Synergistic effects of the dual release of stromal cell-derived factor-1 and bone morphogenetic protein-2 from hydrogels on bone regeneration.

The objective of this study is to evaluate the activity of gelatin hydrogels incorporating combined stromal cell-derived factor-1 (SDF-1) and bone morphogenetic protein-2 (BMP-2) on the in vivo bone regeneration at an ulna critical-sized defect and subcutaneous site of rats, and compared with that of those incorporating either SDF-1 or BMP-2. The similar release profile of SDF-1 and BMP-2 from the hydrogels was observed with or without the combination of BMP-2 and SDF-1, respectively. An enhanced bone regeneration by the hydrogels incorporating combined SDF-1 and BMP-2 was observed. In addition, the implantation of hydrogels incorporating combined SDF-1 and BMP-2 enhanced the expression level of CXC chemokine cell-surface receptor-4 (Cxcr4), Runt-related factor-2 (Runx2), and Osteocalcin genes. The experiments with green fluorescent protein (GFP)-positive Chimeric mice revealed that the recruitment of bone marrow-derived cells was promoted and a vascular-like structure together with strong accumulation of CD31- and CD34-positive cells was observed at the site of hydrogels incorporating combined SDF-1 and BMP-2 implanted. In addition, a large fraction of CD29- and CD44-positive non-hematopoietic cells was detected. It is concluded that the combined release of SDF-1 and BMP-2 enhanced the recruitment of osteogenic cells and angiogenesis, resulting in the synergistic effect on bone regeneration.

[1]  H. Hodges,et al.  Transplantation of neural stem cells in a rat model of stroke: assessment of short-term graft survival and acute host immunological response , 2002, Brain Research.

[2]  A. Nordheim,et al.  Id Genes Are Direct Targets of Bone Morphogenetic Protein Induction in Embryonic Stem Cells* , 1999, The Journal of Biological Chemistry.

[3]  C. Wan,et al.  Allogenic peripheral blood derived mesenchymal stem cells (MSCs) enhance bone regeneration in rabbit ulna critical‐sized bone defect model , 2006, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[4]  W. Pu,et al.  Mesenchymal stem/stromal cells (MSC) transfected with stromal derived factor 1 (SDF-1) for therapeutic neovascularization: enhancement of cell recruitment and entrapment. , 2007, Medical hypotheses.

[5]  Y. Joung,et al.  Controlled dual release of basic fibroblast growth factor and indomethacin from heparin-conjugated polymeric micelle. , 2008, International journal of pharmaceutics.

[6]  Y. Tabata,et al.  Experimental tissue regeneration by DDS technology of bio-signaling molecules. , 2007, Journal of dermatological science.

[7]  J. Folkman.  Angiogenesis: an organizing principle for drug discovery? , 2007, Nature reviews. Drug discovery.

[8]  M. Ferguson,et al.  Cytokine gene expression in a murine wound healing model. , 2005, Cytokine.

[9]  V. Velebný,et al.  Isolation and characterization of mesenchymal stem cell population entrapped in bone marrow collection sets , 2008, Cell biology international.

[10]  J. Lieberman,et al.  Influence of short-term adenoviral vector and prolonged lentiviral vector mediated bone morphogenetic protein-2 expression on the quality of bone repair in a rat femoral defect model. , 2008, Bone.

[11]  Yasuhiko Tabata,et al.  Controlled release of bone morphogenetic protein-2 enhances recruitment of osteogenic progenitor cells for de novo generation of bone tissue. , 2010, Tissue engineering. Part A.

[12]  Yasuhiko Tabata,et al.  Osteogenic differentiation of mesenchymal stem cells in biodegradable sponges composed of gelatin and beta-tricalcium phosphate. , 2005, Biomaterials.

[13]  Geert Carmeliet,et al.  Placental growth factor mediates mesenchymal cell development, cartilage turnover, and bone remodeling during fracture repair. , 2006, The Journal of clinical investigation.

[14]  Geoffrey C Gurtner,et al.  Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1 , 2004, Nature Medicine.

