Zayed Mohammed, Kim Yong-Chan, Jeong Byung-Hoon
Korea Zoonosis Research Institute, Jeonbuk National University, Iksan, 54531, Republic of Korea.
Department of Bioactive Material Sciences and Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju, 54896, Republic of Korea.
Stem Cell Res Ther. 2025 Mar 28;16(1):154. doi: 10.1186/s13287-025-04273-x.
Prion diseases are characterized by accumulation of misfolded host prion proteins (PrP) that produce aggregates in brain tissue. Mesenchymal stem cells (MSCs) have been identified as potential therapeutic candidates for prion diseases. However, it has been demonstrated that MSCs maintained and expressed PrP levels following inoculation, raising concerns regarding their safe and effective use in medical applications. Prion infectivity has been reported in fat tissues, thus the response of adipose-derived MSCs (AdMSCs) to prion infection needs to be fully studied.
For this study, we analyzed the properties of AdMSCs isolated from mice infected with the ME7 scrapie strain and compared them with negative controls. We investigated morphology, viability, immunophenotyping, markers of inflammation, migration activity, and neurotrophic factors. RNA sequencing (RNA-Seq) was performed to identify transcriptome profile changes.
AdMSCs derived from ME7-infected mice displayed immunophenotypes similar to cells from negative controls, but they were larger with lower viability (p < 0.05). ME7 infection caused higher expression of inflammatory mediators CCL5, TNF-α, C3, and IL6 (p < 0.05 and p < 0.01) and low expression of the stem cell marker, CXCR4 (p < 0.05) which was confirmed by immunofluorescence staining. The results showed decreased migration activity and wound closure ability of AdMSCs isolated from ME7-infected mice as confirmed by Transwell migration and scratch wound assays (p < 0.05 and p < 0.001), respectively. The RNA-Seq results detected 367 differentially expressed genes between AdMSCs from ME7-infected mice and those from the negative controls, and negative regulation of locomotion, extracellular matrix (ECM) organization, collagen-containing ECM, and extracellular structure organization genes were common in AdMSCs from ME7-infected mice. Transcriptomic analysis revealed that pathways enriched in AdMSCs from ME7-infected mice included those involved in the PI3K-Akt signaling pathway, cell adhesion, protein digestion and absorption, and cytokine-cytokine receptor interactions. Interestingly, genes related to the regulation of iron storage, such as Hp and hepcidin, were upregulated in AdMSCs isolated from ME7-infected mice.
Based on these data, therapeutic strategies for AdMSCs in prion disease should be further investigated.
朊病毒疾病的特征是错误折叠的宿主朊病毒蛋白（PrP）在脑组织中积累并形成聚集体。间充质干细胞（MSCs）已被确定为朊病毒疾病潜在的治疗候选细胞。然而，已有研究表明，接种后MSCs能维持并表达PrP水平，这引发了人们对其在医学应用中安全有效使用的担忧。脂肪组织中已报道存在朊病毒感染性，因此需要全面研究脂肪来源的间充质干细胞（AdMSCs）对朊病毒感染的反应。
在本研究中，我们分析了从感染ME7羊瘙痒病株的小鼠中分离出的AdMSCs的特性，并与阴性对照进行比较。我们研究了细胞形态、活力、免疫表型、炎症标志物、迁移活性和神经营养因子。进行RNA测序（RNA-Seq）以鉴定转录组谱的变化。
来自ME7感染小鼠的AdMSCs表现出与阴性对照细胞相似的免疫表型，但细胞更大且活力较低（p < 0.05）。ME7感染导致炎症介质CCL5、TNF-α、C3和IL6的表达升高（p < 0.05和p < 0.01），而干细胞标志物CXCR4的表达降低（p < 0.05），免疫荧光染色证实了这一点。Transwell迁移实验和划痕伤口实验结果分别表明，从ME7感染小鼠中分离出的AdMSCs的迁移活性和伤口愈合能力下降（p < 0.05和p < 0.001）。RNA-Seq结果检测到来自ME7感染小鼠的AdMSCs与阴性对照之间有367个差异表达基因，在来自ME7感染小鼠的AdMSCs中，运动的负调控、细胞外基质（ECM）组织、含胶原ECM和细胞外结构组织基因较为常见。转录组分析显示，来自ME7感染小鼠的AdMSCs中富集的通路包括参与PI3K-Akt信号通路、细胞粘附、蛋白质消化和吸收以及细胞因子-细胞因子受体相互作用的通路。有趣的是，与铁储存调节相关的基因，如Hp和铁调素，在从ME7感染小鼠中分离出的AdMSCs中上调。
基于这些数据，应进一步研究AdMSCs在朊病毒疾病中的治疗策略。
