Adult mouse fibroblasts retain organ-specific transcriptomic identity.

Hieu T Nim,Mirana Ramialison,Elvira Forte,Andrew G Elefanty,Mauro W Costa,Jacky Y Li,Sarah Boyd,Milena B Furtado,Madison Mara,Rachel Cohn,Edouard G Stanley,John Travis Hinson,Sandra L Daigle,Nadia A Rosenthal

doi:10.7554/elife.71008

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 interorgan heterogeneity, we compare the gene expression of murine fibroblasts from different tissues (tail, skin, lung, liver, heart, kidney, and 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.

Highlights

Fibroproliferative disorders are the main cause of mortality and morbidity in developed countries, accounting for about 45% of deaths in the United States [1]
Having previously reported that fibroblasts isolated from the adult mouse heart retain a cardiogenic transcriptional program [23], we show here that fibroblasts isolated from different adult organs retain the expression of transcription factors and other gene sets involved in the determination of organ formation and patterning during embryonic development
We previously reported that fibroblasts isolated from the adult mouse heart retain a cardiogenic transcriptional program [23]

Summary

Introduction

Fibroproliferative disorders are the main cause of mortality and morbidity in developed countries, accounting for about 45% of deaths in the United States [1]. Recent literature poses the organ fibroblast as a major regulatory hub that senses local microenvironment imbalances and controls tissue remodeling [4] upon activation and phenotypic differentiation into the pro-fibrotic myofibroblast [5] They are involved in immunomodulation [6], by producing and responding to cytokines that activate immune cells of the innate and adaptive immune systems [7, 8], through organ specific regulatory networks [9]. Having previously reported that fibroblasts isolated from the adult mouse heart retain a cardiogenic transcriptional program [23], we show here that fibroblasts isolated from different adult organs retain the expression of transcription factors and other gene sets involved in the determination of organ formation and patterning during embryonic development. Our study uncovers stable expression of organ specific, development-related signature genes in adult fibroblasts, offering new prospects for possible anti-fibrotic therapies

Methods

Results

Conclusion