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Page 4 of 8 Kim et al. Plast Aesthet Res 2018;5:31 I http://dx.doi.org/10.20517/2347-9264.2018.26

teins, enzymes and various cytokines that jointly facilitate dermis restoration. Finally, the fibroblasts adopt
a contractile myofibroblast phenotype during the remodeling phase which inter alia replaces immature col-
lagen III into contractile collagen I fibres forming the ultimate scar.

ASCs are a natural component of the subcutaneous adipose tissue that lies in immediate proximity to cuta-
neous wounds and takes part in the delicate physiological course of wound healing. Due to their migratory
[18]
ability ASCs also are believed to infiltrate the wound and thereby additionally foster wound repair .
First of all, the abundant secretome of ASCs may orchestrate wound healing in a paracrine fashion. Nearly
all growth factors that participate in cutaneous wound healing including keratinocyte growth factor, hepa-
tocyte growth factor, epidermal growth factor, members of the vascular endothelial growth factor (VEGF)
family, basic fibroblast growth factor (bFGF), platelet-derived growth factor-BB, insulin-like growth factor-1
and key enzymes such as matrix metallothioneine-9 (MMP-9) and many more are secreted by ASCs [19-21] .
Without going into detail, the mentioned soluble factors instigate fibroblast and keratinocyte migration,
proliferation and differentiation. The literature also suggests ASCs to attenuate inflammation by secretion of
[22]
soluble factors such as interleukin-10 and other cytokines implicated in leukocyte action . Thereby, ASCs
also may exert beneficial effects on cutaneous diseases or wounds such as non-healing ulcers that involve a
pathologically pro-longed inflammatory state.

In addition to their remarkable secretome, ASCs are known to directly differentiate into keratinocytes and
fibroblasts to regenerate epidermal and dermal layers that further promote cuntaneous wound repair in
vitro [23,24] . However, until the afore-mentioned experimental in vitro studies are supported by further inves-
tigation in a proper in vivo model, there is no firm evidence for a physiological differentiation of ASCs into
keratinocytes that would allow a translation into the clinical context. ASCs also appear to have an impact
on fibroblasts although the evidence is scarce. In vitro studies indicated an increase in fibroblast prolifera-
[25]
tion by direct cell-to-cell contact with ASCs but also by soluble factors released by ASCs . The authors
observed up-regulation of fibronectin, collagen I, collagen III as well as a down-regulation of MMP-1. The
same authors supported their in vitro findings by additional in vivo experiments, where they found acceler-
ated wound healing in mice by ASC treatment. However, those in vivo observations were of pure descriptive
nature and did not look into the molecular or cellular effect (e.g., ASC-fibroblast interaction) in more detail.

Proper vascularization is of paramount importance to wound healing. Mounting evidence portrays the pro-
angiogenic effect of ASCs, predominantly by release of prominent vasculogenic factors such as VEGF-A and
[26]
bFGF, and differentiation into endothelial cells .

Eventually, through differentiation into myofibroblasts and paracrine modulation of myofibroblast function
[27]
ASCs dynamically influence wound maturation during the remodeling phase .

EXPERIMENTAL DATA ON THE EFFECT OF ASCS IN CUTANEOUS WOUND REPAIR
Particularly in non-healing wounds that experience a depletion of ASCs/impairment of ASC function, the
transplantation of “fresh” ASCs from distant donor sites by fat grafting or stem cell therapy appears to be
[28]
invaluable . But also physiological cutaneous wounds appear to benefit from ASC treatment.
In vitro experiments with simple co-cultures or ASC-derived supernatants have shown that human lipoaspi-
rates and ASCs enhance keratinocyte proliferation, stratification and migration [29,30] . Comparable experi-
mental settings show enhanced fibroblast proliferation with beneficial effects on collagen synthesis and ECM
[31]
remodeling .