Osteogenesis of Adipose-Derived Stem Cells

Current treatment options for skeletal repair, including immobilization, rigid fixation, alloplastic materials and bone grafts, have significant limitations. Bone tissue engineering offers a promising method for the repair of bone deficieny caused by fractures, bone loss and tumors. The use of adipose derived stem cells (ASCs) has received attention because of the self-renewal ability, high proliferative capacity and potential of osteogenic differentiation in vitro and in vivo studies of bone regeneration. Although cell therapies using ASCs are widely promising in various clinical fields, no large human clinical trials exist for bone tissue engineering. The aim of this review is to introduce how they are harvested, examine the characterization of ASCs, to review the mechanisms of osteogenic differentiation, to analyze the effect of mechanical and chemical stimuli on ASC osteodifferentiation, to summarize the current knowledge about usage of ASC in vivo studies and clinical trials, and finally to conclude with a general summary of the field and comments on its future direction.

[1]  V. Rosen,et al.  Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo. , 1996, Growth factors.

[2]  Kotaro Yoshimura,et al.  Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirates , 2006, Journal of cellular physiology.

[3]  J. Lieberman,et al.  Genetic Modification of Stem Cells to Enhance Bone Repair , 2004, Annals of Biomedical Engineering.

[4]  K. Leong,et al.  The Notch pathway in prostate development and cancer. , 2008, Differentiation; research in biological diversity.

[5]  J-Z Qin,et al.  Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-κB and PPARγ , 2002, Cell Death and Differentiation.

[6]  P. Simmons,et al.  Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. , 1991, Blood.

[7]  J. H. Kim,et al.  In vivo osteogenic differentiation of human adipose-derived stem cells in an injectable in situ-forming gel scaffold. , 2009, Tissue engineering. Part A.

[8]  H. Lorenz,et al.  Multilineage cells from human adipose tissue: implications for cell-based therapies. , 2001, Tissue engineering.

[9]  K. Tezuka,et al.  Stimulation of Osteoblastic Cell Differentiation by Notch , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[10]  K. Harii,et al.  Cell-Assisted Lipotransfer for Cosmetic Breast Augmentation: Supportive Use of Adipose-Derived Stem/Stromal Cells , 2007, Aesthetic Plastic Surgery.

[11]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.

[12]  R. Albin.  Regeneration , 1993, Neurology.

[13]  G. Evans,et al.  In vivo osteogenic potential of human adipose-derived stem cells/poly lactide-co-glycolic acid constructs for bone regeneration in a rat critical-sized calvarial defect model. , 2007, Tissue engineering.

[14]  A. Montag,et al.  CCN1/Cyr61 Is Regulated by the Canonical Wnt Signal and Plays an Important Role in Wnt3A-Induced Osteoblast Differentiation of Mesenchymal Stem Cells , 2006, Molecular and Cellular Biology.

[15]  R. Suuronen,et al.  Novel maxillary reconstruction with ectopic bone formation by GMP adipose stem cells. , 2009, International journal of oral and maxillofacial surgery.

[16]  A. Yamaguchi,et al.  Induction of osteogenic differentiation by hedgehog proteins. , 1997, Biochemical and biophysical research communications.

[17]  A. Braccini,et al.  The osteogenicity of implanted engineered bone constructs is related to the density of clonogenic bone marrow stromal cells , 2007, Journal of tissue engineering and regenerative medicine.

[18]  J. Emmersen,et al.  Adipose-derived stem cells from the brown bear (Ursus arctos) spontaneously undergo chondrogenic and osteogenic differentiation in vitro. , 2011, Stem cell research.

[19]  J. Rhie,et al.  Osteogenic differentiation of human adipose tissue-derived stromal cells (hASCs) in a porous three-dimensional scaffold. , 2008, Biochemical and biophysical research communications.

[20]  J. Westendorf,et al.  Wnt signaling in osteoblasts and bone diseases. , 2004, Gene.

[21]  G. Boland,et al.  Wnt signaling during BMP‐2 stimulation of mesenchymal chondrogenesis , 2002, Journal of cellular biochemistry.

[22]  M. van Griensven,et al.  Human adipose derived stem cells reduce callus volume upon BMP-2 administration in bone regeneration. , 2011, Injury.

