Adipocytic Progenitor Cells Give Rise to Pathogenic Myofibroblasts: Adipocyte-to-Mesenchymal Transition and Its Emerging Role in Fibrosis in Multiple Organs

Abstract

Purpose of review: Adipocytes have recently been shown to be able to reprogram to a myofibroblastic phenotype in a process termed adipocyte mesenchymal transition (AMT). This review seeks to discuss the relevance of this process to disease and explore its mechanisms.

Recent findings: AMT occurs in multiple organs and diseases, transdifferentiation goes through a precursor cell and there is a reversible process that can be influenced by metabolic stress, myeloid cells, immune dysregulation, and pharmacological intervention. AMT is a newly appreciated and highly relevant process in multiple forms of fibrosis. Targeting AMT may serve as a novel method of treating fibrosis.

Keywords: Adipocyte; Adipose mesenchymal transition; Fibroblast; Fibrosis; Myofibroblast; Scleroderma.

Fig. 1

Schematic of cellular mechanism of adipocyte-mesenchymal transition (AMT). In response to fibrotic stimuli (TGF-ß, Wnts, Hypoxia, etc.), adipocytic cells downregulate adipogenic gene expression including PPAR-γ. In the absence of these signals, fibrotic pathways become predominant and lead this cell to undergo cellular reprogramming and change morphology. These cells can either transition to a preadipocyte/mesenchymal progenitor cell or directly to a myofibroblast phenotype. This process is reversible in some circumstances. Below, adipocytes (marked by perilipin staining, purple) were treated with TGF-ß. After 24 h, these cells begin transitioning as marked by smooth muscle actin (α-SMA staining, red) in cells also expressing perilipin. By 72 h, these cells have completed the transition to a myofibroblastic phenotype as marked by prominent expression of α-SMA+-stress fibers with substantial loss of perilipin

Fig. 2

Loss of dermal white adipose tissue (dWAT) and replacement with collagen in systemic sclerosis (SSc). Skin biopsies from healthy control (left) and patient with diffuse cutaneous SSc and active disease (right) stained for H&E. In contrast to control in which there are multiple areas of dense healthy adipocytic tissue, in SSc, there is almost complete loss of dWAT and replacement with fibrous matrix. Note smaller adipocytes (solid arrow) and remnants of adipocytes without nuclei (dashed arrow) surrounded by inflammatory infiltrate forming crown-like structures (arrowhead). Bars = 500 μm (insets = 100 μm)

Fig. 3

Mature intradermal adipocytes undergo phenotypic transition to myofibroblast through adipocyte-mesenchymal transition (AMT). Adiponectin-Cre transgenic mice were crossed with Ai14 (tdTomato, tdT]) reporter mice to generate progeny expressing tdTomato fluorescent protein restricted to mature adipocytes (left panel). To trace the fate of intradermal adipocytes during fibrosis, mice were given subcutaneous injections of bleomycin (middle and right panels). Confocal imaging of tdT (red) and immunostained skin for perilipin (white) and α-smooth muscle actin (α-SMA, green) demonstrated that tdT+ cell change morphology from adipocyte to fibroblast, no longer co-stain with adipocyte marker perilipin and co-localize with myofibroblast marker α-SMA. Hoechst 33342 (blue) counterstained