Mechanics and mechanobiology of mesenchymal stem cell-based engineered cartilage.

In this review, we outline seminal and recent work highlighting the potential of mesenchymal stem cells (MSCs) in producing cartilage-like tissue equivalents. Specific focus is placed on the mechanical properties of engineered MSC-based cartilage and how these properties relate to that of engineered cartilage based on primary chondrocytes and to native tissue properties. We discuss current limitations and/or concerns that must be addressed for the clinical realization of MSC-based cartilage therapeutics, and provide some insight into potential underpinnings for the observed deviations from chondrocyte-based engineered constructs. We posit that these differences reveal specific deficits in terms of our description of chondrogenesis, and suggest that new benchmarks must be developed towards this end. Further, we describe the growing body of literature on the mechanobiology of MSC-based cartilage, highlighting positive findings with regards to the furtherance of the chondrogenic phenotype. We likewise discuss the failure of early molecular changes to translate directly into engineered constructs with improved mechanical properties. Finally, we highlight recent work from our group and others that may point to new strategies for enhancing the formation of engineered cartilage based on MSCs.

[1]  Mauro Alini,et al.  Surface motion upregulates superficial zone protein and hyaluronan production in chondrocyte-seeded three-dimensional scaffolds. , 2005, Tissue engineering.

[2]  Farshid Guilak,et al.  Chondrogenic differentiation of adipose-derived adult stem cells in agarose, alginate, and gelatin scaffolds. , 2004, Biomaterials.

[3]  R. Tuan,et al.  Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  D. Kaplan,et al.  Comparative chondrogenesis of human cell sources in 3D scaffolds , 2009, Journal of tissue engineering and regenerative medicine.

[5]  F. Guilak,et al.  Clonal analysis of the differentiation potential of human adipose‐derived adult stem cells , 2006, Journal of cellular physiology.

[6]  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.

[7]  Jason A. Burdick,et al.  Differential maturation and structure-function relationships in mesenchymal stem cell- and chondrocyte-seeded hydrogels. , 2009, Tissue engineering. Part A.

[8]  A. Poustka,et al.  Subtractive gene expression profiling of articular cartilage and mesenchymal stem cells: serpins as cartilage-relevant differentiation markers. , 2008, Osteoarthritis and cartilage.

[9]  H. Cheung,et al.  Chondrogenesis of human bone marrow-derived mesenchymal stem cells in agarose culture. , 2004, The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology.

[10]  E. Caterson,et al.  Three-dimensional cartilage formation by bone marrow-derived cells seeded in polylactide/alginate amalgam. , 2001, Journal of biomedical materials research.

[11]  F. Barry,et al.  Gelatin-based resorbable sponge as a carrier matrix for human mesenchymal stem cells in cartilage regeneration therapy. , 2000, Journal of biomedical materials research.

[12]  A I Caplan,et al.  In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. , 1998, Experimental cell research.

[13]  A. Broadus,et al.  Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice. , 2008, Arthritis and rheumatism.

[14]  Hans Hauner,et al.  Cartilage-like gene expression in differentiated human stem cell spheroids: a comparison of bone marrow-derived and adipose tissue-derived stromal cells. , 2003, Arthritis and rheumatism.

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

[16]  S. Ayad,et al.  Collagen type I , 1998 .

[17]  F. Guilak,et al.  Effects of Transforming Growth Factor β1 and Dexamethasone on the Growth and Chondrogenic Differentiation of Adipose-Derived Stromal Cells , 2003 .

[18]  R. Tuan,et al.  Transient exposure to transforming growth factor beta 3 improves the mechanical properties of mesenchymal stem cell-laden cartilage constructs in a density-dependent manner. , 2009, Tissue engineering. Part A.

[19]  Wan-Ju Li,et al.  Intervertebral disc tissue engineering using a novel hyaluronic acid-nanofibrous scaffold (HANFS) amalgam. , 2008, Tissue engineering. Part A.

[20]  A. K. Williamson,et al.  Growth of immature articular cartilage in vitro: correlated variation in tensile biomechanical and collagen network properties. , 2003, Tissue engineering.

[21]  B. A. Byers,et al.  The beneficial effect of delayed compressive loading on tissue-engineered cartilage constructs cultured with TGF-beta3. , 2007, Osteoarthritis and cartilage.

[22]  J. Elisseeff,et al.  The differential effect of scaffold composition and architecture on chondrocyte response to mechanical stimulation. , 2009, Biomaterials.

[23]  Thomas Aigner,et al.  Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice. , 2006, Arthritis and rheumatism.

