Behavioral and histological characterization of intrahippocampal grafts of human bone marrow-derived multipotent progenitor cells in neonatal rats with hypoxic-ischemic injury
Behavioral and histological characterization of intrahippocampal grafts of human bone marrow-derived multipotent progenitor cells in neonatal rats with hypoxic-ischemic injury
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DOI：
10.3727/000000006783982034
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发表时间：
2006-01-01
影响因子：
3.3
通讯作者：
Borlongan, Cesar V.
中科院分区：
文献类型：
--
作者：
Yasuhara, Takao;Matsukawa, Noriyuki;Borlongan, Cesar V.
新生儿缺氧缺血性脑损伤（HI）占活产婴儿的显着数量，其中没有临床治疗。有限的干细胞治疗的临床试验已经开始在一些神经系统疾病，但基于细胞的治疗新生儿HI损伤的临床前证据仍处于起步阶段。一个主要的假设机制，潜在的干细胞治疗的治疗效益涉及刺激内源性神经发生通过移植外源性干细胞。为此，移植针对神经原性位点，如海马，用于脑保护和修复。海马体已被证明分泌生长因子，特别是在出生后期间，这表明该大脑区域是细胞存活的高度有利的微环境。基于其神经源性和神经营养因子分泌的特征，海马是干细胞治疗的一个有吸引力的靶点。在这里，我们研究了海马内移植多能祖细胞（MPC）的疗效，MPC是具有分化成神经元谱系能力的多能祖细胞。7日龄的Sprague-Dawley大鼠最初受到单侧HI损伤，其涉及永久性结扎右颈总动脉并随后暴露于缺氧环境。在HI损伤后第7天，动物接受来自Sprague-Dawley大鼠（同基因）或Fisher大鼠（同种异体）的载体或冷冻保存的MPC（在移植前解冻）的立体定位海马注射。所有动物在整个存活期内每日接受免疫抑制治疗。在移植后第7天和第14天进行了行为测试，使用升高的身体摆动试验和旋转棒，以揭示一般和协调的运动功能。MPC移植的动物表现出减少运动不对称性和更长的时间花费在旋转杆上比那些接受车辆输注。同基因和异基因MPC移植损伤动物在两个测试期的行为改善方面没有显着差异。移植后第14天的行为学测试后，免疫组织化学评价移植物存活，显示同基因和异基因移植的MPC在海马区存活。这些结果首次表明，移植MPC改善与HI损伤相关的运动缺陷。鉴于同基因和同种异体MPC移植物产生的相当的行为恢复，同种异体移植成为具有直接临床应用的可行且有效的细胞替代策略。同样重要的发现是观察结果支持海马作为干细胞治疗HI损伤的极好靶脑区。
Children born with hypoxic-ischemic (HI) brain injury account for a significant number of live births wherein no clinical treatment is available. Limited clinical trials of stem cell therapy have been initiated in a number of neurological disorders, but the preclinical evidence of a cell-based therapy for neonatal HI injury remains in its infancy. One major postulated mechanism underlying therapeutic benefits of stem cell therapy involves stimulation of endogenous neurogenesis via transplantation of exogenous stem cells. To this end, transplantation has targeted neurogenic sites, such as the hippocampus, for brain protection and repair. The hippocampus has been shown to secrete growth factors, especially during the postnatal period, suggesting that this brain region presents as highly conducive microenvironment for cell survival. Based on its neurogenic and neurotrophic factor- secreting features, the hippocampus stands as an appealing target for stem cell therapy. Here, we investigated the efficacy of intrahippocampal transplantation of multipotent progenitor cells (MPCs), which are pluripotent progenitor cells with the ability to differentiate into a neuronal lineage. Seven-day-old Sprague-Dawley rats were initially subjected to unilateral HI injury, which involved permanent ligation of the right common carotid artery and subsequent exposure to hypoxic environment. At day 7 after HI injury, animals received stereotaxic hippocampal injections of vehicle or cryopreserved MPCs (thawed just prior to transplantation) derived either from Sprague-Dawley rats (syngeneic) or Fisher rats (allogeneic). All animals were treated with daily immunosuppression throughout the survival period. Behavioral tests were conducted on posttransplantation days 7 and 14 using the elevated body swing test and the rotarod to reveal general and coordinated motor functions. MPC transplanted animals exhibited reduced motor asymmetry and longer time spent on the rotarod than those that received the vehicle infusion. Both syngeneic and allogeneic MPC transplanted injured animals did not significantly differ in their behavioral improvements at both test periods. lmmunohistochemical evaluations of graft survival after behavioral testing at day 14 posttransplantation revealed that syngeneic and allogeneic transplanted MPCs survived in the hippocampal region. These results demonstrate for the first time that transplantation of MPCs ameliorated motor deficits associated with HI injury. In view of comparable behavioral recovery produced by syngeneic and allogeneic MPC grafts, allogeneic transplantation poses as a feasible and efficacious cell replacement strategy with direct clinical application. An equally major finding is the observation lending support to the hippocampus as an excellent target brain region for stem cell therapy in treating HI injury.