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  • Review Article
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Receptor control in mesenchymal stem cell engineering

Abstract

Materials science offers a powerful tool to control mesenchymal stem cell (MSC) growth and differentiation into functional phenotypes. A complex interplay between the extracellular matrix and growth factors guides MSC phenotypes in vivo. In this Review, we discuss materials-based bioengineering approaches to direct MSC fate in vitro and in vivo, mimicking cell–matrix–growth factor crosstalk. We first scrutinize MSC–matrix interactions and how the properties of a material can be tailored to support MSC growth and differentiation in vitro, with an emphasis on MSC self-renewal mechanisms. We then highlight important growth factor signalling pathways and investigate various materials-based strategies for growth factor presentation and delivery. Integrin–growth factor crosstalk in the context of MSC engineering is introduced, and bioinspired material designs with the potential to control the MSC niche phenotype are considered. Finally, we summarize important milestones on the road to MSC engineering for regenerative medicine.

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Figure 1: Correlation between stem cell adhesion and growth.
Figure 2: Mechanical memory of mesenchymal stem cells.
Figure 3: Mechanisms of materials control of mesenchymal stem cell self-renewal.
Figure 4: Mesenchymal stem cells in the bone marrow niche.
Figure 5: Soluble and matrix-bound growth factor delivery.
Figure 6: Strategies for solid-phase presentation of growth factors.
Figure 7: Integrin–growth factor crosstalk.

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References

  1. Akhurst, R. J. & Hata, A. Targeting the TGFbeta signalling pathway in disease. Nat. Rev. Drug Discov. 11, 790–811 (2012).

    Article  CAS  Google Scholar 

  2. Benoit, D. S., Schwartz, M. P., Durney, A. R. & Anseth, K. S. Small functional groups for controlled differentiation of hydrogel-encapsulated human mesenchymal stem cells. Nat. Mater. 7, 816–823 (2008).

    Article  CAS  Google Scholar 

  3. Curran, J. M., Chen, R. & Hunt, J. A. The guidance of human mesenchymal stem cell differentiation in vitro by controlled modifications to the cell substrate. Biomaterials 27, 4783–4793 (2006).

    Article  CAS  Google Scholar 

  4. Wen, J. H. et al. Interplay of matrix stiffness and protein tethering in stem cell differentiation. Nat. Mater. 13, 979–987 (2014).

    Article  CAS  Google Scholar 

  5. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    Article  CAS  Google Scholar 

  6. Trappmann, B. et al. Extracellular-matrix tethering regulates stem-cell fate. Nat. Mater. 11, 642–649 (2012).

    Article  CAS  Google Scholar 

  7. Dalby, M. J. et al. The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder. Nat. Mater. 6, 997–1003 (2007).

    Article  CAS  Google Scholar 

  8. Tsimbouri, P. M. et al. Using nanotopography and metabolomics to identify biochemical effectors of multipotency. ACS Nano 6, 10239–10249 (2012).

    CAS  Google Scholar 

  9. Chen, C. S., Mrksich, M., Huang, S., Whitesides, G. & Ingber, D. E. Geometric control of cell life and death. Science 276, 1425–1428 (1997).

    Article  CAS  Google Scholar 

  10. McBeath, R., Pirone, D. M., Nelson, C. M., Bhadriraju, K. & Chen, C. S. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell 6, 483–495 (2004).

    Article  CAS  Google Scholar 

  11. Kilian, K. A., Bugarija, B., Lahn, B. T. & Mrksich, M. Geometric cues for directing the differentiation of mesenchymal stem cells. Proc. Natl Acad. Sci. USA 107, 4872–4877 (2010).

    Article  CAS  Google Scholar 

  12. Celiz, A. D. et al. Discovery of a novel polymer for human pluripotent stem cell expansion and multilineage differentiation. Adv. Mater. 27, 4006–4012 (2015).

    Article  CAS  Google Scholar 

  13. Kingham, E., White, K., Gadegaard, N., Dalby, M. J. & Oreffo, R. O. Nanotopographical cues augment mesenchymal differentiation of human embryonic stem cells. Small 9, 2140–2151 (2013).

