Repetitive Intrathecal Catheter Delivery of Bone Marrow Mesenchymal Stromal Cells Improves Functional Recovery in a Rat Model of Contusive Spinal Cord Injury
Repetitive Intrathecal Catheter Delivery of Bone Marrow Mesenchymal Stromal Cells Improves Functional Recovery in a Rat Model of Contusive Spinal Cord Injury
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DOI：
10.1089/neu.2010.1413
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发表时间：
2011-09-01
影响因子：
4.2
通讯作者：
Radonak, Jozef
中科院分区：
文献类型：
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作者：
Cizkova, Dasa;Novotna, Ivana;Radonak, Jozef
骨髓间充质干细胞（MSCs）移植已被证明可以改善各种脊髓损伤（SCI）模型的功能恢复。然而，MSC应用的最佳剂量、时机和途径是实现有益治疗结果的关键因素。本研究的目的是标准化大鼠脊髓损伤后鞘内（IT）导管输送大鼠骨髓间充质干细胞。在SCI后3或7天，通过IT递送将PKH-67标记的MSC作为以下治疗方案之一给予大鼠：（1）单次注射（5 x 10（5）MSC/大鼠），或（2）每日注射3次（5 X 10（5）MSC/大鼠/天，总共1.5 X 10（6）MSC/大鼠，持续3天，在SCI后第3、4和5天或第7、8和9天注射。使用Basso、Beattie和Bresnahan（BBB）运动评定量表对动物进行为期4周的行为学测试，并在28天后对MSC存活、分布和植入特性进行组织学评估。在损伤后3或7天用单次注射MSC治疗的大鼠显示出移植的MSC的功能和低存活率的适度的、非显著的改善，发现移植的MSC附着于软脑膜或积聚在脊髓前动脉周围。相比之下，在第7、8和9天每天注射三次MSC治疗的大鼠，但在第3、4和5天没有，在损伤后14 - 28天显示出显著更高的运动功能恢复（BBB评分16.8 +/-1.7）。移植的PKH-67间充质干细胞能够迁移并融入中央病变。然而，在受损的白色物质中仅观察到有限数量的存活MSC，范围为24，128 +/-1170至116，258 +/-8568个细胞/移植物。这些结果表明，重复IT移植，这对动物的负担最小，可以改善行为功能时，剂量，时间和有针对性的IT交付的MSC病变腔进行了优化。
Transplantation of bone marrow mesenchymal stromal cells (MSCs) has been shown to improve the functional recovery in various models of spinal cord injury (SCI). However, the issues of the optimal dose, timing, and route of MSC application are crucial factors in achieving beneficial therapeutic outcomes. The objective of this study was to standardize the intrathecal (IT) catheter delivery of rat MSCs after SCI in adult rats. MSCs labeled with PKH-67 were administered by IT delivery to rats at 3 or 7 days after SCI as one of the following treatment regimens: (1) a single injection (5 x 10(5) MSCs/rat), or (2) as three daily injections (5 x 10(5) MSCs/rat/d for a total of 1.5 x 10(6) MSCs/rat over 3 days, injected on days 3, 4, and 5, or days 7, 8, and 9 following SCI. The animals were behaviorally tested for 4 weeks using the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale, and histologically assessed for MSC survival, distribution, and engraftment properties after 28 days. Rats treated with a single injection of MSCs at 3 or 7 days post-injury showed a modest, non-significant improvement in function and low survival of grafted MSCs, which were found attached to the pia mater or accumulated around the anterior spinal artery. In contrast, rats treated with three daily injections of MSCs at days 7, 8, and 9, but not on days 3, 4, and 5, showed significantly higher motor function recovery (BBB score 16.8 +/- 1.7) at 14-28 days post-injury. Transplanted PKH-67 MSCs were able to migrate and incorporate into the central lesion. However, only a limited number of surviving MSCs, ranging from 24,128 +/- 1170 to 116,258 +/- 8568 cells per graft, were observed within the damaged white matter. These results suggest that repetitive IT transplantation, which imposes a minimal burden on the animals, may improve behavioral function when the dose, timing, and targeted IT delivery of MSCs towards the lesion cavity are optimized.