様において、iTR因子は、外傷、外科手術、疾患、及び火傷の後の皮膚の瘢痕のない再生を促進するために使用する。
iTM及びiCM因子は、EFTマーカーを欠く胚細胞(たとえば、非限定的な例として、COX7A1を発現しない間質細胞)をさまざまな薬剤に曝露し、前記マーカー、たとえばCOX7A1又はレポーター構築物、たとえばCOX7A1遺伝子プロモーターを使用して発現したGFPの誘導に関してアッセイすることによって同定してもよい。エクソソームは、細胞を再プログラミングして新規の成長、遊走及び分化特性を与えることが可能な強力なタンパク質及びRNA因子を保有しているため、これらが、すなわちiTM及びiCMが細胞の発生状況を再プログラミングが可能かどうかを調査した。したがって、胚細胞における成体遺伝子の誘導に関して、成体細胞からのエクソソームを試験した。一連の15hESC派生クローン胚祖細胞株のイルミナマイクロアレイ分析を使用して全RNA発現プロファイルを評価し、これらをさまざまな解剖学的位置から得られた18個の初代内皮の細胞株(新生児から成体)と比較した(図示していない)。EFTを経た細胞からのエクソソームは、以前はそのような発現が欠如していた胚細胞においてCOX7A1の発現を誘導し、本明細書に記載する他のマーカーを使用した細胞を成熟させることが可能なことを判定した。
iTRマーカーとしてのCOX7A1発現の減少をアッセイするためのPCRを使用したiTR因子に関する成体ヒト皮膚線維芽細胞のスクリーニング
加齢細胞又はCSCにおいてセノリシスを誘導することが可能なiTR因子に関するスクリーニング
遺伝子発現が胎児前パターンの細胞により予測されるアポトーシスの増加を識別するために、最適化された条件を同定した。胚及び成体由来間葉細胞(それぞれ4D20.8及びMSC)、並びに胚及び成体由来血管内皮細胞(それぞれ30MV2−6及びHAEC)を、カンプトセシン(CPT)、H2O2、及びタプシガルギン(TG)の各2つの濃度で、並びにビヒクル対照を含む多様な刺激で処理し、アポトーシスを誘導した。分析の24時間前に化合物で処理した。処理後、アポトーシスを、製造業者の取扱説明書に従ってin situ細胞死検出キット(Roche、カタログ番号12156792910)を使用してTUNEL染色により観察した。図7に示すように、3.7nMのタプシガルギンは、内皮細胞のみならず、胚間葉細胞のアポトーシスにおいて、その成体対応物と比較して、強力で統計的に有意な増加をもたらした。したがって、このアッセイは、加齢細胞及びCSCでのセノリシスの誘導におけるiTR因子の有効性判定に有用である。
ハイスループットiTRスクリーニングにおいて使用するCOX7A1発現のためのEGFPレポーターを調製する方法
TERT不死化ヒト包皮線維芽細胞におけるCOX7A1遺伝子座の下流に、IRES−EGFPを挿入した。これを達成するために、COX7A1遺伝子座を標的とする2つのガイドRNA(gRNA)候補を設計し、クローン化した。gRNA介在CRISPR/Cas9改変は、標的となる二本鎖切断(DSB)をもたらした。IRES−EGFPカセットを有するドナープラスミドを、DNA修復鋳型として機能するように、活性gRNAの位置に基づいて構築した。gRNA及びドナープラスミドのTERT不死化ヒト包皮線維芽細胞へのコトランスフェクションは、相同組換え修復(HDR)により、COX7A1の標的領域におけるIRES−EGFPのノックインを可能にした(図7)。
サンプルの最初のセットでは、5〜8継代のヒト皮膚線維芽細胞(MDW1)を、6ウェルコーニング組織培養プレートを用い、1ウェル当たり約50,000細胞で、成長培地DMEM+10%FBS中に播種した。
カクテルを以下に説明する(10%KSR、10%FBS、2mM グルタマックス、1%NEAA、0.055mM 2-メルカプトエタノール、10,000U/mlペニシリン−ストレプトマイシンが添加されたノックアウトDMEM培地中に含まれる)。
1.MDW-1 P8 D41 10μM CHIR99021+RepSox(10μM)+10μMトラニルシプロミン(パルネート)+50μMフォルスコリン+5μM TTNPB+100nM DZNep+1μM PD0325901+50ng/ml FGF2+5μM EPZ004777+5μM SGC0946+10μM RSC133+1μM CI994
2.MDW-1 P5 D39 10μM CHIR99021+RepSox(10μM)+10μMトラニルシプロミン(パルネート)+50μMフォルスコリン+5μM TTNPB+100nM DZNep+1μM PD0325901+50ng/ml FGF2+1μM OAC3+5μM EPZ004777+5μM SGC0946+10μM RSC133+1μM CI994+20μM SB216763+1μM SAHA+250ng/ml OCT4+50nM AM580