    Article  CAS  Google Scholar 

  14. Bible, E. et al. The support of neural stem cells transplanted into stroke-induced brain cavities by PLGA particles. Biomaterials 30, 2985–2994 (2009).

    Article  CAS  Google Scholar 

  15. Gilbert, P. M. et al. Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329, 1078–1081 (2010).

    Article  CAS  Google Scholar 

  16. Guilak, F. et al. Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell 5, 17–26 (2009).

    Article  CAS  Google Scholar 

  17. Celiz, A. D. et al. Materials for stem cell factories of the future. Nat. Mater. 13, 570–579 (2014).

    Article  CAS  Google Scholar 

  18. Discher, D. E., Mooney, D. J. & Zandstra, P. W. Growth factors, matrices, and forces combine and control stem cells. Science 324, 1673–1677 (2009).

    Article  CAS  Google Scholar 

  19. Kasemo, B. & Lausmaa, J. Biomaterial and implant surfaces: a surface science approach. Int. J. Oral Maxillofac. Implants 3, 247–259 (1988).

    CAS  Google Scholar 

  20. Keselowsky, B. G., Collard, D. M. & Garcia, A. J. Surface chemistry modulates fibronectin conformation and directs integrin binding and specificity to control cell adhesion. J. Biomed. Mater. Res. 66A, 247–259 (2003).

    Article  CAS  Google Scholar 

  21. Ngandu Mpoyi, E. et al. Protein adsorption as a key mediator in the nanotopographical control of cell behavior. ACS Nano 10, 6638–6647 (2016).

    Article  CAS  Google Scholar 

  22. Lee, J., Abdeen, A. A., Tang, X., Saif, T. A. & Kilian, K. A. Geometric guidance of integrin mediated traction stress during stem cell differentiation. Biomaterials 69, 174–183 (2015).

    Article  CAS  Google Scholar 

  23. Cavalcanti-Adam, E. A., Aydin, D., Hirschfeld-Warneken, V. C. & Spatz, J. P. Cell adhesion and response to synthetic nanopatterned environments by steering receptor clustering and spatial location. HFSP J. 2, 276–285 (2008).

    Article  CAS  Google Scholar 

  24. Cavalcanti-Adam, E. A. et al. Cell spreading and focal adhesion dynamics are regulated by spacing of integrin ligands. Biophys. J. 92, 2964–2974 (2007).

    Article  CAS  Google Scholar 

  25. Bershadsky, A. D., Tint, I. S., Neyfakh, A. A. Jr & Vasiliev, J. M. Focal contacts of normal and RSV-transformed quail cells. Hypothesis of the transformation-induced deficient maturation of focal contacts. Exp. Cell Res. 158, 433–444 (1985).

    Article  CAS  Google Scholar 

  26. Biggs, M. J. et al. The use of nanoscale topography to modulate the dynamics of adhesion formation in primary osteoblasts and ERK/MAPK signalling in STRO-1+ enriched skeletal stem cells. Biomaterials 30, 5094–5103 (2009).

    Article  CAS  Google Scholar 

  27. Kanchanawong, P. et al. Nanoscale architecture of integrin-based cell adhesions. Nature 468, 580–584 (2010).

    Article  CAS  Google Scholar 

  28. Massia, S. P. & Hubbell, J. A. An RGD spacing of 440 nm is sufficient for integrin alpha V beta 3-mediated fibroblast spreading and 140 nm for focal contact and stress fiber formation. J. Cell Biol. 114, 1089–1100 (1991).

    Article  CAS  Google Scholar 

  29. McMurray, R. J. et al. Nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency. Nat. Mater. 10, 637–644 (2011).

    Article  CAS  Google Scholar 

  30. Roberts, J. N. et al. Dynamic surfaces for the study of mesenchymal stem cell growth through adhesion regulation. ACS Nano 10, 6667–6679 (2016).

