The Miami Project to Cure Paralysis and Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL, 33136, USA.
John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
Mol Neurobiol. 2018 Aug;55(8):6637-6660. doi: 10.1007/s12035-017-0837-3. Epub 2018 Jan 11.
This study comprehensively addresses the phenotype, function, and whole transcriptome of primary human and rodent Schwann cells (SCs) and highlights key species-specific features beyond the expected donor variability that account for the differential ability of human SCs to proliferate, differentiate, and interact with axons in vitro. Contrary to rat SCs, human SCs were insensitive to mitogenic factors other than neuregulin and presented phenotypic variants at various stages of differentiation, along with a mixture of proliferating and senescent cells, under optimal growth-promoting conditions. The responses of human SCs to cAMP-induced differentiation featured morphological changes and cell cycle exit without a concomitant increase in myelin-related proteins and lipids. Human SCs efficiently extended processes along those of other SCs (human or rat) but failed to do so when placed in co-culture with sensory neurons under conditions supportive of myelination. Indeed, axon contact-dependent human SC alignment, proliferation, and differentiation were not observed and could not be overcome by growth factor supplementation. Strikingly, RNA-seq data revealed that ~ 44 of the transcriptome contained differentially expressed genes in human and rat SCs. A bioinformatics approach further highlighted that representative SC-specific transcripts encoding myelin-related and axon growth-promoting proteins were significantly affected and that a deficient expression of key transducers of cAMP and adhesion signaling explained the fairly limited potential of human SCs to differentiate and respond to axonal cues. These results confirmed the significance of combining traditional bioassays and high-resolution genomics methods to characterize human SCs and identify genes predictive of cell function and therapeutic value.
这项研究全面探讨了原代人和啮齿动物雪旺细胞（SCs）的表型、功能和全转录组，并强调了关键的种属特异性特征，这些特征超出了供体变异性的预期，解释了人 SC 体外增殖、分化和与轴突相互作用的能力的差异。与大鼠 SC 不同，人 SC 对神经调节蛋白以外的有丝分裂原因子不敏感，并且在最佳促生长条件下，在分化的各个阶段表现出表型变体，同时存在增殖和衰老细胞的混合物。人 SC 对 cAMP 诱导分化的反应表现为形态变化和细胞周期退出，而没有髓鞘相关蛋白和脂质的同时增加。人 SC 能够有效地沿着其他 SC（人或大鼠）的轴突延伸突起，但在支持髓鞘形成的条件下与人感觉神经元共培养时则无法做到这一点。事实上，没有观察到轴突接触依赖性的人 SC 排列、增殖和分化，并且生长因子补充也无法克服这一问题。引人注目的是，RNA-seq 数据显示，约 44%的转录组在人源和大鼠源 SC 中存在差异表达基因。生物信息学方法进一步强调，代表性的 SC 特异性转录本编码髓鞘相关和轴突生长促进蛋白的表达显著受到影响，并且 cAMP 和粘附信号转导的关键转导因子表达不足，解释了人 SC 分化和对轴突线索反应的相当有限的潜力。这些结果证实了结合传统生物测定和高分辨率基因组学方法来表征人 SC 并鉴定预测细胞功能和治疗价值的基因的重要性。