3.MDW-1 P5 D39 10μM CHIR99021+RepSox(10μM)+10μMトラニルシプロミン(パルネート)+50μMフォルスコリン+5μM TTNPB+100nM DZNep+1μM PD0325901+50ng/ml FGF2+1μM OAC3+5μM EPZ004777+5μM SGC0946+10μM RSC133+1μM CI994+20μM SB216763+1μM SAHA+250ng/ml OCT4+50nM AM580+10μM PP1
4.MDW-1 P5 D42 10μM CHIR99021+RepSox(10μM)+10μMトラニルシプロミン(パルネート)+50μMフォルスコリン+5μM TTNPB+100nM DZNep+1μM PD0325901+50ng/ml FGF2+5μM EPZ004777+5μM SGC0946+10μM RSC133+1μM CI994+20μM SB216763+1μM SAHA+50nM AM580+10μM PP1
5.MDW-1 P8 D42 1μM MS−275+10μM CHIR99021+RepSox(10μM)+10μMトラニルシプロミン(パルネート)+50μMフォルスコリン+5μM TTNPB+100nM DZNep+1μM PD0325901+50ng/ml FGF2+1μM OAC3+5μM EPZ004777+5μM SGC0946+10μM RSC133+1μM CI994
6.MDW-1 P8 D27 1μM MS−275+10μM CHIR99021+RepSox(10μM)+10μMトラニルシプロミン(パルネート)+50μMフォルスコリン+5μM TTNPB+100nM DZNep+1μM PD0325901+50ng/ml FGF+1μM OAC3+5μM EPZ004777。
カクテル処理後の組織再生及び細胞増殖のスクラッチアッセイ
8継代のBJ−TERT線維芽細胞を、6ウェルプレートのDMEM10%FBS中に50,000細胞/ウェルで播種した。翌日、細胞を、以下に示すさまざまなカクテルで2週間処理した。
対照:成長培地のみ
A:4μg/ml LIN28A−11R(LD Biopharma HTF 0046)
B:0.5mMバルプロ酸(Cayman 13033)
C:4μg/ml LIN28A−11R+0.5mMバルプロ酸
D:1μM MS−275(Cayman 13284)+10μM CHIR99021(Cayman 13122)+10μM RepSox(Sigma R0158)+10μMトラニルシプロミン(パルネート)(Sigma 616431)+50μMフォルスコリン(Cayman 11018)+5μM TTNPB(Cayman 16144)+100nM DZNep(Cayman 13128)+1μM PD0325901(Cayman 13034)+50ng/ml FGF2(Peprotech AF-100-18B)+1μM OAC3(Cayman 14104)+5μM EPZ004777(Cayman 16173)+5μM SGC0946(Cayman 13967)+10μM RSC133(Cayman 90018139)
E:4μg/ml LIN28A+0.5mM VPA、10μM CHIR99021、10μM RepSox、10μMパルネート、50μMフォルスコリン、5μM TTNPB、+100nM DZNep+1μM PD0325901、hES媒体(DMEM/F12 10%KSR、10%FBS、1%グルタマックス、1%NEAA、0.055mM 2-メルカプトエタノール、50ng/ml bFGF)。
再プログラミング薬剤で処理された線維芽細胞は、後期継代細胞に対して老化細胞除去活性を示し、細胞数を減少させる
Xgene線維芽細胞(ヒト包皮、Xgene, Sausilito CAから入手)を、継代初期(P9)及び後期(P33)で、20,000細胞/ウェル(0.1%ゼラチン被覆24ウェルプレート)の成長培地(DMEM+10%FBS)中に播種した。翌日、以下に示す添加物を含む培地を1週間再供給し、1日おきに供給し、次いで計数した。
対照 添加物不含、
A.4μg/ml LIN28A−11R(LD Biopharma HTF 0046)、
B.0.5mMバルプロ酸(Cayman 13033)、
C.4μg/ml LIN28A+0.5mMバルプロ酸
