Transplantation of RADA16-BDNF peptide scaffold with human umbilical cord mesenchymal stem cells forced with CXCR4 and activated astrocytes for repair of traumatic brain injury
Transplantation of RADA16-BDNF peptide scaffold with human umbilical cord mesenchymal stem cells forced with CXCR4 and activated astrocytes for repair of traumatic brain injury
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CXCR4强制的人脐带间充质干细胞和活化的星形胶质细胞移植RADA16-BDNF肽支架修复创伤性脑损伤
DOI：
10.1016/j.actbio.2016.09.001
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发表时间：
2016-11-01
影响因子：
9.7
通讯作者：
Chen, J.
中科院分区：
文献类型：
--
作者：
Shi, W.;Huang, C. J.;Chen, J.
由于脑组织的自我再生能力较差，干细胞移植疗法据称可以替代脑外伤（TBI）后丢失的神经元。大脑再生的主要挑战是移植的细胞能否在病变区域存活并发挥神经元功能。大脑是一个复杂的神经元网络，由各种类型的细胞组成，彼此之间存在显着影响，植入大脑中的干细胞的存活很大程度上受到周围细胞的影响。尽管基于干细胞的治疗正在迅速发展，但之前的大多数研究仅集中于应用单一类型的干细胞作为细胞来源。在这里，我们发现直接与活化的星形胶质细胞共培养人脐带间充质干细胞（hUC-MSC）有利于hUC-MSC的体外增殖和神经元分化。在这项研究中，hUC-MSCs和活化的星形胶质细胞被接种在RADA16-BDNF肽支架（R-B-SPH支架）（一种特殊的自组装肽水凝胶）中，其中的环境促进典型神经元样细胞的分化，神经突在三维方向上延伸。此外，结果显示hUC-MSCs和活化的星形胶质细胞的共培养促进更多的BDNF分泌，这可能有利于外源性hUC-MSCs的神经分化和内源性神经发生。为了促进移植的hUC-MSCs迁移到宿主大脑，hUC-MSCs被迫接受CXC趋化因子受体4（CXCR4）。我们发现，通过移植 hUC-MSCscxcR4 和嵌入 R-B-SPH 支架中的活化星形胶质细胞，可以修复中等大小的病变空腔，但不能修复 TBI 引起的大空腔。本研究证明的TBI功能性神经修复主要归功于双细胞、hUC-MSCs和活化星形胶质细胞的移植系统。我们相信，这种新型细胞移植系统为TBI的细胞替代疗法提供了一种有前景的治疗选择。 意义声明在这一方面，我们将一种源自BDNF的功能性肽RGIDKRHWNSQ与RADARADARADARADA（RADA16）的C端特异性连接，以构建功能性自组装肽水凝胶支架RADA16-BDNF（R-B-SPH支架），以更好地移植双细胞单元。此外，新型支架还用作移植双细胞单位（hUC-MSCs/星形胶质细胞）的细胞载体，用于治疗创伤性脑损伤。本研究结果表明，R-B-SPH支架柔韧、柔韧，能够贴合脑病变腔，并在体外和体内促进hUC-MSC来源的神经元轴突和树突的生长，表明3D R-B-SPH支架为hUC-MSC的存活、增殖和分化提供了合适的微环境。此外，我们的结果表明，双细胞移植系统（hUC-MSC5/星形胶质细胞）可能是一种新型的基于细胞的 TBI 后神经再生治疗策略，具有潜在的临床应用价值。 (C) 2016 Acta Materialia Inc. 由 Elsevier Ltd 出版。保留所有权利。
Due to the poor self-regeneration of brain tissue, stem cell transplantation therapy is purported to enable the replacement of lost neurons after traumatic brain injury (TBI). The main challenge of brain regeneration is whether the transplanted cells can survive and carry out neuronal functions in the lesion area. The brain is a complex neuronal network consisting of various types of cells that significantly influence on each other, and the survival of the implanted stem cells in brain is critically influenced by the surrounding cells. Although stem cell-based therapy is developing rapidly, most previous studies just focus on apply single type of stem cells as cell source. Here, we found that co-culturing human umbilical cord mesenchymal stem cells (hUC-MSCs) directly with the activated astrocytes benefited to the proliferation and neuron differentiation of hUC-MSCs in vitro. In this study, hUC-MSCs and the activated astrocytes were seeded in RADA16-BDNF peptide scaffold (R-B-SPH scaffold), a specifical self-assembling peptide hydrogel, in which the environment promoted the differentiation of typical neuron-like cells with neurites extending in three-dimensional directions. Moreover, the results showed co-culture of hUC-MSCs and activated astrocytes promoted more BDNF secretion which may benefit to both neural differentiation of ectogenic hUC-MSCs and endogenic neurogenesis. In order to promote migration of the transplanted hUC-MSCs to the host brain, the hUC-MSCs were forced with CXC chemokine receptor 4 (CXCR4). We found that the moderate-sized lesion cavity, but not the large cavity caused by TBI was repaired via the transplantation of hUC-MSCscxcR4 and activated astrocytes embedded in R-B-SPH scaffolds. The functional neural repair for TBI demonstrated in this study is mainly due to the transplantation system of double cells, hUC-MSCs and activated astrocytes. We believe that this novel cell transplantation system offers a promising treatment option for cell replacement therapy for TBI.Statement of SignificanceIn this reach, we specifically linked RGIDKRHWNSQ a functional peptide derived from BDNF, to the C-terminal of RADARADARADARADA (RADA16) to structure a functional self-assembling peptide hydro gel scaffold, RADA16-BDNF (R-B-SPH scaffold) for the better transplantation of the double cell unit. Also, the novel scaffold was used as cell-carrier for transplantation double cell unit (hUC-MSCs/astrocyte) for treating traumatic brain injury. The results of this study showing that R-B-SPH scaffold was pliancy and flexibility to fit the brain lesion cavity and promotes the outgrowth of axons and dendrites of the neurons derived from hUC-MSCs in vitro and in vivo, indicating the 3D R-B-SPH scaffold provided a suitable microenvironment for hUC-MSC survival, proliferation and differentiation. Also, our results showing the double-cells transplantation system (hUC-MSC5/astrocyte) may be a novel cell-based therapeutic strategy for neuroregeneration after TBI with potential value for clinical application. (C) 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.