Mesenchymal stem cells (MSCs) hold great promise for therapeutic application in non-healing ulcers and tissue regeneration because of their multi-lineage differentiation potential. MSCs delivered may migrate to the sites of injury and improve wound healing by stimulating angiogenesis and promoting revascularization. The incidence of type 2 diabetes mellitus (T2DM) is increasing worldwide. It is associated with peripheral neuropathy and peripheral arterial occlusive disease (PAOD), which predispose patients to develop non-healing foot ulcers following minor trauma. A high rate of amputation exists among diabetic patients due to non-healing foot ulcers, which are a significant burden for the society despite new therapeutic protocols developed. In recent years, stem cell transplantation has been considered as a new therapeutic option for diabetic foot ulcers (DFUs). The regeneration potential of MSCs has been demonstrated in the experimental and clinical trials. Here we review the potential efficacy and systematic use of MSCs for the treatment of non-healing DFUs, current advances, MSC delivery systems, and possible options to enhance the therapeutic potential of stem cell for wound healing.
Get full access to this article
View all access options for this article.
References
1.
WildSG, RoglicA, GreenR, SicreeR, KingH. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care, 2004; 27:1047–1053.
2.
BoultonAJ, VileikyteL, Ragnarson-TennvallG, ApelqvistJ. The global burden of diabetic foot disease. Lancet, 2005; 366:1719–1724.
3.
BoweringCK. Diabetic foot ulcers: Pathophysiology, assessment, and therapy. Can Fam Physician, 2001; 47:1007–1016.
4.
DashNR, DashSN, RoutrayP, MohapatraS, MohapatraPC. Targeting nonhealing ulcers of lower extremity in human through autologous bone marrow-derived mesenchymal stem cells. Rejuvenation Res, 2009; 12:359–366.
VojtassakJ, DanisovicL, KubesM, BakosD, JarabekL, UlicnaM, BlaskoM. Autologous biograft and mesenchymal stem cells in treatment of the diabetic foot. Neuro Endocrinol Lett, 2006; 27(Suppl. 2):134–137.
ApelqvistJ, BakkerK, van HoutumWH, SchaperNC. International Working Group on the Diabetic Foot (IWGDF) Editorial Board. Practical guidelines on the management and prevention of the diabetic foot: Based upon the International Consensus on the Diabetic Foot (2007) Prepared by the International Working Group on the Diabetic Foot. Diabetes Metab Res Rev, 2008; 24(Suppl 1):S181–S187.
9.
FrykbergRG, ZgonisT, ArmstrongDG, DriverVR, GiuriniJM, KravitzSR, LandsmanAS, LaveryLA, MooreJC, SchuberthJM, WukichDK, AndersenC, VanoreJV. American College of Foot and Ankle Surgeons. Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg, 2006; 45(5 Suppl):S1–S66.
10.
AulivolaB, HileCN, HamdanAD, SheahanMG, VeraldiJR, SkillmanJJ, CampbellDR, ScovellSD, LoGerfoFW, PomposelliFBJr. Major lower extremity amputation: Outcome of a modern series. Arch of Surg, 2004; 139:395–399.
11.
BhowmikD, ChiranjibB, YadavJ. ChandiraMR. Role of community pharmacist in management and prevention diabetic foot ulcer and infections. J Chem Pharmaceut Res, 2009; 1:38–53.
KeastDH, BoweringCK, EvansAW, MackeanGL, BurrowsC, D'SouzaL. MEASURE: A proposed assessment framework for developing best practice recommendations for wound assessment. Wound Repair Regen, 2004; 12(3 Suppl):S1–S17.
FriedensteinAJ, Piatetzky-ShapiroI, PetrakovaKV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morph, 1966; 16:381–390.
16.
JacksonKA, MajkaSM, WangH, PociusJ, HartleyCJ, MajeskyMW, EntmanML, MichaelLH, HirschiKK, GoodellMA. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest, 2001; 107:1395–1402.
17.
KobayashiT, HamanoK, LiTS, KatohT, KobayashiS, MatsuzakiM, EsatoK. Enhancement of angiogenesis by the implantation of self-bone marrow cells in a rat ischemic heart model. J Surg Res, 2000; 89:189–195.
18.
Al-KhalidiA, Al-SabitiH, GalipeauJ, LachapelleK. Therapeutic angiogenesis using autologous bone marrow stromal cells improved blood flow in chronic limb ischemia model. Ann Thoracic Surg, 2003; 75:204–209.
19.
FalangaV, IwamotoS, ChartierM, YufitT, ButmarcJ, KouttabN, ShrayerD, CarsonP. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng, 2007; 13:1299–1312.
