JP7157742B2 - ヒト多能性幹細胞からの心房および心室心筋細胞系列の生成 - Google Patents
ヒト多能性幹細胞からの心房および心室心筋細胞系列の生成 Download PDFInfo
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Description
本出願は、2016年12月4日に出願された米国仮出願シリアル番号第62/429,823号および2016年12月6日に出願された米国仮出願シリアル番号第62/430,815号への米国特許法第119条の優先権を主張する。これらの先行特許出願の内容全体は、以下に限定されないが、明細書、請求の範囲、および要約書のそれぞれの他に、あらゆる図面、表またはその図を含めて、参照することにより本明細書に明示的に組み込まれる。
特定の実施形態では、例えば、以下が提供される:
(項目1)
心室心筋細胞が濃縮された心筋細胞の集団であって、ペースメーカー細胞を本質的に含まない、集団。
(項目2)
ペースメーカー細胞を欠いている、項目1に記載の集団。
(項目3)
患者における心不全または心筋梗塞を治療するための医薬組成物であって、項目1または2に記載の心筋細胞の集団および薬学的に許容される担体を含む、組成物。
(項目4)
心室心筋細胞が濃縮された心筋細胞の集団を製造する方法であって、
中胚葉誘導培地中で多能性幹細胞をインキュベートすることであって、前記中胚葉誘導培地が、心室中胚葉を生成するために充分なBMP成分および有効量のアクチビン成分を含む、前記インキュベートすること、およびその後に、
好適な培地中で前記インキュベートされた細胞を培養して、心室心筋細胞が濃縮された心筋細胞の集団を生成させること
を含む、方法。
(項目5)
前記アクチビン成分の濃度が前記BMP成分の濃度より高い、項目4に記載の方法。
(項目6)
前記アクチビン成分に対する前記BMP成分の比が、約0.3~1:1、約0.5:1、または約0.8:1である、項目4または5に記載の方法。
(項目7)
前記アクチビン成分の濃度が、CD235aを発現する中胚葉細胞のレベルを測定すること、およびこれをRALDH2を発現する中胚葉細胞のレベルに対して比較することにより決定される、項目4~6のいずれか1項に記載の方法。
(項目8)
前記アクチビン成分の濃度が、RALDH2を発現する中胚葉細胞と比較してより多くのCD235aを発現する中胚葉細胞を結果として優先的にもたらす濃度を決定することにより選択される、項目4~7のいずれか1項に記載の方法。
(項目9)
前記アクチビン成分が、約4ng/ml~約20ng/mlの量で加えられる、項目4~8のいずれか1項に記載の方法。
(項目10)
前記アクチビン成分の濃度が6~20ng/mlである、項目4~9のいずれか1項に記載の方法。
(項目11)
前記BMP成分の濃度が約3ng/ml~約20ng/mlである、項目4~10のいずれか1項に記載の方法。
(項目12)
前記BMP成分の濃度が5ng/mlまたは10ng/mlである、項目4~11のいずれか1項に記載の方法。
(項目13)
前記アクチビン成分の濃度が12ng/mlである、項目4~12のいずれか1項に記載の方法。
(項目14)
前記BMP成分がBMP4である、項目4~13のいずれか1項に記載の方法。
(項目15)
前記アクチビン成分がアクチビンAである、項目4~14のいずれか1項に記載の方法。
(項目16)
生成された心筋細胞の前記集団の少なくとも一部分が、心臓の修復を必要とする対象を治療するために使用される、項目4~15のいずれか1項に記載の方法。
(項目17)
心臓の修復を必要とする前記対象が、心不全のリスクがある、心不全を患っているかつ/または心筋梗塞の発症を患っている、項目16に記載の方法。
(項目18)
前記治療が、心筋梗塞の発症の前、間または後に為される、項目17に記載の方法。
(項目19)
心房心筋細胞が濃縮された心筋細胞の集団を製造する方法であって、
中胚葉誘導培地中で多能性幹細胞をインキュベートすることであって、前記中胚葉誘導培地が、心房中胚葉を生成するために充分なBMP成分および有効量のアクチビン成分を含む、前記インキュベートすること、およびその後に、
レチノイン酸成分を前記細胞に加えることであって、前記レチノイン酸成分を前記加えることが、中胚葉誘導培地中での前記インキュベーションの間または後に行われる、前記加えること、および、
心房心筋細胞が濃縮された心筋細胞の集団が生成されるように前記インキュベートされた細胞を培養すること
を含む、方法。
(項目20)
前記レチノイン酸成分が、前記細胞がRALDH2陽性かつCD235a陰性である時に加えられる、項目19に記載の方法。
(項目21)
前記アクチビン成分に対する前記BMP成分の比が約1.5対1またはそれより高い、項目19または20に記載の方法。
(項目22)
