JPWO2020172589A5 - - Google Patents
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本発明のその他の目的、特色、および利点は、以下の詳細な説明から明らかになる。しかし、詳細な説明および特定の実施例は、本発明の特定の実施形態を示しているが、説明のためのみに提供していることを理解されたい。それは、本発明の精神および範囲内で種々の変形および改変がこの詳細な説明から当業者には明らかになるからである。
本発明は、例えば、以下の項目を提供する。
(項目１)
ヒト誘導多能性幹細胞に由来する未熟な心筋細胞の成熟化のための方法であって、
（ａ）ヒト誘導多能性幹細胞に由来する未熟な心筋細胞（未熟なｈｉＰＳＣ－ＣＭ）を提供するステップ；
（ｂ）羊水から単離された細胞からｉｎ ｖｉｔｒｏで誘導された細胞外マトリックス（ＡＦＣ－ＥＣＭ）を提供するステップ；
（ｃ）前記未熟なｈｉＰＳＣ－ＣＭを前記ＡＦＣ－ＥＣＭと接触させるステップ；および
（ｄ）培養培地中で前記未熟なｈｉＰＳＣ－ＣＭを前記ＡＦＣ－ＥＣＭと共に培養して、前記未熟なｈｉＰＳＣ－ＣＭの成熟化を誘導し、それにより成熟心筋細胞を形成するステップ；
を含み、前記成熟心筋細胞が、成人ヒト心組織と似た区別できるサルコメア構造を有するロッド状細胞によって特徴付けられる、方法。
(項目２)
前記未熟なｈｉＰＳＣ－ＣＭが、前記ＡＦＣ－ＥＣＭ上にプレーティングされる、項目１に記載の方法。
(項目３)
前記成熟心筋細胞が、前記ＡＦＣ－ＥＣＭ上に単層を形成し、それにより、前記ＡＦＣ－ＥＣＭ上に成熟心筋細胞の単層を含む細胞構築物を形成し、前記成熟心筋細胞が、前記ＡＦＣ－ＥＣＭ上に整列される、項目１または２のいずれか一項に記載の方法。
(項目４)
前記未熟なｈｉＰＳＣ－ＣＭが、内向き整流性カリウムチャネルＫｉｒ２．１を発現しない、項目１から３のいずれか一項に記載の方法。
(項目５)
羊水から単離された細胞からｉｎ ｖｉｔｒｏで誘導された細胞外マトリックス（ＡＦＣ－ＥＣＭ）上に成熟心筋細胞の単層を含む細胞構築物であって、前記成熟心筋細胞が、ＡＦＣ－ＥＣＭ培養した、ヒト誘導多能性幹細胞に由来する心筋細胞（ｈｉＰＳＣ－ＣＭ）であり、前記成熟心筋細胞が、成人ヒト心組織と似た区別できるサルコメア構造を有するロッド状細胞によって特徴付けられる、細胞構築物。
(項目６)
成熟心筋細胞の前記単層が、前記ＡＦＣ－ＥＣＭ上に整列される、項目５に記載の細胞構築物。
(項目７)
線維トラックが前記構築物上に存在する、項目５または６のいずれか一項に記載の細胞構築物。
(項目８)
前記ＡＦＣ－ＥＣＭが、ラミニン、コラーゲンアルファ－１（ＸＶＩＩＩ）、基底膜特異的ヘパラン硫酸プロテオグリカンコアタンパク質、アグリン、ビメンチン、およびコラーゲンアルファ－２（ＩＶ）、ならびに／またはそれらのアイソフォームを含む、項目５から７のいずれか一項に記載の細胞構築物。
(項目９)
前記コラーゲンアルファ－１（ＸＶＩＩＩ）のアイソフォームが、アイソフォーム２であり、および／または前記アグリンのアイソフォームが、アイソフォーム６である、項目８に記載の細胞構築物。
(項目１０)
前記ＡＦＣ－ＥＣＭが、フィブロネクチンおよび／またはそのアイソフォームをさらに含む、項目８または９のいずれか一項に記載の細胞構築物。
(項目１１)
前記ＡＦＣ－ＥＣＭが、デコリン、ペルレカン、および／またはコラーゲン（ＩＩＩ）を含まない、項目５から１０のいずれか一項に記載の細胞構築物。
(項目１２)
羊水から単離された細胞からｉｎ ｖｉｔｒｏで誘導された細胞外マトリックス（ＡＦＣ－ＥＣＭ）上に成熟心筋細胞の細胞構築物を作成するための方法であって、
（ａ）ヒト誘導多能性幹細胞に由来する未熟な心筋細胞（未熟なｈｉＰＳＣ－ＣＭ）を提供するステップ、
