Supramolecular Nanofibers Enhance Growth Factor Signaling by Increasing Lipid Raft Mobility

The nanostructures of self-assembling biomaterials have been previously designed to tune the release of growth factors in order to optimize biological repair and regeneration. We report here on the discovery that weakly cohesive peptide nanostructures in terms of intermolecular hydrogen bonding, when combined with low concentrations of osteogenic growth factor, enhance both BMP-2 and Wnt mediated signaling in myoblasts and bone marrow stromal cells, respectively. Conversely, analogous nanostructures with enhanced levels of internal hydrogen bonding and cohesion lead to an overall reduction in BMP-2 signaling. We propose that the mechanism for enhanced growth factor signaling by the nanostructures is related to their ability to increase diffusion within membrane lipid rafts. The phenomenon reported here could lead to new nanomedicine strategies to mediate growth factor signaling for translational targets.

[1]  Julian H. George,et al.  Exploring and Engineering the Cell Surface Interface , 2005, Science.

[2]  S. Stupp,et al.  The role of bioactive nanofibers in enamel regeneration mediated through integrin signals acting upon C/EBPα and c-Jun. , 2013, Biomaterials.

[3]  M. Levitt.  Conformational preferences of amino acids in globular proteins. , 1978, Biochemistry.

[4]  Samuel I Stupp,et al.  Supramolecular assembly of multifunctional maspin-mimetic nanostructures as a potent peptide-based angiogenesis inhibitor. , 2015, Acta biomaterialia.

[5]  D. Mooney,et al.  Growth factor delivery-based tissue engineering: general approaches and a review of recent developments , 2011, Journal of The Royal Society Interface.

[6]  J. Massagué,et al.  How cells read TGF-β signals , 2000, Nature Reviews Molecular Cell Biology.

[7]  Kai Simons,et al.  Revitalizing membrane rafts: new tools and insights , 2010, Nature Reviews Molecular Cell Biology.

[8]  L. Rajendran,et al.  Lipid rafts and membrane dynamics , 2005, Journal of Cell Science.

[9]  Samuel I. Stupp,et al.  Gel Scaffolds of BMP‐2‐Binding Peptide Amphiphile Nanofibers for Spinal Arthrodesis , 2015, Advanced healthcare materials.

[10]  A. Ho,et al.  Cholera toxin binds to lipid rafts but has a limited specificity for ganglioside GM1 , 2007, Immunology and cell biology.

[11]  Kai Simons,et al.  Lipid rafts and signal transduction , 2000, Nature Reviews Molecular Cell Biology.

[12]  E. Helmreich.  Environmental influences on signal transduction through membranes: a retrospective mini-review. , 2002, Biophysical chemistry.

[13]  L. Christophorou.  Science , 2018, Emerging Dynamics: Science, Energy, Society and Values.

[14]  S. Stupp,et al.  Induction of cancer cell death by self-assembling nanostructures incorporating a cytotoxic peptide. , 2010, Cancer research.

[15]  J. Hartgerink,et al.  Self-assembly of peptide-amphiphile nanofibers: the roles of hydrogen bonding and amphiphilic packing. , 2006, Journal of the American Chemical Society.

[16]  D. Berman,et al.  The VIVA Trial: Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis , 2003, Circulation.

[17]  D. Huylebroeck,et al.  New intracellular components of bone morphogenetic protein/Smad signaling cascades , 2003, FEBS letters.

[18]  E. Lai.  Lipid rafts make for slippery platforms , 2003, The Journal of cell biology.

[19]  Joan Massagu,et al.  How cells read TGF-|[beta]| signals , 2000 .

[20]  R. Shah,et al.  Supramolecular design of self-assembling nanofibers for cartilage regeneration , 2010, Proceedings of the National Academy of Sciences of the United States of America.

[21]  L. Chernomordik,et al.  Cell-penetrating peptide induces leaky fusion of liposomes containing late endosome-specific anionic lipid. , 2010, Biophysical journal.

[22]  Samuel I Stupp,et al.  Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair , 2011, Proceedings of the National Academy of Sciences.

[23]  O. MacDougald,et al.  The influence of Leucine-rich amelogenin peptide on MSC fate by inducing Wnt10b expression. , 2011, Biomaterials.

[24]  A. Wear.  CIRCULATION , 1964, The Lancet.

[25]  Michael Cross,et al.  Growth factors in development, transformation, and tumorigenesis , 1991, Cell.

[26]  Olgun Guvench,et al.  Supramolecular Assemblies of a Conjugate of Nucleobase, Amino Acids, and Saccharide Act as Agonists for Proliferation of Embryonic Stem Cells and Development of Zygotes , 2014, Bioconjugate chemistry.

[27]  Nicholas Stephanopoulos,et al.  The Powerful Functions of Peptide-Based Bioactive Matrices for Regenerative Medicine , 2014, Annals of Biomedical Engineering.

