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HSPGs glypican-1 and glypican-4 are human neuronal proteins characteristic of different neural phenotypes.
Journal of Neuroscience Research ( IF 4.2 ) Pub Date : 2020-06-19 , DOI: 10.1002/jnr.24666
Lotta E Oikari 1 , Chieh Yu 1 , Rachel K Okolicsanyi 1 , Nesli Avgan 1 , Ian W Peall 1 , Lyn R Griffiths 1 , Larisa M Haupt 1
Affiliation  

Generating neurons from human stem cells has potential for brain damage therapy and neurogenesis modeling, but current efficacy is limited by culture heterogeneity and the lack of markers. We have previously reported the heparan sulfate proteoglycans (HSPGs) glypican‐1 (GPC1) and ‐4 (GPC4) as the markers of lineage‐specific human neural stem cells (hNSCs) and mediators of hNSC lineage potential. Here, we further examined phenotypical characteristics and GPC1 and GPC4 during neural differentiation of hNSCs in the presence of two neurogenic growth factors reported to bind to heparan sulfate: brain‐derived neurotrophic factor (BDNF) and platelet‐derived growth factor‐B (PDGF‐B). In hNSC neural cultures, GPC1 and GPC4 were expressed along neurites and cell bodies in long‐term (40–60 days) neural differentiation cultures demonstrating the areas of differential localization—suggesting potentially different functions. Neural differentiation cultures in the presence of BDNF or PDGF‐B generated phenotypically different neural cells with BDNF treatment associated with higher GPC4 versus GPC1 expression, increased heterogeneity, and differential neuron subtype marker expression to PDGF‐B cultures. PDGF‐B cultures exhibited higher levels of spontaneous activity and reduced heterogeneity over long‐term culture associated with decreased GPC4 . Untreated neural cultures were highly variable, supporting the use of neuroregulatory growth factors for guided differentiation. Targeted siRNA downregulation of GPC1/4 reduced neural differentiation markers and altered response to exogenous BDNF and PDGF‐B. This work confirms GPC1 and GPC4 as regulators of human neural differentiation and supports their use as novel markers of neural cell characterization.

中文翻译:

HSPGs glypican-1 和 glypican-4 是具有不同神经表型特征的人类神经元蛋白质。

从人类干细胞生成神经元具有用于脑损伤治疗和神经发生建模的潜力,但目前的功效受到培养异质性和缺乏标记物的限制。我们之前曾报道过硫酸乙酰肝素蛋白聚糖 (HSPGs) glypican-1 (GPC1) 和 ‐4 (GPC4) 作为谱系特异性人类神经干细胞 (hNSCs) 的标记物和 hNSC 谱系潜能的介质。在这里,我们进一步检查了 hNSCs 神经分化过程中的表型特征和 GPC1 和 GPC4,据报道存在两种与硫酸乙酰肝素结合的神经源性生长因子:脑源性神经营养因子 (BDNF) 和血小板源性生长因子-B (PDGF- B)。在 hNSC 神经培养物中,GPC1 和 GPC4 在长期(40-60 天)的神经分化培养物中沿神经突和细胞体表达,证明了差异定位区域——表明潜在的不同功能。BDNF 或 PDGF-B 存在下的神经分化培养物产生表型不同的神经细胞,BDNF 治疗与更高GPC4GPC1 的表达、增加的异质性以及对 PDGF-B 培养物的差异神经元亚型标记表达。与GPC4降低相关的长期培养中,PDGF-B 培养物表现出更高水平的自发活动和减少的异质性。未经处理的神经培养物变化很大,支持使用神经调节生长因子进行引导分化。GPC1/4 的靶向 siRNA 下调减少了神经分化标志物并改变了对外源性 BDNF 和 PDGF-B 的反应。这项工作证实 GPC1 和 GPC4 作为人类神经分化的调节剂,并支持它们作为神经细胞表征的新标记物的用途。
更新日期:2020-06-25
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