（ｂ）羊水から単離された細胞からｉｎ ｖｉｔｒｏで誘導された細胞外マトリックス（ＡＦＣ－ＥＣＭ）を提供するステップ；
（ｃ）前記ＡＦＣ－ＥＣＭ上に前記未熟なｈｉＰＳＣ－ＣＭをプレーティングするステップ；
（ｄ）培養培地中で前記ＡＦＣ－ＥＣＭ上にプレーティングされた前記未熟なｈｉＰＳＣ－ＣＭを培養して、前記未熟なｈｉＰＳＣ－ＣＭの成熟心筋細胞への成熟化を誘導し、前記ＡＦＣ－ＥＣＭ上に前記成熟心筋細胞の単層を形成し、それにより前記細胞構築物を形成するステップ；
を含み、前記成熟心筋細胞が、成人ヒト心組織と似た区別できるサルコメア構造を有するロッド状細胞によって特徴付けられる、方法。
(項目１３)
成熟心筋細胞の前記単層が、前記ＡＦＣ－ＥＣＭ上に整列される、項目１２に記載の方法。
(項目１４)
線維トラックが前記細胞構築物上に存在する、項目１２または１３のいずれか一項に記載の方法。
(項目１５)
薬物化合物の心毒性および／または催不整脈効果をｉｎ ｖｉｔｒｏで決定するための方法であって、前記薬物化合物を、項目５から１１のいずれか１つに記載の細胞構築物の前記成熟心筋細胞と接触させるステップ、ならびに前記成熟心筋細胞の電気生理学における変化を観察して、前記薬物化合物が前記成熟心筋細胞に対する心毒性および／または催不整脈効果を有するかどうかを確認するステップ、を含む方法。
(項目１６)
前記成熟心筋細胞の電気生理学における前記変化が、活動電位持続時間（ＡＰＤ）の延長であり、ＡＰＤの延長が、前記薬物化合物が前記成熟心筋細胞に対する心毒性および／または催不整脈効果を有することを裏付ける、項目１５に記載の方法。
(項目１７)
前記成熟心筋細胞の電気生理学における前記変化が、早期後脱分極（ＥＡＤ）であり、早期後脱分極（ＥＡＤ）が、前記薬物化合物が前記成熟心筋細胞に対する心毒性および／または催不整脈効果を有することを裏付ける、項目１５に記載の方法。
(項目１８)
前記成熟心筋細胞の電気生理学における前記変化が、遅延後脱分極（ＤＡＤ）であり、遅延後脱分極（ＤＡＤ）が、前記薬物化合物が前記成熟心筋細胞に対する心毒性および／または催不整脈効果を有することを裏付ける、項目１５に記載の方法。
(項目１９)
前記成熟心筋細胞の電気生理学における前記変化が、活動電位持続時間（ＡＰＤ）プラスローターであり、ＡＰＤの延長プラスローターが、前記薬物化合物が前記成熟心筋細胞に対する心毒性および／または催不整脈効果を有することを裏付ける、項目１５に記載の方法。
(項目２０)
前記成熟心筋細胞の電気生理学における前記変化が、不整脈であり、前記不整脈が、前記薬物化合物が前記成熟心筋細胞に対する心毒性および／または催不整脈効果を有することを裏付ける、項目１５に記載の方法。
Other objects, features, and advantages of the present invention will become apparent from the detailed description below. It should be understood, however, that the detailed description and specific examples, while indicating specific embodiments of the invention, are provided for purposes of illustration only. Various variations and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
The present invention provides, for example, the following items.
