Analysis of host-mediated repair mechanisms after human CNS-stem cell transplantation for spinal cord injury: correlation of engraftment with recovery.
Analysis of host-mediated repair mechanisms after human CNS-stem cell transplantation for spinal cord injury: correlation of engraftment with recovery.
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DOI：
10.1371/journal.pone.0005871
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发表时间：
2009-06-11
期刊：
影响因子：
3.7
通讯作者：
Cummings BJ
中科院分区：
文献类型：
--
作者：
Hooshmand MJ;Sontag CJ;Uchida N;Tamaki S;Anderson AJ;Cummings BJ
人类中枢神经系统干细胞作为神经球（hCNS-SCns）生长，可以自我更新，具有多能性，并且在脊髓创伤后具有潜在的治疗应用。我们之前已经展示了接受中度脊髓挫伤（SCI）和损伤后 9 天（dpi）hCNS-SCns 移植的免疫缺陷小鼠的运动恢复。移植的 hCNS-SCns 表现出向髓鞘少突胶质细胞和突触形成神经元的终末分化。此外，使用白喉毒素（DT）选择性消融人类细胞消除了这种范例中的运动恢复，这表明人类细胞在小鼠宿主内的整合是运动改善的可能机制。然而，hCNS-SCns 可以改变宿主微环境作为额外或替代恢复机制的假设仍未得到探索；我们在本研究中检验了这一假设。使用人类特异性细胞质标记物对人类细胞进行体视定量，证明在所有 hCNS-SCns 移植动物中细胞成功植入、存活、迁移和有限增殖。移植后 16 周进行 DT 治疗消除了 80.5% 的 hCNS-SCns。对病变体积、组织保留、下行血清素能宿主纤维出芽、硫酸软骨素蛋白聚糖沉积、神经胶质疤痕形成和血管生成的体视定量表明，没有证据表明 hCNS-SCns 移植导致小鼠脊髓内宿主发生改变。生化分析补充了体视学数据，支持神经干细胞介导的宿主修复不存在。然而，植入 hCNS-SCns 数量与水平梯梁任务错误数量的线性回归分析显示，这些变量之间存在很强的相关性（r = −0.78，p<0.05），表明存活和植入与恢复的定量测量直接相关。总而言之，数据表明与 hCNS-SCns 移植相关的运动改善并非由于宿主微环境内的改变所致，这支持了这样的假设：宿主电路内的人类细胞整合介导了延迟移植 9 天后的功能恢复。
Human central nervous system-stem cells grown as neurospheres (hCNS-SCns) self-renew, are multipotent, and have potential therapeutic applications following trauma to the spinal cord. We have previously shown locomotor recovery in immunodeficient mice that received a moderate contusion spinal cord injury (SCI) and hCNS-SCns transplantation 9 days post-injury (dpi). Engrafted hCNS-SCns exhibited terminal differentiation to myelinating oligodendrocytes and synapse-forming neurons. Further, selective ablation of human cells using Diphtheria toxin (DT) abolished locomotor recovery in this paradigm, suggesting integration of human cells within the mouse host as a possible mechanism for the locomotor improvement. However, the hypothesis that hCNS-SCns could alter the host microenvironment as an additional or alternative mechanism of recovery remained unexplored; we tested that hypothesis in the present study. Stereological quantification of human cells using a human-specific cytoplasmic marker demonstrated successful cell engraftment, survival, migration and limited proliferation in all hCNS-SCns transplanted animals. DT administration at 16 weeks post-transplant ablated 80.5% of hCNS-SCns. Stereological quantification for lesion volume, tissue sparing, descending serotonergic host fiber sprouting, chondroitin sulfate proteoglycan deposition, glial scarring, and angiogenesis demonstrated no evidence of host modification within the mouse spinal cord as a result of hCNS-SCns transplantation. Biochemical analyses supplemented stereological data supporting the absence of neural stem-cell mediated host repair. However, linear regression analysis of the number of engrafted hCNS-SCns vs. the number of errors on a horizontal ladder beam task revealed a strong correlation between these variables (r = −0.78, p<0.05), suggesting that survival and engraftment were directly related to a quantitative measure of recovery. Altogether, the data suggest that the locomotor improvements associated with hCNS-SCns transplantation were not due to modifications within the host microenvironment, supporting the hypothesis that human cell integration within the host circuitry mediates functional recovery following a 9 day delayed transplant.
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DOI：
10.1523/jneurosci.2823-08.2008
发表时间：
2008-12-17
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Galvan MD;Luchetti S;Burgos AM;Nguyen HX;Hooshmand MJ;Hamers FP;Anderson AJ
通讯作者：
Anderson AJ
影响因子：
82.9
作者：
Crowe, MJ;Bresnahan, JC;Beattie, MS
通讯作者：
Beattie, MS
影响因子：
2.7
作者：
Cummings, Brian J.;Engesser-Cesar, Christie;Anderson, Aileen J.
通讯作者：
Anderson, Aileen J.
影响因子：
3.4
作者：
Davies, JE;Tang, XF;Davies, SJA
通讯作者：
Davies, SJA
影响因子：
64.8
作者：
Davies, SJA;Fitch, MT;Silver, J
通讯作者：
Silver, J