Host blood circulating stem cells are an important cell source that participates in the repair of damaged tissues. The clinical challenge is how to improve the recruitment of circulating stem cells into the local wound area and enhance tissue regeneration. Stromal-derived factor-1 (SDF-1) has been shown to be a potent chemoattractant of blood circulating stem cells into the local wound microenvironment. In order to investigate effects of SDF-1 on bone development and the repair of a large bone defect beyond host self-repair capacity, the BMP-induced subcutaneous ectopic bone formation and calvarial critical-sized defect murine models were used in this preclinical study. A dose escalation of SDF-1 were loaded into collagen scaffolds containing BMP, VEGF, or PDGF, and implanted into subcutaneous sites at mouse dorsa or calvarial critical-sized bone defects for 2 and 4 weeks. The harvested biopsies were examined by microCT and histology. The results demonstrated that while SDF-1 had no effect in the ectopic bone model in promoting de novo osteogenesis, however, in the orthotopic bone model of the critical-sized defects, SDF-1 enhanced calvarial critical-sized bone defect healing similar to VEGF, and PDGF. These results suggest that SDF-1 plays a role in the repair of large critical-sized defect where more cells are needed while not impacting de novo bone formation, which may be associated with the functions of SDF-1 on circulating stem cell recruitment and angiogenesis.
References
[1]
Fodor WL (2003) Tissue engineering and cell based therapies, from the bench to the clinic: the potential to replace, repair and regenerate. Reprod Biol Endocrinol 1: 102.
[2]
Kinzebach S, Bieback K (2013) Expansion of Mesenchymal Stem/Stromal Cells under Xenogenic-Free Culture Conditions. Adv Biochem Eng Biotechnol 129: 33–57. doi: 10.1007/10_2012_134
[3]
Guo CJ, Gao Y, Hou D, Shi DY, Tong XM, et al. (2011) Preclinical transplantation and safety of HS/PCs expanded from human umbilical cord blood. World J Stem Cells 3: 43–52. doi: 10.4252/wjsc.v3.i5.43
[4]
Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F 3rd (2011) Concise review: Dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells 29: 11–19. doi: 10.1002/stem.559
Bleul CC, Farzan M, Choe H, Parolin C, Clark-Lewis I, et al. (1996) The lymphocyte chemoattractant SDF-1 is a ligand for LESTR/fusin and blocks HIV-1 entry. Nature 382: 829–833. doi: 10.1038/382829a0
[7]
Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S, et al. (1996) Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382: 635–638. doi: 10.1038/382635a0
[8]
Nagasawa T (2001) Role of chemokine SDF-1/PBSF and its receptor CXCR4 in blood vessel development. Ann N Y Acad Sci 947: 112–115 discussion 115–116. doi: 10.1111/j.1749-6632.2001.tb03933.x
[9]
Odemis V, Lamp E, Pezeshki G, Moepps B, Schilling K, et al. (2005) Mice deficient in the chemokine receptor CXCR4 exhibit impaired limb innervation and myogenesis. Mol Cell Neurosci 30: 494–505. doi: 10.1016/j.mcn.2005.07.019
[10]
Lucas D, Battista M, Shi PA, Isola L, Frenette PS (2008) Mobilized hematopoietic stem cell yield depends on species-specific circadian timing. Cell Stem Cell 3: 364–366. doi: 10.1016/j.stem.2008.09.004
[11]
Moser B, Wolf M, Walz A, Loetscher P (2004) Chemokines: multiple levels of leukocyte migration control. Trends Immunol 25: 75–84. doi: 10.1016/j.it.2003.12.005
[12]
Ratajczak MZ, Zuba-Surma E, Kucia M, Reca R, Wojakowski W, et al. (2006) The pleiotropic effects of the SDF-1-CXCR4 axis in organogenesis, regeneration and tumorigenesis. Leukemia 20: 1915–1924. doi: 10.1038/sj.leu.2404357
[13]
Kucia M, Wojakowski W, Reca R, Machalinski B, Gozdzik J, 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. doi: 10.1007/s00005-006-0015-1