[15]  Laura J Suggs,et al.  Controlled release of stromal cell-derived factor-1 alpha in situ increases c-kit+ cell homing to the infarcted heart. , 2007, Tissue engineering.

[16]  R. Alon,et al.  Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. , 1999, Science.

[17]  Robert Langer,et al.  EDITORIAL: TISSUE ENGINEERING: PERSPECTIVES, CHALLENGES, AND FUTURE DIRECTIONS , 2007 .

[18]  Antonios G Mikos,et al.  Dual growth factor delivery from degradable oligo(poly(ethylene glycol) fumarate) hydrogel scaffolds for cartilage tissue engineering. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[19]  D J Mooney,et al.  Regulating Bone Formation via Controlled Scaffold Degradation , 2003, Journal of dental research.

[20]  Fan Zhang,et al.  Cytokine-mediated deployment of SDF-1 induces revascularization through recruitment of CXCR4+ hemangiocytes , 2006, Nature Medicine.

[21]  J O Hollinger,et al.  The critical size defect as an experimental model to test bone repair materials. , 1990, The Journal of craniofacial surgery.

[22]  Yasuhiko Tabata,et al.  Controlled Release of Stromal-Cell-Derived Factor-1 from Gelatin Hydrogels Enhances Angiogenesis , 2010, Journal of biomaterials science. Polymer edition.

[23]  E. Bonifacio,et al.  Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. , 2005, Blood.

[24]  David J Mooney,et al.  Locally enhanced angiogenesis promotes transplanted cell survival. , 2004, Tissue engineering.

[25]  V. Paralkar,et al.  Osteogenin and recombinant bone morphogenetic protein 2B are chemotactic for human monocytes and stimulate transforming growth factor beta 1 mRNA expression. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[26]  G. Viglietto,et al.  Role of soluble mediators in angiogenesis. , 1996, European journal of cancer.

[27]  Y. Tabata,et al.  In vivo degradability of hydrogels prepared from different gelatins by various cross-linking methods , 2005, Journal of biomaterials science. Polymer edition.

[28]  S. Papapoulos,et al.  Bone Morphogenetic Proteins Stimulate Angiogenesis through Osteoblast-Derived Vascular Endothelial Growth Factor A. , 2002, Endocrinology.

[29]  T. Mikawa,et al.  BMP signals promote proepicardial protrusion necessary for recruitment of coronary vessel and epicardial progenitors to the heart. , 2010, Developmental cell.

[30]  T. Springer,et al.  The Chemokine SDF-1 Is a Chemoattractant for Human CD34+ Hematopoietic Progenitor Cells and Provides a New Mechanism to Explain the Mobilization of CD34+ Progenitors to Peripheral Blood , 1997, The Journal of experimental medicine.

[31]  K. Satomura,et al.  Circulating Skeletal Stem Cells , 2001, The Journal of cell biology.

[32]  S. Milz,et al.  Influence of in vitro cultivation on the integration of cell-matrix constructs after subcutaneous implantation. , 2007, Tissue engineering.

[33]  T. Wagner.  Bone morphogenetic protein signaling in stem cells − one signal, many consequences , 2007, The FEBS journal.

[34]  J. Schantz,et al.  Cell guidance in tissue engineering: SDF-1 mediates site-directed homing of mesenchymal stem cells within three-dimensional polycaprolactone scaffolds. , 2007, Tissue engineering.

[35]  R. Markwald,et al.  BMP-2 induces cell migration and periostin expression during atrioventricular valvulogenesis. , 2008, Developmental biology.

[36]  Q. Gao,et al.  Effects of bone morphogenetic protein-2 on proliferation and angiogenesis in oral squamous cell carcinoma. , 2010, International journal of oral and maxillofacial surgery.

[37]  Ulrich Joos,et al.  VEGF-activated angiogenesis during bone regeneration. , 2005, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[38]  B. Frenkel,et al.  A Novel Regulatory Role for Stromal-derived Factor-1 Signaling in Bone Morphogenic Protein-2 Osteogenic Differentiation of Mesenchymal C2C12 Cells* , 2007, Journal of Biological Chemistry.

