It is with great interest that we reviewed the paper by Hong et al. [1] entitled ‘Topically Delivered Adipose Derived Stem Cells Show An Activated-fibroblast Phenotype And Enhance Granulation Tissue Formation In Skin Wounds‘.
Improving wound healing remains a great challenge and is of utmost importance with an aging population and an ever increasing number of patients with difficult to heal wounds such as diabetic ulcers, vascular ulcers and pressure sores. We agree with the authors that cell therapies offer potential for stimulating various phases of wound repair. The authors have well described the various phases of wound healing, focusing particularly upon granulation tissue production. It is important to note however that from a clinical perspective, epithelialisation is often the definitive factor required for complete healing. As a result, primary endpoints in most clinical wound healing studies generally relate time to closure and/or reduction of wound surface area. Unfortunately topically applied ASCs did not promote epithelialisation over controls bringing in to question their immediate therapeutic potential.
Somewhat unexpected we read that dermal fibroblasts did not enhance wound healing in the animal experiments by Hong et al.. Unfortunately and despite a variety of experimental reports and multiple randomized clinical studies using fibroblast based substitutes for the promotion of hard to heal wounds [2,3], the authors did not elect to elucidate on this. Biosynthetic materials such as Dermagraft® (Advanced BioHealing, Inc., La Jolla, California)(allogeneic neonatal fibroblast cultured in a polyglactin mesh) have demonstrated promising in vitro results supporting keratinocyte adherence and migration [4,5]. Subsequently numerous clinical trials in both venous as well as diabetic ulcers have shown a statistically significant improvement over standard therapy leading to FDA approval.
Fibroblast source and characterization may be a reason for the negative results observed by Hong et al. The authors have focused on a smooth muscle expressing cell type. It is however important to note that this fibroblast type has been most strongly linked to wound contracture as opposed to regenerative wound healing [6]. Furthermore the authors relate that fibroblasts are poorly characterized. There is however an increasing number of reports characterizing subpopulations of fibroblasts and emerging evidence has demonstrated a diversity of fibroblasts in the dermis as well other tissues. We have previously reported on the importance of fibroblast subtypes especially in evolving tissue engineering cell based wound healing strategies [7]. While spindle shaped progenitor fibroblast represent the mitogenic subpopulation of dermal fibroblasts, polygonal shaped fibroblasts show senescent associated markers and are therefore termed post mitotic fibroblasts. The latter resemble a growth factor and matrix secreting cell type. Specialized matrix production has been observed in fibroblast seeded polyglactin mesh supporting keratinocyte migration [4, 5]. It is critical to specifically identify and utilize the precise subpopulation of fibroblast introduced into a wound.
Major disadvantages of most cellular based products are production time and cost. While allogeneic products such as Dermagraft offer off the shelf availability, autologous products require lengthy periods of time until sufficient material is generated. Hong et al. used 1 x 105 ASCs for a 7mm wound. If one were to consider the large wound dimensions commonly faced in the problem wound healing clinical arena one would anticipate the need to provide enormous numbers of ASCs. In addition as the authors state, it remains to be investigated how underlying disease like diabetes affect cell growth and the performance of autologous cell based products including ASCs.
Current cell based therapies like cultured keratinocytes and fibroblast based products have demonstrated that to date autologous point of care products are less expensive and easier to implement as compared to stem cell therapies. As with so many technological innovations future potential, production efficiencies and adoption remains promising. Economies of scale will certainly continue to guide our choices. This is an exciting time for the field and with little doubt ASCs will likely play a significant role in that promise.

[1] Hong SJ, Jia SX, Xie P, Xu W, Leung KP, Mustoe TA, Galiano RD. Topically delivered adipose derived stem cells show an activated –fibroblast phenotype and enhance granulation tissue formation in skin wounds. PLOS one 2013, 8, e55640
[2] Marston WA, Hanft J, Norwood P, Pollak R, Dermagraft diabetic foot ulcer group. The efficacy and safety of Dermagraft in improving the healing of chronic diabetic foot ulcers: results of a prospective randomized trial. Diabetes Care 2003, 26, 1701-5
[3] Harding K, Sumner M, Cardinal M. A prospective, multicentre, randomized controlled study of human fibroblast-derived dermal substitute (Dermagraft) in patients with venous leg ulcers. Int Wound J 2013, 10, 132-7
[4] Rennekampff HO, Hansbrough JF, Woods V Jr, Kiessig V. Integrin and matrix molecule expression in cultured skin replacements. J Burn Care Rehabil 1996, 17, 213-21
[5] Krejci-Papa NC, Hoang A, Hansbrough JF. Fibroblast sheets enable epithelialization of sounds that do not support keratinocyte migration. Tissue Eng 1999, 5, 555-62
[6] Desmouliere A, Gabbini G. the role of the myofibroblast in wound healing and fibrocontractive diseases. In: Clark RAF, ed. The molecular and cellular basis of wound repair. Plenum Press 2nd ed., New York. 1996 pp391-414
[7] Nolte SV, Xu W, Rennekampff HO, Rodemann HP. Diversity of fibroblasts- a review on implications for skin tissue engineering. Cells Tissues Organs 2007 doi 10.1159/000111805

Dr. Mayer Tenenhaus, M.D., F.A.C.S.
Clinical Professor of Surgery,
Division of Plastic Surgery
University of California San Diego, Medical Center Hillcrest
200 W. Arbor Drive
San Diego, CA 92103-8890
Email: m.tenenhaus@sbcglobal.net

Dr. Nicole Ann Gaid, M.B. B.Ch. B.A.O
University of California San Diego, Department of Surgery Postdoctoral Research Scholar

Prof. Dr. Hans-Oliver Rennekampff, MD,
Department of Plastic Surgery, Hand Surgery, Burn Center,
University of Aachen,
Pauwelsstrasse 30
52074 Aachen , Germany
Email: hrennekampff@ukaachen.de