Li Yi, Chen Jieli, Zhang Chun Ling, Wang Lei, Lu Dunyue, Katakowski Mark, Gao Qi, Shen Li Hong, Zhang Jing, Lu Mei, Chopp Michael
Department of Neurology, Henry Ford Health Sciences Center, Detroit, MI 48202, USA.
Glia. 2005 Feb;49(3):407-17. doi: 10.1002/glia.20126.
The long-term (4-month) responses to treatment of stroke in the older adult rat, using rat bone marrow stromal cells (MSCs), have not been investigated. Retired breeder rats were subjected to middle cerebral artery occlusion (MCAo) alone, or injected intravenously with 3 x 10(6) MSCs, at 7 days after MCAo. Functional recovery was measured using an adhesive-removal patch test and a modified neurological severity score. Bromodeoxyuridine, a cell proliferation marker, was injected daily for 14 before sacrifice. Animals were sacrificed 4 months after stroke. Double immunostaining was used to identify cell proliferation and cell types for axons, astrocytes, microglia, and oligodendrocytes. MSC treatment induced significant improvement in neurological outcome after MCAo compared with control rats. MSC treatment reduced the thickness of the scar wall (P < 0.05) and reduced the numbers of microglia/macrophages within the scar wall (P < 0.01). Double staining showed increased expression of an axonal marker (GAP-43), among reactive astrocytes in the scar boundary zone and in the subventricular zone in the treated rats. Bromodeoxyuridine in cells preferentially colocalized with markers of astrocytes (GFAP) and oligodendrocytes (RIP) in the ipsilateral hemisphere, and gliogenesis was enhanced in the subventricular zone of the rats treated with MSCs. This is the first report to show that MSCs injected at 7 days after stroke improve long-term neurological outcome in older animals. Brain tissue repair is an ongoing process with reactive gliosis, which persists for at least 4 months after stroke. Reactive astrocytes responding to MSC treatment of ischemia may also promote axonal regeneration during long-term recovery.
使用大鼠骨髓基质细胞（MSCs）对老年成年大鼠中风治疗的长期（4个月）反应尚未得到研究。将退役种鼠单独进行大脑中动脉闭塞（MCAo），或在MCAo后7天静脉注射3×10⁶个MSCs。使用粘胶去除贴片试验和改良神经功能缺损评分来测量功能恢复情况。在处死前14天每天注射细胞增殖标记物溴脱氧尿苷。中风后4个月处死动物。采用双重免疫染色来鉴定细胞增殖以及轴突、星形胶质细胞、小胶质细胞和少突胶质细胞的细胞类型。与对照大鼠相比，MSCs治疗可显著改善MCAo后的神经功能结局。MSCs治疗可降低瘢痕壁的厚度（P<0.05），并减少瘢痕壁内小胶质细胞/巨噬细胞的数量（P<0.01）。双重染色显示，在治疗大鼠的瘢痕边界区和脑室下区的反应性星形胶质细胞中，轴突标记物（GAP-43）的表达增加。同侧半球细胞中的溴脱氧尿苷优先与星形胶质细胞（GFAP）和少突胶质细胞（RIP）的标记物共定位，并且在接受MSCs治疗的大鼠脑室下区，神经胶质生成增强。这是第一份表明中风后7天注射MSCs可改善老年动物长期神经功能结局的报告。脑组织修复是一个伴有反应性胶质增生的持续过程，在中风后至少持续4个月。对缺血的MSCs治疗产生反应的反应性星形胶质细胞也可能在长期恢复过程中促进轴突再生。