[39]  J. Hayakawa,et al.  Dextran sulfate and stromal cell derived factor-1 promote CXCR4 expression and improve bone marrow homing efficiency of infused hematopoietic stem cells. , 2009, Journal of Nippon Medical School = Nippon Ika Daigaku zasshi.

[40]  Liping Tang,et al.  The effect of incorporation of SDF-1alpha into PLGA scaffolds on stem cell recruitment and the inflammatory response. , 2010, Biomaterials.

[41]  Hideki Yoshikawa,et al.  Bone marrow-derived osteoblast progenitor cells in circulating blood contribute to ectopic bone formation in mice. , 2007, Biochemical and biophysical research communications.

[42]  Eben Alsberg,et al.  Dual growth factor delivery and controlled scaffold degradation enhance in vivo bone formation by transplanted bone marrow stromal cells. , 2004, Bone.

[43]  Robert Langer,et al.  Tissue engineering: perspectives, challenges, and future directions. , 2007, Tissue engineering.

[44]  L. David,et al.  Emerging role of bone morphogenetic proteins in angiogenesis. , 2009, Cytokine & growth factor reviews.

[45]  R. Reis,et al.  Osteoinduction in human fat-derived stem cells by recombinant human bone morphogenetic protein-2 produced in Escherichia coli , 2007, Biotechnology Letters.

[46]  E. Langenfeld,et al.  Expression of bone morphogenetic proteins in human lung carcinomas. , 2005, The Annals of thoracic surgery.

[47]  O. Boachie-Adjei,et al.  Stromal derived factor-1 regulates bone morphogenetic protein 2-induced osteogenic differentiation of primary mesenchymal stem cells. , 2010, The international journal of biochemistry & cell biology.

[48]  H. Kleinman,et al.  Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: In vivo neovascularization induced by stromal-derived factor-1alpha. , 1999, The American journal of pathology.

[49]  M. Casal,et al.  Bone morphogenetic proteins in tissue engineering: the road from laboratory to clinic, part II (BMP delivery) , 2008, Journal of tissue engineering and regenerative medicine.

[50]  Christoph Dehio,et al.  VEGF-A and PlGF-1 stimulate chemotactic migration of human mesenchymal progenitor cells. , 2005, Biochemical and biophysical research communications.

[51]  Yasuhiko Tabata,et al.  Significance of release technology in tissue engineering. , 2005, Drug discovery today.

[52]  Sebastian Brenner,et al.  Stromal cell-derived factor-1alpha-directed chemoattraction of transiently CXCR4-overexpressing bone marrow stromal cells into functionalized three-dimensional biomimetic scaffolds. , 2009, Tissue engineering. Part C, Methods.

[53]  J. Szemraj,et al.  The positive correlation between gene expression of the two angiogenic factors: VEGF and BMP-2 in lung cancer patients. , 2009, Lung cancer.

[54]  Tomoko Nakanishi,et al.  ‘Green mice’ as a source of ubiquitous green cells , 1997, FEBS letters.

[55]  Hideki Yoshikawa,et al.  Circulating Bone Marrow‐Derived Osteoblast Progenitor Cells Are Recruited to the Bone‐Forming Site by the CXCR4/Stromal Cell‐Derived Factor‐1 Pathway , 2008, Stem cells.

[56]  Rinat Abramovitch,et al.  VEGF-Induced Adult Neovascularization: Recruitment, Retention, and Role of Accessory Cells , 2006, Cell.

[57]  E. Langenfeld,et al.  Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. , 2004, Molecular cancer research : MCR.

[58]  K. Seuwen,et al.  Bone morphogenetic protein 2 induces placental growth factor in mesenchymal stem cells. , 2003, Bone.

[59]  O. Kozawa,et al.  Involvement of p70 S6 kinase in bone morphogenetic protein signaling: Vascular endothelial growth factor synthesis by bone morphogenetic protein‐4 in osteoblasts , 2001, Journal of cellular biochemistry.