Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis
Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis
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DOI：
10.1016/j.expneurol.2005.10.029
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发表时间：
2006-03-01
影响因子：
5.3
通讯作者：
Phinney, DG
中科院分区：
文献类型：
--
作者：
Crigler, L;Robey, RC;Phinney, DG
间充质干细胞（MSC）移植到神经损伤部位被认为是通过产生诱导宿主神经元存活和再生的营养因子来促进功能恢复。为了进一步评估这一现象，我们量化了人MSC中神经营养因子的表达水平及其对神经元细胞存活和轴突发生的影响。筛选人MSC cDNA文库显示表达的转录本编码BDNF和β-NGF，但不编码NT-3和NT-4。免疫组化显示BDNF和β-NGF蛋白仅限于特定的MSC亚群，这一点通过ELISA分析56个独立的亚群得到证实。使用共培养试验，我们还证明了BDNF表达水平与MSC群体或亚细胞诱导SH-SY 5 Y神经母细胞瘤细胞系存活和神经突生长的能力相关。然而，这些MSC诱导的作用仅部分抑制了中和抗BDNF抗体。MSC也显示出促进背根神经节外植体内的神经突生长，尽管分泌的β-NGF水平低25倍，需要外源性地产生类似的效果。人MSC转录组的询问鉴定了编码各种神经突诱导因子、轴突导向和神经细胞粘附分子的表达mRNA。此外，这些转录本的一个子集被证明与MSC亚细胞中的BDNF表达相关。总的来说，这些研究揭示了MSC亚群的存在，这些亚群共表达神经营养蛋白和其他有效的神经调节分子，这有助于MSC诱导的对神经元细胞存活和神经再生的影响。这些亚群可能是治疗各种神经系统疾病的更有效的载体。(c)2005年爱思唯尔公司All rights reserved.
Mesenchymal stem cells (MSCs) transplanted at sites of nerve injury are thought to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. To evaluate this phenomenon further, we quantified in human MSCs neurotrophin expression levels and their effects on neuronal cell survival and neuritogenesis. Screening a human MSC cDNA library revealed expressed transcripts encoding BDNF and beta-NGF but not NT-3 and NT-4. Immunostaining demonstrated that BDNF and beta-NGF proteins were restricted to specific MSC subpopulations, which was confirmed by ELISA analysis of 56 separate subelones. Using a co-culture assay, we also demonstrated that BDNF expression levels correlated with the ability of MSC populations or subelones to induce survival and neurite outgrowth in the SH-SY5Y neuroblastoma cell line. However, these MSC-induced effects were only partially inhibited by a neutralizing anti-BDNF antibody. MSCs were also shown to promote neurite outgrowth within dorsal root ganglion explants despite secreting 25-fold lower level of beta-NGF required exogenously to produce a similar effect. Interrogation of the human MSC transcriptome identified expressed mRNAs encoding various neurite-inducing factors, axon guidance and neural cell adhesion molecules. Moreover, a subset of these transcripts was shown to correlate with BDNF expression in MSC subelones. Collectively, these studies reveal the existence of MSC subpopulations that co-express neurotrophins and other potent neuro-regulatory molecules, which contribute to MSC-induced effects on neuronal cell survival and nerve regeneration. These subpopulations may represent more potent vectors for treating a variety of neurological disorders. (c) 2005 Elsevier Inc. All rights reserved.