Adipose-derived stem cells in wound healing: recent Stem ... · Page 1 of 6 Critical review icensee...

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Critical review

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For citation purposes: Fromm-Dornieden C, Koenen P. Adipose-derived stem cells in wound healing: recent results in vitro and in vivo. OA Molecular & Cell Biology 2013 Dec 20;1(1):8. Co

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Stem

Cel

ls Adipose-derived stem cells in wound healing: recent results in vitro and in vivo

C Fromm-Dornieden1*, P Koenen1,2

AbstractIntroductionChronic wounds represent a major problem in medicine today as their incidence is continuously increas-ing due to an ageing population and a rise in the incidence of underlying diseases. Cutaneous wound heal-ing is a complex biological process. Chronic wounds are characterised by a prolonged inflammation, per-sistent infections, formation of drug-resistant microbial biofilms and the inability of dermal and/or epidermal cells to respond to regenerative stim-uli. As conventional treatment strat-egies often fail, innovative therapies have been investigated over the last decade, including stem cell-based therapies. After the initial use of em-bryonic stem cells, the focus has been set on autologous mesenchymal stem cells over the past years. They can be isolated in large amounts from vari-ous tissues and hold no ethical con-cerns. A promising and cost-effective source of autologous mesenchymal stem cells is subcutaneous adipose tissue. Recent in vitro and in vivo studies have shown that adipose-derived stem cells have a positive impact on wound healing, as they are attracted to the wound site and influence regeneration processes via paracrine mechanisms. They are pluripotent and secrete a variety of growth factors. The aim of this criti-

cal review was to discuss adipose-derived stem cells in wound healing.ConclusionMesenchymal stem cells-derived from adipose tissue are a promis-ing alternative to embryonic or bone marrow-derived stem cells in the therapy of chronic wounds. Because the use of adipose-derived stem cells in wound healing applications is still limited by a lack of clinical data, fur-ther studies have to pave the way for their routine clinical application.

IntroductionDue to demographic changes the number of patients with multimor-bidity is continuously increasing in western countries. One of the associ-ated disorders is the chronic wound. This includes a rise in the incidence of impaired wound healing, caus-ing a reduced patients’ quality of life and rising health care costs. Conven-tional therapies of chronic wounds are increasingly reaching their limits, motivating the search for alternative treatment options, including stem cell-based therapies1. This paper dis-cusses the recent in vitro and in vivo results of adipose-derived stem cells (ASCs) in wound healing.

Physiological wound healingWound healing is a complex biologi-cal process consisting of the four dif-ferent but partially overlying steps coagulation, inflammation, forma-tion of granulation tissue (prolifera-tive phase) and remodelling or scar formation.

After injury, initiation of a blood-clotting cascade prevents excessive bleeding and provides temporary protection of the wound area. During this process platelet-derived growth

factor and transforming growth fac-tors A1 and 2 (TGF-A1 and TGF-2) are released, causing attraction of in-flammatory cells such as leukocytes and macrophages.

Within a few days after injury, ap-optosis of inflammatory cells occurs. Anti-inflammatory cytokines such as TGF-A1 and Interleukin (IL) 1 as well as bioactive lipids are assumed to be involved in this process (Figure 1).

In the following proliferative phase, production of growth fac-tors and activation of dermal and epidermal cells lead to new tissue formation. Endothelial progenitor cells, which are essential for physio-logical wound healing, are mobilised by nitric oxide, vascular endothe-lial growth factor (VEGF) and matrix metalloproteinase (MMP9). Forma-tion of extra-cellular matrix (ECM)-rich tissue occurs in response to stromal cell-derived factor (SDF)-1 and insulin-like growth factor (IGF).

In the last step of wound healing, matrix remodelling and/or scar for-mation through cellular migration, proliferation and angiogenic induc-tion is initiated by TGF-A, MMPs and tumour necrosis factor (TNF)2.