[24]  Koichi Masuda,et al.  Tensile mechanical properties of bovine articular cartilage: Variations with growth and relationships to collagen network components , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

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

[26]  Scott L. Diamond,et al.  High-Throughput Screening for Modulators of Mesenchymal Stem Cell Chondrogenesis , 2008, Annals of Biomedical Engineering.

[27]  J. Connelly,et al.  Dynamic Compression Regulates the Expression and Synthesis of Chondrocyte‐Specific Matrix Molecules in Bone Marrow Stromal Cells , 2007, Stem cells.

[28]  Wan-Ju Li,et al.  Mold-shaped, nanofiber scaffold-based cartilage engineering using human mesenchymal stem cells and bioreactor. , 2008, The Journal of surgical research.

[29]  S. Thorpe,et al.  Dynamic compression can inhibit chondrogenesis of mesenchymal stem cells. , 2008, Biochemical and biophysical research communications.

[30]  Sottile,et al.  Multi-lineage potential of human mesenchymal stem cells following clonal expansion. , 2001, Journal of musculoskeletal & neuronal interactions.

[31]  G A Ateshian,et al.  Functional tissue engineering of articular cartilage through dynamic loading of chondrocyte-seeded agarose gels. , 2000, Journal of biomechanical engineering.

[32]  P. Prendergast,et al.  Involvement of stretch-activated ion channels in strain-regulated glycosaminoglycan synthesis in mesenchymal stem cell-seeded 3D scaffolds. , 2008, Journal of biomechanics.

[33]  A. Bellingham Human Bone Marrow , 1976 .

[34]  Lorenzo Moroni,et al.  Differential Response of Adult and Embryonic Mesenchymal Progenitor Cells to Mechanical Compression in Hydrogels , 2007, Stem cells.

[35]  J. Lotz,et al.  Chondrogenic differentiation of human mesenchymal stem cells in three-dimensional alginate gels. , 2008, Tissue engineering. Part A.

[36]  Patrick J. Prendergast,et al.  Regulatory Effects of Mechanical Strain on the Chondrogenic Differentiation of MSCs in a Collagen-GAG Scaffold: Experimental and Computational Analysis , 2008, Annals of Biomedical Engineering.

[37]  Seungju M. Yu,et al.  Enhanced chondrogenesis of mesenchymal stem cells in collagen mimetic peptide-mediated microenvironment. , 2008, Tissue engineering. Part A.

[38]  Antonios G. Mikos,et al.  Injectable biodegradable hydrogel composites for rabbit marrow mesenchymal stem cell and growth factor delivery for cartilage tissue engineering. , 2007, Biomaterials.

[39]  Ching-Fang Chang,et al.  Three-dimensional collagen fiber remodeling by mesenchymal stem cells requires the integrin-matrix interaction. , 2007, Journal of biomedical materials research. Part A.

[40]  A. Reddi,et al.  Gene expression profiling of mouse articular and growth plate cartilage. , 2007, Tissue engineering.

[41]  Darwin J. Prockop,et al.  In vitro cartilage formation by human adult stem cells from bone marrow stroma defines the sequence of cellular and molecular events during chondrogenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Moonsoo Jin,et al.  Effects of dynamic compressive loading on chondrocyte biosynthesis in self-assembling peptide scaffolds. , 2004, Journal of biomechanics.

[43]  Rocky S Tuan,et al.  Functional characterization of hypertrophy in chondrogenesis of human mesenchymal stem cells. , 2008, Arthritis and rheumatism.

[44]  B. A. Byers,et al.  Regulation of Cartilaginous ECM Gene Transcription by Chondrocytes and MSCs in 3D Culture in Response to Dynamic Loading , 2007, Biomechanics and modeling in mechanobiology.

[45]  Manas Kumar Majumdar,et al.  BMP‐2 and BMP‐9 promotes chondrogenic differentiation of human multipotential mesenchymal cells and overcomes the inhibitory effect of IL‐1 , 2001, Journal of cellular physiology.

[46]  Ross Crawford,et al.  Clonal isolation and characterization of bone marrow stromal cells from patients with osteoarthritis. , 2007, Tissue engineering.

[47]  G. Im,et al.  Chondrogenic differentiation of mesenchymal stem cells isolated from patients in late adulthood: the optimal conditions of growth factors. , 2006, Tissue engineering.

[48]  G. Beaupré,et al.  Hydrostatic Pressure Enhances Chondrogenic Differentiation of Human Bone Marrow Stromal Cells in Osteochondrogenic Medium , 2008, Annals of Biomedical Engineering.

[49]  S. Gronthos,et al.  Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow , 2003, Journal of Cell Science.

[50]  Andrés J. García,et al.  Inhibition of in vitro chondrogenesis in RGD-modified three-dimensional alginate gels. , 2007, Biomaterials.

