FGF2-induced effects on transcriptome associated with regeneration competence in adult human fibroblasts

Abstract

BackgroundAdult human fibroblasts grown in low oxygen and with FGF2 supplementation have the capacity to tip the healing outcome of skeletal muscle injury – by favoring regeneration response in vivo over scar formation. Here, we compare the transcriptomes of control adult human dermal fibroblasts and induced regeneration-competent (iRC) fibroblasts to identify transcriptional changes that may be related to their regeneration competence.ResultsWe identified a unique gene-expression profile that characterizes FGF2-induced iRC fibroblast phenotype. Significantly differentially expressed genes due to FGF2 treatment were identified and analyzed to determine overrepresented Gene Ontology terms. Genes belonging to extracellular matrix components, adhesion molecules, matrix remodelling, cytoskeleton, and cytokines were determined to be affected by FGF2 treatment.ConclusionsTranscriptome analysis comparing control adult human fibroblasts with FGF2-treated fibroblasts identified functional groups of genes that reflect transcriptional changes potentially contributing to their regeneration competence. This comparative transcriptome analysis should contribute new insights into genes that characterize cells with greater regenerative potential.

Fibroblast Growth Factor 2 as an Antifibrotic: Antagonism of Myofibroblast Differentiation and Suppression of Pro-Fibrotic Gene Expression

“…Coupled with the in vitro data, it appears that one of the mechanisms by which FGF2 inhibits fibrosis in vivo may be via JNK-dependent activation of HGF [111]. Other reports have indicated that FGF2 upregulates HGF expression in fibroblasts as well, suggesting a degree of generality to this relationship [104, 110]. HGF has recently been implicated in the scarless wound healing phenotype of human oral mucosa fibroblasts, as knockdown of HGF was sufficient to sensitize oral mucosa fibroblasts to activation by TGF-β [112].…”

“…FGF2-treated fibroblasts demonstrated decreased expression of transcripts encoding collagen I , collagen III, α-SMA, and the interstitial collagenase MMP-1 [104]. MMP-1 has also been demonstrated to be sensitive to FGF2 stimulation in varied cell types including osteoblasts and osteoblast-enriched calvariae [105–107] and smooth muscle cells [108], alongside additional reports in fibroblasts [109, 110]. MMP-1 degrades interstitial collagen fibrils, including those of type I collagen, which is deposited in large quantities during the process of fibrosis.…”

“…Our lab demonstrated, in a transcriptome-wide analysis, a similar shift in the gene expression of FGF2-treated adult primary human dermal fibroblasts to a less fibrotic profile. This shift included dysregulation of a substantial number of genes involved in inflammation, cytokine signaling, extracellular matrix deposition, and cytoskeletal activity, processes intimately involved in the development and maintenance of fibrosis at the cellular and tissue levels [110]. Specifically, exogenous FGF2 resulted in a substantial downregulation of expression of the pro-fibrotic cytokine interleukin 6 (IL-6), a finding that has also been described elsewhere, though this activity appears to be context-dependent and/or cell type-specific [119–122].…”

Minireview: Syndecans and their crucial roles during tissue regeneration

“…For example, FGF-2 stimulates fibroblast proliferation [73] and keratinocyte migration [74] in skin, while FGF-6 is increased and contributes to repair in injured skeletal muscle [75,76]. For example, FGF-2 stimulates fibroblast proliferation [73] and keratinocyte migration [74] in skin, while FGF-6 is increased and contributes to repair in injured skeletal muscle [75,76].…”

Targeting the Achilles’ heel of drug-resistant cancer stem cells

“…Aside from cancer, αvβ3 has been implicated in adult tissue regeneration and remodeling 5 , 6 . Differential expression of αvβ3 has been reported during angiogenesis, organ development, and wound healing 7 .…”