• 特约评述 •
洪源1,2,3, 刘妍1,4,5
收稿日期:
2023-12-01
修回日期:
2024-05-29
出版日期:
2024-06-03
通讯作者:
刘妍
作者简介:
基金资助:
Yuan HONG1,2,3, Yan LIU1,4,5
Received:
2023-12-01
Revised:
2024-05-29
Online:
2024-06-03
Contact:
Yan LIU
摘要:
脑类器官是一种基于人多能干细胞的三维体外模型,能够模拟人脑的细胞异质性、结构和功能。再生医学是一个多学科交叉的领域,致力于应用工程学和生物学手段修复因年龄、疾病或外伤而受损的组织或器官。脑类器官技术作为再生医学领域的一种重要手段,具有广阔的应用前景和重要的科学意义。近年来,利用组织工程和诱导因子分化技术,研究人员成功构建出不同脑区的脑类器官模型,可用于模拟脑损伤或修复病变组织。本文将系统介绍包括大脑皮层、海马、纹状体、中脑、丘脑及下丘脑、小脑和视网膜在内的脑区特异类器官构建技术的最新进展,总结其在再生医学领域中的应用,并概括当前脑类器官应用面临的挑战,如异质性大、缺乏脉管系统和成熟度较低等。这将加深对人类大脑的理解,并增强脑类器官在基础研究和临床研究中的进一步应用。
中图分类号:
洪源, 刘妍. 脑类器官在再生医学中的研究进展[J]. 合成生物学, DOI: 10.12211/2096-8280.2023-102.
Yuan HONG, Yan LIU. Research progress of brain organoids in regenerative medicine[J]. Synthetic Biology Journal, DOI: 10.12211/2096-8280.2023-102.
脑区类型 | 年份 | 课题组 | 分化方法 | 参考文献 |
---|---|---|---|---|
大脑皮层 | 2008 | Yoshiki Sasai | PSCs在含有Dkk -1和Lefty-1的神经分化培养基中自组织形成SFEBq培养物。 | [ |
2013 | Juergen A. Knoblich | 先将PSCs重聚成拟胚体,并生成神经外胚层,随后将其嵌入Matrigel,在没有外源性生长因子的条件下悬浮培养。 | [ | |
2015 | Sergiu P. Paşca | hiPSCs形成拟胚体后使用Dorsomorphin和SB431542进行神经诱导分化,6天后转移至含FGF2和EGF的培养基中,体外培养第25天更换成BDNF和NT3。 | [ | |
2016 | Hongjun Song & Guo-li Ming | iPSCs重聚的拟胚体先在dorsomorphin和A-83的条件下培养7天,并用基质胶包埋后添加CHIR99021、WNT3A和SB431542因子培养一周后转移至微型旋转生物反应器继续培养。 | [ | |
海马体 | 2015 | Yoshiki Sasai | hESCs重聚形成SFEBq后,添加IWR1e和 SB431542培养18天,随后加入CHIR和BMP4诱导海马体分化。 | [ |
纹状体 | 2020 | Sergiu P. Paşca | hiPSCs形成拟胚体后,添加DMH1和SB431542培养6天,随后在第6-22天添加Activin A、IWP2和SR11237促进纹状体的分化。 | [ |
2022 | Lixiang Ma | PSCs重聚后在含LDN-193189和SB431542的培养基中培养10天,随后在purmorphamine的诱导下培养至第25天。 | [ | |
中脑 | 2016 | Huck-Hui Ng | hESCs重聚成拟胚体后第4天开始添加SHH-C25II和FGF8诱导中脑分化命运,神经外胚层出现后包埋类器官,转移至低吸附六孔板中培养。 | [ |
2016 | Hongjun Song & Guo-li Ming | iPSCs重聚后加入SHH、FGF-8、SB431542、LDN193189和CHIR99021诱导中脑命运,并在第14天时将其转移至微型旋转生物反应器继续培养。 | [ | |
丘脑和 下丘脑 | 2016 | Hongjun Song & Guo-li Ming | iPSCs重聚后先加入SB431542 和LDN193189,分化第4至7天,加入WNT3A,SHH和purmorphamine诱导下丘脑命运,随后持续添加FGF2和CNTF促进类器官成熟。 | [ |
2017 | In-Hyun Park | hESCs重聚后添加SB431542、LDN193189和insulin促进尾侧的神经诱导,第8天开始添加PD0325901和BMP7诱导丘脑分化。 | [ | |
2021 | Hongjun Song & Guo-li Ming | hiPSCs经过双SMAD抑制诱导神经外胚层命运,同时加入IWR1-endo、SAG、PMA和SHH促进弓状核分化,第12天开始与小鼠下丘脑星形胶质细胞共培养。 | [ | |
小脑 | 2015 | Yoshiki Sasai | 将hESC重聚为SFEBq,第2至14天在含有胰岛素和SB431542的培养基中,持续添加重组人FGF2,并在后期加入FGF19和SDF1促进极性结构的形成。 | [ |
