Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; Systems Biology Institute Australia, Clayton, Australia; Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, Australia
Hieu T Nim
Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; Systems Biology Institute Australia, Clayton, Australia; Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, Australia
Madison Mara
The Jackson Laboratory, Bar Harbor, United States
Jacky Y Li
Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, Australia
Rachel Cohn
The Jackson Laboratory, Farmington, United States
Sandra L Daigle
The Jackson Laboratory, Bar Harbor, United States
Sarah Boyd
Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia
Edouard G Stanley
Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, Australia; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Australia; Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia
Andrew G Elefanty
Murdoch Children’s Research Institute, The Royal Children’s Hospital, Parkville, Australia
John Travis Hinson
The Jackson Laboratory, Farmington, United States; Cardiology Center, UConn Health, Farmington, United States
Mauro W Costa
The Jackson Laboratory, Bar Harbor, United States; Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
Nadia A Rosenthal
The Jackson Laboratory, Bar Harbor, United States; Australian Regenerative Medicine Institute, Monash University, Clayton, Australia; National Heart and Lung Institute, Imperial College London, London, United Kingdom
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.