前記アクチビン成分に対する前記BMP成分の比が3:2である、項目19~21のいずれか1項に記載の方法。
(項目23)
前記BMP成分が約3ng/ml~約100ng/mlの濃度で存在する、項目19~22のいずれか1項に記載の方法。
(項目24)
前記BMP成分が約3ng/mlの量で存在する、項目19~23のいずれか1項に記載の方法。
(項目25)
前記アクチビン成分が約0.01ng/ml~約6ng/mlの量で存在する、項目19~24のいずれか1項に記載の方法。
(項目26)
前記アクチビン成分が約2ng/mlの量で存在する、項目19~25のいずれか1項に記載の方法。
(項目27)
前記レチノイン酸成分がトランスレチノイン酸またはレチノールである項目19~26のいずれか1項に記載の方法。
(項目28)
前記レチノイン酸成分が50nm~5μΜの濃度で加えられる、項目19~27のいずれか1項に記載の方法。
(項目29)
前記レチノイン酸成分が500nMの濃度で加えられる、項目19~28のいずれか1項に記載の方法。
(項目30)
前記BMP成分がBMP4である、項目19~29のいずれか1項に記載の方法。
(項目31)
前記アクチビン成分がアクチビンAである、項目19~30のいずれか1項に記載の方法。
(項目32)
前記BMP成分が1日後に前記中胚葉誘導培地に加えられる、項目19~31のいずれか1項に記載の方法。
(項目33)
前記アクチビン成分が1日後に前記中胚葉誘導培地に加えられる、項目19~31のいずれか1項に記載の方法。
(項目34)
前記レチノイン酸成分が前記方法の約3~5日目に加えられる、項目19~33のいずれか1項に記載の方法。
(項目35)
追加のBMP成分が前記方法の3日目に前記中胚葉誘導培地に加えられない、項目19~34のいずれか1項に記載の方法。
(項目36)
FGF阻害剤が前記方法の3日目に前記中胚葉誘導培地に入れられない、項目19~35のいずれか1項に記載の方法。
(項目37)
前記中胚葉誘導培地中で前記多能性幹細胞をインキュベートする前に、凝集および/または胚様体形成のために好適な培地中で前記多能性幹細胞をインキュベートすることをさらに含む、項目4~36のいずれか1項に記載の方法。
(項目38)
前記方法により製造された細胞が、潜在的な治療用化合物をスクリーニングするためのin vitroアッセイにおいて利用される、項目4~37のいずれか1項に記載の方法。
(項目39)
心房心筋細胞が濃縮された心筋細胞の単離された集団であって、少なくとももしくは約50%の心房心筋細胞、少なくとももしくは約60%の心房心筋細胞、少なくとももしくは約70%の心房心筋細胞、少なくとももしくは約80%の心房心筋細胞、または少なくとももしくは約90%の心房心筋細胞を含む、集団。
(項目40)
項目18~38のいずれか1項に記載の方法にしたがって得られた、項目39に記載の心筋細胞の集団。
(項目41)
心室心筋細胞が濃縮された心筋細胞の単離された集団であって、少なくとももしくは約50%の心室心筋細胞、少なくとももしくは約60%の心室心筋細胞、少なくとももしくは約70%の心室心筋細胞、少なくとももしくは約80%の心室心筋細胞、または少なくとももしくは約90%の心室心筋細胞を含む、集団。
(項目42)
ペースメーカー細胞を本質的に含まない、またはペースメーカー細胞を欠いている、項目41に記載の集団。
(項目43)
項目4~17のいずれか1項に記載の方法にしたがって得られた、項目41または42に記載の集団。
(項目44)
心臓の修復を必要とする対象を治療する方法であって、前記対象に項目1、2、または41~43のいずれか1項に記載の心筋細胞の集団を投与することを含む、方法。
(項目45)
前記対象が、心不全のリスクがある、心不全を患っているかつ/または心筋梗塞の発症を経験している、項目44に記載の方法。
(項目46)
前記心筋梗塞が前記患者の心室中のものである、項目45に記載の方法。
(項目47)
心臓の修復を必要とする対象の治療において使用するための、項目1、2、または40~42のいずれか1項に記載の心筋細胞の集団。
(項目48)
心臓の修復を必要とする対象を治療するための医薬の調整における、項目1、2、または41~43のいずれか1項に記載の心筋細胞の集団の使用。
(項目49)
中胚葉細胞の集団中の心房中胚葉を検出する方法であって、RALDH2を検出することを含み、RALDH2の存在が心房中胚葉を指し示す、方法。
(項目50)
中胚葉細胞の集団中の心室中胚葉を検出する方法であって、CD235aを検出することを含み、CD235aの存在が心室中胚葉を指し示す、方法。
(項目51)
洞房結節のペースメーカー細胞または心外膜細胞が濃縮された心筋細胞の集団を製造する方法であって、
中胚葉誘導培地中で多能性幹細胞をインキュベートすることであって、前記中胚葉誘導培地が、ALDH+/CD235-中胚葉を生成するために充分な量のBMP成分およびアクチビン成分をさらに含む、前記インキュベートすること、およびその後に、