Impaired wound healingA chronic wound is defined as a wound that does not heal in a certain period of time in spite of appropri-ate therapy. However, the exact-time point is in discussion. Most authors refer to a chronic wound as a wound that exists for more than three months3. Impaired wound healing is associated with senescence, is-chaemia and bacterial colonisation. Wound chronification is caused by local factors such as infection, venous insufficiency, mechanical trauma,

* Corresponding authorEmail: [email protected] Institute for Research in Operative Medicine,

University of Witten/Herdecke, Ostmer-heimer Str. 200, D-51109 Cologne, Germany

2 Department of Trauma and Orthopaedic Sur-gery, Cologne-Merheim Medical Center, Uni-versity of Witten/Herdecke, Cologne, Germany

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degradation of growth factors and their receptors. Although the pro-duction of growth factors is often in-creased in CWF compared with acute wound fluid (AWF), their quantity and bioavailability are decreased2.

Adipose-derived stem cells in regenerative medicineAfter initially focussing on embryonic stem cells in regenerative medicine, the focus has been set on autologous mesenchymal stem cells (MSCs) over the last years. In contrast to embry-onic stem cells MSCs can be isolated in large amounts from various tis-sues and hold no ethical concerns4,5. According to the minimal criteria of the International Society for Cellular Therapy MSCs are plastic adherent in standard culture conditions, the phenotype is positive for CD73, CD90 and CD105 as well as negative to CD11b or CD14, CD19 or CD79α and HLA-DR. They are inducible to differ-entiate into adipocytes, osteoblasts and chondrocytes in vitro6.

A promising and cost-effective source of autologous MSCs is subcu-taneous adipose tissue. ASCs are very stable under cell culture conditions, a normal haploid karyotype remains after 100 duplications. The content of ASCs per gram tissue is five-fold higher than in bone marrow. Adipose tissue can be extracted as solid adipose tissue or by liposuction, which is a less inva-sive and safer procedure than bone bi-opsies. For harvesting ASCs solid adi-pose tissue is mechanically chopped, enzymatically digested by collagenase and centrifuged according to specific protocols. Isolated stem cells can then be cultivated in cell culture. Using spe-cific differentiation media, these cells can be differentiated into various cell types, which can be used to fill up leaks in bones and cartilage or to support healing of chronic ulcers4,5,7.

DiscussionThe authors have referenced some of their own studies in this review. The protocols of these studies have been

Figure 1: Simplified view of physiological and impaired wound healing. The processes of physiological and impaired wound healing and some of the involved factors are represented schematically. In contrast to an acute wound (left side) the chronic wound (right side) is characterised by a persistent inflammation as well as an impaired extra-cellular matrix synthesis and neovascularisation which lead to an impaired healing process. EPC, endothelial progenitor cell; FGF, fibroblast growth factor; IGF, insulin-like growth factor; IL, Interleukin; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; TGF, transforming growth factors; TNF, tumour necrosis factor; VEGF vascular endothelial growth factor.

tissue maceration, ingrown foreign objects and others. Chronic diseases such as diabetes, renal failure or can-cer as well as congenital disorders, smoking, alcoholism, drugs, uraemia and nutritional deficiencies are sys-temic factors which also cause im-paired wound healing. Venous ulcers, pressure ulcers and diabetic ulcers are the most common types of chron-ic wounds, representing 90% of all chronic wounds1.

The characteristics of chronic wounds are prolonged inflammatory

phase, persistent infections, forma-tion of drug-resistant microbial bio-films and the inability of dermal and/or epidermal cells to respond to re-generative stimuli (Figure 1). Accu-mulated inflammatory cells produce reactive oxygen species that damage structural elements of the ECM and cell membranes and lead to prema-ture cell senescence. Furthermore, in chronic wound fluid (CWF) proin-flammatory cytokines such as TNF-α, IL-1 as well as MMPs and neutrophil elastase are enhanced, leading to

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Homing of adipose-derived stem cells to wound siteASC migration and attachment to en-dothelial cells are prerequisites for entering the target tissue and there-fore the positive effects of ASC at the site of injury. After tissue injury several cytokines are released. As ASCs express a variety of chemokine receptors including CXCR4, chemoat-tractants such as SDF-1 induce their migration to the site of injury10. The exact mechanisms by which ASCs enter the target tissue are not fully understood yet. But leucocyte migra-tion into inflammatory tissue seems to involve adhesion molecules such as P-selectin12.

