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神经系统疾病研究的新兴工具：脑类器官

义翘神州

2024/10/24

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生命科学仪器综合讨论

前言

大脑复杂的细胞组成和特定的结构，使得体外建模难度极大。近年来大脑类器官概括了大脑发育的许多关键特征，激发全球神经学领域相关科研人员的兴趣，研究成果不断的发表于高分期刊，将脑类器官用于各种生理和病理研究。细胞因子作为类器官培养基中的添加试剂，可以引导细胞按特定器官谱系进行分化。为助力脑类器官的培养与分化，义翘神州可提供人EGF、FGF2、NOG、BMP4等一系列脑类器官培养相关产品。

01 脑类器官研究新进展

目前大多数脑部模型主要是人类死后脑组织、非人灵长类动物组织或者体外2D细胞。由于资源限制和动物模型的物种差异性等原因，使脑类器官成为潜在研究脑部生理和病理的模型。脑类器官主要源自胚胎干细胞（ESC）或者诱导性多能干细胞（iPSC）。对于体外神经生物学和神经发育障碍的疾病的研究，也会用到不同部位的脑类器官，比如前脑、中脑、海马脑类器官等。目前使用脑类器官模型涉及到阿尔茨海默症、帕金森病、自闭症、精神分裂等，甚至包括渐冻症、结节性硬化症等罕见病。

体外神经生物学和神经发育障碍疾病模型的脑类器官
Type of organoid	Disease modeled/potential application
Cerebral/early brain organoids	Genetically caused microcephaly Zika virus mediated microcephaly Miller–Dieker syndrome
Midbrain organoids	Potential to model Parkinson's disease
Hypothalamus organoids	Potential to model hormonal and metabolic disorders including Prader–Willi syndrome
Adenohypophysis organoids	Potential to model pituitary dysfunction
Hippocampus organoids	Potential to model cognitive dysfunctions due to Alzheimer's disease
Cerebellum organoids	Potential to model SCA and Dandy–Walker syndrome
Dorsaltelencephalon organoids	ASD
Forebrain assembloids	Timothy syndrome

ASD, autism spectrum disorders; POMC, pro-opiomelanocortin.

（源自：https://doi.org/10.1002/bies.201900011）

02细胞因子在脑类器官中的应用

细胞因子在类器官培养过程中发挥重要作用。在多能干细胞（PSC）培养中加入了FGF2构建3D脑类器官模型。对于不同部位的脑类器官的培养，会加入不同的细胞因子，比如对于用于研究脊髓小脑共济失调疾病的小脑类器官培养中，会加入FGF2、FGF19、SDF1等细胞因子。

用于生成特异性脑类器官的因子摘要
Type of organoid	Cultured with
Midbrain organoids	Wnt activators and SMAD inhibitors
Hypothalamus organoids	Inhibitors that blocks TGF‐β pathways BMP-4 ligand and Wnt agonists
Adenohypophysis organoids	DAPT, SAG, BIO, BMP4, dorsomorphin, Wnt4, Wnt5, FGF8, Nodal, iWP2
Hippocampus organoids	Wnt inhibitor IWR1e, TGF‐β inhibitor SB431542, 10% FBS, GSK3 inhibitor CHIR99021, BMP4
Cerebellum organoids	SB431542, FGF2, FGF19, SDF1
Dorsaltelencephalon organoids	Noggin, FGF2, rhDKK1, EGF, ascorbic acid, BDNF, GDNF, cAMP
Dorsaltelencephalon organoids	Dorsomorphin, SB431542, FGF2, EGF Subpallium: IWP2, SHH agonist SAG, BDNF, NT3, allopregnalone, retinoic acid Pallium: BDNF, NT3
Photosensitive organoids	BDNF
Retinal organoids	IWR1e, Matrigel, 10% FBS, SAG, CHIR99021, retinoic acid
Hypothalamus organoids	SMAD, BMP, Nodal and activin signaling pathway inhibitors
Cerebellar plate neuroepithelium	FGF2,4,8, SAG, retinoic acid, BDNF, GDNF, NT3

BDNF, brain‐derived neurotrophic factor; BMP, bone morphogenetic protein; cAMP, cyclic adenosine monophosphate; EGF, epidermal growth factor; FBS, fetal bovine serum; FGF, fibroblast growth factor; GDNF, glial cell‐derived neurotrophic factor. （源自：https://doi.org/10.1002/bies.201900011）

?义翘神州细胞因子产品数据

Human FGF2 Protein, Cat: GMP-10014-HNAE

高纯度：

≥ 95 % as determined by SDS-PAGE.

结合活性

Cell proliferation assay using Balb/C 3T3 mouse embryonic fibroblasts. The specific activity is >1,000 IU/μg.

Human Noggin Protein, Cat: 10267-HNAH

高纯度：

≥95% as determined by SDS-PAGE. ≥95% as determined by SEC-HPLC.

高批间一致性

Inhibit BMP4-induced alkaline phosphatase production by MC3T3E1 mouse preosteoblast cells.

脑类器官培养相关的细胞因子
货号	靶点	内毒素	纯度及活性
10605-HNAE	EGF	<5 EU/mg	≥95%^☆，Active
GMP-10605-HNAE	EGF	<5 EU/mg	≥95%^☆，Active
GMP-10014-HNAE	FGF2	<10 EU/mg	≥95%，Active
10609-HNAE2	BMP4	<1 EU/mg	≥95%，Active
10267-HNAH	NOG	<10 EU/mg	≥95%^☆，Active

☆：SDS-PAGE & SEC-HPLC

【参考文献】

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5. Jay Gopalakrishnan. The Emergence of Stem Cell-Based Brain Organoids: Trends and Challenges. BioEssays, 2019. https://doi.org/10.1002/bies.201900011.

6. Madeline A. Lancaster and Juergen A. Knoblich. Generation of Cerebral Organoids from Human Pluripotent Stem Cells. Nature Protocols, 2014. https://doi.org/10.1038/nprot.2014.158.

7. Sebastian, R., et al. Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human brain organoids. Nat Commun, 2023. https://doi.org/10.1038/s41467-023-39420-6

8. Jimena Andersen, et al. Generation of Functional Human 3D Cortico-Motor Assembloids. Cell, 2020, doi:10.1016/j.cell.2020.11.017.

9. Yueqi Wang, et al. Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes. Nature Communications, 2022. https://doi.org/10.1038/s41467-022-33364-z

10. Fleck, J.S., et al. Inferring and perturbing cell fate regulomes in human brain organoids. Nature, 2022. https://doi.org/10.1038/s41586-022-05279-8

11. Oliver L. Eichmüller, et al. Amplification of human interneuron progenitors promotes brain tumors and neurological defects. Science, 2022. Doi: 10.1126/science.abf5546