WNT、FGFiおよびBMPの1つまたは複数を含む好適な培地中で前記インキュベートされた細胞を培養して、洞房結節のペースメーカー細胞または心外膜細胞が濃縮された心筋細胞の集団を生成させること
を含む、方法。
(項目52)
項目51に記載の方法により製造された心筋細胞の集団。
(項目53)
試験化合物または剤の潜在的な心毒性をスクリーニングまたは評価する方法であって、先行する細胞集団の項目のいずれかに記載の心筋細胞の集団を前記試験化合物に曝露するステップ、ならびに、生存能力、収縮性、電位の変化および/または細胞の他の機能を評価するステップを含む、方法。
異なる中胚葉集団の心臓分化能力をさらに研究するために、我々の元々のサイトカインの組合せ(10B/6A;混合誘導MI)または心室(5B/12A;心室誘導VI)もしくは心房(3B/2A;心房誘導AI)運命に最適化された組合せで誘導したEBから生成された20日目のNKX2-5+SIRPアルファ+CD90-心筋細胞を単離した。予想の通り、CTNTの発現レベルは、選別された集団中で類似していた(図6A)。VIのEBから生成された心筋細胞は、MIまたはAIのEBに由来する心筋細胞よりも、MYL2、IRX4およびMYH7などの心室筋細胞に関連する遺伝子を有意に高いレベルで発現した(図6B)。VIのEBに由来する集団は、最も高い頻度のMCL2V+心筋細胞を有し(VIのEBから80%±2%、MIのEBから56%±4%、およびAIのEBから25%±5%)、向上した心室発現プロファイルは、部分的に、濃縮された頻度の心室様心筋細胞によることを示唆した(図13A)。心筋細胞の集団のMLC2V含有量の差異が免疫染色分析により確認された(図13B)。
Claims (16)
- 心室心筋細胞が濃縮された心筋細胞の集団を製造する方法であって、
中胚葉誘導培地中で多能性幹細胞をインキュベートすることであって、前記中胚葉誘導培地が、心室中胚葉を生成するために充分なBMP成分および有効量のアクチビン成分を含む、前記インキュベートすること、およびその後に、
好適な培地中で前記インキュベートされた細胞を培養して、心室心筋細胞が濃縮された心筋細胞の集団を生成させること
を含み、
前記BMP成分の濃度が3ng/ml~20ng/mlであり、前記アクチビン成分の濃度が4ng/ml~20ng/mlであり、前記アクチビン成分の濃度が前記BMP成分の濃度よりも高い、方法。 - 前記アクチビン成分に対する前記BMP成分の比が、0.3~1:1である、請求項1に記載の方法。
- 前記アクチビン成分に対する前記BMP成分の比が、0.5:1である、請求項2に記載の方法。
- 前記アクチビン成分に対する前記BMP成分の比が、0.8:1である、請求項2に記載の方法。
- 前記アクチビン成分の濃度が、CD235aを発現する中胚葉細胞のレベルを測定すること、これをRALDH2を発現する中胚葉細胞のレベルに対して比較すること、および、RALDH2を発現する中胚葉細胞と比較してより多くのCD235aを発現する中胚葉細胞を結果として優先的にもたらす濃度を決定することにより選択される、請求項1~4のいずれか1項に記載の方法。
- 前記アクチビン成分の濃度が6~20ng/mlである、請求項1~5のいずれか1項に記載の方法。
- 前記BMP成分の濃度が5ng/mlまたは10ng/mlである、請求項1~6のいずれか1項に記載の方法。
- 前記アクチビン成分の濃度が12ng/mlである、請求項1~7のいずれか1項に記載の方法。
- 前記BMP成分がBMP4である、請求項1~8のいずれか1項に記載の方法。
- 前記アクチビン成分がアクチビンAである、請求項1~9のいずれか1項に記載の方法。
- 生成された心筋細胞の前記集団の少なくとも一部分が、心臓の修復を必要とする対象を治療する際に使用するためのものである、請求項1~10のいずれか1項に記載の方法。
- 心臓の修復を必要とする前記対象が、心不全のリスクがある、心不全を患っているかつ/または心筋梗塞の発症を患っている、請求項11に記載の方法。
- 前記治療が、心筋梗塞の発症の前、間または後に為される、請求項12に記載の方法。
- 前記中胚葉誘導培地中で前記多能性幹細胞をインキュベートする前に、凝集および/または胚様体形成のために好適な培地中で前記多能性幹細胞をインキュベートすることをさらに含む、請求項1~13のいずれか1項に記載の方法。
- 前記方法により製造された細胞が、潜在的な治療用化合物をスクリーニングするためのin vitroアッセイにおいて利用される、請求項1~14のいずれか1項に記載の方法。
- ヒト多能性幹細胞由来の心臓分化細胞の集団中の心室中胚葉を検出する方法であって、CD235aを検出することを含み、CD235aの存在が心室中胚葉を指し示す、方法。
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