Introduction

Stromal cell derived factor-1a (SDF-1a) and its receptor CXCR4 modulate stem cell recruitment to neural injury sites. SDF-1a gradients originating from injury sites contribute to chemotactic cellular recruitment. To capitalize on this injury-induced cell recruitment, further investigation of SDF-1a/CXCR4 signaling dynamics are warranted. Here, we studied how exogenous SDF-1a delivery strategies impact spatiotemporal SDF-1a levels and the role autocrine/paracrine signaling plays.

Methods

We first assessed total SDF-1a and CXCR4 levels over the course of 7 days following intracortical injection of either bolus SDF-1a or SDF-1a loaded nanoparticles in CXCR4-EGFP mice. We then investigated cellular contributors to SDF-1a autocrine/paracrine signaling via time course in vitro measurements of SDF-1a and CXCR4 gene expression following exogenous SDF-1a application. Lastly, we created mathematical models that could recapitulate our in vivo observations.

Results

In vivo, we found sustained total SDF-1a levels beyond 3 days post injection, indicating endogenous SDF-1a production. We confirmed in vitro that microglia, astrocytes, and brain endothelial cells significantly change SDF-1a and CXCR4 expression after exposure. We found that diffusion-only based mathematical models were unable to capture in vivo SDF-1a spatial distribution. Adding autocrine/paracrine mechanisms to the model allowed for SDF-1a temporal trends to be modeled accurately, indicating it plays an essential role in SDF-1a sustainment.

Conclusions

We conclude that autocrine/paracrine dynamics play a role in endogenous SDF-1a levels in the brain following exogenous delivery. Implementation of these dynamics are necessary to improving SDF-1a delivery strategies. Further, mathematical models introduced here may be utilized in predicting future outcomes based upon new biomaterial designs.

中文翻译：

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基质细胞衍生因子 1a 自分泌/旁分泌信号传导有助于大脑中的时空梯度

 介绍

基质细胞衍生因子 1a (SDF-1a) 及其受体 CXCR4 调节干细胞向神经损伤部位的募集。源自损伤部位的 SDF-1a 梯度有助于趋化细胞募集。为了利用这种损伤诱导的细胞募集，有必要进一步研究 SDF-1a/CXCR4 信号动力学。在这里，我们研究了外源性 SDF-1a 递送策略如何影响时空 SDF-1a 水平以及自分泌/旁分泌信号传导的作用。

 方法

我们首先在 CXCR4-EGFP 小鼠皮质内注射推注 SDF-1a 或负载 SDF-1a 的纳米颗粒后 7 天的时间内评估总 SDF-1a 和 CXCR4 水平。然后，我们通过体外测量外源 SDF-1a 后 SDF-1a 和 CXCR4 基因表达的时间过程，研究了 SDF-1a 自分泌/旁分泌信号传导的细胞贡献者。最后，我们创建了可以概括我们体内观察结果的数学模型。

 结果

在体内，我们发现注射后 3 天后总 SDF-1a 水平持续存在，表明内源性 SDF-1a 产生。我们在体外证实，小胶质细胞、星形胶质细胞和脑内皮细胞在暴露后显着改变 SDF-1a 和 CXCR4 表达。我们发现仅基于扩散的数学模型无法捕获体内SDF-1a 空间分布。在模型中添加自分泌/旁分泌机制可以对 SDF-1a 时间趋势进行准确建模，表明它在 SDF-1a 维持中发挥着重要作用。

 结论

我们得出结论，自分泌/旁分泌动力学在外源性递送后大脑中的内源性 SDF-1a 水平中发挥作用。实施这些动态对于改进 SDF-1a 递送策略是必要的。此外，这里介绍的数学模型可用于根据新的生物材料设计预测未来的结果。