2024 | Giorgia Quadrato | hiPSCs重聚后第0至16天加入SB431542、Noggin、FGF8b和CHIR99021诱导后脑分化命运,并在第30天开始加入T3和BDNF促进后脑成熟,加入SDF1a完成小脑模式化。 | [ | |
视网膜 | 2012 | Yoshiki Sasai | hESCs重聚形成SFEBq后,在 IWR1e、FBS、SAG和CHIR99021的诱导下,自组织形成视网膜类器官。 | [ |
2014 | M Valeria Canto-Soler | 将hiPSCs重聚后,分化第7天时用基质胶包埋,并在第4周手动分离神经视网膜结构域,从第42天开始向培养基中添加FBS、Taurine和GlutaMAX。在培养过程中,每天都需添加RA以促进光感受器的成熟。 | [ |
表1 脑区特异类器官的分化流程
Table 1 The differentiation methods of brain region-specific organoids
脑区类型 | 年份 | 课题组 | 分化方法 | 参考文献 |
---|---|---|---|---|
大脑皮层 | 2008 | Yoshiki Sasai | PSCs在含有Dkk -1和Lefty-1的神经分化培养基中自组织形成SFEBq培养物。 | [ |
2013 | Juergen A. Knoblich | 先将PSCs重聚成拟胚体,并生成神经外胚层,随后将其嵌入Matrigel,在没有外源性生长因子的条件下悬浮培养。 | [ | |
2015 | Sergiu P. Paşca | hiPSCs形成拟胚体后使用Dorsomorphin和SB431542进行神经诱导分化,6天后转移至含FGF2和EGF的培养基中,体外培养第25天更换成BDNF和NT3。 | [ | |
2016 | Hongjun Song & Guo-li Ming | iPSCs重聚的拟胚体先在dorsomorphin和A-83的条件下培养7天,并用基质胶包埋后添加CHIR99021、WNT3A和SB431542因子培养一周后转移至微型旋转生物反应器继续培养。 | [ | |
海马体 | 2015 | Yoshiki Sasai | hESCs重聚形成SFEBq后,添加IWR1e和 SB431542培养18天,随后加入CHIR和BMP4诱导海马体分化。 | [ |
纹状体 | 2020 | Sergiu P. Paşca | hiPSCs形成拟胚体后,添加DMH1和SB431542培养6天,随后在第6-22天添加Activin A、IWP2和SR11237促进纹状体的分化。 | [ |
2022 | Lixiang Ma | PSCs重聚后在含LDN-193189和SB431542的培养基中培养10天,随后在purmorphamine的诱导下培养至第25天。 | [ | |
中脑 | 2016 | Huck-Hui Ng | hESCs重聚成拟胚体后第4天开始添加SHH-C25II和FGF8诱导中脑分化命运,神经外胚层出现后包埋类器官,转移至低吸附六孔板中培养。 | [ |
2016 | Hongjun Song & Guo-li Ming | iPSCs重聚后加入SHH、FGF-8、SB431542、LDN193189和CHIR99021诱导中脑命运,并在第14天时将其转移至微型旋转生物反应器继续培养。 | [ | |
丘脑和 下丘脑 | 2016 | Hongjun Song & Guo-li Ming | iPSCs重聚后先加入SB431542 和LDN193189,分化第4至7天,加入WNT3A,SHH和purmorphamine诱导下丘脑命运,随后持续添加FGF2和CNTF促进类器官成熟。 | [ |
2017 | In-Hyun Park | hESCs重聚后添加SB431542、LDN193189和insulin促进尾侧的神经诱导,第8天开始添加PD0325901和BMP7诱导丘脑分化。 | [ | |
2021 | Hongjun Song & Guo-li Ming | hiPSCs经过双SMAD抑制诱导神经外胚层命运,同时加入IWR1-endo、SAG、PMA和SHH促进弓状核分化,第12天开始与小鼠下丘脑星形胶质细胞共培养。 | [ | |
小脑 | 2015 | Yoshiki Sasai | 将hESC重聚为SFEBq,第2至14天在含有胰岛素和SB431542的培养基中,持续添加重组人FGF2,并在后期加入FGF19和SDF1促进极性结构的形成。 | [ |
2024 | Giorgia Quadrato | hiPSCs重聚后第0至16天加入SB431542、Noggin、FGF8b和CHIR99021诱导后脑分化命运,并在第30天开始加入T3和BDNF促进后脑成熟,加入SDF1a完成小脑模式化。 | [ | |
视网膜 | 2012 | Yoshiki Sasai | hESCs重聚形成SFEBq后,在 IWR1e、FBS、SAG和CHIR99021的诱导下,自组织形成视网膜类器官。 | [ |
2014 | M Valeria Canto-Soler | 将hiPSCs重聚后,分化第7天时用基质胶包埋,并在第4周手动分离神经视网膜结构域,从第42天开始向培养基中添加FBS、Taurine和GlutaMAX。在培养过程中,每天都需添加RA以促进光感受器的成熟。 | [ |
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