[51]  F. Barry,et al.  Chondrogenic differentiation of human mesenchymal stem cells within an alginate layer culture system , 2002, In Vitro Cellular & Developmental Biology - Animal.

[52]  D. Chan,et al.  In vitro chondrogenic differentiation of human mesenchymal stem cells in collagen microspheres: influence of cell seeding density and collagen concentration. , 2008, Biomaterials.

[53]  A. Grodzinsky,et al.  Dynamic compression stimulates proteoglycan synthesis by mesenchymal stem cells in the absence of chondrogenic cytokines. , 2009, Tissue engineering. Part A.

[54]  J. Jansen,et al.  Effect of dual growth factor delivery on chondrogenic differentiation of rabbit marrow mesenchymal stem cells encapsulated in injectable hydrogel composites. , 2009, Journal of biomedical materials research. Part A.

[55]  R. Tuan,et al.  Identification and Functional Analysis of Candidate Genes Regulating Mesenchymal Stem Cell Self‐Renewal and Multipotency , 2006, Stem cells.

[56]  Jerry C. Hu,et al.  The effects of intermittent hydrostatic pressure on self-assembled articular cartilage constructs. , 2006, Tissue engineering.

[57]  B. A. Byers,et al.  Transient exposure to transforming growth factor beta 3 under serum-free conditions enhances the biomechanical and biochemical maturation of tissue-engineered cartilage. , 2008, Tissue engineering. Part A.

[58]  A. Caplan,et al.  Dilution of human mesenchymal stem cells with dermal fibroblasts and the effects on in vitro and in vivo osteochondrogenesis , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[59]  G. Vunjak‐Novakovic,et al.  Cartilage-like tissue engineering using silk scaffolds and mesenchymal stem cells. , 2006, Tissue engineering.

[60]  K. Anseth,et al.  Chondrogenic differentiation potential of human mesenchymal stem cells photoencapsulated within poly(ethylene glycol)-arginine-glycine-aspartic acid-serine thiol-methacrylate mixed-mode networks. , 2007, Tissue engineering.

[61]  F. Barry,et al.  Chondrogenic differentiation of mesenchymal stem cells from bone marrow: differentiation-dependent gene expression of matrix components. , 2001, Experimental cell research.

[62]  J. Connelly,et al.  The influence of cyclic tension amplitude on chondrocyte matrix synthesis: experimental and finite element analyses. , 2004, Biorheology.

[63]  Boon Chin Heng,et al.  Combined effects of TGFβ1 and BMP2 in serum-free chondrogenic differentiation of mesenchymal stem cells induced hyaline-like cartilage formation , 2005, Growth factors.

[64]  J. Burdick,et al.  The influence of degradation characteristics of hyaluronic acid hydrogels on in vitro neocartilage formation by mesenchymal stem cells. , 2009, Biomaterials.

[65]  Stuart B Goodman,et al.  Effects of hydrostatic pressure and transforming growth factor-beta 3 on adult human mesenchymal stem cell chondrogenesis in vitro. , 2006, Tissue engineering.

[66]  L. Kanz,et al.  Heterogeneity among human bone marrow-derived mesenchymal stem cells and neural progenitor cells. , 2003, Haematologica.

[67]  W. Richter,et al.  Chondrogenesis of mesenchymal stem cells in gel-like biomaterials in vitro and in vivo. , 2008, Frontiers in bioscience : a journal and virtual library.

[68]  G. Finkenzeller,et al.  Mesenchymal stem cells maintain TGF-beta-mediated chondrogenic phenotype in alginate bead culture. , 2006, Tissue engineering.

[69]  R. Tuan,et al.  Adult mesenchymal stem cells: characterization, differentiation, and application in cell and gene therapy , 2004, Journal of cellular and molecular medicine.

[70]  W. Lu,et al.  Mesenchymal Stem Cell-Based Repair of Articular Cartilage with Polyglycolic Acid-Hydroxyapatite Biphasic Scaffold , 2008, The International journal of artificial organs.

[71]  J. Jukes,et al.  Endochondral bone tissue engineering using embryonic stem cells , 2008, Proceedings of the National Academy of Sciences.

[72]  D. Prockop Marrow Stromal Cells as Stem Cells for Nonhematopoietic Tissues , 1997, Science.

[73]  R. Tuan,et al.  Chondrogenic differentiation and functional maturation of bovine mesenchymal stem cells in long-term agarose culture. , 2006, Osteoarthritis and cartilage.