20.
GalianoRD, TepperOM, PeloCR, BhattKA, CallaghanM, BastidasN, BuntingS, SteinmetzHG, GurtnerGC. Topical vascular endothelial growth factor accelerates diabetic wound healing through increased angiogenesis and by mobilizing and recruiting bone marrow derived cells. Am J Pathol, 2004; 164:1935–1947.
21.
UsasA, HoAM, CooperGM, OlshanskiA, PengH, HuardJ. Bone regeneration mediated by BMP4-expressing muscle-derived stem cells is affected by delivery system. Tissue Eng Part A, 2009; 15:285–293.
22.
MatsumotoT, CooperGM, GharaibehB, MeszarosLB, LiG, UsasA, FuFH, HuardJ. Cartilage repair in a rat model of osteoarthritis through intraarticular transplantation of muscle-derived stem cells expressing bone morphogenetic protein 4 and soluble Flt-1. Arth Rheum, 2009; 60:1390–1405.
ScheersI, LombardC. NajimiM, SokalE. Cell therapy for the treatment of metabolic liver disease: An update on the umbilical cord derived stem cells candidates. Open Tissue Eng Regen Med J, 2011; 4:48–53.
25.
KhooMLM, TaoH, MaDDF. Mesenchymal stem cell-based therapies for Parkinson's disease: Progress, controversies and lessons for the future. J Stem Cell Res Ther, 2011; S2:005.
YamadaKM, ClarkRAF. Provisional matrix. In: ClarkRAF, ed. The Molecular and Cellular Biology of Wound Repair, 2nd ed. Plenum Press, London, 1996, pp. 51–94.
28.
GorenI, MullerE, PfelischifterJ, FrankS. Severely impaired insulin signaling in chronic wounds of diabetic ob/ob mice: A potential role of tumor necrosis factor-alpha. Am J Pathol, 2006; 168:765–777.
MaruyamaK, AsaiJ, IiM, ThorneT, LosordoDW, D'AmorePA. Decreased macrophage number and activation leads to reduced lymphatic vessel formation and contribute to impair diabetic wound healing. Am J Pathol, 2007; 170:1178–1191.
31.
WuY, ChenL, ScottPG, TredgetEE. Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells, 2007; 25:2648–2659.
32.
JacksonWM, NestiLJ, TuanRS. Mesenchymal stem cell therapy for attenuation of scar formation during wound healing. Stem Cell Res Ther, 2012; 3:20.
33.
TassoR, AugelloA, BoccardoS, SalviS, CaridàM, PostiglioneF, FaisF, TruiniM, CanceddaR, PennesiG. Recruitment of a host's osteoprogenitor cells using exogenous mesenchymal stem cells seeded on porous ceramic. Tissue Eng Part A, 2009; 15:2203–2212.
34.
BadiavasEV, FalangaV. Treatment of chronic wounds with bone marrow-derived cells. Arch Dermatol, 2003; 139:510–516.
35.
ZiegelhoefferT, FernandezB, KostinS, HeilM, VoswinckelR, HelischA, SchaperW. Bone marrow-derived cells do not incorporate into the adult growing vasculature. Circ Res, 2004; 94:230–238.
36.
ChenL, TredgetEE, WuPY, WuY. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One, 2008; 2;3:e1886.
37.
ZhangQZ, SuWR, ShiSH, Wilder-SmithP, XiangAP, WongA, NguyenAL, KwonCW, LeAD. Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing. Stem Cells, 2010; 28:1856–1868.
38.
NémethK, LeelahavanichkulA, YuenPS, MayerB, ParmeleeA, DoiK, RobeyPG, LeelahavanichkulK, KollerBH, BrownJM, HuX, JelinekI, StarRA, MezeyE. Bone marrow stromal cells attenuate sepsis via prostaglandin E (2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med, 2009; 15:42–49.
39.
RenG, ZhangL, ZhaoX, XuG, ZhangY, RobertsAI, ZhaoRC, ShiY. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell, 2008; 2:141–150.
40.
NagasawaT, NakajimaT, TachibanaK, IizasaH, BleulCC, YoshieO, MatsushimaK, YoshidaN, SpringerTA, KishimotoT. Molecular cloning and characterization of a murine pre-B-cell growth-stimulating factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptorfusin. Proc Natl Acad Sci USA, 1996; 93:14726–14729.
41.
YamaguchiJ, KusanoKF, MasuoO, KawamotoA, SilverM, MurasawaS, Bosch-MarceM, MasudaH, LosordoDW, IsnerJM, AsaharaT. Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation, 2003; 107:1322–1328.
42.