[28]  T. Yoneda,et al.  Smad5 and DPC4 Are Key Molecules in Mediating BMP-2-induced Osteoblastic Differentiation of the Pluripotent Mesenchymal Precursor Cell Line C2C12* , 1998, The Journal of Biological Chemistry.

[29]  S. Stupp,et al.  Nanofiber-mediated inhibition of focal adhesion kinase sensitizes glioma stemlike cells to epidermal growth factor receptor inhibition. , 2013, Neuro-oncology.

[30]  S. Retterer,et al.  Manipulating the lateral diffusion of surface-anchored EGF demonstrates that receptor clustering modulates phosphorylation levels. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[31]  R. Bitton,et al.  Electrostatic control of bioactivity. , 2011, Angewandte Chemie.

[32]  A. Montag,et al.  Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells , 2007, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[33]  Ying E. Zhang,et al.  Smad-dependent and Smad-independent pathways in TGF-β family signalling , 2003, Nature.

[34]  A. Lanzavecchia,et al.  T lymphocyte costimulation mediated by reorganization of membrane microdomains. , 1999, Science.

[35]  Richard O. Hynes,et al.  The Extracellular Matrix: Not Just Pretty Fibrils , 2009, Science.

[36]  R. Nussinov,et al.  Mechanism of membrane permeation induced by synthetic β-hairpin peptides. , 2013, Biophysical journal.

[37]  Joe W. Gray,et al.  Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2 , 2010, Science.

[38]  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.

[39]  I. Hamley,et al.  Interaction between a Cationic Surfactant-like Peptide and Lipid Vesicles and Its Relationship to Antimicrobial Activity , 2013, Langmuir : the ACS journal of surfaces and colloids.

[40]  D. Wilson,et al.  The BMP type II receptor is located in lipid rafts, including caveolae, of pulmonary endothelium in vivo and in vitro. , 2006, Vascular pharmacology.

[41]  P. Bauer,et al.  Caveolin-1 regulates BMPRII localization and signaling in vascular smooth muscle cells. , 2008, Biochemical and biophysical research communications.

[42]  Antonios G Mikos,et al.  Biomimetic materials for tissue engineering. , 2003, Biomaterials.

[43]  David J. Mooney,et al.  Growth Factors, Matrices, and Forces Combine and Control Stem Cells , 2009, Science.

[44]  S. Stupp,et al.  Tuning supramolecular mechanics to guide neuron development. , 2013, Biomaterials.

[45]  Melinda Fitzgerald,et al.  Immunol. Cell Biol. , 1995 .

[46]  Christopher S. Chen,et al.  Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition , 2012, Molecular biology of the cell.

[47]  Kai Simons,et al.  Lipid Rafts As a Membrane-Organizing Principle , 2010, Science.

[48]  S. Laufer,et al.  The decrease of cell membrane fluidity by the non-steroidal anti-inflammatory drug Licofelone inhibits epidermal growth factor receptor signalling and triggers apoptosis in HCA-7 colon cancer cells. , 2012, Cancer letters.

[49]  R. Zandi,et al.  Alginate-peptide amphiphile core-shell microparticles as a targeted drug delivery system. , 2015, RSC advances.

[50]  R. Misra,et al.  Biomaterials , 2008 .

[51]  G. Schatz,et al.  Cell death versus cell survival instructed by supramolecular cohesion of nanostructures , 2014, Nature Communications.

[52]  B. Frenkel,et al.  Leucine-rich amelogenin peptide induces osteogenesis by activation of the Wnt pathway. , 2009, Biochemical and biophysical research communications.

[53]  D. Rifkin,et al.  Extracellular microfibrils: contextual platforms for TGFbeta and BMP signaling. , 2009, Current opinion in cell biology.

[54]  C. Deng,et al.  TGF-β and BMP Signaling in Osteoblast Differentiation and Bone Formation , 2012, International journal of biological sciences.

[55]  V. Rosen,et al.  Bone morphogenetic protein-2 converts the differentiation pathway of C2C12 myoblasts into the osteoblast lineage [published erratum appears in J Cell Biol 1995 Feb;128(4):following 713] , 1994, The Journal of cell biology.

[56]  A. Kenworthy,et al.  Mechanisms Underlying the Confined Diffusion of Cholera Toxin B-Subunit in Intact Cell Membranes , 2012, PloS one.

[57]  Eiki Takahashi,et al.  The significance of membrane fluidity of feeder cell-derived substrates for maintenance of iPS cell stemness , 2015, Scientific Reports.

[58]  S. Stock,et al.  Bone regeneration with low dose BMP-2 amplified by biomimetic supramolecular nanofibers within collagen scaffolds. , 2013, Biomaterials.