Ross R A, Spengler B A, Domènech C, Porubcin M, Rettig W J, Biedler J L
Department of Biological Sciences, Fordham University, Bronx, New York 10458, USA.
Cell Growth Differ. 1995 Apr;6(4):449-56.
Human neuroblastoma I-type cells isolated from cell lines in vitro are morphologically intermediate between neuroblastic (N) cells, with properties of embryonic sympathoblasts, and substrate-adherent (S) cells having properties of embryonic Schwann/glial/melanocytic cells of the neural crest. I cells have biochemical features of both N and S cells. We propose that the I-type cell represents a malignant neural crest stem cell. The strongest evidence in support of this hypothesis is that: (a) I cells can generate progeny that have neuronal properties, i.e., are committed neuroblasts, or properties of nonneuronal, embryonic neural crest-derived cells; and (b) I-type cells can generate multipotent I-type progeny, indicating their capacity for self-renewal, a feature of stem cells. We report here that I-type cells, derived from four different human neuroblastoma cell lines and experimentally induced to differentiate, give rise to cells with distinct N or S cell phenotypes, indicative of I cell multipotentiality. Experiments with a large panel of I-type subclones, isolated from clonal I-type BE(2)-C cells and exposed to retinoic acid to induce neuronal differentiation or 5-bromo-2'-deoxyuridine to obtain S-type cells, demonstrated that differentiation occurs via induction and selection and not by selection of spontaneously arising variants. The differentiation phenotype was stable. We conclude that human neuroblastoma I-type cells are multipotent embryonic precursor cells of the peripheral nervous system, capable of either neuronal or nonneuronal neural crest cell differentiation.
从体外细胞系分离出的人神经母细胞瘤I型细胞在形态上介于具有胚胎交感母细胞特性的成神经细胞（N）和具有神经嵴胚胎雪旺氏/神经胶质/黑素细胞特性的贴壁底物细胞（S）之间。I型细胞具有N细胞和S细胞的生化特征。我们提出I型细胞代表一种恶性神经嵴干细胞。支持这一假说的最有力证据是：（a）I型细胞能够产生具有神经元特性（即已定向分化的神经母细胞）或非神经元、胚胎神经嵴衍生细胞特性的后代；（b）I型细胞能够产生多能性的I型后代，表明它们具有自我更新能力，这是干细胞的一个特征。我们在此报告，来自四种不同人神经母细胞瘤细胞系并经实验诱导分化的I型细胞，会产生具有不同N或S细胞表型的细胞，这表明I型细胞具有多能性。对从克隆的I型BE(2)-C细胞分离出的大量I型亚克隆进行实验，将其暴露于视黄酸以诱导神经元分化，或暴露于5-溴-2'-脱氧尿苷以获得S型细胞，结果表明分化是通过诱导和选择发生的，而不是通过选择自发产生的变体。分化表型是稳定的。我们得出结论，人神经母细胞瘤I型细胞是外周神经系统的多能胚胎前体细胞，能够分化为神经元或非神经元神经嵴细胞。
