Dermatopontin-expressing fibroblasts mediate an essential skin macrophage niche

Vollmers, A. C.; Wu, S. Z.; Altieri, A.; McCartney, E. E.; Bender, H.; Lee, W. P.; Zhang, J.; Hu, C.; Uttarwar, S.; Vander Heiden, J. A.; Davidson, C.; Chung, Y.; Ortiz, W.; Long, M.; Asuncion, R.; Yang, Y. A.; Jiang, J.; Modrusan, Z.; Krishnamurty, A.; Fu, W.; Müller, S.; Buechler, M. B.; Turley, S.

doi:10.1101/2024.11.21.624708

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bioRxiv · 10.1101/2024.11.21.624708

Dermatopontin-expressing fibroblasts mediate an essential skin macrophage niche

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Abstract

Fibroblasts are present in all tissues and are crucial for maintaining tissue homeostasis. We previously identified fibroblasts marked by Dermatopontin (Dpt) but their role in supporting macrophage homeostasis remains unclear. Here, we generated novel mesenchymal lineage-restricted genetic tools to target Dpt expressing fibroblasts and elucidate their role in supporting skin macrophages. Transcriptional profiling, flow cytometry, and in situ hybridization uncovered two broad populations of F4/80-expressing skin macrophages, denoted by high expression of CD206 and CD64 (CD206hiCD64+), or CD11c. Targeted depletion of Dpt+ fibroblasts resulted in a profound loss of both macrophage populations. Conditional deletion of colony-stimulating factor-1 (Csf1) in Dpt+ fibroblasts revealed that CD206hiCD64+, and not CD11c+, macrophages are acutely dependent on fibroblast-derived Csf1, consistent with their higher expression of the Csf1 receptor. Following Csf1 deletion in Dpt+ fibroblasts, loss of CD206hiCD64+ macrophages were observed across the dermis, dermal white adipose tissue (dWAT), and adventitia, accompanied by a modest upregulation of fibroblast-related and extracellular matrix (ECM) genes and structural changes to the skin. Alterations to the skin network upon loss of fibroblast-derived Csf1 and CD206hiCD64+ macrophages led to a significant delay in wound healing. We also demonstrate the CSF1-CSF1R signaling pathway is functionally relevant in human systemic sclerosis, or scleroderma, as elevated levels of CSF1 produced by fibroblasts and an increased abundance of macrophages both correlate with disease severity. Our findings demonstrate the role of Dpt+ fibroblasts in regulating a Csf1-dependent macrophage niche in skin and orchestrating responses in injury and disease.

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Vollmers, A. C., Wu, S. Z., Altieri, A., McCartney, E. E., Bender, H., Lee, W. P., Zhang, J., Hu, C., Uttarwar, S., Vander Heiden, J. A., Davidson, C., Chung, Y., Ortiz, W., Long, M., Asuncion, R., Yang, Y. A., Jiang, J., Modrusan, Z., Krishnamurty, A., Fu, W., Müller, S., Buechler, M. B., Turley, S.. 2024-11-22. Dermatopontin-expressing fibroblasts mediate an essential skin macrophage niche. https://doi.org/10.1101/2024.11.21.624708

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