[23]  Dong-Woo Cho,et al.  Surface modification with fibrin/hyaluronic acid hydrogel on solid-free form-based scaffolds followed by BMP-2 loading to enhance bone regeneration. , 2011, Bone.

[24]  M. Matúšková,et al.  Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. , 2007, Cancer research.

[25]  S. Majumdar,et al.  Insulin‐Like Growth Factor I Is Required for the Anabolic Actions of Parathyroid Hormone on Mouse Bone , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[26]  Wilfredo B. Carada.  Development Paradigms and Operational Principles of DevelopmentManagement : An Integrative Analysis , 1995 .

[27]  K. Lyons,et al.  Wnt10b Deficiency Results in Age-Dependent Loss of Bone Mass and Progressive Reduction of Mesenchymal Progenitor Cells , 2010, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[28]  新藤 健太郎.  Osteogenic differentiation of the mesenchymal progenitor cells, Kusa is suppressed by Notch signaling , 2003 .

[29]  N. Itoh,et al.  FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. , 2002, Genes & development.

[30]  M. Karin,et al.  A dual role for Ikk alpha in tooth development. , 2004, Developmental cell.

[31]  J. Griffin,et al.  Modulation of Notch signaling by mastermind-like (MAML) transcriptional co-activators and their involvement in tumorigenesis. , 2004, Seminars in cancer biology.

[32]  S. Chiba.  Concise Review: Notch Signaling in Stem Cell Systems , 2006 .

[33]  J. Polak,et al.  Stem cells: sources and applications. , 2002, Clinical otolaryngology and allied sciences.

[34]  Wei Tang,et al.  Effects of gamma-secretase inhibition on the proliferation and vitamin D(3) induced osteogenesis in adipose derived stem cells. , 2010, Biochemical and biophysical research communications.

[35]  Skylar W. Marvel,et al.  Osteogenic Effects of Rest Inserted and Continuous Cyclic Tensile Strain on hASC Lines with Disparate Osteodifferentiation Capabilities , 2009, Annals of Biomedical Engineering.

[36]  Jeffrey C. Wang,et al.  Comparison of Human Mesenchymal Stem Cells Derived From Adipose Tissue and Bone Marrow for Ex Vivo Gene Therapy in Rat Spinal Fusion Model , 2008, Spine.

[37]  Benjamin M. Wu,et al.  Human Adipose Derived Stromal Cells Heal Critical Size Mouse Calvarial Defects , 2010, PloS one.

[38]  M. Long,et al.  Osteogenic differentiation of human mesenchymal stem cells is regulated by bone morphogenetic protein‐6 , 2006, Journal of cellular biochemistry.

[39]  Andrew L. Goertzen,et al.  Viability and proliferation potential of adipose-derived stem cells following labeling with a positron-emitting radiotracer , 2011, European Journal of Nuclear Medicine and Molecular Imaging.

[40]  S. Wenisch,et al.  Further insights into the characterization of equine adipose tissue-derived mesenchymal stem cells , 2011, Veterinary Research Communications.

[41]  A. Zapata,et al.  Low doses of bone morphogenetic protein 4 increase the survival of human adipose-derived stem cells maintaining their stemness and multipotency. , 2011, Stem cells and development.

[42]  Benjamin M. Wu,et al.  Bone morphogenetic protein 2 and retinoic acid accelerate in vivo bone formation, osteoclast recruitment, and bone turnover. , 2005, Tissue engineering.

[43]  Sun-Woong Kang,et al.  Enhancement of bone regeneration by gene delivery of BMP2/Runx2 bicistronic vector into adipose-derived stromal cells. , 2010, Biomaterials.

[44]  Sanjin Zvonic,et al.  Immunophenotype of Human Adipose‐Derived Cells: Temporal Changes in Stromal‐Associated and Stem Cell–Associated Markers , 2006, Stem cells.

[45]  D. Ornitz,et al.  The FGF ligand–receptor signaling system in chondrogenesis, osteogenesis and vascularization of the endochondral skeleton , 2007 .

[46]  R. Ruberg.  Cell-Assisted Lipotransfer for Facial Lipoatrophy: Efficacy of Clinical Use of Adipose-Derived Stem Cells , 2010 .

