Single Cell Transcriptomics Reveals Mesenchymal and Monocytic Lineages Involved in Dupuytren Disease
Janos A Barrera, MD1, Zeshaan N Maan, MD, MSc1, Dominic Henn, MD1, Kellen Chen, PhD2, Alexander Y. Li, MD, MS3, Jagannath Padmanabhan, PhD1, Clark A Bonham, BS4, Kay Hung, MD1, Catherine Curtin, MD5, Michael Januszyk, MD, PhD6, Vincent R. Hentz, MD7 and Geoffrey Gurtner, MD8, (1)Stanford University, Stanford, CA, (2)University of Arizona, Tucson, CA, (3)The Buncke Clinic, San Francisco, CA, (4)Stanford University, Stanford, Uganda, (5)Stanford Hospital and Clinics, Palo Alto, CA, (6)Plastic and Reconstructive Surgery, Stanford University, Stanford, CA, (7)Department of Plastic Surgery, Stanford University, Palo Alto, CA, (8)University of Arizona, Tucson, AZ
Dupuytren disease (DD) is a fibroproliferative disorder of the palmar fascia of the hand leading to debilitating contractures. While several therapeutic approaches exist, recurrence is common, and a limited understanding of disease pathogenesis has impaired the development of more targeted therapies. To better understand the cell populations and signaling pathways governing its pathogenesis, we employed single cell RNA sequencing (scRNAseq) on human DD and control tissue. Using scRNAseq, we identify the human Dupuytren myofibroblast and describe its transcriptional profile. In addition, we further identify a highly fibroproliferative matrix-forming fibroblast in human Dupuytren tissue that is characterized by the expression of DPP4, TNC, TGFB1, and POSTN. This matrix-forming fibroblast appears to be more transcriptionally active in DD, compared to the myofibroblast. Using RNA velocity, we identify the Dupuytren fibroblast progenitor cell that differentiates into pathologic matrix-forming fibroblasts in humans. The transcriptional changes that define this differentiation pathway are elucidated using Pseudotime. Additionally, we identify a putative Dupuytren fibrocyte as well as its monocytic progenitor. Finally, we demonstrate that expression of CXCL14 and its receptor CXCR4 is upregulated in Dupuytren tissue, suggesting an important role for this cytokine-receptor axis during disease pathogenesis. These findings shed new insight into the cellular and molecular mechanisms governing the pathogenesis of DD and identify novel therapeutic targets for future study.
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