Uncovering the periosteum for skeletal regeneration: the stem cell that lies beneath.

The cartilage- and bone-forming properties of the periosteum have long since been recognized. As one of the major sources of skeletal progenitor cells, the periosteum plays a crucial role not only in bone development and growth, but also during bone fracture healing. Aided by the continuous expansion of tools and techniques, we are now starting to acquire more insight into the specific role and regulation of periosteal cells. From a therapeutic point of view, the periosteum has attracted much attention as a cell source for bone tissue engineering purposes. This interest derives not only from the physiological role of the periosteum during bone repair, but is also supported by the unique properties and marked bone-forming potential of expanded periosteum-derived cells. We provide an overview of the current knowledge of periosteal cell biology, focusing on the cellular composition and molecular regulation of this remarkable tissue, as well as the application of periosteum-derived cells in regenerative medicine approaches. This article is part of a Special Issue entitled "Stem Cells and Bone".

[1]  Xinping Zhang,et al.  Expression of endogenous BMP-2 in periosteal progenitor cells is essential for bone healing. , 2011, Bone.

[2]  A. Simpson,et al.  The blood supply of the periosteum. , 1985, Journal of anatomy.

[3]  R. Schmelzeisen,et al.  Making bone: implant insertion into tissue-engineered bone for maxillary sinus floor augmentation-a preliminary report. , 2003, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[4]  D. Ornitz,et al.  Fibroblast growth factor expression during skeletal fracture healing in mice , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[5]  Steven Boonen,et al.  Skeletal sexual dimorphism: relative contribution of sex steroids, GH-IGF1, and mechanical loading. , 2010, The Journal of endocrinology.

[6]  R. Guldberg,et al.  Structural bone allograft combined with genetically engineered mesenchymal stem cells as a novel platform for bone tissue engineering. , 2006, Tissue engineering.

[7]  E. Orwoll.  Androgens: Basic Biology and Clinical Implication , 2001, Calcified Tissue International.

[8]  Hana Chang,et al.  Concise Review: The Periosteum: Tapping into a Reservoir of Clinically Useful Progenitor Cells , 2012, Stem cells translational medicine.

[9]  Geert Carmeliet,et al.  Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. , 2010, Developmental cell.

[10]  B. Sacchetti,et al.  Self-Renewing Osteoprogenitors in Bone Marrow Sinusoids Can Organize a Hematopoietic Microenvironment , 2007, Cell.

[11]  David E. Komatsu,et al.  Modulation of Wnt signaling influences fracture repair , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[12]  Francesco Dell'Accio,et al.  Mesenchymal multipotency of adult human periosteal cells demonstrated by single-cell lineage analysis. , 2006, Arthritis and rheumatism.

[13]  C. Colnot,et al.  Skeletal Cell Fate Decisions Within Periosteum and Bone Marrow During Bone Regeneration , 2008, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[14]  M. Chanavaz.  Anatomy and histophysiology of the periosteum: quantification of the periosteal blood supply to the adjacent bone with 85Sr and gamma spectrometry. , 1995, The Journal of oral implantology.

[15]  A. McMahon,et al.  Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. , 2001, The Journal of clinical investigation.

[16]  T A Einhorn,et al.  Growth Factor Regulation of Fracture Repair , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[17]  R. Johnson,et al.  Interaction of Ihh and BMP/Noggin signaling during cartilage differentiation. , 1999, Developmental biology.

[18]  D. Hu,et al.  Molecular aspects of healing in stabilized and non‐stabilized fractures , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[19]  E. Schwarz,et al.  Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. , 2002, The Journal of clinical investigation.

[20]  D. Marsh,et al.  The biology of fracture healing: optimising outcome. , 1999, British medical bulletin.

[21]  Marie-Christine Chaboissier,et al.  The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. , 2002, Genes & development.

[22]  Y. Sakaguchi,et al.  Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. , 2005, Arthritis and rheumatism.

[23]  Jan Schrooten,et al.  Expansion of Murine Periosteal Progenitor Cells with Fibroblast Growth Factor 2 Reveals an Intrinsic Endochondral Ossification Program Mediated by Bone Morphogenetic Protein 2 , 2014, Stem cells.

