Lineage tracing of Foxd1‐expressing embryonic progenitors to assess the role of divergent embryonic lineages on adult dermal fibroblast function

Abstract

Recent studies have highlighted the functional diversity of dermal fibroblast populations in health and disease, with part of this diversity linked to fibroblast lineage and embryonic origin. Fibroblasts derived from foxd1-expressing progenitors contribute to the myofibroblast populations present in lung and kidney fibrosis in mice but have not been investigated in the context of dermal wound repair. Using a Cre/Lox system to genetically track populations derived from foxd1-expressing progenitors, lineage-positive fibroblasts were identified as a subset of the dermal fibroblast population. During development, lineage-positive cells were most abundant within the dorsal embryonic tissues, contributing to the developing dermal fibroblast population, and remaining in this niche into adulthood. In adult mice, assessment of fibrosis-related gene expression in lineage-positive and lineage-negative populations isolated from wounded and unwounded dorsal skin was performed, identifying an enrichment of transcripts associated with matrix synthesis and remodeling in the lineage-positive populations. Using a novel excisional wound model, ventral skin healed with a Accepted Article greatly reduced frequency of foxd1 lineage-positive cells. This work supports that the embryonic origin of fibroblasts is an important predictor of fibroblast function, but also highlights that within disparate regions, fibroblasts of different lineages likely undergo convergent differentiation contributing to phenotypic similarities.

Single‐Cell RNA Sequencing Reveals Heterogeneity of Myf5‐Derived Cells and Altered Myogenic Fate in the Absence of SRSF2

“…On the other hand, we designed the Mesen_3 subcluster as dermal fibroblasts because Foxd1 was enriched, and Foxd1 ‐expressing progenitors contributed to dermal fibroblast population. [ 24 ] It is clear that loss of SRSF2 forced mesenchymal cell progenitors to change cell fate from skeletal muscle fibroblasts to the dermal fibroblasts. Moreover, differential gene expression analysis further revealed that expression of major components of extracellular matrix (ECM) Postn , CD44 , Ndn , and Col4a1 were significantly decreased in the Mesen_1 subcluster, indicating that the functional ECM production was severely damaged in the mutant muscles.…”

“…This randomly dispersed pattern was companied by drastically impaired myogenesis and exhaustion of MPCs in the mutant mice. scRNA‐seq analysis revealed that almost 50% of Myf5‐drived cells contributed to the Mesen population, and subclustering analysis of this population confirmed that Foxd1 ‐enriched dermal fibroblasts [ 24 ] were abundant in the mutant mice at the expense of Thbs4 / Col3a1 ‐enriched skeletal muscle fibroblasts. These findings indicated that loss of SRSF2 also severely impaired development of mesenchymal cells surrounding muscle cells.…”

Contact Guidance of Connective Tissue Fibroblasts on Submicrometer Anisotropic Topographical Cues Is Dependent on Tissue of Origin, β1 Integrins, and Tensin-1 Recruitment

“…Our results demonstrate that on nanogrooves, HDFs and HGFs maintain this difference in adhesion formation, suggesting intrinsic difference within fibroblast response that are most likely due to the tissue of origin. Based on lineage tracing studies and cell separation, , it is becoming clear that embryonic origin of cells and the microenvironment of the tissue they reside in confer distinct properties to them, or ″intrinsic″ characteristics . Intrinsic differences encompass gene expression, epigenetics, signaling molecules, transcription factors, and adhesion .…”

The Role of Myofibroblasts in Physiological and Pathological Tissue Repair

“…These specific cell features help to discriminate fibroblasts from all the above-mentioned wound cells that also express the intermediate filament protein vimentin, an often used "fibroblast" marker in histology (Younesi et al 2021). While vascular endothelial cells (Zhao et al 2021) and circulating CD45-positive cells (fibrocytes, macrophages) (Sinha et al 2018;Chong et al 2019) seem to be possiblebut more exotic-myofibroblast sources in healing and fibrotic skin, different fibroblast types (Chang et al 2002;Jiang and Rinkevich 2018;Rognoni et al 2018;Mascharak et al 2020;Correa-Gallegos and Rinkevich 2021;Walker et al 2021b), adipocytes (Festa et al 2011;Marangoni et al 2015;Shook et al 2018), pericytes, and MSC are among the main contributors to the myofibroblast pool in the skin and other organs (Jiang and Scharffetter-Kochanek 2020;Soliman et al 2021;Yokota et al 2021).…”