D.4μg/ml LIN28A+0.5mM VPA、10μM CHIR99021(Cayman 13122)、10μM Repsox(Sigma R0158)、10μMパルネート(Sigma 616431)、50μMフォルスコリン(Cayman 11018)、5μM TTNPB(Cayman 16144)、100nM DZNep(Cayman 13128)及び1μM PD0325901(Cayman 13034)。
iTRのための1mMでのバルプロ酸の使用
成体由来の皮膚線維芽細胞を、6ウェルプレートのウェル中のDMEM10%FBS中で培養し、0.5mM及び1mMのバルプロ酸で28日間処理した。28日目に培地を除去し、細胞をPBSで洗浄し、次いでβ-メルカプトエタノールを含むRLT(Qiagenカタログ番号79216)を使用して溶解した。全RNAを、製造業者の取扱説明書に従ってQiagen RNeasyミニキット(Qiagenカタログ番号74106)を使用して抽出した。次いで、cDNAをThermoFisher III(カタログ番号18080044)を使用して調製した。qPCRを、SDSv2.3ソフトウェアを用いたApplied Biosystems 7500リアルタイムPCRシステムで行い、(成体表現型の決定的な指標である)GAPDHに対するCOX7A1の発現を評価した。
Claims (19)
- 出生後の哺乳動物細胞の遺伝的プロファイルを変化させるのに好適な組成物であって、
a 0.5〜5.0mMのバルプロ酸、7〜10μMの6-[[2-[[4(2,4-ジクロロフェニル)-5-(5-メチル-1H-イミダゾール-2-イル)-2-ピリミジニル]アミノ]エチル]アミノ]-3-ピリジンカルボニトリル(CHIR99021)、4.0〜10μMの2-(3-(6-メチルピリジン-2-イル)-1H-ピラゾール-4-イル)-1,5-ナフチリジン(RepSox)、2.0〜10μMのトラニルシプロミン(パルネート)、0.5〜50μMのフォルスコリン及び1.0〜5μMの4-[(E)-2-(5,5,8,8-テトラメチル-6,7-ジヒドロナフタレン-2-イル)プロパ-1-エニル]安息香酸(TTNPB)を含む第1の組成物;
b 0.5〜5.0mMのバルプロ酸、7〜10μMのCHIR99021、4.0〜10μMのRepSox、2.0〜10μMのトラニルシプロミン(パルネート)、0.5〜50μMのフォルスコリン、1.0〜5μMのTTNPB及び50nM〜240nMの3-デアザネプラノシンA(DZNep)を含む第2の組成物;
c 0.1〜1.0μMのN-[(2R)-2,3-ジヒドロキシプロポキシ]-3,4-ジフルオロ-2-(2-フルオロ-4-ヨードアニリノ)ベンズアミド(PD0325901)及び7.0〜10μMの6-[[2-[[4(2,4-ジクロロフェニル)-5-(5-メチル-1H-イミダゾール-2-イル)-2-ピリミジニル]アミノ]エチル]アミノ]-3-ピリジンカルボニトリル(CHIR99021)を含む第3の組成物;並びに
d.哺乳動物細胞においてTERT遺伝子を発現させるための好適な発現ベクターを含む第4の組成物、
を含む組成物。 - 前記第1、第2及び第3の組成物が細胞培養培地中にある、請求項1に記載の組成物。
- 前記第1、第2及び第3の組成物がヒアルロン酸を含むヒドロゲル中にある、請求項1に記載の組成物。
- 出生後の哺乳動物細胞の遺伝的プロファイルを変化させるのに好適な組成物であって、
a 0.5〜5.0mMのバルプロ酸、7〜10μMの6-[[2-[[4(2,4-ジクロロフェニル)-5-(5-メチル-1H-イミダゾール-2-イル)-2-ピリミジニル]アミノ]エチル]アミノ]-3-ピリジンカルボニトリル(CHIR99021)、4.0〜10μMの2-(3-(6-メチルピリジン-2-イル)-1H-ピラゾール-4-イル)-1,5-ナフチリジン(RepSox)、2.0〜10μMのトラニルシプロミン(パルネート)、0.5〜50μMのフォルスコリン及び1.0〜5μMの4-[(E)-2-(5,5,8,8-テトラメチル-6,7-ジヒドロナフタレン-2-イル)プロパ-1-エニル]安息香酸(TTNPB)を含む第1の組成物;
b 0.5〜5.0mMのバルプロ酸、7〜10μMのCHIR99021、4.0〜10μMのRepSox、2.0〜10μMのトラニルシプロミン(パルネート)、0.5〜50μMのフォルスコリン、1.0〜5μMのTTNPB及び50nM〜240nMの3-デアザネプラノシンA(DZNep)を含む第2の組成物;並びに
