Published online Feb 26, 2022. doi: 10.4252/wjsc.v14.i2.200
Peer-review started: February 23, 2021
First decision: April 20, 2021
Revised: May 1, 2021
Accepted: February 15, 2022
Article in press: February 15, 2022
Published online: February 26, 2022
The successful anti-fibrotic effect of clinical fat grafting has been described extensively in literature. However, the mechanisms leading to fibrosis and how adipose-derived stomal cells (ADSCs) can interact with these mechanisms to reduce fibrosis, are far from clarified today.
Fibrosis is increasingly recognized as an important cause for morbidity and mortality. Moreover, the increasing clinical use of radiotherapy results in an enhanced incidence of severe tissue damage by fibrosis. Therefore, an efficient anti-fibrotic treatment and a thorough understanding of its mechanism-of-action is mandatory.
The objective of this systematic review was to obtain an in-depth understanding of the complex mechanisms underlying fibrosis, and more specifically, the potential mechanisms-of-action of ADSCs in realizing their anti-fibrotic effect.
This systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) methodology. We clearly defined a set of objectives with pre-defined eligibility criteria. We performed a thorough and disciplined literature search to obtain all relevant studies that met the eligibility criteria.Each citation is associated with a set of Mesh terms that describe the content.
Systematic assessment of available literature was performed by two reviewers and one control to avoid bias. This process resulted in 80 references cited as reported in the PRISMA flow diagram. These references served as basic scientific platform to investigate the previously mentioned research objectives. Due to some contradictory findings in the molecular balances, we performed a supplementary literature search trying to elucidate some of the more specific mechanisms-of-action. This review has shown that the understanding of the complex interaction between extracellular matrix (ECM) accumulation, immune response and vascularization, is vital for the effectiveness of treatments against fibrosis, like fat grafting.
ADSCs have the ability to interact intensively with the healing environment via multiple mechanisms of action. Through their capacity to directly differentiate into key cell types that influence the wound healing process, as well as secrete multiple paracrine factors, ADSCs meticulously alter distinctive mechanisms underlying fibrosis. ADSCs stimulate ECM degradation by modifying the fibroblast-to-myofibroblast differentiation, by favoring matrix metalloproteinase over tissue inhibitors of metalloproteinases, by positively influencing collagen organization, and by inhibiting the pro-fibrotic effects of transforming growth factor-beta 1. In addition, ADSCs influence both the innate and adaptive immune response system. The pro-angiogenic effect of ADSCs exerted by direct differentiation into ECs, as well as by the secretion of pro-angiogenic cytokines such as stromal cell-derived factor-1 and vascular endothelial growth factor. ADSCs intelligently steer these molecular balances in a delicate manner. It is by these synergistic actions that ADSCs injected through fat grafts successfully soften fibrotic scars.
This thorough systematic review describes the intensive and cross talk of ADSCs with surrounding cells and active molecules all having a significant effect on the outcome of fibrosis. This manuscript invites to further research to unravel the complex interactions of ADSCs and the seemingly contradictory effects depending on time and place of occurrence.