Insights into Fibroblast Plasticity

Verteporfin inhibits the persistent fibrotic phenotype of lesional scleroderma dermal fibroblasts

“…Microarrays were conducted, essentially as previously described (Guo et al 2011; Tsang et al 2020), at the London Regional Genomics Centre using Affymetrix GeneChip Mouse Gene 2.0 ST arrays (Affymetrix, Santa Clara, CA). DAVID Functional Annotation Software version 6.7 (https://david.ncifcrf.gov) was employed for cluster analysis.…”

“…Myofibroblasts are characterized by the presence of actin stress fibers, allowing for contraction of the ECM (Tomasek et al 2002; Schulz et al 2018; Hinz et al 2019). In fibrotic conditions, including scleroderma, myofibroblasts are persistent, as they stably differentiate from a fibroblast‐derived progenitor‐like cell, often called a fibroadipogenic precursor (Shi‐wen et al 2012; Xu et al 2009; Tsang et al 2020). It is the persistence of this cell type and the presence of highly‐crosslinked, collagen‐rich scar tissue that produces an autocrine proadhesive signaling loop that perpetuates the fibrotic phenotype, including that of lesional SSc fibroblasts (Schulz et al 2018; Parapuram et al 2011).…”

“…CCN2, a matricellular protein, is a non‐structural ECM component that interacts with signaling molecules, constituents of the ECM, and cell surface receptors, including integrins, to regulate a variety of cellular processes including adhesion, migration and proliferation (Leask 2020). Over‐expression of CCN2 has been observed in various fibrotic disorders; CCN2 is required for differentiation of fibroblast‐derived progenitor cells into myofibroblasts, therefore targeting fibroblast‐specific expression of CCN2 is considered a bona fide antifibrotic therapeutic approach (Tsang et al 2020; Leask 2020; Makino et al 2017; Liu et al 2013). Intriguingly, fibroblast‐specific deletion of CCN2 had no significant impact on normal cutaneous wound repair (Liu et al 2014).…”

CCN2 (Cellular Communication Network factor 2) in the bone marrow microenvironment, normal and malignant hematopoiesis

“…As described above, CCN2 enhances differentiation of cultured human BM MSCs into (myo)fibroblasts when stimulated subsequently with TGF‐β (Lee et al 2010). CCN2 is required for the differentiation of progenitor cells into contractile myofibroblasts through the regulation of extracellular matrix, cytoskeleton, cell adhesion, and cell migration genes, at least in dermal fibroblasts, as well as for the recruitment of progenitor cells to the fibrotic lesion in response to bleomycin, as has been shown by two different mouse models (Liu et al 2014; Tsang et al 2020; Liu et al 2014). Another mouse fibrosis model has shown that either CCN2 mRNA or an application of exogenous CCN2 protein seems required for the development of persistent fibrosis (Mori et al 1999).…”

Breathe, breathe in the air: the anti-CCN2 antibody pamrevlumab (FG-3019) completes a successful phase II clinical trial for idiopathic pulmonary fibrosis

“…However, it has awaited the generation of genetically modified mice to definitively demonstrate that expression of endogenous CCN2 plays a direct role in experimental lung and scleroderma fibrosis (Liu et al 2011; Parapuram et al 2015; Makino et al 2017) as well as skeletal muscle and the kidney (Kinashi et al 2017; Petrosino et al 2019). CCN2 appears to be essential for activation of fibroblasts to myofibroblasts, the critical effector cells of fibrosis, likely via progenitor cell intermediates (Tsang et al 2019). Collectively, these data, again, contradict the analyst’s aforementioned report that CCN2 has no role in fibrosis.…”