c 0.1〜1.0μMのN-[(2R)-2,3-ジヒドロキシプロポキシ]-3,4-ジフルオロ-2-(2-フルオロ-4-ヨードアニリノ)ベンズアミド(PD0325901)及び7.0〜10μMの6-[[2-[[4(2,4-ジクロロフェニル)-5-(5-メチル-1H-イミダゾール-2-イル)-2-ピリミジニル]アミノ]エチル]アミノ]-3-ピリジンカルボニトリル(CHIR99021)を含む第3の組成物、
を含む組成物。 - 前記第1、第2及び第3の組成物が細胞培養培地中にある、請求項4に記載の組成物。
- 前記第1、第2及び第3の組成物がヒアルロン酸含有ヒドロゲル中にある、請求項5に記載の組成物。
- 組織再生の誘導(iTR)が可能な薬剤を同定する方法であって、1)出生後の哺乳動物細胞を、組織再生の誘導が疑われる1つ以上の外因性薬剤への前記細胞の曝露を促進する形式で培養すること、2)前記細胞を前記1つ以上の外因性薬剤と接触させること、3)前記細胞における胚−胎児転換(EFT)遺伝的マーカーの発現を測定することを含み、前記発現の変化が、iTRをもたらす薬剤の能力を示す、方法。
- 胚−胎児転換(EFT)遺伝的マーカーが、COX7A1、ADIRFのうちの1つ以上から選択される、請求項7に記載の方法。
- 前記遺伝的マーカーがCOX7A1である、請求項7に記載の方法。
- 前記出生後の哺乳動物細胞が、前記EFTをシグナル伝達するレポーター遺伝子を保有しているZERT不死化成体ヒト皮膚線維芽細胞である、請求項7に記載の方法。
- 組織再生の誘導(iTR)が可能な薬剤を同定する方法であって、1)出生後の哺乳動物細胞を、組織再生の誘導が疑われる1つ以上の外因性薬剤への前記細胞の曝露を促進する形式で培養すること、2)前記細胞を前記1つ以上の外因性薬剤と接触させること、3)前記細胞からRNAを調製し、前記細胞における胚−胎児転換(EFT)転写物のレベルを測定して、前記1つ以上の薬剤がiTRをもたらすかどうかを判定することを含む方法。
- 胚−胎児転換(EFT)遺伝的マーカーが、COX7A1、ADIRFのうちの1つ以上から選択される、請求項11に記載の方法。
- 前記遺伝子マーカーがCOX7A1である、請求項11に記載の方法。
- 前記出生後の哺乳動物細胞が、EFTをシグナル伝達するレポーター遺伝子を保有しているTERT不死化成体ヒト皮膚線維芽細胞である、請求項11に記載の方法。
- 出生後の細胞の遺伝的プロファイルを変化させる方法であって、前記方法が、
a 1つ以上の出生後の哺乳動物細胞を、0.5〜5.0mMのバルプロ酸、7〜10μMのCHIR99021、4〜10μMのRepSox、2.0〜10μMのトラニルシプロミン(パルネート)、0.5〜50μMのフォルスコリン、1.0〜5μMのTTNPBを含む第1の組成物とおよそ17日間接触させること;
b 工程(a)の1つ以上の細胞を、0.5〜5.0mMのバルプロ酸、7.0〜10μMのCHIR99021、4〜10μMのRepSox、2.0〜10μMのトラニルシプロミン(パルネート)、0.5〜50μMのフォルスコリン、1.0〜5μMのTTNPB及び50〜240nMの3-デアザネプラノシンA(DZNep)を含む第2の組成物と14日間接触させること;並びに
c 工程(b)の前記1つ以上の細胞を、0.1〜1.0μMのPD0325901及び7.0〜10μMのCHIR99021を含む第3の組成物とおよそ7日間接触させること
を含む方法。 - COX7A1、ADIRF及びTNFRSF11Bの1つ以上の発現が胚性幹細胞と関連する発現レベルまで減少した場合に、前記1つ以上の細胞が変化した遺伝的プロファイルを有すると考えられる、請求項15に記載の方法。
- COX7A1の発現が胚性幹細胞と関連する発現レベルまで減少した場合に、前記1つ以上の細胞が変化した遺伝的プロファイルを有すると考えられる、請求項15に記載の方法。
- 前記第1、第2及び第3の組成物が細胞培養培地中にある、請求項15に記載の方法。
- 前記第1、第2及び第3の組成物がヒアルロン酸含有ヒドロゲル中にある、請求項15に記載の方法。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003111588A (ja) * | 2000-01-11 | 2003-04-15 | Geron Corp | ヒト多能性幹細胞の増殖および分化のための技術 |
WO2007058671A1 (en) * | 2005-11-21 | 2007-05-24 | West Michael D | Novel uses of cells with prenatal patterns of gene expression |
