Intraspinal application of endothelin results in focal ischemic injury of spinal gray matter and restricts the differentiation of engrafted neural stem cells
Intraspinal application of endothelin results in focal ischemic injury of spinal gray matter and restricts the differentiation of engrafted neural stem cells
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DOI：
10.1007/s11064-005-6875-7
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发表时间：
2005-06-01
影响因子：
4.4
通讯作者：
Whittemore, SR
中科院分区：
文献类型：
--
作者：
Benton, RL;Woock, JP;Whittemore, SR
先前的数据表明，移植到挫伤脊髓中的多能干细胞仅沿着星形胶质细胞谱系分化。未知的限制性线索似乎相当严格，因为即使是神经元限制性前体在类似移植到挫伤的脊髓后也无法分化为它们在体外表现出的成熟潜力。据推测，这种有效的谱系限制部分是由于脊髓挫伤后观察到的灰质和白质显着损失的结果，这引起了大规模的急性炎症反应，并通过剧烈的囊性空洞长期表现出来。为了评估灰质成分，我们使用强效血管收缩剂内皮素 (ET-1) 开发了局灶性灰质缺血性损伤的临床相关模型，并表征了移植到该非创伤性血管 SCI 中的多能干细胞的分化。结果表明，低剂量 ET-1 显微注射到颈椎灰质中会导致炎症反应，其时间上与创伤性 SCI 后观察到的炎症反应相当，并且会导致慢性灰质损失，但没有明显的囊性空洞或白质变性。然而，尽管宿主脊髓实质得到了保存，但没有从移植的干细胞或前体细胞中观察到神经元表型的形成。这些结果表明，造成这种谱系限制的共同病理成分存在于挫伤性 SCI 和 ET-1 介导的局灶性缺血性 SCI 之间。
Previous data have shown that pluripotent stem cells engrafted into the contused spinal cord differentiate only along an astrocytic lineage. The unknown restrictive cues appear to be quite rigid as even neuronal-restricted precursors fail to differentiate to the mature potential they exhibit in vitro after similar grafting into the contused spinal cord. It has been hypothesized that this potent lineage restriction is, in part, the result of the significant loss of both gray and white matter observed following spinal contusion, which elicits a massive acute inflammatory response and is manifested chronically by dramatic cystic cavitation. To evaluate the gray matter component, we developed a clinically relevant model of focal gray matter ischemic injury using the potent vasoconstrictor endothelin (ET-1) and characterized the differentiation of pluripotent stem cells transplanted into this atraumatic vascular SCI. Results demonstrate that low dose ET-1 microinjection into cervical spinal gray matter results in an inflammatory response that is temporally comparable to that observed following traumatic SCI, as well as chronic gray matter loss, but without significant cystic cavitation or white matter degeneration. However, despite the preservation of host spinal parenchyma, no elaboration of neuronal phenotypes was observed from engrafted stem or precursor cells. These results suggest that a common pathologic component responsible for this lineage restriction exists between contusive SCI and ET-1 mediated focal ischemic SCI.