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Orgun et al. Regenerative mechanisms of adipose-derived stem cells

A fraction of these studies initiated by plastic surgeons due to their paracrine abilities. [26]
attempt to utilize the angiogenic potential of ASCs
primarily to introduce effective treatment modalities There are also several studies which investigated
for debilitating chronic wounds. ASCs have shown the effects of ASCs administration on renovascular
to induce angiogenesis and increase the survival diseases. Administration of ASCs in pigs with renal
of ischemic tissues in these preclinical studies. The artery stenosis restored renal hemodynamics
exact mechanisms for these phenomena are not well and function. In addition, increased VEGF levels,
established, but it is suggested that the release of pro- angiogenesis promotion and normalized vessel
angiogenic growth factors by ASCs could be mainly diameters were observed in the renal tissue. [27]
responsible.
In our recent studies, we have also acquired results
There is also evidence that ASCs could integrate into which convinced us that growth factor secretion by
tubular structures in vivo and express CD31, a marker ASCs is quite important. Our group has demonstrated
for endothelial cells. [22] However, there is no evidence that the osteogenic regeneration potential of ASCs
that ASCs could directly differentiate into proper combined with platelet rich plasma (PRP) was greater
endothelium or fully functional blood vessels. than ASCs alone. [28] In vitro studies showed that ASCs
increased concentrations of transforming growth
Suga et al. [23] implanted green fluorescent protein (GFP) factor beta-1 (TGF-β1), VEGF, IGF-1 and HGF when
expressing ASCs into ischemic inguinal fat pads of mice co-cultured with PRP. We concluded that improved
in order to investigate their fate. They found out that osteogenesis could be related to increased growth
although the transplanted ASCs gradually diminished factor secretion. Moreover, co-administration of ASCs
after implantation, there was less tissue atrophy and with basic fibroblast growth factor (bFGF) on murine
higher vascular density in the ASC treated group ischemic hindlimbs resulted in increased angiogenesis
compared with control. Tissue expression of vascular and the enhancement of blood flow to the ischemic
endothelial growth factor (VEGF) and hepatocyte limb. Secretion of several angiogenic growth factors
growth factor (HGF) were also found to be higher. was enhanced with bFGF, suggesting that a possible
positive feedback mechanism might be responsible for
Several studies on cardiac regeneration also revealed the enhancement of blood flow to the ischemic limbin
the importance of paracrine secretions of ASCs. this study. [29]
Sadat et al. [13] documented that ASCs have
cardioprotective effects via secretion of insulin like growth External changes in physiological factors also seem
factor-I (IGF-I) and VEGF. Another study by Cai et al. [24] to be influencing the paracrine abilities of ASCs.
suggests that the improvement seen with the Rehman et al. [30] demonstrated that, when cultured in
administration of ASCs after myocardial infarction (MI) hypoxic conditions, VEGF secretion of ASCs increases
is not due to the cardiomyocyte differentiation of ASCs by 5-fold. The conditioned media obtained from ASCs
but due to their ability to augment angiogenesis by cultured in hypoxic conditions are found to be superior
paracrine mechanisms. They showed that the density in enhancing endothelial cell growth compared
of newly formed vessels in the developing infarct was with media obtained from ASCs cultured in normal
significantly higher in the group treated with ASCs. conditions. This might be due to an increased secretion
This is supported by the results of another study which of growth factors by ASCs in hypoxic conditions.
demonstrated that the post-MI administration of ASCs
augmented vessel density and prevented abnormal The effects of ASCs transplantation on flap viability have
remodeling of the infarct area in pigs. [25] Transplanted also been investigated in detail. Suartz et al. has
[32]
[31]
ASCs failed to stay engrafted in the myocardium, showed that ASCs injection increased the viability of
suggesting that their indirect paracrine effects could be random pattern dorsal skin flaps in rats. This application
responsible for the improved outcome. also seems to increase the viability of interpolation
flaps and reduce the time until pedicle division, due
Another study showed that ASCs implanted in ischemic to increased vascularity of the flap. [33] Our group also
hind limb of mice neither differentiate into endothelial demonstrated that ASCs treatment improves the
cells nor integrate into the host capillary vasculature, survival of flaps with venous congestion or provides
however promote angiogenesis and formation of protection against ischemia-reperfusion injury. [34]
collateral vessels with amplified angiogenic signals Moreover, when the ASCs were preconditioned in
(via VEGF/mTOR/Akt pathway). Similarly, these cells hypoxic conditions then implanted to skin flaps, they
show low survival rates when implanted, which once were shown to increase flap survival. This phenomenon
again supports that the regenerative effects could be is thought to be due to the increased release of VEGF
Plastic and Aesthetic Research ¦ Volume 4 ¦ March 22, 2017 35