[24]  A C Masquelet,et al.  Induced membranes secrete growth factors including vascular and osteoinductive factors and could stimulate bone regeneration , 2004, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[25]  R. Guldberg,et al.  COX-2 from the injury milieu is critical for the initiation of periosteal progenitor cell mediated bone healing. , 2008, Bone.

[26]  Carsten Perka,et al.  Bone engineering on the basis of periosteal cells cultured in polymer fleeces , 1999, Journal of materials science. Materials in medicine.

[27]  Jan Schrooten,et al.  Engineering Vascularized Bone: Osteogenic and Proangiogenic Potential of Murine Periosteal Cells , 2012, Stem cells.

[28]  J. Schrooten,et al.  Probing the osteoinductive effect of calcium phosphate by using an in vitro biomimetic model. , 2011, Tissue engineering. Part A.

[29]  P. Bianco,et al.  Evaluation of the osteoconductive potential of bone substitutes embedded with schneiderian membrane- or maxillary bone marrow-derived osteoprogenitor cells. , 2013, Clinical oral implants research.

[30]  F. Luyten,et al.  Species specificity of ectopic bone formation using periosteum-derived mesenchymal progenitor cells. , 2006, Tissue engineering.

[31]  S. Lepreux,et al.  Behaviour of cancellous bone graft placed in induced membranes. , 2002, British journal of plastic surgery.

[32]  Sylvain Catros,et al.  Subcutaneous‐induced membranes have no osteoinductive effect on macroporous HA‐TCP in vivo , 2009, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[33]  J. Schrooten,et al.  Enhancement of osteogenic gene expression for the differentiation of human periosteal derived cells. , 2011, Stem cell research.

[34]  E. Orwoll.  Toward an Expanded Understanding of the Role of the Periosteum in Skeletal Health , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[35]  C. Kaps,et al.  Human periosteum-derived progenitor cells express distinct chemokine receptors and migrate upon stimulation with CCL2, CCL25, CXCL8, CXCL12, and CXCL13. , 2008, European journal of cell biology.

[36]  D. Coutu,et al.  Inhibition of cellular senescence by developmentally regulated FGF receptors in mesenchymal stem cells. , 2011, Blood.

[37]  Thomas A Einhorn,et al.  Differential Temporal Expression of Members of the Transforming Growth Factor β Superfamily During Murine Fracture Healing , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[38]  Ben D. MacArthur,et al.  Mesenchymal and haematopoietic stem cells form a unique bone marrow niche , 2010, Nature.

[39]  H. Kronenberg,et al.  Developmental regulation of the growth plate , 2003, Nature.

[40]  P. Giannoudis,et al.  Induced periosteum a complex cellular scaffold for the treatment of large bone defects. , 2013, Bone.

[41]  E. Schwarz,et al.  The effect of mesenchymal stem cell sheets on structural allograft healing of critical sized femoral defects in mice. , 2014, Biomaterials.

[42]  Thomas A Einhorn,et al.  The biology of fracture healing. , 2011, Injury.

[43]  L. Ollier.  Traité expérimental et clinique de la régénération des os et de la production artificielle du tissu osseux , 1867 .

[44]  Roland Baron,et al.  WNT signaling in bone homeostasis and disease: from human mutations to treatments , 2013, Nature Medicine.

[45]  J. Schrooten,et al.  Mapping calcium phosphate activated gene networks as a strategy for targeted osteoinduction of human progenitors. , 2013, Biomaterials.

[46]  G. Van den Berghe,et al.  Humanized Culture of Periosteal Progenitors in Allogeneic Serum Enhances Osteogenic Differentiation and In Vivo Bone Formation , 2014, Stem cells translational medicine.

[47]  Liesbet Geris,et al.  The combined bone forming capacity of human periosteal derived cells and calcium phosphates. , 2011, Biomaterials.

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

[49]  Matthew R Allen,et al.  Periosteum: biology, regulation, and response to osteoporosis therapies. , 2004, Bone.

[50]  G. Hsiue,et al.  Bioengineered periosteal progenitor cell sheets to enhance tendon-bone healing in a bone tunnel. , 2012, Biomedical journal.

[51]  R. Schmelzeisen,et al.  Tissue-engineered bone for maxillary sinus augmentation. , 2004, Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons.

