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to TGF‑b as well as solutions that decrease the activity   availability  and fewer  ethical  issues,  adult stem  cells are
          of connexin 43, a mediator of TGF‑b signaling,  has been   the  most commonly used type of stem  cells in  medical
          shown  to  reduce the  inflammatory  response  and scar   practice.
          formation. [85,86]  Evidence of success using TGF‑b‑related   Mesenchymal  stem  cells are  derived from  bone  marrow,
          strategies  was provided by  a study  showing  that   adipose tissue, umbilical cord, periosteum,  tendons,
          the  exogenous addition to wounds of fibromodulin,   muscle  and skin.   The  most  commonly  used  source
                                                                              [96]
                                       [87]
          a TGF‑b modulator, reduces scar.  Decorin is a small   is  adipose tissue.  Stem  cells affect all stages  of wound
          chondroitin/dermatan sulfate proteoglycan that limits  the   healing.  They have significant  anti‑inflammatory  and
          duration of TGF‑b influence on inflammation  and tissue   immunomodulatory  effects  in  the  inflammation  phase of
          repair, promoting regenerative  repair and limiting  tissue   healing.   In  the  proliferative  phase,  they  also stimulate
                                                                     [97]
          fibrosis.  Other novel strategies include the application   fibroblasts, keratinocytes  and endothelial cells, thereby
                 [88]
          of antifibrotic human recombinant growth factors    accelerating wound  closure. Uysal  et  al.  demonstrated
                                                                                                 [98]
          and  cytokines, anti‑inflammatory substances, protease   that wound healing time  was reduced in rats treated
          inhibitors and molecules that interfere with profibrotic   by  patchy  skin  grafts  and mesenchymal  stem  cells.  In
          cytokine function (e.g.  TGF‑b) and collagen synthesis  at   addition, wound contraction was reduced, angiogenesis
          the wound site. [89]                                was increased, epithelialization progressed rapidly. [99]

          FETAL WOUND HEALING                                 Stem  cell therapy can be  administered either  topically
                                                              or systemically.  Falanga  et  al. [100]   demonstrated  a  topical
                                                              application of  mesenchymal  stem  cells with  either
          Fetal wound healing is an area of great interest because it   fibrinogen or thrombin applied to chronic wounds in the
          is characterized by scar‑less, regenerative wound healing.   form of a spray. This spray is converted into a gel form
          This process is age‑dependent, like postnatal healing,   over the wound and helps in retaining  the stem cells
          wounds in third‑trimester  cause scarring.  The exact   over the wound. [100]  To improve the retention  of stem
                                               [90]
          mechanism  responsible  for scar‑less healing  in  the  first   cells in the wound, cells are now applied on an adequate
          and second trimesters  is  not  yet  clearly understood. The   support/scaffold‑like collagen, skin substitutes. This helps
          proposed mechanisms  include decreased inflammation,   in maintaining  the viability  of the cells and facilitates
          unique  properties of fetal cells, altered cytokine milieu,   migration in the wound bed. [101]
                                                  [91]
          variable  gene  expression  and ECM  deposition.   Recent
          fields of research revolve around the role of TGF, IL‑10 and   CONCLUSION
          mast cells. King et al.  described a major role for IL‑10 in
                            [92]
          scar‑less wound healing. The authors propose a “cytokine   Cutaneous  wound healing  is  a  complex and dynamic
          hypothesis” centered on the anti‑inflammatory properties   biological process requiring the interaction and

          of IL‑10. IL‑10 protects against excess deposition of   coordination of many  different  cell types  and molecules,
          collagen, maintains elevated hyaluronic levels, enhances   including growth factors and cytokines. Tremendous
          fibroblast  function,  prevents  differentiation  of fibroblast   strides  have  been  made  in  delineating  the  myriad  of
          to myofibroblasts and increases survival of endothelial   factors involved in  normal  and  delayed/excessive  healing.
          progenitor cells and angiogenesis.  Research in a mouse   However,  this  increased understanding  has not led to
                                       [92]
          model demonstrated the scarring potential of mast cells in   significant  advances in  patient  care.  Administration  of
          fetal wounds. In early fetal life (day 15), scar‑less wounds   exogenous growth factors and cytokines has shown
          were  associated with  a  lesser  number  of mast  cells with   promise in improving healing results in wounds. As wound
          reduced degranulation as compared to later scarring   healing involves multiple molecular mechanisms, no single
          wounds.  Another factor implicated in  fetal wound   agent therapy is likely to be successful in accelerating or
                 [93]
          healing is the growth factor TGF‑b. Of the three isoforms,   modulating wound healing.
          TGF‑b1 is responsible  for fibrosis.  TGF‑b3 isoform is the
          predominant  isotype in  fetal wound healing,  and altered   Financial support and sponsorship
          profiling  of the  isoform  may  be  a  factor responsible  for   Nil.
          scarless healing. Other additional  mechanisms include   Conflicts of interest
          mediators  of TGF pathway such as  connective tissue   There are no conflicts of interest.
          growth factor, proteoglycan, decorin and P311. [94]
                                                              REFERENCES
          ROLE OF STEM CELLS IN WOUND
          HEALING                                             1.   Singer AJ, Clark RA. Cutaneous wound healing. N Engl  J Med 1999;341:738‑46.
                                                              2.   Enoch S, Grey JE, Harding KG. Recent advances and emerging treatments.
                                                                  BMJ 2006;332:962‑5.
          Stem cells are a specialized group of cells with the potential   3.   Guo  S, Dipietro  LA. Factors affecting wound healing.  J  Dent Res
          for self‑renewal, as well as the ability to differentiate into   2010;89:219‑29.
          various cell lineages. Stem cells can be classified according   4.   Köse O, Waseem A. Keloids and hypertrophic scars: are they two different
          to their origin  (embryonic,  fetal and adult) or based on   sides of the same coin? Dermatol Surg 2008;34:336‑46.
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                                                                  Plastic Surgery: Craniofacial, Head and Neck Surgery and Pediatric Plastic
          multipotent  and unipotent).  Due to the ease  of       Surgery. 3rd ed. Vol. 3. Philadelphia: Saunders; 2012. p. 240‑66.
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