Engineered hydrogels increase the post-transplantation survival of encapsulated hESC-derived midbrain dopaminergic neurons
Engineered hydrogels increase the post-transplantation survival of encapsulated hESC-derived midbrain dopaminergic neurons
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DOI：
10.1016/j.biomaterials.2017.05.008
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发表时间：
2017-08-01
期刊：
影响因子：
14
通讯作者：
Schaffer, David V.
中科院分区：
文献类型：
--
作者：
Adil, Maroof M.;Vazin, Tandis;Schaffer, David V.
细胞替代疗法具有广阔的生物医学潜力；然而，移植后细胞存活率低和功能整合差是阻碍临床受益的主要障碍。例如，在纹状体移植中脑多巴胺(MDA)能神经元治疗帕金森病(PD)后，在临床前模型和临床试验中，通常只有1%-5%的神经元存活。一般来说，资源密集型的大量细胞的产生和植入是为了弥补移植后细胞存活率低的问题。移植物存活率低通常归因于细胞在植入过程中和之后所经历的不利的生化、机械和/或免疫应激。为了应对这些挑战，我们开发了一种基于透明质酸(HA)的功能化水凝胶，用于人多能干细胞(HPSC)来源的神经前体细胞的体外成熟和中枢神经系统(CNS)移植。具体地说，我们通过点击化学方法将含有RGD和肝素(HEP)的HA水凝胶功能化，并定制其硬度以促进神经元成熟、存活和长期保持所需的MDA表型。重要的是，与从常用2D表面获取的未包裹的神经元相比，水凝胶包裹的丙二醛神经元移植后在大鼠纹状体中存活的比例接近5倍。因此，这种工程化的生物材料可能会增加治疗潜力，并减轻成功植入神经元的制造负担。(C)2017爱思唯尔有限公司。保留所有权利。
Cell replacement therapies have broad biomedical potential; however, low cell survival and poor functional integration post-transplantation are major hurdles that hamper clinical benefit. For example, following striatal transplantation of midbrain dopaminergic (mDA) neurons for the treatment of Parkinson's disease (PD), only 1-5% of the neurons typically survive in preclinical models and in clinical trials. In general, resource-intensive generation and implantation of larger numbers of cells are used to compensate for the low post-transplantation cell-survival. Poor graft survival is often attributed to adverse biochemical, mechanical, and/or immunological stress that cells experience during and after implantation. To address these challenges, we developed a functionalized hyaluronic acid (HA)-based hydrogel for in vitro maturation and central nervous system (CNS) transplantation of human pluripotent stem cell (hPSC)-derived neural progenitors. Specifically, we functionalized the HA hydrogel with RGD and heparin (hep) via click-chemistry and tailored its stiffness to encourage neuronal maturation, survival, and long-term maintenance of the desired mDA phenotype. Importantly, similar to 5 times more hydrogel-encapsulated mDA neurons survived after transplantation in the rat striatum, compared to unencapsulated neurons harvested from commonly used 2D surfaces. This engineered biomaterial may therefore increase the therapeutic potential and reduce the manufacturing burden for successful neuronal implantation. (C) 2017 Elsevier Ltd. All rights reserved.