Transcription factor 21 (TCF21) promotes proinflammatory interleukin 6 expression and extracellular matrix remodeling in visceral adipose stem cells

Abstract

The visceral (VIS) and subcutaneous (SQ) fat pads are developmentally distinct white adipose tissue depots and contribute differently to inflammation and insulin resistance associated with obesity. The basic helix-loop-helix transcriptional regulator, transcription factor 21 (TCF21), is a marker gene for white adipose tissues and is abundantly expressed in VIS-derived adipose stem cells (ASCs), but not in SQ-derived ASCs. However, TCF21's role in regulating fat depot-specific gene expression and function is incompletely understood. Here, using siRNA-mediated knockdowns and lentiviral gene transfer of in mouse ASCs, we demonstrate that TCF21 is required for the VIS ASC-specific expression of interleukin 6 (IL6), a key cytokine that contributes to the proinflammatory nature of VIS depots. Concurrently, TCF21 promotes MMP-dependent collagen degradation and type IV collagen deposition through the regulation of the extracellular matrix (ECM) modifiers, matrix metalloproteinase (MMP) 2, MMP13, and tissue inhibitor of MMP1 (TIMP1), as well as collagen type IV α1 chain (COL4A1) in VIS ASCs. We also found that although IL6 mediates the expression of and in VIS ASCs, the TCF21-dependent expression of and is IL6-independent. These results suggest that TCF21 contributes to the proinflammatory environment in VIS fat depots and to active ECM remodeling of these depots by regulating IL6 expression and MMP-dependent ECM remodeling in a spatiotemporally coordinated manner.

Concise Review: Adipose-Derived Stem Cells (ASCs) and Adipocyte-Secreted Exosomal microRNA (A-SE-miR) Modulate Cancer Growth and proMote Wound Repair

“…As reported in a study by Akama et al [91] they found that IL6 mediates the expression of Mmp13 and Timp1 in visceral fat derived-ASCs and the TCF21-dependent expression of Mmp2 and Col4a1 is IL6-independent. The basic helix-loop-helix transcriptional regulator, transcription factor 21 (TCF21), is a marker gene for white adipose tissues and is abundantly expressed in visceral-derived ASCs.…”

Fibro-Adipogenic Remodeling of the Diaphragm in Obesity-Associated Respiratory Dysfunction

“…FAPs from HFD-fed mice were nonetheless qualitatively different, exhibiting elevated expression of specific adipocyte-related genes. Tcf21, a WAT marker (42), recently shown to be enriched in visceral adipose stem cells (38), was induced in FAPs with HFD feeding, as was Il6, a TCF21-regulated gene (38). HFD feeding also upregulated FAP-specific expression of Ucp1, corresponding with presence of scattered UCP1 + unilocular Figure 5-Isolated FAPs demonstrate obesity-induced fibrotic gene expression signature, with increased ex vivo proliferation and collagen deposition.…”

“…Those allocated for adipogenesis were cultured for 5 days (reaching full confluence), then switched to standard medium plus adipogenic cocktail (1 mg/mL insulin, 250 nmol/L dexamethasone, 10 mmol/L troglitazone, and 10 nmol/L triiodothyronine) for 7 days, and then switched to standard medium plus insulin (1 mg/mL) for 3 days. After each experiment, cells were fixed, blocked, and immunostained as previously described (38). For Ki67 staining, wash buffers and antibody diluents contained 0.2% Tween-20.…”

Distinct fibroblast functional states drive clinical outcomes in ovarian cancer and are regulated by TCF21

“…TCF21 is expressed in epicardial progenitor cells that give rise to coronary artery smooth muscle cells and cardiac fibroblasts ( Nurnberg et al, 2015 ), the latter of which are a source of activated myofibroblasts in the infarcted heart ( Kanisicak et al, 2016 ). TCF21 is also a marker for white adipose tissue and is abundantly expressed in visceral fat-derived stem cells ( Akama and Chun, 2018 ). When we overexpressed TCF21 in FAP-high CAFs, our results indicated that TCF21 on its own can significantly dampen the ability FAP-high CAFs to promote gel contraction, invasion, chemoresistance, and in vivo tumor growth.…”