[47]  Cun-Yu Wang,et al.  Noncanonical Wnt-4 Signaling Enhances Bone Regeneration of Mesenchymal Stem Cells in Craniofacial Defects through Activation of p38 MAPK* , 2007, Journal of Biological Chemistry.

[48]  I. Kalajzic,et al.  In vivo and in vitro comparison of the effects of FGF-2 null and haplo-insufficiency on bone formation in mice. , 2006, Biochemical and biophysical research communications.

[49]  G. Weinmaster,et al.  Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts. , 1999, Development.

[50]  Prosper Benhaim,et al.  Bone induction by BMP‐2 transduced stem cells derived from human fat , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[51]  R. Nusse,et al.  Mechanisms of Wnt signaling in development. , 1998, Annual review of cell and developmental biology.

[52]  T. Tsukazaki,et al.  Critical Regulation of Bone Morphogenetic Protein-induced Osteoblastic Differentiation by Delta1/Jagged1-activated Notch1 Signaling* , 2005, Journal of Biological Chemistry.

[53]  Laurence Vico,et al.  Ex Vivo bone formation in bovine trabecular bone cultured in a dynamic 3D bioreactor is enhanced by compressive mechanical strain. , 2008, Tissue engineering. Part A.

[54]  J. Gimble,et al.  Adipose-derived stem cells for regenerative medicine. , 2007, Circulation research.

[55]  Byung-Soo Kim,et al.  Effects of BMP-2 and vitamin D3 on the osteogenic differentiation of adipose stem cells. , 2011, Biochemical and biophysical research communications.

[56]  Diane Gershon,et al.  Complex political, ethical and legal issues surround research on human embryonic stem cells. , 2003, Nature.

[57]  Wei Tang,et al.  Bone regeneration by BMP-2 enhanced adipose stem cells loading on alginate gel , 2008, Histochemistry and Cell Biology.

[58]  K. Miyazono,et al.  TGF-beta signalling from cell membrane to nucleus through SMAD proteins. , 1997, Nature.

[59]  K. Dai,et al.  Effects of flow shear stress and mass transport on the construction of a large-scale tissue-engineered bone in a perfusion bioreactor. , 2009, Tissue engineering. Part A.

[60]  A. Aono,et al.  Potent ectopic bone-inducing activity of bone morphogenetic protein-4/7 heterodimer. , 1995, Biochemical and biophysical research communications.

[61]  K. Olbrich,et al.  Effects of glutamine, glucose, and oxygen concentration on the metabolism and proliferation of rabbit adipose-derived stem cells. , 2006, Tissue engineering.

[62]  G. Balian,et al.  Growth and differentiation factor-5 (GDF-5) stimulates osteogenic differentiation and increases vascular endothelial growth factor (VEGF) levels in fat-derived stromal cells in vitro. , 2007, Bone.

[63]  P. Schultz,et al.  Purmorphamine induces osteogenesis by activation of the hedgehog signaling pathway. , 2004, Chemistry & biology.

[64]  Robert E Guldberg,et al.  Cyclic mechanical compression increases mineralization of cell-seeded polymer scaffolds in vivo. , 2007, Journal of biomechanical engineering.

[65]  Tatsuya Kobayashi,et al.  Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation , 2008, Nature Medicine.

[66]  Hiko Hyakusoku,et al.  Periodontal tissue regeneration with adipose-derived stem cells. , 2008, Tissue engineering. Part A.

[67]  J. Klein-Nulend,et al.  Osteogenesis versus chondrogenesis by BMP-2 and BMP-7 in adipose stem cells. , 2006, Biochemical and biophysical research communications.

[68]  J. Gimble,et al.  Human adipose-derived adult stem cells produce osteoid in vivo. , 2004, Tissue engineering.

[69]  Á. Raya,et al.  Activation of Notch signaling pathway precedes heart regeneration in zebrafish , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[70]  A. Yayon,et al.  Skeletal Dysplasia and Defective Chondrocyte Differentiation by Targeted Overexpression of Fibroblast Growth Factor 9 in Transgenic Mice , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[71]  M. Longaker,et al.  Differential expression of specific FGF ligands and receptor isoforms during osteogenic differentiation of mouse Adipose-derived Stem Cells (mASCs) recapitulates the in vivo osteogenic pattern. , 2008, Gene.

