Department of Neurology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, 32224, USA.
Stem Cell Res Ther. 2021 Mar 18;12(1):187. doi: 10.1186/s13287-021-02241-9.
Mesenchymal stromal cells (MSCs) have been studied with increasing intensity as clinicians and researchers strive to understand the ability of MSCs to modulate disease progression and promote tissue regeneration. As MSCs are used for diverse applications, it is important to appreciate how specific physiological environments may stimulate changes that alter the phenotype of the cells. One need for neuroregenerative applications is to characterize the spectrum of MSC responses to the cerebrospinal fluid (CSF) environment after their injection into the intrathecal space. Mechanistic understanding of cellular biology in response to the CSF environment may predict the ability of MSCs to promote injury repair or provide neuroprotection in neurodegenerative diseases.
In this study, we characterized changes in morphology, metabolism, and gene expression occurring in human adipose-derived MSCs cultured in human (hCSF) or artificial CSF (aCSF) as well as examined relevant protein levels in the CSF of subjects treated with MSCs for amyotrophic lateral sclerosis (ALS).
Our results demonstrated that, under intrathecal-like conditions, MSCs retained their morphology, though they became quiescent. Large-scale transcriptomic analysis of MSCs revealed a distinct gene expression profile for cells cultured in aCSF. The aCSF culture environment induced expression of genes related to angiogenesis and immunomodulation. In addition, MSCs in aCSF expressed genes encoding nutritional growth factors to expression levels at or above those of control cells. Furthermore, we observed a dose-dependent increase in growth factors and immunomodulatory cytokines in CSF from subjects with ALS treated intrathecally with autologous MSCs.
Overall, our results suggest that MSCs injected into the intrathecal space in ongoing clinical trials remain viable and may provide a therapeutic benefit to patients.
间充质基质细胞（MSCs）作为临床医生和研究人员的研究对象越来越多，他们努力理解 MSCs 调节疾病进展和促进组织再生的能力。由于 MSCs 被用于多种应用，因此了解特定生理环境如何刺激改变细胞表型的变化非常重要。神经再生应用的一个需求是描述 MSCs 在注入鞘内空间后对脑脊液（CSF）环境的反应谱。对 CSF 环境的细胞生物学的机制理解可能预测 MSCs 在神经退行性疾病中促进损伤修复或提供神经保护的能力。
在这项研究中，我们在人（hCSF）或人工 CSF（aCSF）中培养人脂肪来源的 MSC，描述细胞形态、代谢和基因表达的变化，并检查接受 MSCs 治疗的肌萎缩侧索硬化症（ALS）患者 CSF 中的相关蛋白水平。
我们的结果表明，在鞘内样条件下，MSC 保持其形态，但变得静止。对 MSC 进行的大规模转录组分析显示，在 aCSF 中培养的细胞具有独特的基因表达谱。aCSF 培养环境诱导了与血管生成和免疫调节相关的基因表达。此外，aCSF 中的 MSC 表达编码营养生长因子的基因，其表达水平达到或高于对照细胞。此外，我们观察到鞘内注射自体 MSCs 的 ALS 患者 CSF 中的生长因子和免疫调节细胞因子呈剂量依赖性增加。
总体而言，我们的结果表明，正在进行的临床试验中注入鞘内空间的 MSC 仍然具有活力，并可能为患者提供治疗益处。
