Enhancing neural stem cell response to SDF-1α gradients through hyaluronic acid-laminin hydrogels.
Enhancing neural stem cell response to SDF-1α gradients through hyaluronic acid-laminin hydrogels.
复制标题
DOI：
10.1016/j.biomaterials.2015.08.041
复制
发表时间：
2015-12
期刊：
影响因子：
14
通讯作者：
Stabenfeldt SE
中科院分区：
文献类型：
--
作者：
Addington CP;Heffernan JM;Millar-Haskell CS;Tucker EW;Sirianni RW;Stabenfeldt SE
创伤性脑损伤(TBI)引起一种广泛的生化损伤，这在很大程度上是与TBI相关的长期功能障碍的原因；然而，目前的临床治疗未能解决这些潜在的后遗症。临床前研究使用干细胞移植取得了一定的成功，但存活率和植入率低得惊人(2-4%)。因此，为细胞移植提供在移植微环境中更好地动态响应与损伤相关的信号的方法可能会提高移植存活率和植入率。趋化因子基质细胞衍生因子-1α(SDF-1α)是一种很强的趋化信号，在脑外伤后很容易出现。在这项研究中，我们试图开发一种移植载体，以最终提高神经移植对损伤诱导的SDF-1α的反应性。具体地说，我们假设透明质酸(HA)和层粘连蛋白(LM)水凝胶将促进1.神经前体/干细胞(NPSC)上调SDF-1α受体CXCR4的表达；2.神经干细胞对SDF-1α梯度的反应迁移。我们成功地开发了HA-LM水凝胶，并利用标准蛋白质和细胞分析来检测NPSC CXCR4的表达和NPSC的趋化迁移。结果表明，NPSCs在HA-LM凝胶上培养48小时后，CXCR4的表达显著增加，这一方式严重依赖于HA和层粘连蛋白。此外，在48小时后，HA-LM水凝胶显著增加了神经干细胞对SDF-1α的趋化迁移，这一效应严重依赖于HA、层粘连蛋白和SDF-1α梯度。因此，这种水凝胶的作用是：1.为损伤微环境启动NPSCs；2.提供适当的基础设施，支持向周围组织的迁移，为细胞配备工具，以更有效地应对损伤微环境。
Traumatic brain injury (TBI) initiates an expansive biochemical insult that is largely responsible for the long-term dysfunction associated with TBI; however, current clinical treatments fall short of addressing these underlying sequelae. Pre-clinical investigations have used stem cell transplantation with moderate success, plagued by staggeringly low survival and engraftment rates (2–4%). As such, providing cell transplants with the means to better dynamically respond to injury-related signals within the transplant microenvironment may afford improved transplantation survival and engraftment rates. The chemokine stromal cell-derived factor-1α (SDF-1α) is a potent chemotactic signal that is readily present after TBI. In this study, we sought to develop a transplantation vehicle to ultimately enhance the responsiveness of neural transplants to injury-induced SDF-1α. Specifically, we hypothesize that a hyaluronic acid (HA) and laminin (Lm) hydrogel would promote 1. upregulated expression of the SDF-1α receptor CXCR4 in neural progenitor/stem cells (NPSCs) and 2. NPSC migration in response to SDF-1α gradients. We demonstrated successful development of a HA-Lm hydrogel and utilized standard protein and cellular assays to probe NPSC CXCR4 expression and NPSC chemotactic migration. The findings demonstrated that NPSCs significantly increased CXCR4 expression after 48 hrs of culture on the HA-Lm gel in a manner critically dependent on both HA and laminin. Moreover, the HA-Lm hydrogel significantly increased NPSC chemotactic migration in response to SDF-1α at 48 hrs, an effect that was critically dependent on HA, laminin and the SDF-1α gradient. Therefore, this hydrogel serves to 1. prime NPSCs for the injury microenvironment and 2. provide the appropriate infrastructure to support migration into the surrounding tissue, equipping cells with the tools to more effectively respond to the injury microenvironment.