Recent work in vitroThe stimulatory effects of ASCs on regeneration processes are thought to be mainly mediated by paracrine mechanisms. Lee et al.13 treated im-mortalised human keratinocytes (HaCaT cells) and human dermal fibroblasts with 50% conditioned medium of human ASCs (ASC-CM). Proliferation of HaCaTs and fibro-blasts as well as in vitro wound heal-ing of HaCaTs was promoted by ASC-CM. Their results demonstrate an improved keratinocyte and fibroblast function in wound healing via ASCs in a paracrine fashion13.

To utilise paracrine effects of ASCs in a low cytotoxic way for wound healing applications, Hassan et al.14 generated a living dressing system. They encapsulated human ASCs in situ in a water-soluble, thermo re-sponsive hyper-branched polyethyl-ene glycol-based copolymer. Cell vi-ability in this hydrogel was high for up to 7 days under cell culture con-ditions. While cellular secretion of growth factors such as VEGF and pla-cental-derived growth factor produc-tion increased over 7 days, cellular proliferation was inhibited and IL-2 and IFNγ release were unaffected14.

In a recent study it has been shown that the bacterial strains Es-cherichia coli, Staphylococcus aureus

healing processes via paracrine mechanisms as well as fusion and differentiation, for example, into ke-ratinocytes or fibroblasts8–10.

Recent in vitro and in vivo experi-ments have shown that ASCs can exhib-it antioxidant effects, which are mainly mediated via paracrine mechanisms by the activation of dermal fibroblasts and keratinocytes. ASCs secrete a variety of growth factors such as basic fibro-blast growth factor (bFGF), keratino-cyte growth factor, TGF-β, hepatocyte growth factor (HGF) and VEGF11. An overview of ASC functions in wound healing is summarised in Figure 2.

approved by the relevant ethics com-mittees related to the institution in which they were performed.

Chronic wounds are a rising prob-lem in daily clinical routine. As con-ventional treatment strategies often fail, stem cell-based therapies have been investigated over the last dec-ade. Recent in vitro and in vivo stud-ies have shown that ASCs are a de-sirable alternative to embryonic or bone marrow-derived stem cells.

ASCs have already been shown to have a positive impact on wound healing, as they are attracted to the wound site and influence wound

Figure 2: ASC function in wound healing and influencing conditions. ASCs are shown to have a positive impact on healing of chronic wounds via paracrine mechanisms, as scaffold material as well as fusion and differentiation, for example, into keratinocytes or fibroblasts (green). Success of ASC application in chronic wound treatment can be influenced by several conditions (yellow) such as donor/host specificity, chronic wound fluid and further aspects. ASC, adipose-derived stem cells.

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improve ASC motility, retention and proliferation10.

Limitations of the use of adipose-derived stem cellsDonor specificity is a well-known phenomenon. Recent studies have investigated ASC function in the con-text of donor’s age and gender.

Guercio et al.26 have shown a high-er proliferation capacity of ASCs of younger dogs than older animals. Donor specificity of human ASCs has been shown by Shu et al.27, who observed a relation of donor age and cell differentiation as well as anti-apoptosis ability. Another study with human ASCs showed that, in-dependently from donor’s age, equal amounts of ASCs could be iso-lated. However, infant-derived cells showed different morphology and enhanced angiogenic and osteogenic capabilities28.

So far, there is little evidence on the effects of gender on ASC potential. Fossett and Khan29 summarised that females have a significantly higher yield of MSCs than males and that oestrogens have an excitatory role controlling levels of cytokines and growth factor production29. Moreo-ver, gender of ASC donors influenced the proliferation, differentiation, par-acrine and anti-apoptosis abilities of human ASCs27.

Besides age and gender, body mass index, chronic diseases, western life-style and many other features cause donor-specific differences. For pro-genitor cells it has been shown that cells harvested from patients with chronic diseases have a reduced re-generative potential30,31. Whether these individual factors have an in-fluence of the regeneration potential of ASC is still unclear and has to be focused in future studies.

ASCs from streptozotocin-induced type 1 diabetic mice showed a decreased proliferate potential and reduced migration. Additionally, a re-duction of stem cell marker- positive cells was shown. The release of the

treatment with ASCs initiated small-er wound sizes and was associated with the development of new blood vessels20.