[72]  L. Lin,et al.  Runx2 Overexpression Enhances Osteoblastic Differentiation and Mineralization in Adipose - Derived Stem Cells in vitro and in vivo , 2006, Calcified Tissue International.

[73]  G. Vunjak‐Novakovic,et al.  Bone grafts engineered from human adipose-derived stem cells in perfusion bioreactor culture. , 2010, Tissue engineering. Part A.

[74]  S. Christakos,et al.  The Vitamin D Receptor, Runx2, and the Notch Signaling Pathway Cooperate in the Transcriptional Regulation of Osteopontin* , 2005, Journal of Biological Chemistry.

[75]  K. M. Lin,et al.  Mechanical strain modulates age-related changes in the proliferation and differentiation of mouse adipose-derived stromal cells , 2010, BMC Cell Biology.

[76]  R. Reis,et al.  Adipose tissue-derived stem cells and their application in bone and cartilage tissue engineering. , 2009, Tissue engineering. Part B, Reviews.

[77]  H. Fujioka,et al.  Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. , 2007, Osteoarthritis and cartilage.

[78]  Min Zhu,et al.  Human adipose tissue is a source of multipotent stem cells. , 2002, Molecular biology of the cell.

[79]  Michael J. Terry,et al.  Repair of Palatal Bone Defects Using Osteogenically Differentiated Fat-Derived Stem Cells , 2006, Plastic and reconstructive surgery.

[80]  J. Rubin,et al.  The Osteogenic Potential of Adipose-Derived Stem Cells for the Repair of Rabbit Calvarial Defects , 2006, Annals of plastic surgery.

[81]  S. Chiba.  Notch signaling in stem cell systems. , 2006, Stem cells.

[82]  T. Yen,et al.  The role of adipose-derived stem cells engineered with the persistently expressing hybrid baculovirus in the healing of massive bone defects. , 2011, Biomaterials.

[83]  G. Lin,et al.  Defining adipose tissue-derived stem cells in tissue and in culture. , 2010, Histology and histopathology.

[84]  Wei Tang,et al.  Osteogenic differentiation of adipose derived stem cells promoted by overexpression of osterix , 2007, Molecular and Cellular Biochemistry.

[85]  D. Ornitz,et al.  Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. , 2002, Genes & development.

[86]  J. Rubin,et al.  Role of Gender and Anatomical Region on Induction of Osteogenic Differentiation of Human Adipose-derived Stem Cells , 2008, Annals of plastic surgery.

[87]  C. Kim,et al.  NF‐κB activation stimulates osteogenic differentiation of mesenchymal stem cells derived from human adipose tissue by increasing TAZ expression , 2010, Journal of cellular physiology.

[88]  E. Canalis,et al.  Notch 1 Overexpression Inhibits Osteoblastogenesis by Suppressing Wnt/β-Catenin but Not Bone Morphogenetic Protein Signaling* , 2006, Journal of Biological Chemistry.

[89]  D. Taşkıran,et al.  Stimulatory effect of 17β-estradiol on osteogenic differentiation potential of rat adipose tissue-derived stem cells. , 2011, General physiology and biophysics.

[90]  L. Gilboa,et al.  Bone morphogenetic protein receptor complexes on the surface of live cells: a new oligomerization mode for serine/threonine kinase receptors. , 2000, Molecular biology of the cell.

[91]  Michael J Gardner,et al.  In vivo cyclic axial compression affects bone healing in the mouse tibia , 2006, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[92]  E. Canalis,et al.  Notch Signaling in Osteoblasts , 2008, Science Signaling.

[93]  Ayse B. Celil,et al.  Bone tissue engineering:recent advances and promising therapeutic agents , 2003, Expert opinion on biological therapy.

[94]  Yilin Cao,et al.  Repair of cranial bone defects with adipose derived stem cells and coral scaffold in a canine model. , 2007, Biomaterials.

[95]  Brendan H. Lee,et al.  Dimorphic effects of Notch signaling in bone homeostasis , 2008, Nature Medicine.

[96]  G. Im,et al.  Electroporation-mediated transfer of Runx2 and Osterix genes to enhance osteogenesis of adipose stem cells. , 2011, Biomaterials.

