North Hilary A, Pan Liuliu, McGuire Tammy L, Brooker Sarah, Kessler John A
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611.
J Neurosci. 2015 Mar 4;35(9):3725-33. doi: 10.1523/JNEUROSCI.4546-14.2015.
Astrogliosis after spinal cord injury (SCI) is a major impediment to functional recovery. More than half of new astrocytes generated after SCI are derived from ependymal zone stem cells (EZCs). We demonstrate that expression of β1-integrin increases in EZCs following SCI in mice. Conditional knock-out of β1-integrin increases GFAP expression and astrocytic differentiation by cultured EZCs without altering oligodendroglial or neuronal differentiation. Ablation of β1-integrin from EZCs in vivo reduced the number of EZC progeny that continued to express stem cell markers after SCI, increased the proportion of EZC progeny that differentiated into GFAP+ astrocytes, and diminished functional recovery. Loss of β1-integrin increased SMAD1/5/8 and p38 signaling, suggesting activation of BMP signaling. Coimmunoprecipitation studies demonstrated that β1-integrin directly interacts with the bone morphogenetic protein receptor subunits BMPR1a and BMPR1b. Ablation of β1-integrin reduced overall levels of BMP receptors but significantly increased partitioning of BMPR1b into lipid rafts with increased SMAD1/5/8 and p38 signaling. Thus β1-integrin expression by EZCs reduces movement of BMPR1b into lipid rafts, thereby limiting the known deleterious effects of BMPR1b signaling on glial scar formation after SCI.
脊髓损伤（SCI）后的星形胶质细胞增生是功能恢复的主要障碍。SCI后产生的新星形胶质细胞中，超过一半来源于室管膜区干细胞（EZCs）。我们证明，小鼠SCI后EZCs中β1整合素的表达增加。条件性敲除β1整合素可增加培养的EZCs中胶质纤维酸性蛋白（GFAP）的表达和星形胶质细胞分化，而不改变少突胶质细胞或神经元的分化。体内从EZCs中去除β1整合素可减少SCI后继续表达干细胞标志物的EZCs后代数量，增加分化为GFAP+星形胶质细胞的EZCs后代比例，并削弱功能恢复。β1整合素的缺失增加了SMAD1/5/8和p38信号传导，提示骨形态发生蛋白（BMP）信号通路激活。免疫共沉淀研究表明，β1整合素直接与骨形态发生蛋白受体亚基BMPR1a和BMPR1b相互作用。去除β1整合素可降低BMP受体的总体水平，但显著增加BMPR1b向脂筏的分配，同时增加SMAD1/5/8和p38信号传导。因此，EZCs中β1整合素的表达减少了BMPR1b向脂筏的移动，从而限制了BMPR1b信号通路对SCI后胶质瘢痕形成的已知有害影响。
