RU2019118438A - Индуцирование панкреатических бета-клеток посредством дифференцировки стволовых клеток под действием рнк - Google Patents
Индуцирование панкреатических бета-клеток посредством дифференцировки стволовых клеток под действием рнк Download PDFInfo
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- cells
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- pancreatic
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- 210000004027 cell Anatomy 0.000 title claims 11
- 210000000130 stem cell Anatomy 0.000 title claims 6
- 230000024245 cell differentiation Effects 0.000 title claims 3
- 230000006698 induction Effects 0.000 title 1
- 108020004999 messenger RNA Proteins 0.000 claims 20
- 238000000034 method Methods 0.000 claims 16
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 6
- 239000008103 glucose Substances 0.000 claims 6
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 claims 5
- 102000004877 Insulin Human genes 0.000 claims 4
- 108090001061 Insulin Proteins 0.000 claims 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 4
- 210000004039 endoderm cell Anatomy 0.000 claims 4
- 229940125396 insulin Drugs 0.000 claims 4
- 230000003248 secreting effect Effects 0.000 claims 4
- 101001062354 Xenopus tropicalis Forkhead box protein A2 Proteins 0.000 claims 3
- 230000004069 differentiation Effects 0.000 claims 3
- 230000001939 inductive effect Effects 0.000 claims 3
- 102100028096 Homeobox protein Nkx-6.2 Human genes 0.000 claims 2
- 101000578254 Homo sapiens Homeobox protein Nkx-6.1 Proteins 0.000 claims 2
- 101000578258 Homo sapiens Homeobox protein Nkx-6.2 Proteins 0.000 claims 2
- 102100041030 Pancreas/duodenum homeobox protein 1 Human genes 0.000 claims 2
- 101710183548 Pyridoxal 5'-phosphate synthase subunit PdxS Proteins 0.000 claims 2
- 238000004113 cell culture Methods 0.000 claims 2
- 238000012258 culturing Methods 0.000 claims 2
- 201000010099 disease Diseases 0.000 claims 2
- 208000035475 disorder Diseases 0.000 claims 2
- 210000003890 endocrine cell Anatomy 0.000 claims 2
- 230000007613 environmental effect Effects 0.000 claims 2
- 210000004263 induced pluripotent stem cell Anatomy 0.000 claims 2
- OGQSCIYDJSNCMY-UHFFFAOYSA-H iron(3+);methyl-dioxido-oxo-$l^{5}-arsane Chemical compound [Fe+3].[Fe+3].C[As]([O-])([O-])=O.C[As]([O-])([O-])=O.C[As]([O-])([O-])=O OGQSCIYDJSNCMY-UHFFFAOYSA-H 0.000 claims 2
- 230000035800 maturation Effects 0.000 claims 2
- 230000009996 pancreatic endocrine effect Effects 0.000 claims 2
- 208000011580 syndromic disease Diseases 0.000 claims 2
- 238000001890 transfection Methods 0.000 claims 2
- 230000007704 transition Effects 0.000 claims 2
- 101100518002 Danio rerio nkx2.2a gene Proteins 0.000 claims 1
- -1 Hlxb9 Proteins 0.000 claims 1
- 108700014808 Homeobox Protein Nkx-2.2 Proteins 0.000 claims 1
- 102100027886 Homeobox protein Nkx-2.2 Human genes 0.000 claims 1
- 101100460496 Homo sapiens NKX2-2 gene Proteins 0.000 claims 1
- 101000819074 Homo sapiens Transcription factor GATA-4 Proteins 0.000 claims 1
- 101000819088 Homo sapiens Transcription factor GATA-6 Proteins 0.000 claims 1
- 101100310648 Mus musculus Sox17 gene Proteins 0.000 claims 1
- 102000007354 PAX6 Transcription Factor Human genes 0.000 claims 1
- 101150081664 PAX6 gene Proteins 0.000 claims 1
- 101150075928 Pax4 gene Proteins 0.000 claims 1
- 101150106167 SOX9 gene Proteins 0.000 claims 1
- 102100021380 Transcription factor GATA-4 Human genes 0.000 claims 1
- 102100021382 Transcription factor GATA-6 Human genes 0.000 claims 1
- 239000012530 fluid Substances 0.000 claims 1
- 101150070243 ptf1a gene Proteins 0.000 claims 1
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Claims (27)
1. Способ индуцирования дифференцировки стволовых клеток в чувствительные к глюкозе и инсулин-секретирующие панкреатические бета-клетки, где указанный способ включает стадии:
(а) культивирования индуцированных плюрипотентных стволовых клеток в качестве исходных клеток в условиях дифференцировки;
(b) индуцирования указанных исходных клеток для перехода из плюрипотентного состояния в состояние линии дифференцировки в мезоэндодерму;
(c) направления дифференцировки клеток в клетки эндодермы посредством трансфекции клеточной культуры первой комбинацией мРНК в эффективной дозе и в пределах конкретных временных окон;
(d) дополнительного превращения указанных клеток эндодермы в панкреатические клетки-предшественники путем трансфекции второй комбинацией мРНК;
(e) дополнительного созревания указанных панкреатических клеток-предшественников в панкреатические эндокринные клетки с использованием третьей комбинации мРНК; и
(f) сбора кластеров, обогащенных панкреатическими бета-клетками, которые являются восприимчивыми к глюкозе окружающей среды и способны секретировать инсулин в ответ на глюкозу.
