Distinctive mesenchymal-like neurofibroma stem cells shape NF1 clinical phenotypes controlled by BDNF microenvironment.
Distinctive mesenchymal-like neurofibroma stem cells shape NF1 clinical phenotypes controlled by BDNF microenvironment.
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DOI：
10.1016/j.tranon.2023.101852
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发表时间：
2024-02
影响因子：
5
通讯作者：
Wang, Lei
中科院分区：
文献类型：
--
作者：
Shi, Jingcun;Yang, Zihui;Zhang, Yuhan;Abdelrehem, Ahmed;Wu, Ziqian;Zhang, Bingqing;Xiao, Meng;Zhang, Shijian;Zhang, Zhen;Wang, Lei
I型神经纤维瘤（NF 1）由于基因突变，常表现为多种临床表型。本研究的目的是确定NF 1患者肿瘤微环境的表型和治疗相关性。使用荧光激活细胞分选（FACS）和集落形成实验分离和培养来自NF 1的肿瘤干细胞（TSC）。流式细胞仪检测细胞表面标志物，并进行成骨、成脂分化实验。裸鼠皮下成瘤实验证实了其成瘤能力。免疫组化染色进行神经纤维瘤组织从头部和躯干不同的表型。采用Elisa和免疫组化法检测神经纤维瘤组织中BDNF的表达。Western Blotting检测p38 MAPK通路在TSCs中的表达。观察BDNF中和抗体对肿瘤干细胞成瘤性的影响。在此，我们主张NF 1包含一个新的间充质样神经纤维瘤干细胞（MNSCs）亚群。这种集落形成的MNSCs保留了自我更新，多重分化和致瘤能力。更有趣的是，从同一患者的神经纤维瘤组织中分离的具有不同表型的MNSCs呈现位点特异性能力。此外，神经纤维瘤组织中不同水平的脑源性神经营养因子（BDNF）可通过激活TrkB/p38 MAPK通路影响MNSCs。全身给予BDNF中和抗体抑制MNSCs的特性。我们证明了BDNF可以调节MNSCs，从而控制头部和躯干区域之间的不同肿瘤表型。BDNF中和抗体的应用可能抑制p38 MAPK通路，因此提供了一个有希望的策略来管理NF 1。
Neurofibroma type I (NF1) often presents with multiple clinical phenotypes due to mutations of NF1 gene. The aim of this study was to determine the phenotypic and therapeutic relevance of tumor microenvironment in NF1 patients. Tumor stem cells (TSCs) from NF1 were isolated and cultured using fluorescence activated cell sorting (FACS) and colony formation experiments. Then, flow cytometry was used to detect the surface markers, osteogenic and adipogenic differentiation were performed as well. Its tumorigenesis ability was confirmed by subcutaneous tumorigenesis in nude mice. Immunohistochemical staining was performed on neurofibroma tissues from the head and trunk with different phenotypes. The expression of BDNF in neurofibroma tissues was detected by Elisa and immunohistochemical staining. Western Blotting was used to detect the expression of p38 MAPK pathway in TSCs. The effect of BDNF neutralizing antibody on the tumorigenesis of TSCs was observed. Herein, we advocate that NF1 contain a new subgroup of mesenchymal-like neurofibroma stem cells (MNSCs). Such colony-forming MNSCs preserved self-renewal, multiple differentiation and tumorigenic capabilities. More interestingly, the MNSCs isolated from neurofibroma tissues of the same patient with different phenotypes presented site-specific capabilities. Moreover, different levels of brain-derived neurotrophic factor (BDNF) in neurofibroma tissues can impact the MNSCs by activating the TrkB/p38 MAPK pathway. Systemic administration of BDNF neutralizing antibodies inhibited MNSCs’ characteristics. We demonstrated that BDNF can modulate MNSCs and thereby controlling different tumor phenotypes between the head and trunk regions. Application of BDNF neutralizing antibodies may inhibit p38 MAPK pathway, therefore providing a promising strategy for managing NF1.
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影响因子：
3.5
作者：
Jin, S. H.;Lee, J. E.;Park, J. B.
通讯作者：
Park, J. B.
影响因子：
5.2
作者：
Choi, Bo Young;Hong, Dae Ki;Suh, Sang Won
通讯作者：
Suh, Sang Won
NF1中的基因型 - 表型相关性：与影响NF1密码子844-848的错义突变有关的更严重表型的证据。
影响因子：
9.8
作者：
Koczkowska M;Chen Y;Callens T;Gomes A;Sharp A;Johnson S;Hsiao MC;Chen Z;Balasubramanian M;Barnett CP;Becker TA;Ben-Shachar S;Bertola DR;Blakeley JO;Burkitt-Wright EMM;Callaway A;Crenshaw M;Cunha KS;Cunningham M;D'Agostino MD;Dahan K;De Luca A;Destrée A;Dhamija R;Eoli M;Evans DGR;Galvin-Parton P;George-Abraham JK;Gripp KW;Guevara-Campos J;Hanchard NA;Hernández-Chico C;Immken L;Janssens S;Jones KJ;Keena BA;Kochhar A;Liebelt J;Martir-Negron A;Mahoney MJ;Maystadt I;McDougall C;McEntagart M;Mendelsohn N;Miller DT;Mortier G;Morton J;Pappas J;Plotkin SR;Pond D;Rosenbaum K;Rubin K;Russell L;Rutledge LS;Saletti V;Schonberg R;Schreiber A;Seidel M;Siqveland E;Stockton DW;Trevisson E;Ullrich NJ;Upadhyaya M;van Minkelen R;Verhelst H;Wallace MR;Yap YS;Zackai E;Zonana J;Zurcher V;Claes K;Martin Y;Korf BR;Legius E;Messiaen LM
通讯作者：
Messiaen LM
影响因子：
82.9
作者：
Fisher MJ;Shih CS;Rhodes SD;Armstrong AE;Wolters PL;Dombi E;Zhang C;Angus SP;Johnson GL;Packer RJ;Allen JC;Ullrich NJ;Goldman S;Gutmann DH;Plotkin SR;Rosser T;Robertson KA;Widemann BC;Smith AE;Bessler WK;He Y;Park SJ;Mund JA;Jiang L;Bijangi-Vishehsaraei K;Robinson CT;Cutter GR;Korf BR;Neurofibromatosis Clinical Trials Consortium;Blakeley JO;Clapp DW
通讯作者：
Clapp DW
影响因子：
6
作者：
Francois, Sabine;Usunier, Benoit;Chapel, Alain
通讯作者：
Chapel, Alain