[74]  A. Grodzinsky,et al.  Chondrocytes in agarose culture synthesize a mechanically functional extracellular matrix , 1992, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[75]  H. Moses,et al.  Effect of IGF‐I in the Chondrogenesis of Bone Marrow Mesenchymal Stem Cells in the Presence or Absence of TGF‐β Signaling , 2005, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[76]  Borjana Mikic,et al.  Mechanical Modulation of Cartilage Structure and Function During Embryogenesis in the Chick , 2004, Annals of Biomedical Engineering.

[77]  M. Pittenger,et al.  Multilineage potential of adult human mesenchymal stem cells. , 1999, Science.

[78]  Steven A. Goldstein,et al.  Chondrocyte Differentiation is Modulated by Frequency and Duration of Cyclic Compressive Loading , 2001, Annals of Biomedical Engineering.

[79]  David L Kaplan,et al.  Growth factor gradients via microsphere delivery in biopolymer scaffolds for osteochondral tissue engineering. , 2009, Journal of controlled release : official journal of the Controlled Release Society.

[80]  F. Guilak,et al.  Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6. , 2006, Arthritis and rheumatism.

[81]  E. Hunziker,et al.  Differential effects of embryonic immobilization on the development of fibrocartilaginous skeletal elements. , 2000, Journal of rehabilitation research and development.

[82]  S. Goldstein,et al.  Effect of compressive loading on chondrocyte differentiation in agarose cultures of chick limb‐bud cells , 2000, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[83]  Junzo Tanaka,et al.  Growth factor combination for chondrogenic induction from human mesenchymal stem cell. , 2004, Biochemical and biophysical research communications.

[84]  K. Jepsen,et al.  Cyclic hydrostatic pressure enhances the chondrogenic phenotype of human mesenchymal progenitor cells differentiated in vitro , 2003, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[85]  F. Guilak,et al.  Effects of transforming growth factor beta1 and dexamethasone on the growth and chondrogenic differentiation of adipose-derived stromal cells. , 2003, Tissue engineering.

[86]  P. Angele,et al.  Cyclic, mechanical compression enhances chondrogenesis of mesenchymal progenitor cells in tissue engineering scaffolds. , 2004, Biorheology.

[87]  W. Hozack,et al.  Transforming Growth Factor-β-mediated Chondrogenesis of Human Mesenchymal Progenitor Cells Involves N-cadherin and Mitogen-activated Protein Kinase and Wnt Signaling Cross-talk* , 2003, Journal of Biological Chemistry.

[88]  Clifford J. Tabin,et al.  Regulation of Rate of Cartilage Differentiation by Indian Hedgehog and PTH-Related Protein , 1996, Science.

[89]  R. Tuan,et al.  A three-dimensional nanofibrous scaffold for cartilage tissue engineering using human mesenchymal stem cells. , 2005, Biomaterials.

[90]  F. Guilak,et al.  Chondrogenic differentiation of adipose-derived adult stem cells by a porous scaffold derived from native articular cartilage extracellular matrix. , 2009, Tissue engineering. Part A.

[91]  Elizabeth G Loboa,et al.  Differential effects on messenger ribonucleic acid expression by bone marrow-derived human mesenchymal stem cells seeded in agarose constructs due to ramped and steady applications of cyclic hydrostatic pressure. , 2007, Tissue engineering.

[92]  R. Kandel,et al.  Cyclic compressive mechanical stimulation induces sequential catabolic and anabolic gene changes in chondrocytes resulting in increased extracellular matrix accumulation. , 2006, Matrix biology : journal of the International Society for Matrix Biology.

[93]  N. Kulagina,et al.  Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. , 1974, Experimental Hematology.

[94]  H. Cheung,et al.  Temporal Expression Patterns and Corresponding Protein Inductions of Early Responsive Genes in Rabbit Bone Marrow–Derived Mesenchymal Stem Cells Under Cyclic Compressive Loading , 2005, Stem cells.

[95]  Jennifer L West,et al.  Design and characterization of poly(ethylene glycol) photopolymerizable semi-interpenetrating networks for chondrogenesis of human mesenchymal stem cells. , 2007, Tissue engineering.

[96]  J. Burdick,et al.  Influence of three-dimensional hyaluronic acid microenvironments on mesenchymal stem cell chondrogenesis. , 2009, Tissue engineering. Part A.

[97]  Andre Steinert,et al.  Gene-induced chondrogenesis of primary mesenchymal stem cells in vitro. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[98]  P. Prendergast,et al.  Mechanisms of strain-mediated mesenchymal stem cell apoptosis. , 2008, Journal of biomechanical engineering.

[99]  A H Huang,et al.  Tensile properties of engineered cartilage formed from chondrocyte- and MSC-laden hydrogels. , 2008, Osteoarthritis and cartilage.