Recent clinical studiesSince the end of 19th century autolo-gous transplantation of fatty tissue was used as filler in plastic surgery. A continuous improvement of methods and purification of material through specific centrifugation protocols in-creased the predictability and sta-bility of results. Techniques based on the use of stem cell niches from adipose tissue are already important applications in plastic and cosmetic surgery21. Gir et al.22 listed 174 pub-lished cases of clinical applications of ASCs in plastic surgery involving soft-tissue augmentation, wound healing and tissue engineering. No adverse effects have been reported in these studies.

Akita et al.23 described the success-ful use of non-cultured autologous ASCs for treatment of chronic ra-diation injury. In the excised irradi-ated skin defect ASCs were applied together with bFGF and an artificial dermis.

Improving aspects for adipose-derived stem cellsJiang et al.24 demonstrated that a surface carrier of medical-grade sili-cone coated by plasma polymerisa-tion with a thin layer of acrylic acid allows high-efficiency transfer of ASCs to wounds in an in vivo murine model. ASCs delivered by the carrier significantly accelerated wound heal-ing similar to those delivered by in-tradermal injection24.

To improve their therapeutic potential, ASCs were genetically modified. Treated cells showed an extended proliferation period, an in-creased secretion of VEGF, a higher migration potential and after, injec-tion into a mouse wound model, a promoted wound healing25. Further-more, overexpression of the SDF-1 receptor CXCR4 has been shown to

and Streptococcus pyogenes have no considerable cytotoxic effects on ASCs. Exposure of ASCs to these bac-teria and their components has no negative effect on ASC proliferation. Therefore Fiedler et al.15 presumed, that ASCs can support wound healing even at bacterially infected wound sites.

Recent work in vivoIn an animal-based model it has al-ready been shown that transplanted MSCs can migrate to impaired tissues and activate regeneration processes16.

Hong et al.17 showed in a rabbit ear in vivo model that topically delivered rabbit ASCs are engrafted and prolif-erate in wounds, where they exhibit-ed an activated fibroblast phenotype. Furthermore, ASCs led to increased endothelial cell and macrophage recruitment. In contrast to bone marrow-derived MSCs and dermal fi-broblasts they increased granulation tissue formation17. Improved skin re-generation after ASC transplantation in vivo has been shown by Sheng et al.18 correspondingly. The presence of ASCs induced expression of epi-dermal and VEGF and increased cell proliferation and neovascularisa-tion. The regenerated skin was much thicker compared with controls. The transplanted ASCs were detectable in subcutaneous tissue, vascular ves-sels and hair follicles for 4 weeks18.

Similar to healthy animal models positive effects of ASCs on wound healing could also be shown for ani-mals with chronic diseases or artifi-cially induced impaired wound heal-ing. As, consequence of ASC transfer an increase in capillary density, col-lagen intensity, VEGF and TGF-β3 expression was displayed. Animals with autologous ASC transplanta-tion on wounds showed significantly increased survival, angiogenesis and epithelialisation19. ASCs accelerated wound healing of radiation ulcers in a modified rat model, where they were co-localised with endothelial cell markers in ulcerated tissues. The

