Restricted accessResearch articleFirst published online 2013-06
Stromal Cell-Derived Factor-1 Receptor CXCR4-Overexpressing Bone Marrow Mesenchymal Stem Cells Accelerate Wound Healing by Migrating into Skin Injury Areas
Stromal cell-derived factor-1 (SDF-1) and its membrane receptor C-X-C chemokine receptor type 4 (CXCR4) are involved in the homing and migration of multiple stem cell types, neovascularization, and cell proliferation. This study investigated the hypothesis that bone marrow–derived mesenchymal stem cells (BMSCs) accelerate skin wound healing in the mouse model by overexpression of CXCR4 in BMSCs. We compared SDF-1 expression and skin wound healing times of BALB/c mice, severe combined immunodeficiency (SCID) mice, and immune system–deficient nude mice after 60Co radiation–induced injury of their bone marrow. The occurrence of transplanted adenovirus-transfected CXCR4-overexpressing male BMSCs in the wound area was compared with the occurrence of untransfected male BALB/c BMSCs in 60Co-irradiated female mice skin wound healing areas by Y chromosome marker analyses. The wound healing time of BALB/c mice was 14.00±1.41 days, whereas for the nude and SCID mice it was 17.16±1.17 days and 19.83±0.76 days, respectively. Male BMSCs could be detected in the surrounding areas of 60Co-irradiated female BALB/c mice wounds, and CXCR4-overexpressing BMSCs accelerated the wound healing time. CXCR4-overexpressing BMSCs migrate in an enhanced manner to skin wounds in a SDF-1–expression-dependent manner, thereby reducing the skin wound healing time.
Get full access to this article
View all access options for this article.
References
1.
AttingerC.E., JanisJ.E., SteinbergJ., SchwartzJ., Al-AttarA., CouchK.2006. Clinical approach to wounds: Debridement and wound bed preparation including the use of dressings and wound-healing adjuvants. Plast. Reconstr. Surg., 117,7 Suppl:72S–109S.
2.
BesseA., TrimoreauF., PraloranV., DenizotY.2000. Effect of cytokines and growth factors on the macrophage colony-stimulating factor secretion by human bone marrow stromal cells. Cytokine, 12:522–525.
CeradiniD.J., KulkarniA.R., CallaghanM.J., TepperO.M., BastidasN., KleinmanM.E.et al.2004. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat. Med., 10:858–864.
5.
DelormeB., ChateauvieuxS., CharbordP.2006. The concept of mesenchymal stem cells. Regen. Med., 1:497–509.
6.
GnecchiM., ZhangZ., NiA., DzauV.J.2008. Paracrine mechanisms in adult stem cell signaling and therapy. Circ. Res., 103:1204–1219.
7.
GottrupF.2008. Trends in surgical wound healing. Scand. J. Surg., 97:220–225; discussion 225–226.
8.
HonczarenkoM., LeY., SwierkowskiM., GhiranI., GlodekA.M., SilbersteinL.E.2006. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells, 24:1030–1041.
9.
KahnJ., BykT., Jansson-SjostrandL., PetitI., ShivtielS., NaglerA.et al.2004. Overexpression of CXCR4 on human CD34+ progenitors increases their proliferation, migration, and NOD/SCID repopulation. Blood, 103:2942–2949.
10.
KrauseD.S., TheiseN.D., CollectorM.I., HenegariuO., HwangS., GardnerR.et al.2001. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell, 105:369–377.
11.
KuciaM., WojakowskiW., RecaR., MachalinskiB., GozdzikJ., MajkaM.et al.2006. The migration of bone marrow-derived non-hematopoietic tissue-committed stem cells is regulated in an SDF-1-, HGF-, and LIF-dependent manner. Arch. Immunol. Ther. Exp. (Warsz), 54:121–135.
12.
LienC.Y., Chih-Yuan HoK., LeeO.K., BlunnG.W., SuY.2009. Restoration of bone mass and strength in glucocorticoid-treated mice by systemic transplantation of CXCR4 and cbfa-1 co-expressing mesenchymal stem cells. J Bone Miner Res, 24:837–848.
13.
LiuY., DulchavskyD.S., GaoX., KwonD., ChoppM., DulchavskyS.et al.2006. Wound repair by bone marrow stromal cells through growth factor production. J. Surg. Res., 136:336–341.
14.
MantovaniA., SicaA., SozzaniS., AllavenaP., VecchiA., LocatiM.2004. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol., 25:677–686.
15.
MartinezF.O., HelmingL., GordonS.2009. Alternative activation of macrophages: An immunologic functional perspective. Annu. Rev. Immunol., 27:451–483.
16.
MescherA.L., NeffA.W.2005. Regenerative capacity and the developing immune system. Adv. Biochem. Eng. Biotechnol., 93:39–66.
MoseleyR., HiltonJ.R., WaddingtonR.J., HardingK.G., StephensP, ThomasDW. 2004. Comparison of oxidative stress biomarker profiles between acute and chronic wound environments. Wound Repair Regen., 12:419–429.
19.
PonteA.L., MaraisE., GallayN., LangonneA., DelormeB., HeraultO.et al.2007. The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells, 25:1737–1745.
20.
Sanchez-RamosJ., SongS., Cardozo-PelaezF., HazziC., StedefordT., WillingA.et al.2000. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp. Neurol., 164:247–256.
21.
SchierleC.F., De la GarzaM., MustoeT.A., GalianoR.D.2009. Staphylococcal biofilms impair wound healing by delaying reepithelialization in a murine cutaneous wound model. Wound Repair Regen., 17:354–359.
22.
SharmaM., AfrinF., SatijaN., TripathiR.P., GangenahalliG.U.2010. Stromal-derived factor-1/CXCR4 signaling: indispensable role in homing and engraftment of hematopoietic stem cells in bone marrow. Stem Cells Dev., 20:933–946.
23.
ShibaY., TakahashiM., YoshiokaT., YajimaN., MorimotoH., IzawaA.et al.2007. M-CSF accelerates neointimal formation in the early phase after vascular injury in mice: the critical role of the SDF-1–CXCR4 system. Arterioscler. Thromb. Vasc. Biol., 27:283–289.
24.
ShichinoheH., KurodaS., YanoS., HidaK., IwasakiY.2007. Role of SDF-1/CXCR4 system in survival and migration of bone marrow stromal cells after transplantation into mice cerebral infarct. Brain Res., 1183:138–147.
25.
ShiotaM., HeikeT., HaruyamaM., BabaS., TsuchiyaA., FujinoH.et al.2007. Isolation and characterization of bone marrow-derived mesenchymal progenitor cells with myogenic and neuronal properties. Exp. Cell Res., 313:1008–1023.
26.
TangY.L., QianK., ZhangY.C., ShenL., PhillipsM.I.2005. Mobilizing of haematopoietic stem cells to ischemic myocardium by plasmid mediated stromal-cell-derived factor-1alpha (SDF-1alpha) treatment. Regul. Pept., 125:1–8.
27.
TogelF., IsaacJ., HuZ., WeissK., WestenfelderC.2005. Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury. Kidney Int., 67:1772–1784.
28.
WynnR.F., HartC.A., Corradi-PeriniC., O'NeillL., EvansC.A., WraithJ.E.et al.2004. A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood, 104:2643–2645.
29.
ZhangY., OuL., ChengZ., JiaX., GaoN., KongD.2009. Genetic modification of bone marrow mesenchymal stem cells with human CXCR4 gene and migration in vitro. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi, 26:595–600.