WO2012065065A1 (en) * | 2010-11-12 | 2012-05-18 | Follica, Inc. | Methods and compositions for modulating hair growth, wound healing and scar revision |
WO2013111875A1 (ja) * | 2012-01-27 | 2013-08-01 | 国立大学法人京都大学 | 多能性幹細胞の心筋分化誘導法 |
WO2017214342A1 (en) * | 2016-06-07 | 2017-12-14 | Biotime, Inc. | Improved methods for detecting and modulating the embryonic-fetal transition in mammalian species |
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Publication number | Priority date | Publication date | Assignee | Title |
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US6129761A (en) | 1995-06-07 | 2000-10-10 | Reprogenesis, Inc. | Injectable hydrogel compositions |
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US20190282624A1 (en) * | 2015-11-30 | 2019-09-19 | Beihao Stem Cell And Regenerative Medicine Research Institute Co., Ltd. | Improved methods for reprograming non-pluripotent cells into pluripotent stem cells |
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003111588A (ja) * | 2000-01-11 | 2003-04-15 | Geron Corp | ヒト多能性幹細胞の増殖および分化のための技術 |
US6667176B1 (en) * | 2000-01-11 | 2003-12-23 | Geron Corporation | cDNA libraries reflecting gene expression during growth and differentiation of human pluripotent stem cells |
WO2007058671A1 (en) * | 2005-11-21 | 2007-05-24 | West Michael D | Novel uses of cells with prenatal patterns of gene expression |
WO2012065065A1 (en) * | 2010-11-12 | 2012-05-18 | Follica, Inc. | Methods and compositions for modulating hair growth, wound healing and scar revision |
WO2013111875A1 (ja) * | 2012-01-27 | 2013-08-01 | 国立大学法人京都大学 | 多能性幹細胞の心筋分化誘導法 |
WO2017214342A1 (en) * | 2016-06-07 | 2017-12-14 | Biotime, Inc. | Improved methods for detecting and modulating the embryonic-fetal transition in mammalian species |
Non-Patent Citations (2)
Title |
---|
CELL. MOL. LIFE SCI., vol. 74, JPN6023017310, 2017, pages 3553 - 3575, ISSN: 0005053007 * |
INT. J. MOL. SCI., vol. 17, JPN6023017308, 2016, pages 226, ISSN: 0005053008 * |
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