RU2016100433A - КЛЕТКИ SC-β И КОМПОЗИЦИИ И СПОСОБЫ ДЛЯ ИХ СОЗДАНИЯ - Google Patents

КЛЕТКИ SC-β И КОМПОЗИЦИИ И СПОСОБЫ ДЛЯ ИХ СОЗДАНИЯ Download PDF

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RU2016100433A
RU2016100433A RU2016100433A RU2016100433A RU2016100433A RU 2016100433 A RU2016100433 A RU 2016100433A RU 2016100433 A RU2016100433 A RU 2016100433A RU 2016100433 A RU2016100433 A RU 2016100433A RU 2016100433 A RU2016100433 A RU 2016100433A
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cell
glucose
cells
pancreatic
stimulation
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Куинн П. ПЕТЕРСОН
Фелиция Джей. ПАЙЛИУКА
Дуглас А. Мелтон
Джеффри Р. МИЛЛМАН
Майкл Сарис СЕГЕЛ
Мадс ГЮРТЛЕР
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Президент Энд Феллоус Оф Гарвард Колледж
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Claims (37)

1. Композиция, содержащая ненативную панкреатическую β-клетку, при этом:
(a) ненативная панкреатическая β-клетка содержит одну или более кристаллических инсулиновых гранул;
(b) ненативная панкреатическая β-клетка экспрессирует следующие гены: INS, PDX1, NKX6-1 и ZNT8; и
(c) ненативная панкреатическая β-клетка демонстрирует in vitro ответ, состоящий в стимулированной глюкозой секреции инсулина, на первую стимуляцию глюкозой.
2. Композиция по п. 1, отличающаяся тем, что ненативная панкреатическая β-клетка демонстрирует in vitro ответ, состоящий в стимулированной глюкозой секреции инсулина, на первую стимуляцию глюкозой, вторую стимуляцию глюкозой и третью стимуляцию глюкозой, при этом первую стимуляцию глюкозой, вторую стимуляцию глюкозой и третью стимуляцию глюкозой проводят последовательно.
3. Композиция по п. 1, отличающаяся тем, что ненативная панкреатическая β-клетка дополнительно экспрессирует по меньшей мере один ген, выбранный их группы, состоящей из MAFA, РАХ6, NEUROD1, GCK, SLC2A1, PCSK1, KCNJ11, АВСС8, SNAP25, RAB3A, GAD2, PTPRN, NKX2-2 и РАХ4.
4. Композиция по п. 1, отличающаяся тем, что ненативная панкреатическая β-клетка секретирует инсулин в ответ на первую концентрацию глюкозы по сравнению со второй концентрацией глюкозы в соотношении, составляющем по меньшей мере 1,1, при этом первая концентрация глюкозы выше, чем вторая концентрация глюкозы.
5. Композиция по п. 1, отличающаяся тем, что ненативная панкреатическая β-клетка является моногормональной.
6. Композиция по п. 1, отличающаяся тем, что количество инсулина, секретируемого ненативной панкреатической β-клеткой, составляет по меньшей мере 0,5 мкМЕ на 1000 клеток за 30 минут инкубации, при этом ненативную панкреатическую β-клетку обрабатывают по меньшей мере 20 мМ глюкозы.
7. Композиция по п. 1, отличающаяся тем, что секреция инсулина из ненативной панкреатической β-клетки повышается в ответ на противодиабетический агент.
8. Композиция по п. 1, отличающаяся тем, что ненативная панкреатическая β-клетка демонстрирует цитокин-индуцированный апоптоз в ответ на цитокин.
9. Композиция по п. 1, отличающаяся тем, что ненативная панкреатическая β-клетка характеризуется профилем генной экспрессии, который отличается от профиля генной экспрессии нативной β-клетки.
10. Популяция клеток, содержащая одну или более ненативных панкреатических β-клеток по п. 1, отличающаяся тем, что по меньшей мере 10% клеток в популяции клеток являются ненативными панкреатическими β-клетками.
11. Популяция клеток по п. 12, дополнительно содержащая инсулин-позитивные эндокринные клетки.
12. Популяция клеток по п. 12, отличающаяся тем, что популяция клеток содержит одну из следующих клеток:
a. С-пептид-негативную/глюкагон-позитивную клетку;
b. С-пептид-негативную/соматостатин-позитивную клетку;
c. глюкагон-позитивную/соматостатин-негативную клетку;
d. глюкагон-негативную/соматостатин-позитивную клетку; или
e. любую их комбинацию.
13. Популяция клеток по п. 12, отличающаяся тем, что по меньшей мере 3% популяции клеток составляют С-пептид-негативные/глюкагон-позитивные клетки или глюкагон-позитивные/соматостатин-негативные клетки.
14. Искусственные островок или поджелудочная железа, содержащие популяцию клеток по п. 12.
15. Способ дифференцировки клеток-предшественников в панкреатические β-клетки in vitro, включающий культивирование кластера клеток-предшественников в суспензии в культуральной среде, содержащей активатор сигнального пути тиреоидного гормона и ингибитор сигнального пути трансформирующего фактора роста β (TGF-β), вследствие чего происходит дифференцировка клеток-предшественников в панкреатические β-клетки, при этом панкреатические β-клетки демонстрируют in vitro ответ, состоящий в стимулированной глюкозой секреции инсулина, по меньшей мере на первую стимуляцию глюкозой.
16. Способ по п. 15, отличающийся тем, что клетки-предшественники включают инсулин-позитивную эндокринную клетку.
17. Способ по п. 15, отличающийся тем, что клетки-предшественники включают PDX1 -позитивную клетку-предшественник.
18. Способ по п. 15, отличающийся тем, что активатором сигнального пути тиреоидного гормона является трииодотиронин.
19. Способ по п. 18, отличающийся тем, что концентрация трииодотиронина составляет по меньшей мере 0,1 мМ.
20. Способ по п. 15, отличающийся тем, что ингибитором сигнального пути TGF-β является ингибитор II Alk5.
21. Способ по п. 20, отличающийся тем, что концентрация ингибитора II Alk5 составляет по меньшей мере 100 нМ.
22. Способ по п. 20, отличающийся тем, что концентрация ингибитора II Alk5 составляет 100 мкМ или меньше.
23. Способ по п. 15, отличающийся тем, что культивирование включает замену культуральной среды по меньшей мере через день.
24. Способ по п. 15, отличающийся тем, что культивирование длится по меньшей мере семь дней.
25. Способ по п. 15, отличающийся тем, что культуральная среда является бессывороточной культуральной средой.
26. Способ по п. 15, отличающийся тем, что клетки-предшественники культивируют в присутствии низкоадгезивного субстрата.
27. Способ по п. 15, отличающийся тем, что клетки-предшественники являются человеческими клетками-предшественниками.
28. Способ по п. 15, отличающийся тем, что панкреатические β-клетки демонстрируют in vitro ответ, состоящий в стимулированной глюкозой секреции инсулина, на первую стимуляцию глюкозой и вторую стимуляцию глюкозой, при этом первую стимуляцию глюкозой и вторую стимуляцию глюкозой проводят последовательно.
29. Способ по п. 15, отличающийся тем, что панкреатические β-клетки демонстрируют in vitro ответ, состоящий в стимулированной глюкозой секреции инсулина, на первую стимуляцию глюкозой, вторую стимуляцию глюкозой и третью стимуляцию глюкозой, при этом первую стимуляцию глюкозой, вторую стимуляцию глюкозой и третью стимуляцию глюкозой проводят последовательно.
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