Fundamental Research Center, Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China.
Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands.
Cell Transplant. 2022 Jan-Dec;31:9636897221134540. doi: 10.1177/09636897221134540.
Wnts, bone morphogenetic protein (BMP), and fibroblast growth factor (FGF) are paracrine signaling pathways implicated in the niche control of stem cell fate decisions. BMP-on and Wnt-off are the dominant quiescent niche signaling pathways in many cell types, including neural stem cells (NSCs). However, among the multiple inhibitory family members of the Wnt pathway, those with direct action after BMP4 stimulation in NSCs remain unclear. We examined 11 Wnt inhibitors in NSCs after BMP4 treatment. Wnt inhibitory factor 1 (Wif1) has been identified as the main factor reacting to BMP4 stimuli. RNA sequencing confirmed that Wif1 was markedly upregulated after BMP4 treatment in different gene expression analyses. Similar to the functional role of BMP4, Wif1 significantly decreased the cell cycle of NSCs and significantly inhibited cell proliferation ( < 0.05). Combined treatment with BMP4 and Wif1 significantly enhanced the inhibition of cell growth compared with the single treatment ( < 0.05). Wif1 expression was clearly lower in glioblastoma and low-grade glioma samples than in normal samples ( < 0.05). A functional analysis revealed that both BMP4 and Wif1 could decrease glioma cell growth. These effects were abrogated by the BMP inhibitor Noggin. The collective findings demonstrate that Wif1 plays a key role in quiescent NSC homeostasis and glioma cell growth downstream of BMP-on signaling. The functional roles of Wif1/BMP4 in glioma cells may provide a technical basis for regenerative medicine, drug discovery, and personal molecular therapy in future clinical treatments.
Wnt、骨形态发生蛋白（BMP）和纤维母细胞生长因子（FGF）是旁分泌信号通路，参与干细胞命运决定的龛位调控。BMP-on 和 Wnt-off 是许多细胞类型中包括神经干细胞（NSCs）的休眠龛位信号通路的主要信号。然而，在 Wnt 通路的多个抑制性家族成员中，在 NSCs 中直接作用于 BMP4 刺激的那些仍不清楚。我们在 BMP4 处理后检查了 NSCs 中的 11 种 Wnt 抑制剂。Wnt 抑制因子 1（Wif1）已被确定为对 BMP4 刺激反应的主要因素。RNA 测序在不同的基因表达分析中证实，Wif1 在 BMP4 处理后明显上调。与 BMP4 的功能作用相似，Wif1 显著降低了 NSCs 的细胞周期并显著抑制了细胞增殖（<0.05）。与单独处理相比，BMP4 和 Wif1 的联合处理显著增强了对细胞生长的抑制作用（<0.05）。与正常样本相比，神经胶质瘤和低级别神经胶质瘤样本中的 Wif1 表达明显降低（<0.05）。功能分析表明，BMP4 和 Wif1 均可降低神经胶质瘤细胞的生长。这些作用被 BMP 抑制剂 Noggin 所消除。研究结果表明，Wif1 在 BMP-on 信号下游的静止 NSC 稳态和神经胶质瘤细胞生长中起关键作用。Wif1/BMP4 在神经胶质瘤细胞中的功能作用可能为再生医学、药物发现和未来临床治疗中的个体化分子治疗提供技术基础。