[14]
Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, et al. (2004) Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 110: 3300–3305. doi: 10.1161/01.cir.0000147780.30124.cf
[15]
Wang Y, Deng Y, Zhou GQ (2008) SDF-1alpha/CXCR4-mediated migration of systemically transplanted bone marrow stromal cells towards ischemic brain lesion in a rat model. Brain Res 1195: 104–112. doi: 10.1016/j.brainres.2007.11.068
[16]
Gallagher KA, Liu ZJ, Xiao M, Chen H, Goldstein LJ, et al. (2007) Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1 alpha. J Clin Invest 117: 1249–1259. doi: 10.1172/jci29710
[17]
Leveen P, Pekny M, Gebre-Medhin S, Swolin B, Larsson E, et al. (1994) Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities. Genes Dev 8: 1875–1887. doi: 10.1101/gad.8.16.1875
[18]
Soriano P (1994) Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev 8: 1888–1896. doi: 10.1101/gad.8.16.1888
[19]
Jin Q, Anusaksathien O, Webb SA, Printz MA, Giannobile WV (2004) Engineering of tooth-supporting structures by delivery of PDGF gene therapy vectors. Mol Ther 9: 519–526. doi: 10.1016/j.ymthe.2004.01.016
[20]
Nass N, Vogel K, Hofmann B, Presek P, Silber RE, et al. (2010) Glycation of PDGF results in decreased biological activity. Int J Biochem Cell Biol 42: 749–754. doi: 10.1016/j.biocel.2010.01.012
[21]
Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277: 242–245. doi: 10.1126/science.277.5323.242
[22]
Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, et al. (1999) VEGF is required for growth and survival in neonatal mice. Development 126: 1149–1159.
[23]
Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473: 298–307. doi: 10.1038/nature10144
[24]
Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, et al. (1999) VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med 5: 623–628.
[25]
Behr B, Sorkin M, Lehnhardt M, Renda A, Longaker MT, et al. (2012) A comparative analysis of the osteogenic effects of BMP-2, FGF-2, and VEGFA in a calvarial defect model. Tissue Eng Part A 18: 1079–1086. doi: 10.1089/ten.tea.2011.0537
[26]
Hogan BL (1996) Bone morphogenetic proteins: multifunctional regulators of vertebrate development. Genes Dev 10: 1580–1594. doi: 10.1101/gad.10.13.1580
[27]
Giannobile WV, Ryan S, Shih MS, Su DL, Kaplan PL, et al. (1998) Recombinant human osteogenic protein-1 (OP-1) stimulates periodontal wound healing in class III furcation defects. J Periodontol 69: 129–137. doi: 10.1902/jop.1998.69.2.129
[28]
Rutherford RB, Sampath TK, Rueger DC, Taylor TD (1992) Use of bovine osteogenic protein to promote rapid osseointegration of endosseous dental implants. Int J Oral Maxillofac Implants 7: 297–301.
[29]
van den Bergh JP, ten Bruggenkate CM, Groeneveld HH, Burger EH, Tuinzing DB (2000) Recombinant human bone morphogenetic protein-7 in maxillary sinus floor elevation surgery in 3 patients compared to autogenous bone grafts. A clinical pilot study. J Clin Periodontol 27: 627–636. doi: 10.1034/j.1600-051x.2000.027009627.x
[30]
Sampath TK, Reddi AH (1981) Dissociative extraction and reconstitution of extracellular matrix components involved in local bone differentiation. Proc Natl Acad Sci U S A 78: 7599–7603. doi: 10.1073/pnas.78.12.7599
[31]
Shigenobu K, Kaneda K, Nagai N, Kuboki Y (1993) Localization of bone morphogenetic protein-induced bone and cartilage formation on a new carrier: fibrous collagen membrane. Ann Chir Gynaecol Suppl 207: 85–90.
[32]
Ripamonti U, Reddi AH (1992) Growth and morphogenetic factors in bone induction: role of osteogenin and related bone morphogenetic proteins in craniofacial and periodontal bone repair. Crit Rev Oral Biol Med 3: 1–14.
