Anti-fibrotic effect of adipose-derived stem cells on fibrotic scars

BACKGROUND: Sustained injury, through radiotherapy, burns or surgical trauma, can result in fibrosis, displaying an excessive deposition of extracellular matrix (ECM), persisting inflammatory reaction, and reduced vascularization. The increasing recognition of fibrosis as a cause for disease and mortality, and increasing use of radiotherapy causing fibrosis, stresses the importance of a decent anti-fibrotic treatment. AIM: To obtain an in-depth understanding of the complex mechanisms underlying fibrosis, and more specifically, the potential mechanisms-of-action of adipose-derived stomal cells (ADSCs) in realizing their anti-fibrotic effect. METHODS: A systematic review of the literature using PubMed, Embase and Web of Science was performed by two independent reviewers. RESULTS: The injection of fat grafts into fibrotic tissue, releases ADSC into the environment. ADSCs’ capacity to directly differentiate into key cell types (e.g., ECs, fibroblasts), as well as to secrete multiple paracrine factors (e.g., hepatocyte growth factor, basis fibroblast growth factor, IL-10), allows them to alter different mechanisms underlying fibrosis in a combined approach. ADSCs favor ECM degradation by impacting the fibroblast-to-myofibroblast differentiation, favoring matrix metalloproteinases over tissue inhibitors of metalloproteinases, positively influencing collagen organization, and inhibiting the pro-fibrotic effects of transforming growth factor-β1. Furthermore, they impact elements of both the innate and adaptive immune response system, and stimulate angiogenesis on the site of injury (through secretion of pro-angiogenic cytokines like stromal cell-derived factor-1 and vascular endothelial growth factor). CONCLUSION: This review shows that understanding the complex interactions of ECM accumulation, immune response and vascularization, is vital to fibrosis treatments’ effectiveness like fat grafting. It details how ADSCs intelligently steer this complex system in an anti-fibrotic or pro-angiogenic direction, without falling into extreme dilation or stimulation of a single aspect. Detailing this combined approach, has brought fat grafting one step closer to unlocking its full potential as a non-anecdotal treatment for fibrosis.