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7. Locke M, Feisst V, Dunbar PR. Concise review: human adipose-derived stem cells: separating promise from clinical need. Stem Cells [Review]. 2011 Mar; 29(3):404–11.8. Nambu M, Kishimoto S, Nakamura S, Mizuno H, Yanagibayashi S, Yamamoto N, et al. Accelerated wound healing in healing-impaired db/db mice by autolo-gous adipose tissue-derived stromal cells combined with atelocollagen matrix. Ann Plast Surg. 2009 Mar;62(3):317–21.9. Ebrahimian TG, Pouzoulet F, Squiban C, Buard V, Andre M, Cousin B, et al. Cell therapy based on adipose tissue-derived stromal cells promotes physiological and pathological wound healing. Arterioscler Thromb Vasc Biol. [Research Support, Non-U.S. Govt]. 2009 Apr;29(4):503–10.10. Cho HH, Kyoung KM, Seo MJ, Kim YJ, Bae YC, Jung JS. Overexpression of CXCR4 increases migration and proliferation of human adipose tissue stromal cells. Stem Cells Dev. [Research Support, Non-U.S. Govt]. 2006 Dec;15(6):853–64.11. Kim WS, Park BS, Sung JH. The wound-healing and antioxidant effects of adipose-derived stem cells. Expert Opin Biol Ther. [Research Support, Non-U.S. Govt Review]. 2009 Jul;9(7):879–87.12. Liu BH, Yeh HY, Lin YC, Wang MH, Chen DC, Lee BH, et al. Spheroid for-mation and enhanced cardiomyogenic potential of adipose-derived stem cells grown on chitosan. Biores Open Access. 2013 Feb;2(1):28–39.13. Lee SH, Jin SY, Song JS, Seo KK, Cho KH. Paracrine effects of adipose-derived stem cells on keratinocytes and dermal fibroblasts. Ann Dermatol. 2012 May; 24(2):136–43.14. Hassan W, Dong Y, Wang W. En-capsulation and 3D culture of human adipose-derived stem cells in an in-situ crosslinked hybrid hydrogel composed of PEG-based hyperbranched copolymer and hyaluronic acid. Stem Cell Res Ther. 2013 Mar;4(2):32.15. Fiedler T, Salamon A, Adam S, Her-zmann N, Taubenheim J, Peters K. Impact of bacteria and bacterial components on osteogenic and adipogenic differen-tiation of adipose-derived mesenchy-mal stem cells. Exp Cell Res. 2013 Nov; 319(18):2883–92.16. Myers TJ, Granero-Molto F, Longob-ardi L, Li T, Yan Y, Spagnoli A. Mesenchy-mal stem cells at the intersection of cell and gene therapy. Expert Opin Biol Ther.

mechanisms as well as fusion and differentiation, for example, into ke-ratinocytes or fibroblasts.

Because the use of ASCs in wound healing applications is still limited by a lack of clinical data, further studies have to pave the way for their routine clinical application.

Abbreviations listASC, adipose-derived stem cell; AWF, acute wound fluid; bFGF, basic fibro-blast growth factor; CWF, chronic wound fluid; ECM, extra-cellular ma-trix; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IL, Interleukin; MMP, matrix metallo-proteinase; MSC, mesenchymal stem cells; SDF, stromal cell-derived factor; TGF, transforming growth factors; TNF, tumour necrosis factor; VEGF vascular endothelial growth factor.

References1. Cherubino M, Rubin JP, Miljkovic N, Kelmendi-Doko A, Marra KG. Adipose-de-rived stem cells for wound healing appli-cations. Ann Plast Surg. [Review]. 2011 Feb;66(2):210–5.2. Demidova-Rice TN, Hamblin MR, Herman IM. Acute and impaired wound healing: pathophysiology and current methods for drug delivery, part 1: normal and chronic wounds: biology, causes, and approaches to care. Adv Skin Wound Care [Research Support, Non-U.S. Govt]. 2012 Jul;25(7): 304–14.3. Dissemond J. When is a wound chronic?. Hautarzt. 2006 Jan;57(1):55. In German.4. Baer PC, Geiger H. Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and het-erogeneity. Stem Cells Int. 2012;2012: 812693.5. Mizuno H, Tobita M, Uysal AC. Concise review: Adipose-derived stem cells as a novel tool for future regenerative medi-cine. Stem Cells [Review]. 2012 May; 30(5):804–10.6. Dominici M, Le Blanc K, Mueller I, Sla-per-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The Interna-tional Society for Cellular Therapy posi-tion statement. Cytotherapy. 2006;8(4): 315–7.

growth factors HGF, VEGF-A and IGF-1 was significantly reduced in supernatants of ASCs-derived from diabetic mice32.

Another influencing factor on ASC applicability in chronic wound treat-ment is the composition of wound fluid, which significantly differs be-tween acute and chronic wounds. In an in vitro wound model they have been shown to influence ASCs func-tion inversely. Whereas AWF has a strong chemotactic impact and stim-ulates ASC proliferation, CWF has an inhibiting effect on ASC migration and proliferation. CWF strongly in-duces expression of bFGF, VEGF and MMP933.