[33]
Jin QM, Takita H, Kohgo T, Atsumi K, Itoh H, et al. (2000) Effects of geometry of hydroxyapatite as a cell substratum in BMP-induced ectopic bone formation. J Biomed Mater Res 52: 491–499. doi: 10.1002/1097-4636(20000905)51:3<491::aid-jbm25>3.3.co;2-t
[34]
Sampath TK, Reddi AH (1983) Homology of bone-inductive proteins from human, monkey, bovine, and rat extracellular matrix. Proc Natl Acad Sci U S A 80: 6591–6595. doi: 10.1073/pnas.80.21.6591
[35]
Tang JM, Wang JN, Zhang L, Zheng F, Yang JY, et al. (2011) VEGF/SDF-1 promotes cardiac stem cell mobilization and myocardial repair in the infarcted heart. Cardiovasc Res 91: 402–411. doi: 10.1093/cvr/cvr053
[36]
Liu N, Tian J, Cheng J, Zhang J (2013) Migration of CXCR4 gene-modified bone marrow-derived mesenchymal stem cells to the acute injured kidney. J Cell Biochem 114: 2677–2689. doi: 10.1002/jcb.24615
[37]
Suzuki T, Lee CH, Chen M, Zhao W, Fu SY, et al. (2011) Induced migration of dental pulp stem cells for in vivo pulp regeneration. J Dent Res 90: 1013–1018. doi: 10.1177/0022034511408426
[38]
Behnan J, Isakson P, Joel M, Cilio C, Langmoen IA, et al. (2013) Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression. Stem Cells.(Pubmed Identifier:24302539).
[39]
Feisst V, Brooks AE, Chen CJ, Dunbar PR (2014) Characterization of mesenchymal progenitor cell populations directly derived from human dermis. Stem Cells Dev 23: 631–642. doi: 10.1089/scd.2013.0207
[40]
Rath SN, Nooeaid P, Arkudas A, Beier JP, Strobel LA, et al. (2013) Adipose- and bone marrow-derived mesenchymal stem cells display different osteogenic differentiation patterns in 3D bioactive glass-based scaffolds. J Tissue Eng Regen Med.(Pubmed Identifier: 24357645).
[41]
Kumagai K, Vasanji A, Drazba JA, Butler RS, Muschler GF (2008) Circulating cells with osteogenic potential are physiologically mobilized into the fracture healing site in the parabiotic mice model. J Orthop Res 26: 165–175. doi: 10.1002/jor.20477
[42]
Otsuru S, Tamai K, Yamazaki T, Yoshikawa H, Kaneda Y (2008) Circulating bone marrow-derived osteoblast progenitor cells are recruited to the bone-forming site by the CXCR4/stromal cell-derived factor-1 pathway. Stem Cells 26: 223–234. doi: 10.1634/stemcells.2007-0515
[43]
Ji W, Yang F, Ma J, Bouma MJ, Boerman OC, et al. (2013) Incorporation of stromal cell-derived factor-1alpha in PCL/gelatin electrospun membranes for guided bone regeneration. Biomaterials 34: 735–745. doi: 10.1016/j.biomaterials.2012.10.016
[44]
Shinohara K, Greenfield S, Pan H, Vasanji A, Kumagai K, et al. (2011) Stromal cell-derived factor-1 and monocyte chemotactic protein-3 improve recruitment of osteogenic cells into sites of musculoskeletal repair. J Orthop Res 29: 1064–1069. doi: 10.1002/jor.21374
[45]
Fujio M, Yamamoto A, Ando Y, Shohara R, Kinoshita K, et al. (2011) Stromal cell-derived factor-1 enhances distraction osteogenesis-mediated skeletal tissue regeneration through the recruitment of endothelial precursors. Bone 49: 693–700. doi: 10.1016/j.bone.2011.06.024
[46]
Hosogane N, Huang Z, Rawlins BA, Liu X, Boachie-Adjei O, et al. (2010) Stromal derived factor-1 regulates bone morphogenetic protein 2-induced osteogenic differentiation of primary mesenchymal stem cells. Int J Biochem Cell Biol 42: 1132–1141. doi: 10.1016/j.biocel.2010.03.020
[47]
Kim DS, Kim YS, Bae WJ, Lee HJ, Chang SW, et al. (2013) The role of SDF-1 and CXCR4 on odontoblastic differentiation in human dental pulp cells. Int Endod J.(Pubmed Identifiier: 24033610).