GrunewaldM, AvrahamI, DorY, Bachar-LustigE, ItinA, JungS, ChimentiS, LandsmanL, AbramovitchR, KeshetE. VEGF-induced adult neovascularization: Recruitment, retention, and role of accessory cells. Cell, 2006; 124:175–189.
43.
HiasaK, IshibashiM, OhtaniK, InoueS, ZhaoQ, KitamotoS, SataM, IchikiT, TakeshitaA, EgashiraK. Gene transfer of stromal cell-derived factor-1alpha enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway: Next-generation chemokine therapy for therapeutic neovascularization. Circulation, 2004; 109:2454–2461.
44.
AbidMR, ShihSC, OtuHH, SpokesKC, OkadaY, CurielDT, MinamiT, AirdWC. A novel class of vascular endothelial growth factor-responsive genes that require forkhead activity for expression. J Biol Chem, 2006; 281:35544–35553.
45.
ZhengJ, WenY, SongY, WangK, ChenDB, MagnessRR. Activation of multiple signaling pathways is critical for fibroblast growth factor 2- and vascular endothelial growth factor-stimulated ovine fetoplacental endothelial cell proliferation. Biol Reprod, 2008; 78:143–150.
46.
ArnoldF, WestDC. Angiogenesis in wound healing. Pharmacol Ther, 1991; 52:407–422.
47.
KwonDS, GaoX, LiuYB, DulchavskyDS, DanylukAL, BansalM, ChoppM, McIntoshK, ArbabAS, DulchavskySA, GautamSC. Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats. Int Wound J, 2008; 5:453–463.
KimCH, LeeJH, WonJH, ChoMK. Mesenchymal stem cells improve wound healing in vivo via early activation of matrix metalloproteinase-9 and vascular endothelial growth factor. J Korean Med Sci, 2011; 26:726–733.
50.
SchievenbuschS, StrackI, SchefflerM, WennholdK, MaurerJ, NischtR, DienesHP, OdenthalM. Profiling of anti-fibrotic signaling by hepatocyte growth factor in renal fibroblasts. Biochem Biophys Res Commun, 2009; 385:55–61.
51.
BevanD, GherardiE, FanTP, EdwardsD, WarnR. Diverse and potent activities of HGF/SF in skin wound repair. J Pathol, 2004; 203:831–838.
52.
ShuklaMN, RoseJL, RayR, LathropKL, RayA, RayP. Hepatocyte growth factor inhibits epithelial to myofibroblast transition in lung cells via Smad7. Am J Respir Cell Mol Biol, 2009; 40:643–653.
53.
BremH, Tomic-CanicM. Cellular and molecular basis of wound healing in diabetes. J Clin Invest, 2007; 117:1219–1222.
54.
DischerDE, MooneyDJ, ZandstraPW. Growth factors: Matrices, and forces combine and control stem cells. Science, 2009; 324:1673–1677.
55.
GnecchiM, HeH, LiangOD, MeloLG, MorelloF, MuH, NoiseuxN, ZhangL, PrattRE, IngwallJS, DzauVJ. Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med, 2005; 11:367–368.
56.
LuD, ChenB, LiangZ, DengW, JiangY, LiS, XuJ, WuQ, ZhangZ, XieB, ChenS. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: A double-blind, randomized, controlled trial. Diabetes Res Clin Pract, 2011; 92:26–36.
57.
IwaseT, NagayaN, FujiiT, ItohT, MurakamiS, MatsumotoT, KangawaK, KitamuraS. Comparison of angiogenic potency between mesenchymal stem cells and mononuclear cells in a rat model of hind limb ischemia. Cardiovasc Res, 2005; 66:543–551.
58.
YuHS, WonJE, JinGZ, KimHW. Construction of mesenchymal stem cell-containing collagen gel with a macrochanneled polycaprolactone scaffold and the flow perfusion culturing for bone tissue engineering. Biores Open Access, 2012; 1:124–136.
59.
TrombiL, D'AlessandroD, PaciniS, FiorentinoB, ScarpelliniM, FazziR, GalimbertiS, GuazziniS, PetriniM. Good manufacturing practice-grade fibrin gel is useful as a scaffold for human mesenchymal stromal cells and supports in vitro osteogenic differentiation. Transfusion, 2008; 48:2246–2251.
60.
NeussS, StainforthR, SalberJ, SchenckP, BoviM, KnüchelR, Perez-BouzaA. Long-term survival and bipotent terminal differentiation of human mesenchymal stem cells (hMSC) in combination with a commercially available three-dimensional collagen scaffold. Cell Transplant., 2008; 17:977–986.
61.