[97]  M. Hedrick,et al.  The effect of age on osteogenic, adipogenic and proliferative potential of female adipose‐derived stem cells , 2009, Journal of tissue engineering and regenerative medicine.

[98]  P. Gong,et al.  Cyclic tensile stretch modulates osteogenic differentiation of adipose-derived stem cells via the BMP-2 pathway , 2010, Archives of medical science : AMS.

[99]  L. Kedes,et al.  HERP1 Is a Cell Type-specific Primary Target of Notch* , 2002, The Journal of Biological Chemistry.

[100]  M. Urist.  Bone: Formation by Autoinduction , 1965, Science.

[101]  M. Vemuri,et al.  Serum-free, xeno-free culture media maintain the proliferation rate and multipotentiality of adipose stem cells in vitro. , 2009, Cytotherapy.

[102]  Y. Tabata,et al.  Growth and osteogenic differentiation of adipose-derived and bone marrow-derived stem cells on chitosan and chitooligosaccharide films , 2009 .

[103]  R. Ogawa,et al.  Periodontal Tissue Regeneration with Adipose-Derived Stem Cells , 2007 .

[104]  L. Tagliabue,et al.  Bone morphogenetic proteins and tissue engineering: future directions. , 2009, Injury.

[105]  Y. Bae,et al.  Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo. , 2008, Stem cells and development.

[106]  M. Karin,et al.  A Dual Role for Ikkα in Tooth Development , 2004 .

[107]  L. Donahue,et al.  Targeted overexpression of insulin-like growth factor I to osteoblasts of transgenic mice: increased trabecular bone volume without increased osteoblast proliferation. , 2000, Endocrinology.

[108]  M. Longaker,et al.  Concise Review: Adipose‐Derived Stromal Cells for Skeletal Regenerative Medicine , 2011, Stem cells.

[109]  O. Yli-Harja,et al.  Differential gene expression in adipose stem cells cultured in allogeneic human serum versus fetal bovine serum. , 2010, Tissue engineering. Part A.

[110]  Michael L. Blackburn,et al.  A Role for Ethanol-Induced Oxidative Stress in Controlling Lineage Commitment of Mesenchymal Stromal Cells Through Inhibition of Wnt/β-Catenin Signaling , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[111]  E. Canalis,et al.  Notch 1 impairs osteoblastic cell differentiation. , 2003, Endocrinology.

[112]  F. Fernández‐Avilés,et al.  Early Translation of Adipose-Derived Cell Therapy for Cardiovascular Disease , 2009, Cell transplantation.

[113]  J. Nadeau,et al.  Genomic organization and embryonic expression of the mouse fibroblast growth factor 9 gene , 1999, Developmental dynamics : an official publication of the American Association of Anatomists.

[114]  K. Harii,et al.  Progenitor‐Enriched Adipose Tissue Transplantation as Rescue for Breast Implant Complications , 2010, The breast journal.

[115]  G. Brabant,et al.  Wnts differentially regulate colony growth and differentiation of chondrogenic rat calvaria cells. , 2001, Biochimica et biophysica acta.

[116]  Umut A. Gurkan,et al.  The Mechanical Environment of Bone Marrow: A Review , 2008, Annals of Biomedical Engineering.

[117]  M. Matin,et al.  Comparative Analysis of Chemokine Receptor's Expression in Mesenchymal Stem Cells Derived from Human Bone Marrow and Adipose Tissue , 2011, Journal of Molecular Neuroscience.

[118]  Carly M. Kemmis,et al.  Bone morphogenetic protein 6 drives both osteogenesis and chondrogenesis in murine adipose-derived mesenchymal cells depending on culture conditions. , 2010, Biochemical and biophysical research communications.

[119]  K. de Groot,et al.  Material-dependent bone induction by calcium phosphate ceramics: a 2.5-year study in dog. , 2001, Biomaterials.

[120]  C. Picó,et al.  Gene Expression Patterns in Visceral and Subcutaneous Adipose Depots in Rats are Linked to Their Morphologic Features , 2009, Cellular Physiology and Biochemistry.

[121]  Gordana Vunjak-Novakovic,et al.  Effects of initial seeding density and fluid perfusion rate on formation of tissue-engineered bone. , 2008, Tissue engineering. Part A.

