Repeated Mesenchymal Stem Cell Treatment after Neonatal Hypoxia-Ischemia Has Distinct Effects on Formation and Maturation of New Neurons and Oligodendrocytes Leading to Restoration of Damage, Corticospinal Motor Tract Activity, and Sensorimotor Function
Repeated Mesenchymal Stem Cell Treatment after Neonatal Hypoxia-Ischemia Has Distinct Effects on Formation and Maturation of New Neurons and Oligodendrocytes Leading to Restoration of Damage, Corticospinal Motor Tract Activity, and Sensorimotor Function
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DOI：
10.1523/jneurosci.1835-10.2010
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发表时间：
2010-07-14
影响因子：
5.3
通讯作者：
Heijnen, Cobi J.
中科院分区：
文献类型：
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作者：
van Velthoven, Cindy T. J.;Kavelaars, Annemieke;Heijnen, Cobi J.
出生窒息是围产期发病率和死亡率的常见原因，治疗选择有限。我们发现，在出生后第9天的新生小鼠缺氧缺血(HI)后3d进行单一间充质干细胞治疗(MSC-3)，可以改善感觉运动功能并缩小病变范围。在HI后10d再次应用MSC(MSC-3+10)进一步促进感觉运动的改善以及MAP2和MBP(髓鞘碱性蛋白)染色的恢复。用生物素葡聚糖胺(BDA)追踪同侧皮质脊髓顺行束显示HI减少了对侧脊髓的BDA标记。仅MSC-3+10治疗部分恢复对侧脊髓BDA染色，表明轴突重塑增强。MSC-3促进溴脱氧尿苷阳性神经元和少突胶质细胞的形成。有趣的是，第10天的第二次捐赠并没有进一步增加新细胞的形成，而只有MSC-10这样做了。这些发现表明，与MSC-3单独作用相比，MSC-3+10的增强效应是通过不同的途径介导的。我们假设，在颅内注射时，MSCs使其生长和分化因子的产生适应环境的需要。将MSCs对体外培养的反应与第10天从MSC-3或赋形剂处理的动物的HI脑提取液进行路径聚焦PCR阵列分析，发现29个编码分泌因子的基因确实存在差异调控。我们认为MSCs的功能是由受损和再生的脑提供的适应性特异性信号决定的。
Birth asphyxia is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. We show that a single mesenchymal stem cell treatment at 3 d (MSC-3) after neonatal hypoxia-ischemia (HI) in postnatal day 9 mice improved sensorimotor function and reduced lesion size. A second MSC treatment at 10 d after HI (MSC-3+10) further enhanced sensorimotor improvement and recovery of MAP2 and MBP (myelin basic protein) staining. Ipsilateral anterograde corticospinal tract tracing with biotinylated dextran amine (BDA) showed that HI reduced BDA labeling of the contralateral spinal cord. Only MSC-3+10 treatment partially restored contralateral spinal cord BDA staining, indicating enhanced axonal remodeling. MSC-3 enhanced formation of bromodeoxyuridine-positive neurons and oligodendrocytes. Interestingly, the second gift at day 10 did not further increase new cell formation, whereas only MSC-10 did. These findings indicate that increased positive effect of MSC-3+10 compared with MSC-3 alone is mediated via distinct pathways. We hypothesize that MSCs adapt their growth and differentiation factor production to the needs of the environment at the time of intracranial injection. Comparing the response of MSCs to in vitro culture with HI brain extracts obtained at day 10 from MSC-3- or vehicle-treated animals by pathway-focused PCR array analysis revealed that 29 genes encoding secreted factors were indeed differentially regulated. We propose that the function of MSCs is dictated by adaptive specific signals provided by the damaged and regenerating brain.