ZhongW, ZhangW, WangS, QinJ. Regulation of fibrochondrogenesis of mesenchymal stem cells in an integrated microfluidic platform embedded with biomimetic nanofibrous scaffolds. PLoS One, 2013; 8:e61283.
BenoitDS, SchwartzMP, DurneyAR, AnsethKS. Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells. Nat Mater, 2008; 7:816–823.
RustadKC, WongVW, SorkinM, GlotzbachJP, MajorMR, RajadasJ, LongakerMT, GurtnerGC. Enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold. Biomaterials, 2012; 33:80–90.
68.
HorchRE, BannaschH, KoppJ, AndreeC, StarkGB. Single-cell suspensions of cultured human keratinocytes in fibrin-glue reconstitute the epidermis. Cell Transplant, 1998; 7:309–317.
69.
HoW, TawilB, DunnJC, WuBM. The behavior of human mesenchymal stem cells in 3D fibrin clots: Dependence on fibrinogen concentration and clot structure. Tissue Eng, 2006; 12:1587–1595.
70.
BensaidW, TriffittJT, BlanchatC, OudinaK, SedelL, PetiteH. A biodegradeable fibrin scaffold for mesenchymal stem cell transplantation. Biomaterials, 2003; 24:2497–2502.
71.
MogfordJE, TawilB, JiaS, MustoeTA. Fibrin sealant combined with fibroblasts and platelet-derived growth factor enhances wound healing in excisional wounds. Wound Repair Regen, 2009; 17:405–410.
72.
VojtassákJ, DanisovicL, KubesM, BakosD, JarábekL, UlicnáM, BlaskoM. Autologous biograft and mesenchymal stem cells in treatment of the diabetic foot. Neuro Endocrinol Lett, 2006; 27:134–137.
73.
JiangD, QiY, WalkerNG, SindrilaruA, HainzlA, WlaschekM, MacNeilS, Scharffetter-KochanekK. The effect of adipose tissue derived MSCs delivered by a chemically defined carrier on full-thickness cutaneous wound healing. Biomaterials, 2013; 34:2501–2515.
74.
HuangS, LuG, WuY, JirigalaE, XuY, MaK, FuX. Mesenchymal stem cells delivered in a microsphere-based engineered skin contribute to cutaneous wound healing and sweat gland repair. J Dermatol Sci, 2012; 66:169–170.
75.
ClarkRA. Biology of dermal wound repair. Dermatol Clin, 1993; 11:647–666.
KumarV, AbbasAK, FaustoN, AsterJC. Robbins and Cotran Pathologic Basis of Disease, 8th ed. Saunders Elsevier, Philadelphia, 2010.
78.
WangF, LiZ, KhanM, TamamaK, KuppusamyP, WagnerWR, SenCK, GuanJ. Injectable, rapid gelling and highly flexible hydrogel composites as growth factor and cell carriers. Acta Biomater, 2010; 6:1978–1991
79.
TayCY, YuH, PalM, LeongWS, TanNS, NgKW, LeongDT, TanLP. Micropatterned matrix directs differentiation of human mesenchymal stem cells towards myocardial lineage. Exp Cell Res, 2010; 316:1159–1168.
80.
KaroubiG, OrmistonML, StewartDJ, CourtmanDW. Single-cell hydrogel encapsulation for enhanced survival of human marrow stromal cells. Biomaterials, 2009; 30:5445–5455.
81.
NuttelmanCR, TripodiMC, AnsethKS. In vitro osteogenic differentiation of human mesenchymal stem cells photoencapsulated in PEG hydrogels. J Biomed Mater Res A, 2004; 68:773–782.
82.
StupackDG, ChereshDA. Get a ligand, get a life: Integrins, signaling and cell survival. J Cell Sci, 2002; 115:3729–3738.
83.
BryantSJ, AnsethKS. The effects of scaffold thickness on tissue engineered cartilage in photocrosslinked poly (ethylene oxide) hydrogels. Biomaterials, 2001; 22:619–626.
84.
HallB, DembinskiJ, SasserAK, StudenyM, AndreeffM, MariniF. Mesenchymal stem cells in cancer: Tumor-associated fibroblasts and cell-based delivery vehicles. Int J Hematol, 2007; 86:8–16.
85.
SpaethEL, DembinskiJL, SasserAK, WatsonK, KloppA, HallB, AndreeffM, MariniF. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One, 2009; 4:e4992.
86.
HallB, AndreeffM, MariniF. The participation of mesenchymal stem cells in tumor stroma formation and their application as targeted-gene delivery vehicles. Handb Exp Pharmacol, 2007; 180:263–283.
87.