(Item 1)
A method for maturation of immature cardiomyocytes derived from human induced pluripotent stem cells, comprising:
(a) providing immature cardiomyocytes (immature hiPSC-CMs) derived from human induced pluripotent stem cells;
(b) providing an extracellular matrix (AFC-ECM) derived in vitro from cells isolated from amniotic fluid;
(c) contacting said immature hiPSC-CM with said AFC-ECM; and
(d) culturing said immature hiPSC-CMs with said AFC-ECM in a culture medium to induce maturation of said immature hiPSC-CMs, thereby forming mature cardiomyocytes;
wherein said mature cardiomyocytes are characterized by rod-shaped cells with a distinguishable sarcomere structure resembling adult human cardiac tissue.
(Item 2)
The method of item 1, wherein said immature hiPSC-CM are plated on said AFC-ECM.
(Item 3)
said mature cardiomyocytes form a monolayer on said AFC-ECM, thereby forming a cell construct comprising a monolayer of mature cardiomyocytes on said AFC-ECM, wherein said mature cardiomyocytes form a monolayer on said AFC-ECM; 3. The method of any one of items 1 or 2, aligned on an ECM.
(Item 4)
4. The method of any one of items 1-3, wherein said immature hiPSC-CM does not express the inward rectifying potassium channel Kir2.1.
(Item 5)
1. A cell construct comprising a monolayer of mature cardiomyocytes on an extracellular matrix (AFC-ECM) derived in vitro from cells isolated from amniotic fluid, said mature cardiomyocytes cultured in AFC-ECM A cellular construct of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), wherein said mature cardiomyocytes are characterized by rod-shaped cells with a distinguishable sarcomere structure similar to adult human cardiac tissue.
(Item 6)
6. The cell construct of item 5, wherein said monolayer of mature cardiomyocytes is arrayed on said AFC-ECM.
(Item 7)
7. Cellular construct according to any one of items 5 or 6, wherein fiber tracks are present on said construct.
(Item 8)
wherein said AFC-ECM comprises laminin, collagen alpha-1 (XVIII), basement membrane-specific heparan sulfate proteoglycan core protein, agrin, vimentin, and collagen alpha-2 (IV), and/or isoforms thereof 8. A cell construct according to any one of 5-7.
(Item 9)
9. Cell construct according to item 8, wherein said collagen alpha-1 (XVIII) isoform is isoform 2 and/or said agrin isoform is isoform 6.
(Item 10)
10. Cell construct according to any one of items 8 or 9, wherein said AFC-ECM further comprises fibronectin and/or isoforms thereof.
(Item 11)
11. Cell construct according to any one of items 5 to 10, wherein said AFC-ECM does not comprise decorin, perlecan and/or collagen (III).
(Item 12)
1. A method for creating mature cardiomyocyte cell constructs on an extracellular matrix (AFC-ECM) derived in vitro from cells isolated from amniotic fluid, comprising:
(a) providing immature cardiomyocytes (immature hiPSC-CMs) derived from human induced pluripotent stem cells;
(b) providing an extracellular matrix (AFC-ECM) derived in vitro from cells isolated from amniotic fluid;
(c) plating said immature hiPSC-CMs on said AFC-ECMs;
(d) culturing said immature hiPSC-CMs plated on said AFC-ECM in a culture medium to induce maturation of said immature hiPSC-CMs into mature cardiomyocytes; forming a monolayer of said mature cardiomyocytes thereon, thereby forming said cell construct;
wherein said mature cardiomyocytes are characterized by rod-shaped cells with a distinguishable sarcomere structure resembling adult human cardiac tissue.
(Item 13)
13. The method of item 12, wherein said monolayer of mature cardiomyocytes is arrayed on said AFC-ECM.
(Item 14)
14. The method of any one of items 12 or 13, wherein fiber tracks are present on said cell construct.
(Item 15)
12. A method for determining in vitro cardiotoxic and/or proarrhythmic effects of a drug compound comprising contacting said drug compound with said mature cardiomyocytes of the cell construct of any one of items 5-11. and observing changes in the electrophysiology of said mature cardiomyocytes to determine whether said drug compound has cardiotoxic and/or proarrhythmic effects on said mature cardiomyocytes.