2. Способ по п.1, где указанная первая комбинация мРНК содержит мРНК FoxA2.
3. Способ по п.1, где указанная первая комбинация мРНК содержит мРНК Soxl7.
4. Способ по п.1, где указанная первая комбинация мРНК содержит мРНК FoxA2 и Soxl7.
5. Способ по п.1, где указанная первая комбинация мРНК содержит мРНК FoxA2, Sox17, GATA4 и GATA6.
6. Способ по п.1, где указанная вторая комбинация мРНК содержит по меньшей мере одну из мРНК PDX1, Hlxb9, Ptf1a, ixl1, HNF1a и b и Sox9.
7. Способ по п.1, где указанная третья комбинация мРНК содержит по меньшей мере одну из мРНК PDX1, NKX6.1, NKX2.2, Pax6, Pax4, Hlxb9 и Ngn3.
8. Способ по п.1, где мРНК, влияющая на коммитирование панкреатических бета-клеток, содержит по меньшей мере одну из мРНК NKX6.1, MAFA или MAFA.
9. Способ по п.1, где указанные исходные клетки собирают из физиологической жидкости или ткани индивидуума.
10. Клетка, полученная способом по п.1.
11. Композиция для лечения заболевания, расстройства или синдрома, содержащая клетку по п.10.
12. Способ лечения заболевания, расстройства или синдрома, включающий стадию введения индивидууму, нуждающемуся в этом, по меньшей мере одну из клеток по п.9 и композицию по п.11.
13. Способ по п.12, где указанная клетка происходит от индивидуума-реципиента.
14. Способ по п.12, где указанные исходные клетки берут у реципиента.
15. Способ продуцирования индуцированных чувствительных к глюкозе и инсулин-секретирующих панкреатических бета-клеток, где указанный способ включает стадии:
(а) культивирования индуцированных плюрипотентных стволовых клеток в качестве исходных клеток в условиях дифференцировки;
(b) индуцирования указанных исходных клеток для перехода из плюрипотентного состояния в состояние линии дифференцировки в мезоэндодерму;
(c) направления дифференцировки клеток в клетки эндодермы посредством трансфекции клеточной культуры первой комбинацией мРНК в эффективной дозе и в пределах конкретных временных окон;
(d) дополнительного превращения указанных клеток эндодермы в панкреатические клетки-предшественники путем трансфекции второй комбинацией мРНК;
(e) дополнительного созревания указанных панкреатических клеток-предшественников в панкреатические эндокринные клетки с использованием третьей комбинации мРНК; и
(f) сбора кластеров, обогащенных панкреатическими бета-клетками, которые являются восприимчивыми к глюкозе окружающей среды и способны секретировать инсулин в ответ на глюкозу.
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| PCT/US2017/062105 WO2018094114A2 (en) | 2016-11-16 | 2017-11-16 | Induction of pancreatic beta cells by stem cell differentiation with rna |
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| CN109963938A (zh) | 2019-07-02 |
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| WO2018094114A3 (en) | 2018-07-26 |
| KR102587530B1 (ko) | 2023-10-11 |
| CN109963938B (zh) | 2024-04-19 |
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