Laboratory for Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
Stroke. 2011 Aug;42(8):2294-301. doi: 10.1161/STROKEAHA.110.608315. Epub 2011 Jun 23.
Hypoxic-ischemic (HI) brain injury is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. To identify molecules important for cerebral damage and repair, we investigated the growth factor-related gene expression profile after neonatal cerebral HI. We identified osteopontin (OPN) as the most highly upregulated factor early after HI. We therefore explored the role of endogenous OPN in brain damage and repair.
Nine-day-old wild-type mice were exposed to cerebral HI; growth factor-related gene expression profiles were analyzed 1 to 7 days later by reverse transcriptase-polymerase chain reaction arrays. To determine the contribution of OPN to brain damage, we used p9 OPN(-/-) and wild-type mice. HI brain damage, sensorimotor function, and cell proliferation and differentiation were compared.
Gene expression profiling of 150 genes related to growth factors and neurotrophins showed that expression of 52 genes changed during the first 7 days after HI. OPN was the gene with the strongest increase expression at all time points measured. We show here for the first time that in response to neonatal HI, OPN-deficient mice developed increased gray and white matter loss and more pronounced sensorimotor deficits as compared with wild-type littermates. Furthermore, OPN deficiency decreases HI-induced cell proliferation/survival and oligodendrogenesis without affecting neuronal differentiation.
OPN plays an important role in repairing brain injury after neonatal HI by regulating cerebral cell proliferation/survival and oligodendrocyte differentiation after injury. The observed promyelinative effect of OPN may offer novel possibilities for a therapy targeting white matter injury.
缺氧缺血性（HI）脑损伤是围产期发病率和死亡率的常见原因，治疗选择有限。为了确定对脑损伤和修复重要的分子，我们研究了新生鼠大脑 HI 后与生长因子相关的基因表达谱。我们发现骨桥蛋白（OPN）是 HI 后早期上调最明显的因子。因此，我们探索了内源性 OPN 在脑损伤和修复中的作用。
9 日龄野生型小鼠暴露于大脑 HI；HI 后 1 至 7 天通过逆转录聚合酶链反应阵列分析生长因子相关基因表达谱。为了确定 OPN 对脑损伤的贡献，我们使用了 p9 OPN（-/-）和野生型小鼠。比较 HI 脑损伤、感觉运动功能以及细胞增殖和分化。
与生长因子和神经营养因子相关的 150 个基因的基因表达谱显示，在 HI 后前 7 天内有 52 个基因的表达发生变化。OPN 是所有测量时间点表达最强增加的基因。我们首次表明，与野生型同窝仔相比，OPN 缺陷型小鼠在响应新生鼠 HI 时，灰白质丢失增加，感觉运动缺陷更为明显。此外，OPN 缺乏会减少 HI 诱导的细胞增殖/存活和少突胶质细胞分化，而不影响神经元分化。
OPN 通过调节大脑细胞增殖/存活和损伤后少突胶质细胞分化，在新生鼠 HI 后修复脑损伤中发挥重要作用。OPN 的观察到的促进髓鞘形成作用可能为针对白质损伤的治疗提供新的可能性。
