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前 言
大腦復雜的細胞組成和特定的結構，使得體外建模難度極大。近年來大腦類器官概括了大腦發育的許多關鍵特征，激發全-球神經學領域相關科研人員的興趣，研究成果不斷的發表于高分期刊，將腦類器官用于各種生理和病理研究。細胞因子作為類器官培養基中的添加試劑，可以引導細胞按特定器官譜系進行分化。為助力腦類器官的培養與分化，義翹神州可提供人EGF、FGF2、NOG、BMP4等一系列腦類器官培養相關產品。
01 腦類器官研究新進展
目前大多數腦部模型主要是人類死后腦組織、非人靈長類動物組織或者體外2D細胞。由于資源限制和動物模型的物種差異性等原因，使腦類器官成為潛在研究腦部生理和病理的模型。腦類器官主要源自胚胎干細胞（ESC）或者誘導性多能干細胞（iPSC）。對于體外神經生物學和神經發育障礙的疾病的研究，也會用到不同部位的腦類器官，比如前腦、中腦、海馬腦類器官等。目前使用腦類器官模型涉及到阿爾茨海默癥、帕金森病、自閉癥、精神分裂等，甚至包括漸凍癥、結節性硬化癥等罕見病。
體外神經生物學和神經發育障礙疾病模型的腦類器官 | |
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 |
（源自：doi.org/10.1002/bies.201900011）
02細胞因子在腦類器官中的應用
細胞因子在類器官培養過程中發揮重要作用。在多能干細胞（PSC）培養中加入了FGF2構建3D腦類器官模型。對于不同部位的腦類器官的培養，會加入不同的細胞因子，比如對于用于研究脊髓小腦共濟失調疾病的小腦類器官培養中，會加入FGF2、FGF19、SDF1等細胞因子。
用于生成特異性腦類器官的因子摘要 | |
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 |
（源自：doi.org/10.1002/bies.201900011）
?義翹神州細胞因子產品數據
Human FGF2 Protein, Cat: GMP-10014-HNAE
高純度：
≥ 95 % as determined by SDS-PAGE.
結合活性
Cell proliferation assay using Balb/C 3T3 mouse embryonic fibroblasts. The specific activity is >1,000 IU/μg.
Human Noggin Protein, Cat: 10267-HNAH
高純度：
≥95% as determined by SDS-PAGE. ≥95% as determined by SEC-HPLC.
高批間一致性
Inhibit BMP4-induced alkaline phosphatase production by MC3T3E1 mouse preosteoblast cells.
腦類器官培養相關的細胞因子 | |||
貨號 | 靶點 | 內毒素 | 純度及活性 |
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
【參考文獻】
1. Antoine Verger et al. FDA Approval of Lecanemab: The Real Start of Widespread Amyloid PET Use? — The EANM Neuroimaging Committee Perspective. European Journal of Nuclear Medicine and Molecular Imaging, 2023. doi.org/10.1007/s00259-023-06177-5.
2. Yujung Chang et al. Modelling Neurodegenerative Diseases with 3D Brain Organoids. Biological Reviews, 2020. doi.org/10.1111/brv.12626.
3. Jihoon Kim, Bon-Kyoung Koo, and Juergen A. Knoblich, Human Organoids: Model Systems for Human Biology and Medicine, Nature Reviews Molecular Cell Biology, 2020. doi.org/10.1038/s41580-020-0259-3.
4. Guini Song et al. The Application of Brain Organoid Technology in Stroke Research: Challenges and Prospects. Frontiers in Cellular Neuroscience, 2021. frontiersin.org/articles/10.3389/fncel.2021.646921.
5. Jay Gopalakrishnan. The Emergence of Stem Cell-Based Brain Organoids: Trends and Challenges. BioEssays, 2019. 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. 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. 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. 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. 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
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