[52]  C. Colnot,et al.  Immunolocalization of BMPs, BMP antagonists, receptors, and effectors during fracture repair. , 2010, Bone.

[53]  T A Einhorn,et al.  Impaired fracture healing in the absence of TNF-alpha signaling: the role of TNF-alpha in endochondral cartilage resorption. , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[54]  Xu Cao,et al.  The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine , 2013, Nature Medicine.

[55]  K. Lau,et al.  Expression of the Fibroblast Growth Factor Receptor Genes in Fracture Repair , 2002, Clinical orthopaedics and related research.

[56]  L. Bonassar,et al.  Replacement of an avulsed phalanx with tissue-engineered bone. , 2001, The New England journal of medicine.

[57]  J. Schrooten,et al.  Mechanisms of ectopic bone formation by human osteoprogenitor cells on CaP biomaterial carriers. , 2012, Biomaterials.

[58]  D. Graves,et al.  Impaired Fracture Healing in the Absence of TNF‐α Signaling: The Role of TNF‐α in Endochondral Cartilage Resorption , 2003 .

[59]  M. Tsunoda,et al.  Role of fracture hematoma and periosteum during fracture healing in rats: interaction of fracture hematoma and the periosteum in the initial step of the healing process , 2000, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[60]  S. Murakami,et al.  Expression of Indian Hedgehog During Fracture Healing in Adult Rat Femora , 2000, Calcified Tissue International.

[61]  I. Kalajzic,et al.  Analysis of αSMA‐Labeled Progenitor Cell Commitment Identifies Notch Signaling as an Important Pathway in Fracture Healing , 2014, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[62]  H. Declercq,et al.  Isolation and Osteogenic Differentiation of Rat Periosteum-derived Cells , 2005, Cytotechnology.

[63]  Sang-Min Lim,et al.  Isolation of human periosteum-derived progenitor cells using immunophenotypes for chondrogenesis , 2005, Biotechnology Letters.

[64]  Hajime Ohgushi,et al.  Comparison of Osteogenic Ability of Rat Mesenchymal Stem Cells from Bone Marrow, Periosteum, and Adipose Tissue , 2008, Calcified Tissue International.

[65]  V. Rosen,et al.  Periosteal BMP2 activity drives bone graft healing. , 2012, Bone.

[66]  M. Almeida,et al.  Estrogen receptor-α signaling in osteoblast progenitors stimulates cortical bone accrual. , 2013, The Journal of clinical investigation.

[67]  Fanxin Long,et al.  Building strong bones: molecular regulation of the osteoblast lineage , 2011, Nature Reviews Molecular Cell Biology.

[68]  C. Tabin,et al.  BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing , 2006, Nature Genetics.

[69]  Valerie A Longo,et al.  Synthesis of a tissue-engineered periosteum with acellular dermal matrix and cultured mesenchymal stem cells. , 2009, Tissue engineering. Part A.

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

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

[72]  J. Schrooten,et al.  A clinically relevant model of osteoinduction: a process requiring calcium phosphate and BMP/Wnt signalling , 2009, Journal of cellular and molecular medicine.

[73]  Charles P. Lin,et al.  Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. , 2012, Cell stem cell.

[74]  I. Springer,et al.  Two techniques for the preparation of cell-scaffold constructs suitable for sinus augmentation: steps into clinical application. , 2006, Tissue engineering.

[75]  M. Tang,et al.  Overexpressing Sonic Hedgehog Peptide Restores Periosteal Bone Formation in a Murine Bone Allograft Transplantation Model , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[76]  E. Seeman.  Periosteal bone formation--a neglected determinant of bone strength. , 2003, The New England journal of medicine.

[77]  M. Longaker,et al.  Fgf-9 is required for angiogenesis and osteogenesis in long bone repair , 2010, Proceedings of the National Academy of Sciences.

[78]  Diane Hu,et al.  A model for intramembranous ossification during fracture healing , 2002, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[79]  V. Goldberg,et al.  Culture‐expanded human periosteal‐derived cells exhibit osteochondral potential in vivo , 1991, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[80]  C Perka,et al.  Segmental bone repair by tissue-engineered periosteal cell transplants with bioresorbable fleece and fibrin scaffolds in rabbits. , 2000, Biomaterials.

