P08 Dissection of the molecular and cellular heterogeneity of dermal fibroblasts in skin fibrosis

成纤维细胞 纤维化 细胞外基质 伤口愈合 肌成纤维细胞 博莱霉素 炎症 病理 真皮成纤维细胞 医学 生物 细胞生物学 癌症研究 免疫学 细胞培养 内科学 遗传学 化疗
作者
Abubkr Ahmed,Thomas Kirk,Laura Forster,Edel A. O’Toole,Himadri S. Gupta,Emanuel Rognoni
出处
期刊:British Journal of Dermatology [Wiley]
卷期号:189 (1): e17-e17
标识
DOI:10.1093/bjd/ljad174.030
摘要

Abstract 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.
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