[122]  T. Golde,et al.  Notch signaling in cancer. , 2006, Current molecular medicine.

[123]  M. Urist,et al.  Bone Morphogenetic Protein: The Molecularization of Skeletal System Development , 1997, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[124]  J. Lou,et al.  Bone regeneration by implantation of adipose-derived stromal cells expressing BMP-2. , 2007, Biochemical and biophysical research communications.

[125]  M. Urist,et al.  Bone: Formation by Autoinduction , 1965, Science.

[126]  Xiaoxiao Cai,et al.  DAPT Enhances the Apoptosis of Human Tongue Carcinoma Cells , 2009, International Journal of Oral Science.

[127]  J. Szatkowski,et al.  Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery , 2004, Gene Therapy.

[128]  M. Aizawa,et al.  Osteogenesis coordinated in C3H10T1/2 cells by adipogenesis-dependent BMP-2 expression system. , 2000, Tissue engineering.

[129]  P. Farlie,et al.  Bone regeneration in a rabbit critical-sized skull defect using autologous adipose-derived cells. , 2008, Tissue engineering. Part A.

[130]  Q. Yuan,et al.  Mechanical stretch inhibits adipogenesis and stimulates osteogenesis of adipose stem cells , 2012, Cell proliferation.

[131]  P. Handford,et al.  Notch receptor–ligand binding and activation: Insights from molecular studies , 2012, Seminars in cell & developmental biology.

[132]  Larry Kedes,et al.  HES and HERP families: Multiple effectors of the notch signaling pathway , 2003, Journal of cellular physiology.

[133]  John J Lannutti,et al.  Compressive forces induce osteogenic gene expression in calvarial osteoblasts. , 2008, Journal of biomechanics.

[134]  Keith L. March,et al.  Secretion of Angiogenic and Antiapoptotic Factors by Human Adipose Stromal Cells , 2004, Circulation.

[135]  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.

[136]  W. Reichert,et al.  Adult adipose-derived stem cell attachment to biomaterials. , 2007, Biomaterials.

[137]  T. Kadesch,et al.  Notch signaling: the demise of elegant simplicity. , 2004, Current opinion in genetics & development.

[138]  R. Baron,et al.  Sonic hedgehog increases the commitment of pluripotent mesenchymal cells into the osteoblastic lineage and abolishes adipocytic differentiation. , 2001, Journal of cell science.

[139]  G. Karsenty,et al.  Osf2/Cbfa1: A Transcriptional Activator of Osteoblast Differentiation , 1997, Cell.

[140]  Andrés J. García,et al.  Human stem cell delivery for treatment of large segmental bone defects , 2010, Proceedings of the National Academy of Sciences.

[141]  P. Ingham,et al.  Hedgehog signaling in animal development: paradigms and principles. , 2001, Genes & development.

[142]  Christopher R. Jacobs,et al.  Non-Canonical Wnt Signaling and N-Cadherin Related β-Catenin Signaling Play a Role in Mechanically Induced Osteogenic Cell Fate , 2009, PloS one.

[143]  E. Füchtbauer,et al.  Activation of the Notch signaling pathway in response to pulp capping of rat molars. , 2005, European journal of oral sciences.

[144]  William V Giannobile,et al.  Platelet-derived growth factor stimulates bone fill and rate of attachment level gain: results of a large multicenter randomized controlled trial. , 2005, Journal of periodontology.

[145]  M. Mattson,et al.  Notch: from neural development to neurological disorders , 2008, Journal of neurochemistry.

[146]  Glenn D Prestwich,et al.  Osteochondral defect repair with autologous bone marrow-derived mesenchymal stem cells in an injectable, in situ, cross-linked synthetic extracellular matrix. , 2006, Tissue engineering.

[147]  M. Longaker,et al.  The Osteogenic Potential of Adipose-Derived Mesenchymal Cells Is Maintained with Aging , 2005, Plastic and reconstructive surgery.

[148]  E. Loboa,et al.  Effects of serial passaging on the adipogenic and osteogenic differentiation potential of adipose-derived human mesenchymal stem cells. , 2007, Tissue engineering.

[149]  K. Sakamoto,et al.  Osteogenic differentiation of the mesenchymal progenitor cells, Kusa is suppressed by Notch signaling. , 2003, Experimental cell research.