(Item 16)
said alteration in the electrophysiology of said mature cardiomyocytes is a prolongation of action potential duration (APD), and prolongation of APD indicates that said drug compound has cardiotoxic and/or proarrhythmic effects on said mature cardiomyocytes. 16. The method of item 15, wherein:
(Item 17)
said alteration in the electrophysiology of said mature cardiomyocytes is early afterdepolarization (EAD) wherein said drug compound has cardiotoxic and/or proarrhythmia effects on said mature cardiomyocytes 16. The method of item 15, which supports that
(Item 18)
said change in the electrophysiology of said mature cardiomyocytes is delayed after depolarization (DAD), wherein said drug compound has cardiotoxic and/or proarrhythmic effects on said mature cardiomyocytes 16. The method of item 15, which supports that
(Item 19)
said change in the electrophysiology of said mature cardiomyocytes is an action potential duration (APD) plus rotator, and an extended plus rotator of APD indicates that said drug compound has cardiotoxic and/or proarrhythmic effects on said mature cardiomyocytes. 16. The method of item 15, which supports that
(Item 20)
16. The method of item 15, wherein said alteration in electrophysiology of said mature cardiomyocytes is an arrhythmia, and said arrhythmia confirms that said drug compound has a cardiotoxic and/or proarrhythmic effect on said mature cardiomyocytes.
Claims (9)
（ｉ）ヒト誘導多能性幹細胞に由来する未熟な心筋細胞を得ることであって、前記未熟な心筋細胞が、円形形状および単一の核を示す、得ること；
（ｉｉ）前記未熟な心筋細胞を、妊娠期間３７週超のヒトから得られた羊水から単離された細胞を培養することから得られた細胞外マトリックス（ＡＦＣ－ＥＣＭ）と接触させることであって、前記ＡＦＣ－ＥＣＭが、ラミニン、コラーゲンアルファ－１（ＸＶＩＩＩ）、基底膜特異的ヘパラン硫酸プロテオグリカンコアタンパク質、アグリン、ビメンチン、およびコラーゲンアルファ－２（ＩＶ）、またはそれらのアイソフォームを含む、接触させること；
（ｉｉｉ）前記ＡＦＣ－ＥＣＭ上に成熟心筋細胞の単層を形成するために、培養培地中で前記未熟な心筋細胞を前記ＡＦＣ－ＥＣＭと共に培養すること；ならびに
（ｉｖ）前記薬物化合物を成熟心筋細胞と接触させること、および前記薬物化合物が前記成熟心筋細胞に対する心毒性または催不整脈効果を有するかどうかを確認するために、前記成熟心筋細胞の電気生理学における変化を観察すること、を含み、
前記ＡＦＣ－ＥＣＭが、異方的な線維トラックに構造化され、
前記成熟心筋細胞が、ロッド形状および２つの核を示し、かつ
前記成熟心筋細胞が、前記ＡＦＣ－ＥＣＭの前記異方的な線維トラック上に異方的に整列される、方法。 A method for determining the cardiotoxic or proarrhythmic effects of a drug compound in vitro, said method comprising:
(i) obtaining immature cardiomyocytes derived from human induced pluripotent stem cells, said immature cardiomyocytes exhibiting a round shape and a single nucleus;
(ii) contacting said immature cardiomyocytes with an extracellular matrix (AFC-ECM) obtained from culturing cells isolated from amniotic fluid obtained from a human over 37 weeks of gestation; wherein said AFC-ECM comprises laminin, collagen alpha-1 (XVIII), basement membrane-specific heparan sulfate proteoglycan core protein, agrin, vimentin, and collagen alpha-2 (IV), or isoforms thereof to cause;
(iii) culturing said immature cardiomyocytes with said AFC-ECM in a culture medium to form a monolayer of mature cardiomyocytes on said AFC-ECM; and
(iv) contacting the drug compound with mature cardiomyocytes and changes in the electrophysiology of the mature cardiomyocytes to ascertain whether the drug compound has a cardiotoxic or proarrhythmic effect on the mature cardiomyocytes; including observing
wherein the AFC-ECM is structured into anisotropic fiber tracks;
said mature cardiomyocytes exhibit a rod shape and two nuclei, and
A method, wherein said mature cardiomyocytes are anisotropically aligned on said anisotropic fiber tracks of said AFC-ECM .
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| PCT/US2020/019311 WO2020172589A1 (en) | 2019-02-21 | 2020-02-21 | Methods for the maturation of cardiomyocytes on amniotic fluid cell-derived ecm, cellular constructs, and uses for cardiotoxicity and proarrhythmic screening of drug compounds |
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