Adult mouse fibroblasts retain organ-specific transcriptomic identity

Abstract

Organ fibroblasts are essential components of homeostatic and diseased tissues. They participate in sculpting the extracellular matrix, sensing the microenvironment and communicating with other resident cells. Recent studies have revealed transcriptomic heterogeneity among fibroblasts within and between organs. To dissect the basis of inter-organ heterogeneity, we compare the gene expression of murine fibroblasts from different tissues (tail, skin, lung, liver, heart, kidney, gonads) and show that they display distinct positional and organ-specific transcriptome signatures that reflect their embryonic origins. We demonstrate that expression of genes typically attributed to the surrounding parenchyma by fibroblasts is established in embryonic development and largely maintained in culture, bioengineered tissues and ectopic transplants. Targeted knockdown of key organ-specific transcription factors affects fibroblast functions, in particular genes involved in the modulation of fibrosis and inflammation. In conclusion, our data reveal that adult fibroblasts maintain an embryonic gene expression signature inherited from their organ of origin, thereby increasing our understanding of adult fibroblast heterogeneity. The knowledge of this tissue-specific gene signature may assist in targeting fibrotic diseases in a more precise, organ-specific manner.

Origin and diversification of fibroblasts from the sclerotome in zebrafish

“…Recent studies have shown that tissue-resident fibroblasts also play important regulatory roles in wound healing, inflammation, tumor microenvironment, and tissue fibrosis (Kalluri, 2016; Kendall and Feghali-Bostwick, 2014; Plikus et al, 2021). Although fibroblasts have historically been viewed as a homogenous cell population, recent work using single-cell RNA sequencing (scRNA-seq) has revealed a high level of heterogeneity in fibroblast populations from different tissues as well as within the same tissue (Buechler et al, 2021; Forte et al, 2022; Muhl et al, 2020; Tabib et al, 2018; Xie et al, 2018). This raises the question of how the different fibroblast subtypes are generated during embryonic development.…”

Expression of Selected miRNAs in Normal and Cancer-Associated Fibroblasts and in BxPc3 and MIA PaCa-2 Cell Lines of Pancreatic Ductal Adenocarcinoma

“…This developmental difference must be taken into account cautiously. The different origin of these types of normal fibroblasts has a significant effect on their expression profile and presumably a significant influence on their function [ 21 , 22 ]. We therefore prefer to present both fibroblast controls separately and evaluate the statistical significance independently where relevant ( Figure 2 and Figure 3 ).…”

Induction of whole-body gene deletion via R26-regulated tamoxifen-inducible Cre recombinase activity

“…Double fluorescent Cre reporter mice harboring mTOM/mEGFP transgene are widely used to determine the efficacy of Cre-mediated recombination within floxed genes and lineage tracing studies ( Chandran et al, 2021 ; Forte et al, 2022 ; Klein et al, 2022 ). Thus, we utilized mTOM/mEGFP transgene to assess Cre recombination using green fluorescence and immunohistochemical localization of mEGFP, as end-points for protein expression, and the ratio of mEGFP to mTOM transgene expression, as an end-point for gene expression analysis.…”