Embryonic mesothelial-derived hepatic lineage of quiescent and heterogenous scar-orchestrating cells defined but suppressed by WT1

Abstract

Activated hepatic stellate cells (aHSCs) orchestrate scarring during liver injury, with putative quiescent precursor mesodermal derivation. Here we use lineage-tracing from development, through adult homoeostasis, to fibrosis, to define morphologically and transcriptionally discreet subpopulations of aHSCs by expression of WT1, a transcription factor controlling morphological transitions in organogenesis and adult homoeostasis. Two distinct populations of aHSCs express WT1 after injury, and both re-engage a transcriptional signature reflecting embryonic mesothelial origin of their discreet quiescent adult precursor. WT1-deletion enhances fibrogenesis after injury, through upregulated Wnt-signalling and modulation of genes central to matrix persistence in aHSCs, and augmentation of myofibroblastic transition. The mesothelial-derived lineage demonstrates punctuated phenotypic plasticity through bidirectional mesothelial-mesenchymal transitions. Our findings demonstrate functional heterogeneity of adult scar-orchestrating cells that can be whole-life traced back through specific quiescent adult precursors to differential origin in development, and define WT1 as a paradoxical regulator of aHSCs induced by injury but suppressing scarring.

Integration of geoscience frameworks into digital pathology analysis permits quantification of microarchitectural relationships in histological landscapes

“…The distribution of MFB-to-central vein distances (Fig. 8 d) can provide quantitative phenotypic histological data beyond crude cell number 17 . Relative scar axis based on peak MFB density (Fig.…”

Restricted differentiative capacity of Wt1-expressing peritoneal mesothelium in postnatal and adult mice

“…Of note, in contrast to the normal, healthy mesothelium, lineage tracing studies after injury in the lungs, liver, heart and peritoneum have shown that adult mesothelial cells can be activated and undergo a range of physiological changes including epithelial-mesenchymal transition (EMT) into smooth muscle cells and myofibroblasts, and subsequent contribution to scar formation (Chen et al, 2014, Karki et al, 2014, Lua et al, 2015, Namvar et al, 2018, Smart et al, 2011, Kendall et al, 2019).…”

The fibrotic and immune microenvironments as targetable drivers of metastasis

“…64,[75][76][77] This immunological switching of immune cell phenotypes is considered to be an essential trait of tumour initiation and, as a consequence, M2-like macrophages drive remodelling of the ECM through the production of matrix metalloproteinases, as well as supporting fibroblasts to produce pro-angiogenic signals such as vascular endothelial growth factor (VEGF) to facilitate further vascular recruitment. 78,79 Role of HSCs In addition to a complex immune microenvironment, the liver also contains two distinct populations of fibrogenic cells: HSCs in the space of Dissé 80 and portal fibroblasts surrounding the bile duct. 81 Fibroblasts are normally quiescent but, in response to injury, both of these cell types are capable of activation and express classical markers of activated fibroblasts such as α-smooth muscle actin (α-SMA), tissue inhibitors of metalloproteinases and ECM components.…”

“…In addition to a complex immune microenvironment, the liver also contains two distinct populations of fibrogenic cells: HSCs in the space of Dissé 80 and portal fibroblasts surrounding the bile duct. 81 Fibroblasts are normally quiescent but, in response to injury, both of these cell types are capable of activation and express classical markers of activated fibroblasts such as α-smooth muscle actin (α-SMA), tissue inhibitors of metalloproteinases and ECM components.…”