[150]  Yoshihisa Suzuki,et al.  Accelerated bone repair with the use of a synthetic BMP-2-derived peptide and bone-marrow stromal cells. , 2005, Journal of biomedical materials research. Part A.

[151]  M. Radisic,et al.  Biomimetic approach to tissue engineering. , 2009, Seminars in cell & developmental biology.

[152]  M. Ito,et al.  Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. , 2000, The Journal of clinical investigation.

[153]  R. Reis,et al.  A novel method for the isolation of subpopulations of rat adipose stem cells with different proliferation and osteogenic differentiation potentials , 2011, Journal of tissue engineering and regenerative medicine.

[154]  M. Reinhold,et al.  Successful posterior interlaminar fusion at the thoracic spine by sole use of β-tricalcium phosphate , 2006, Archives of Orthopaedic and Trauma Surgery.

[155]  A. Jödicke,et al.  Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report. , 2004, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[156]  Di Chen,et al.  Bone Morphogenetic Proteins , 2004, Growth factors.

[157]  L. Miele.  Notch signaling. , 2006, Clinical cancer research : an official journal of the American Association for Cancer Research.

[158]  G. Pirozzi,et al.  Human CD34+/CD90+ ASCs Are Capable of Growing as Sphere Clusters, Producing High Levels of VEGF and Forming Capillaries , 2009, PloS one.

[159]  Christopher R Jacobs,et al.  Mechanically induced osteogenic differentiation – the role of RhoA, ROCKII and cytoskeletal dynamics , 2009, Journal of Cell Science.

[160]  Toshiro Ohashi,et al.  Regulation of cyclic longitudinal mechanical stretch on proliferation of human bone marrow mesenchymal stem cells. , 2007, Molecular & cellular biomechanics : MCB.

[161]  H. Cheung,et al.  Cyclic compression maintains viability and induces chondrogenesis of human mesenchymal stem cells in fibrin gel scaffolds. , 2009, Stem cells and development.

[162]  Christopher H Contag,et al.  Adipose-derived adult stromal cells heal critical-size mouse calvarial defects , 2004, Nature Biotechnology.

[163]  T. Clemens,et al.  Mesenchymal stem cells expressing osteogenic and angiogenic factors synergistically enhance bone formation in a mouse model of segmental bone defect. , 2010, Molecular therapy : the journal of the American Society of Gene Therapy.

[164]  M. Bouxsein,et al.  Bone response to intermittent parathyroid hormone is altered in mice null for {beta}-Arrestin2. , 2005, Endocrinology.

[165]  D. Prockop.  Repair of tissues by adult stem/progenitor cells (MSCs): controversies, myths, and changing paradigms. , 2009, Molecular therapy : the journal of the American Society of Gene Therapy.

[166]  M. Longaker,et al.  Molecular mechanisms of FGF-2 inhibitory activity in the osteogenic context of mouse adipose-derived stem cells (mASCs). , 2008, Bone.

[167]  K. Le Blanc,et al.  Mesenchymal stem cells: progress toward promise. , 2005, Cytotherapy.

[168]  Benjamin M. Wu,et al.  Adipose-derived stem cells and BMP2: Part 1. BMP2-treated adipose-derived stem cells do not improve repair of segmental femoral defects , 2011, Connective tissue research.

[169]  Wei Tang,et al.  Ectopic and in situ bone formation of adipose tissue-derived stromal cells in biphasic calcium phosphate nanocomposite. , 2007, Journal of biomedical materials research. Part A.

[170]  R. Nusse,et al.  Wnt signaling: a common theme in animal development. , 1997, Genes & development.

[171]  L. Buscail,et al.  Adult Stromal Cells Derived from Human Adipose Tissue Provoke Pancreatic Cancer Cell Death both In Vitro and In Vivo , 2009, PloS one.

[172]  P. Marie,et al.  FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. , 2002, Genes & development.

[173]  N. Ueno,et al.  Sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP‐2 , 2002, Journal of cellular physiology.

[174]  J. Gimble,et al.  The Immunogenicity of Human Adipose‐Derived Cells: Temporal Changes In Vitro , 2006, Stem cells.

[175]  J-Z Qin,et al.  Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. , 2002, Cell death and differentiation.