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

tissue ischemia and fibrosis. [50] The ischemia is due It is being more widely acknowledged that ASCs have
to inadequate vasculature and incompetent vessels in revitalizing effects on stem-cell depleted tissues such
irradiated tissues. The radiated skin shows erythema, as radiation wounds or ischemic fibrotic tissues. [57,58]
teleangiectasia, abnormal pigmentation and dermal Administration of ASCs seems to improve vascularity
atrophy. Once a radiation wound is developed, it and healing capacity for these morbid conditions. This
becomes more and more complicated with necrosis, matter is very promising since there are currently no
infection, and fibrosis. [51] These chronic radiation effective treatments for these conditions.
injuries however could improve by sufficient blood
supply to the tissues since it is a well known fact that THE SYNERGISM BETWEEN ASCS AND
the microvasculature is of utmost importance for proper MACROPHAGES AND THE IMMUNE
wound healing.
REGULATORY EFFECTS OF ASCS
ASCs therapy is promising for the treatment of such Another recent focus of interest on ASCs research
wounds. ASCs residing in the irradiated tissue are is the cells’ relation to immunomodulation. [59] Like
susceptible to radiation injury, [52] but can survive in any other cell, ASCs interact with other cells, and
an irradiated tissue if implanted after the radioactive especially their relations with macrophages have
insult. ASCs administration leads to improved blood recently become a topic of interest. It is known that
perfusion, capillary density and VEGF levels in there are two macrophage subsets; the M1 phenotype
irradiated wounds. [22] Viability of irradiated skin flaps which has pro-inflammatory properties, and the M2
increased when treated with ASC injection in correlation phenotype which has anti-inflammatory effects on
with increased vascularity in the flaps injected with tissue. ASCs are shown to interact especially with
ASC. [53] At cellular level, ASCs were shown to stimulate the M2 subset. [60,61] M2 macrophage activation by the
fibroblast proliferation and increase the expression of interaction with ASCs improves the volume retention
several cytokines such as interleukin-6 (IL-6), bFGF of fat grafts by stimulating angiogenesis. [62] As an
and VEGF secreted by fibroblasts after radioactive explanation of this observation, gene expression of
insult. [54]
several angiogenic cytokines, such as VEGF, HGF,
bFGF, and stromal cell-derived factor-1 were found
The literature is rich in terms of clinical applications to be increased in the macrophages cultured in ASCs
of ASCs to cure radiation injury. Akita et al. [55] injected
ASCs to the chronic radiation wounds of 10 patients conditioned media. Additional studies documented that
who received adjuvant radiotherapy after mastectomy. the host macrophage depletion significantly impairs
Autologous ASCs with human recombinant bFGF ASCs mediated angiogenesis and ASCs mediated
on an artificial dermis were applied on debrided angiogenesis can be prevented with monoclonal
radiation wounds of patients. It is known that MSCs antibody mediated blocking of IL-10 (a cytokine
[63]
are resistant to radiation. The angiogenic growth factor product of macrophages). It was also suggested that
bFGF has proved to be very effective for patients M2 macrophages play an important role in the ASCs
[47]
with severe wounds. Human recombinant bFGF is mediated lymphangiogenesis. Taken together,
clinically approved and widely used for the treatment these findings support the hypothesis that an existing
of chronic wounds in Japan. Artificial skin substitutes association with ASCs and might be an important
provide a favorable environment for both internal and regulator of angiogenesis [Figure 2].
external cells and growth factors. This combination
treatment led to complete healing of radiation wounds, In addition, it was demonstrated that ASCs inhibit and
lasting at least more than 1.5 years. In a similar study, decrease inflammatory cytokines and increase IL-10
Rigotti et al. [56] investigated the effects of lipoaspirate levels in vivo by acting on macrophages. [64] This suggests
administration into the radiation wounds of 20 patients that ASCs might have immunomodulatory effects by
who received adjuvant radiotherapy after mastectomy regulating pro-inflammatory cytokine concentrations in
or quadrantectomy for breast cancer. Dramatic the inflamed tissue. It is most likely due to this effect
improvement of symptoms and complete healing of the that ASCs transplantation in dystrophic muscles of
wound was observed in all patients. This improvement dystrophin-deficient mice improved muscle strength
is believed to be due to the proangiogenic paracrine and resistance to fatigue. [65] It was also documented
effects of ASCs present in the lipoaspirate. Despite that ASCs transplantation induces macrophage
the encouraging clinical results, it should be noted migration and the secretions of ASCs are dependent
that neither of these studies included a patient group on inflammatory cells. [66]
without treatment for comparison. Future studies with
randomized subjects are necessary for a higher level There are other studies regarding the interaction
of evidence. between ASCs and fibroblasts in the literature.
Plastic and Aesthetic Research ¦ Volume 4 ¦ March 22, 2017 37