Fibroblasts are the major cell population in the connective tissue of most organs, where they are essential for their structural integrity. They are best known for their role in remodelling the extracellular matrix, however more recently they have been recognised as a functionally highly diverse cell population that constantly responds and adapts to their environment. Biological memory is the process of a sustained altered cellular state and functions in response to a transient or persistent environmental stimulus. While it is well established that fibroblasts retain a memory of their anatomical location, how other environmental stimuli influence fibroblast behaviour and function is less clear. The ability of fibroblasts to respond and memorise different environmental stimuli is essential for tissue development and homeostasis and may become dysregulated in chronic disease conditions such as fibrosis and cancer. Here we summarise the four emerging key areas of fibroblast adaptation: positional, mechanical, inflammatory, and metabolic memory and highlight the underlying mechanisms and their implications in tissue homeostasis and disease.

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Juvenile bipolar disorder can be a challenging diagnosis, given its atypical presentation and tendency to have other comorbid psychiatric disorders. In this case study, we describe a case of a young patient with some atypical symptoms of early-onset bipolar disorder.

Skin fibrosis, a common scarring condition that currently has no curative treatments, is caused by persistent activation of fibroblasts after tissue injury or inflammation that results in excessive connective tissue deposition, leading to severe disability, organ malfunction and increased morbidity. This study aims to uncover the early and advanced changes in different fibroblast subsets and molecular pathways that are integral to pathological fibroblast activation using a bleomycin-induced skin fibrosis mouse model that recapitulates well the human disease. We have shown that 2 weeks (early) and 4 weeks (advanced) of subcutaneous bleomycin injections result in an increasing severity of skin fibrosis, characterized by increased dermal thickness, collagen deposition, inflammation, and loss of dermal fibroblasts and adipocytes. We performed single-cell RNA sequencing and successfully isolated 14 944 control, 16 344 early and 6860 advanced fibrotic cells. We identified the changes in fibroblast subclusters and gene signatures that are altered across the time course. Using CellChat, we are dissecting the specific signalling crosstalk between different fibroblast subpopulations and other skin cells, promoting a profibrotic phenotype and locking fibroblasts in an activated state. Furthermore, we are intersecting our novel data set with publicly available wound healing transcriptomic data, allowing us to examine how fibroblast subpopulations, behaviour and key signalling pathways vary in healthy wounding healing and pathological scarring. To understand the impact that changes in extracellular matrix biomechanics elicit on profibrotic fibroblast fate, we are correlating our histological and transcriptomic analysis with nanoindentation atomic force microscopy imaging throughout the fibrotic time course. This novel multidisciplinary approach allows us to compare the cellular and molecular changes in early and advanced fibrotic lesions, identifying the key fibroblast subpopulations, molecular regulators and connective tissue alterations promoting fibrotic tissue repair. Our findings will support the development of new fibroblast-targeted fibrosis therapies in skin and potentially other organs.