ThirabanjasakD, TantiwongseK, ThornerPS. Angiomyeloproliferative lesions following autologous stem cell therapy. J Am Soc Nephrol, 2010; 21:1218–1222.
88.
SundinM, OrvellC, RasmussonI, SundbergB, RingdenO, Le BlancK. Mesenchymal stem cells are susceptible to human herpesviruses, but viral DNA cannot be detected in the healthy seropositive individual. Bone Mar Trans, 2006; 37:1051–1059.
BlumbergSN, BergerA, HwangL, PastarI, WarrenSM, ChenW. The role of stem cells in the treatment of diabetic foot ulcers. Diabet Res Clin Pract, 2012; 96:1–9.
92.
LiXY, ZhengZH, LiXY, GuoJ, ZhangY, LiH, WangYW, RenJ, WuZB. Treatment of foot disease in patients with type. 2 diabetes mellitus using human umbilical cord blood mesenchymal stem cells: Response and correction of immunological anomalies. Curr Pharm Des, 2013; 19:4893–4899.
93.
KiranaS, StratmannB, PranteC, ProhaskaW, KoerperichH, LammersD, GastensMH, QuastT, NegreanM, StirbanOA, NandreanSG, GöttingC, MinartzP, KleesiekK, TschoepeD. Autologous stem cell therapy in the treatment of limb ischaemia induced chronic tissue ulcers of diabetic foot patients. Int J Clin Pract, 2012; 66:384–393.
94.
RavariH, Hamidi-AlmadariD, SalimifarM, BonakdaranS, ParizadehMR, KoliakosG. Treatment of non-healing wounds with autologous bone marrow cells, platelets, fibrin glue and collagen matrix. Cytotherapy, 2011; 13:705–711.
95.
JainP, PerakathB, JesudasonMR, NayakS. The effect of autologous bone marrow-derived cells on healing chronic lower extremity wounds: Results of a randomized controlled study. Ostomy Wound Manage, 2011; 57:38–44.
96.
RogersLC, BevilacquaNJ, ArmstrongDG. The use of marrow-derived stem cells to accelerate healing in chronic wounds. Int Wound J, 2008; 5:20–25.
97.
BalliosBG, CookeMJ, van der KooyD, ShoichetMS. A hydrogel-based stem cell delivery system to treat retinal degenerative diseases. Biomaterials, 2010; 31:2555–2564.
98.
LüS, WangH, LuW, LiuS, LinQ, LiD, DuanC, HaoT, ZhouJ, WangY, GaoS, WangC. Both the transplantation of somatic cell nuclear transfer- and fertilization-derived mouse embryonic stem cells with temperature-responsive chitosan hydrogel improve myocardial performance in infarcted rat hearts. Tissue Eng Part A, 2010; 16:1303–1315.
99.
LuWN, LüSH, WangHB, LiDX, DuanCM, LiuZQ, HaoT, HeWJ, XuB, FuQ, SongYC, XieXH, WangCY. Functional improvement of infarcted heart by co-injection of embryonic stem cells with temperature-responsive chitosan hydrogel. Tissue Eng Part A, 2009; 15:1437–1447.
100.
TangJ, WangJ, ZhengF, KongX, GuoL, YangJ, ZhangL, HuangY. Combination of chemokine and angiogenic factor genes and mesenchymal stem cells could enhance angiogenesis and improve cardiac function after acute myocardial infarction in rats. Mol Cell Biochem, 2010; 339:107–118.
101.
ZhangQZ, SuWR, ShiSH, Wilder-SmithP, XiangAP, WongA, NguyenAL, KwonCW, LeAD. Human gingiva derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing. Stem Cells, 2010; 28:1856–1868.
102.
XiongQ, HillKL, LiQ, SuntharalingamP, MansoorA, WangX, JameelMN, ZhangP, SwingenC, KaufmanDS, ZhangJ. A fibrin patch-based enhanced delivery of human embryonic stem cell-derived vascular cell transplantation in a porcine model of postinfarction left ventricular remodeling. Stem Cells, 2011; 29:367–375.
103.
PiaoH, KwonJS, PiaoS, SohnJH, LeeYS, BaeJW, HwangKK, KimDW, JeonO, KimBS, ParkYB, ChoMC. Effects of cardiac patches engineered with bone marrow-derived mononuclear cells and PGCL scaffolds in a rat myocardial infarction model. Biomaterials, 2007; 28:641–649.
104.
BarandonL, CouffinhalT, DufourcqP, AlzieuP, DaretD, DevilleC, DuplaaC. Repair of myocardial infarction by epicardial deposition of bone marrow cell-coated muscle patch in a murine model. Ann Thorac Surg, 2004; 78:1409–1417.