Further aspects on practicality of ASC application are handling and commercialisation, which are diffi-cult as seen from the industrial side. Moreover, the risk of inducing cancer by transplantation of ASCs is not fully excluded yet11 (Figure 2).

Future aspectsCurrently, there are no standardised protocols for the clinical applica-tion of ASCs and no consensus of the number of cells is required for dif-ferent treatment options. To ensure the safety and efficacy of ASC appli-cation standardised protocols and larger randomised controlled trials are needed22. Furthermore, donor specificity has to be investigated in detail and the underlying reasons of different efficacy have to be eluci-dated. However, within the scope of personalised medicine, application of autologous ASCs in chronic wound treatment has to be considered individually.

ConclusionMSCs derived from adipose tissue, called ASCs, are a promising alterna-tive to embryonic or bone marrow-derived stem cells in the therapy of chronic wounds. They are less inva-sive to harvest, migrate to the wound site through paracrine effects and catalyse wound healing via paracrine

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22. Gir P, Oni G, Brown SA, Mojallal A, Rohrich RJ. Human adipose stem cells: current clinical applications. Plast Reconstr Surg. [Review]. 2012 Jun; 129(6):1277–90.23. Akita S, Akino K, Hirano A, Ohtsuru A, Yamashita S. Noncultured autologous adipose-derived stem cells therapy for chronic radiation injury. Stem Cells Int. 2010 Dec;2010:532704.24. Jiang D, Qi Y, Walker NG, Sindrilaru A, Hainzl A, Wlaschek M, et al. The effect of adipose tissue derived MSCs delivered by a chemically defined carrier on full-thick-ness cutaneous wound healing. Biomate-rials [Research Support, Non-U.S. Govt]. 2013 Mar;34(10):2501–15.25. Song SH, Lee MO, Lee JS, Jeong HC, Kim HG, Kim WS, et al. Genetic modifica-tion of human adipose-derived stem cells for promoting wound healing. J Dermatol Sci. [Research Support, Non-U.S. Govt]. 2012 May;66(2):98–107.26. Guercio A, Di Bella S, Casella S, Di Marco P, Russo C, Piccione G. Canine mes-enchymal stem cells (MSCs): characteri-zation in relation to donor age and adi-pose tissue-harvesting site. Cell Biol Int. 2013 Aug;37(8):789–98.27. Shu W, Shu YT, Dai CY, Zhen QZ. Com-paring the biological characteristics of adipose tissue-derived stem cells of dif-ferent persons. J Cell Biochem. [Compara-tive Study]. 2012 Jun;113(6):2020–6.28. Wu W, Niklason L, Steinbacher DM. The effect of age on human adipose- derived

[Research Support, N.I.H., Extramural Re-view]. 2010 Dec;10(12):1663–79.17. Hong SJ, Jia SX, Xie P, Xu W, Leung KP, Mustoe TA, Galiano RD. Topically delivered adipose derived stem cells show an activated-fibroblast pheno-type and enhance granulation tissue formation in skin wounds. PLoS One [Research Support, N.I.H., Extramural Research Support, U.S. Govt, Non-P.H.S.]. 2013;8(1):e55640.18. Sheng L, Yang M, Liang Y, Li Q. Adi-pose tissue-derived stem cells (ADSCs) transplantation promotes regeneration of expanded skin using a tissue expan-sion model. Wound Repair Regen. [Re-search Support, Non-U.S. Govt]. 2013 Sep–Oct;21(5):746–54.19. Zografou A, Papadopoulos O, Tsigris C, Kavantzas N, Michalopoulos E, Chatz-istamatiou T, et al. Autologous trans-plantation of adipose-derived stem cells enhances skin graft survival and wound healing in diabetic rats. Ann Plast Surg. [Research Support, Non-U.S. Govt]. 2013 Aug;71(2):225–32.20. Huang SP, Huang CH, Shyu JF, Lee HS, Chen SG, Chan JY, et al. Promo-tion of wound healing using adipose-derived stem cells in radiation ulcer of a rat model. J Biomed Sci. 2013 Jul; 20(1):51.21. Rigotti G, Marchi A, Sbarbati A. Adi-pose-derived mesenchymal stem cells: past, present, and future. Aesthetic Plast Surg. [Editorial]. 2009 May;33(3):271–3.

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