Center for Regenerative Medicine (CReM), Boston University and Boston Medical Center, 670 Albany Street, Suite 209, Boston, MA 02118, USA; National Emerging Infectious Diseases Laboratories (NEIDL), Boston University, 620 Albany Street, Boston, MA 02118, USA; Department of Microbiology, Boston University School of Medicine, 620 Albany Street, Boston, MA 02118, USA.
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, MA 02139, USA.
Stem Cell Reports. 2022 Oct 11;17(10):2286-2302. doi: 10.1016/j.stemcr.2022.08.003. Epub 2022 Sep 8.
Liver damage and an exacerbated inflammatory response are hallmarks of Ebola virus (EBOV) infection. Little is known about the intrinsic response to infection in human hepatocytes and their contribution to inflammation. Here, we present an induced pluripotent stem cell (iPSC)-derived hepatocyte-like cell (HLC) platform to define the hepato-intrinsic response to EBOV infection. We used this platform to show robust EBOV infection, with characteristic ultrastructural changes and evidence for viral replication. Transcriptomics analysis revealed a delayed response with minimal early transcriptomic changes, followed by a general downregulation of hepatic function and upregulation of interferon signaling, providing a potential mechanism by which hepatocytes participate in disease severity and liver damage. Using RNA-fluorescence in situ hybridization (FISH), we showed that IFNB1 and CXCL10 were mainly expressed in non-infected bystander cells. We did not observe an inflammatory signature during infection. In conclusion, iPSC-HLCs are an immune competent platform to study responses to EBOV infection.
肝损伤和炎症反应加剧是埃博拉病毒（EBOV）感染的标志。目前对于人类肝细胞固有反应及其对炎症的贡献知之甚少。在这里，我们提出了一个诱导多能干细胞（iPSC）衍生的肝细胞样细胞（HLC）平台，以定义EBOV 感染的肝固有反应。我们使用该平台显示出强烈的 EBOV 感染，具有特征性的超微结构变化和病毒复制的证据。转录组学分析显示，反应延迟，早期转录组变化最小，随后肝脏功能普遍下调，干扰素信号上调，为肝细胞参与疾病严重程度和肝损伤提供了潜在机制。通过 RNA-荧光原位杂交（FISH），我们表明 IFNB1 和 CXCL10 主要在未感染的旁观者细胞中表达。在感染过程中未观察到炎症特征。总之，iPSC-HLC 是研究 EBOV 感染反应的免疫功能完备平台。
