神经血管细胞片移植在犬颅内出血模型中的应用

Neurovascular Cell Sheet Transplantation in a Canine Model of Intracranial Hemorrhage.

作者信息

Lee Woo-Jin, Lee Jong Young, Jung Keun-Hwa, Lee Soon-Tae, Kim Hyo Yeol, Park Dong-Kyu, Yu Jung-Suk, Kim So-Yun, Jeon Daejong, Kim Manho, Lee Sang Kun, Roh Jae-Kyu, Chu Kon

机构信息

Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, South Korea.

†Laboratory for Neurotherapeutics, Biomedical Research Institute, Seoul National University Hospital, Seoul, South Korea.

出版信息

Cell Med. 2016 Dec 21;9(3):73-85. doi: 10.3727/215517916X693384. eCollection 2017.

Abstract

Cell-based therapy for intracerebral hemorrhage (ICH) has a great therapeutic potential. However, methods to effectively induce direct regeneration of the damaged neural tissue after cell transplantation have not been established, which, if done, would improve the efficacy of cell-based therapy. In this study, we aimed to develop a cell sheet with neurovasculogenic potential and evaluate its usefulness in a canine ICH model. We designed a composite cell sheet made of neural progenitors derived from human olfactory neuroepithelium and vascular progenitors from human adipose tissue-derived stromal cells. We also generated a physiologic canine ICH model by manually injecting and then infusing autologous blood under arterial pressure. We transplanted the sheet cells (cell sheet group) or saline (control group) at the cortex over the hematoma at subacute stages (2 weeks from ICH induction). At 4 weeks from the cell transplantation, cell survival, migration, and differentiation were evaluated. Hemispheric atrophy and neurobehavioral recovery were also compared between the groups. As a result, the cell sheet was rich in extracellular matrices and expressed neurotrophic factors as well as the markers for neuronal development. After transplantation, the cells successfully survived for 4 weeks, and a large portion of those migrated to the perihematomal site and differentiated into neurons and pericytes (20% and 30% of migrated stem cells, respectively). Transplantation of cell sheets alleviated hemorrhage-related hemispheric atrophy ( = 0.042) and showed tendency for improving functional recovery ( = 0.062). Therefore, we concluded that the cell sheet transplantation technique might induce direct regeneration of neural tissue and might improve outcomes of intracerebral hemorrhage.

摘要

基于细胞的脑出血(ICH)治疗具有巨大的治疗潜力。然而,细胞移植后有效诱导受损神经组织直接再生的方法尚未建立,若能建立,则可提高基于细胞的治疗效果。在本研究中,我们旨在开发一种具有神经血管生成潜力的细胞片,并在犬ICH模型中评估其效用。我们设计了一种复合细胞片,其由源自人嗅神经上皮的神经祖细胞和源自人脂肪组织间充质细胞的血管祖细胞制成。我们还通过在动脉压下手动注射然后注入自体血来建立生理性犬ICH模型。在亚急性期(脑出血诱导后2周),我们将片状细胞(细胞片组)或生理盐水(对照组)移植到血肿上方的皮质。在细胞移植后4周,评估细胞存活、迁移和分化情况。还比较了两组之间的半球萎缩和神经行为恢复情况。结果,细胞片富含细胞外基质,并表达神经营养因子以及神经元发育标志物。移植后,细胞成功存活4周,其中大部分迁移到血肿周围部位并分化为神经元和周细胞(分别占迁移干细胞的20%和30%)。细胞片移植减轻了与出血相关的半球萎缩(P = 0.042),并显示出功能恢复改善的趋势(P = 0.062)。因此,我们得出结论,细胞片移植技术可能诱导神经组织的直接再生,并可能改善脑出血的预后。

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