[81]  D. Graves,et al.  Molecular Mechanisms Controlling Bone Formation during Fracture Healing and Distraction Osteogenesis , 2008, Journal of dental research.

[82]  Peter Dubruel,et al.  Quantitative screening of engineered implants in a long bone defect model in rabbits. , 2008, Tissue engineering. Part C, Methods.

[83]  C. Xian,et al.  Role of FGFs/FGFRs in skeletal development and bone regeneration , 2012, Journal of cellular physiology.

[84]  Xinping Zhang,et al.  Activation of the Hh pathway in periosteum-derived mesenchymal stem cells induces bone formation in vivo: implication for postnatal bone repair. , 2010, The American journal of pathology.

[85]  J. Bilezikian,et al.  Differentiation and proliferation of periosteal osteoblast progenitors are differentially regulated by estrogens and intermittent parathyroid hormone administration. , 2008, Endocrinology.

[86]  A. Kawanami,et al.  Mice expressing GFP and CreER in osteochondro progenitor cells in the periosteum. , 2009, Biochemical and biophysical research communications.

[87]  S. Herring,et al.  Cell replication in craniofacial periosteum: appositional vs. resorptive sites , 2011, Journal of anatomy.

[88]  C. Tabin,et al.  BMP4 is dispensable for skeletogenesis and fracture-healing in the limb. , 2008, The Journal of bone and joint surgery. American volume.

[89]  V. Rosen,et al.  Conditional deletion of BMP7 from the limb skeleton does not affect bone formation or fracture repair , 2010, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[90]  D. Benoit,et al.  Emerging Ideas: Engineering the Periosteum: Revitalizing Allografts by Mimicking Autograft Healing , 2013, Clinical orthopaedics and related research.

[91]  H. Stryhn,et al.  Characterization and osteogenic potential of equine muscle tissue- and periosteal tissue-derived mesenchymal stem cells in comparison with bone marrow- and adipose tissue-derived mesenchymal stem cells. , 2013, American journal of veterinary research.

[92]  M. Randolph.  Tissue Engineered Bone Repair of Calvarial Defects Using Cultured Periosteal Cells , 1998 .

[93]  J. Deng,et al.  Osteo-chondroprogenitor cells are derived from Sox9 expressing precursors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[94]  R. Gutiérrez,et al.  Pericytes as a supplementary source of osteoblasts in periosteal osteogenesis. , 1992, Clinical orthopaedics and related research.

[95]  R. Guldberg,et al.  Periosteal Progenitor Cell Fate in Segmental Cortical Bone Graft Transplantations: Implications for Functional Tissue Engineering , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[96]  I. Asahina,et al.  Effective Bone Engineering with Periosteum-derived Cells , 2007, Journal of dental research.

[97]  V. Goldberg,et al.  In vivo osteochondrogenic potential of cultured cells derived from the periosteum. , 1990, Clinical orthopaedics and related research.

[98]  E. Nkenke,et al.  Guided bone regeneration in pig calvarial bone defects using autologous mesenchymal stem/progenitor cells - a comparison of different tissue sources. , 2012, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[99]  S. Bruder,et al.  In vitro differentiation of bone and hypertrophic cartilage from periosteal-derived cells. , 1991, Experimental cell research.

[100]  R. Nusse,et al.  Wnt Proteins Promote Bone Regeneration , 2010, Science Translational Medicine.

[101]  T. Sugahara,et al.  Osteogenic potential of cultured human periosteum-derived cells - a pilot study of human cell transplantation into a rat calvarial defect model. , 2006, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[102]  I. Sekiya,et al.  Comparison of rat mesenchymal stem cells derived from bone marrow, synovium, periosteum, adipose tissue, and muscle , 2007, Cell and Tissue Research.

[103]  Christopher R Jacobs,et al.  The periosteum as a cellular source for functional tissue engineering. , 2009, Tissue engineering. Part A.

[104]  S. Matsuda,et al.  Periosteal cells are a major source of soft callus in bone fracture , 2013, Journal of Bone and Mineral Metabolism.

[105]  Douglas J Adams,et al.  In Vivo Fate Mapping Identifies Mesenchymal Progenitor Cells , 2011, Stem cells.