Watson Brianna R, Paul Biplab, Rahman Raza Ur, Amir-Zilberstein Liat, Segerstolpe Åsa, Epstein Eliana T, Murphy Shane, Geistlinger Ludwig, Lee Tyrone, Shih Angela, Deguine Jacques, Xavier Ramnik J, Moffitt Jeffrey R, Mullen Alan C
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, 02115, USA.
Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.
Nat Commun. 2025 Jan 2;16(1):319. doi: 10.1038/s41467-024-55325-4.
Single-cell RNA sequencing (scRNA-seq) has advanced our understanding of cell types and their heterogeneity within the human liver, but the spatial organization at single-cell resolution has not yet been described. Here we apply multiplexed error robust fluorescent in situ hybridization (MERFISH) to map the zonal distribution of hepatocytes, spatially resolve subsets of macrophage and mesenchymal populations, and investigate the relationship between hepatocyte ploidy and gene expression within the healthy human liver. Integrating spatial information from MERFISH with the more complete transcriptome produced by single-nucleus RNA sequencing (snRNA-seq), also reveals zonally enriched receptor-ligand interactions. Finally, MERFISH and snRNA-seq analysis of fibrotic liver samples identify two hepatocyte populations that expand with injury and do not have clear zonal distributions. Together these spatial maps of the healthy and fibrotic liver provide a deeper understanding of the cellular and spatial remodeling that drives disease which, in turn, could provide new avenues for intervention and further study.
单细胞RNA测序（scRNA-seq）增进了我们对人类肝脏内细胞类型及其异质性的理解，但单细胞分辨率下的空间组织尚未得到描述。在此，我们应用多重误差稳健荧光原位杂交（MERFISH）来绘制肝细胞的区域分布图谱，在空间上解析巨噬细胞和间充质群体的亚群，并研究健康人类肝脏内肝细胞倍性与基因表达之间的关系。将MERFISH的空间信息与单核RNA测序（snRNA-seq）产生的更完整转录组相结合，还揭示了区域富集的受体-配体相互作用。最后，对纤维化肝脏样本进行的MERFISH和snRNA-seq分析确定了两个随着损伤而扩张且没有明确区域分布的肝细胞群体。健康和纤维化肝脏的这些空间图谱共同提供了对驱动疾病的细胞和空间重塑的更深入理解，进而可为干预和进一步研究提供新途径。