    CAS  Google Scholar 

  31. Lee, L. C. et al. Nanotopography controls cell cycle changes involved with skeletal stem cell self-renewal and multipotency. Biomaterials 116, 10–20 (2017).

    Article  CAS  Google Scholar 

  32. Shotorbani, B. B., Alizadeh, E., Salehi, R. & Barzegar, A. Adhesion of mesenchymal stem cells to biomimetic polymers: a review. Mater. Sci. Eng. C Mater. Biol. Appl. 71, 1192–1200 (2017).

    Article  CAS  Google Scholar 

  33. Murphy, W. L., McDevitt, T. C. & Engler, A. J. Materials as stem cell regulators. Nat. Mater. 13, 547–557 (2014).

    Article  CAS  Google Scholar 

  34. Oria, R. et al. Force loading explains cell spatial sensing of ligands. Nature 552, 219–224 (2017).

    Article  CAS  Google Scholar 

  35. Huang, J. et al. Impact of order and disorder in RGD nanopatterns on cell adhesion. Nano Lett. 9, 1111–1116 (2009).

    Article  CAS  Google Scholar 

  36. Huebsch, N. et al. Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat. Mater. 9, 518–526 (2010).

    Article  CAS  Google Scholar 

  37. Yang, C., Tibbitt, M. W., Basta, L. & Anseth, K. S. Mechanical memory and dosing influence stem cell fate. Nat. Mater. 13, 645–652 (2014).

    Article  CAS  Google Scholar 

  38. Elosegui-Artola, A. et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171, 1397–1410 (2017).

    Article  CAS  Google Scholar 

  39. Aragona, M. et al. A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047–1059 (2013).

    Article  CAS  Google Scholar 

  40. Dupont, S. et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011).

    Article  CAS  Google Scholar 

  41. Driscoll, T. P., Cosgrove, B. D., Heo, S. J., Shurden, Z. E. & Mauck, R. L. Cytoskeletal to nuclear strain transfer regulates YAP signaling in mesenchymal stem cells. Biophys. J. 108, 2783–2793 (2015).

    Article  CAS  Google Scholar 

  42. Cosgrove, B. D. et al. N-Cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells. Nat. Mater. 15, 1297–1306 (2016).

    Article  CAS  Google Scholar 

  43. Bian, L., Guvendiren, M., Mauck, R. L. & Burdick, J. A. Hydrogels that mimic developmentally relevant matrix and N-cadherin interactions enhance MSC chondrogenesis. Proc. Natl Acad. Sci. USA 110, 10117–10122 (2013).

    Article  CAS  Google Scholar 

  44. Vicente, R., Noel, D., Pers, Y. M., Apparailly, F. & Jorgensen, C. Deregulation and therapeutic potential of microRNAs in arthritic diseases. Nat. Rev. Rheumatol. 12, 211–220 (2016).

    Article  CAS  Google Scholar 

  45. Li, C. X. et al. MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells. Nat. Mater. 16, 379–389 (2017).

    Article  CAS  Google Scholar 

  46. Liu, G. et al. miR-21 mediates fibrogenic activation of pulmonary fibroblasts and lung fibrosis. J. Exp. Med. 207, 1589–1597 (2010).

    Article  CAS  Google Scholar 

  47. Zhu, H. et al. MicroRNA-21 in scleroderma fibrosis and its function in TGF-beta-regulated fibrosis-related genes expression. J. Clin. Immunol. 33, 1100–1109 (2013).

    Article  CAS  Google Scholar 

  48. Liang, H. et al. A novel reciprocal loop between microRNA-21 and TGFbetaRIII is involved in cardiac fibrosis. Int. J. Biochem. Cell Biol. 44, 2152–2160 (2012).

    Article  CAS  Google Scholar 

  49. Thum, T. et al. MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts. Nature 456, 980–984 (2008).

    Article  CAS  Google Scholar 

  50. Yao, Q. et al. Micro-RNA-21 regulates TGF-beta-induced myofibroblast differentiation by targeting PDCD4 in tumor-stroma interaction. Int. J. Cancer 128, 1783–1792 (2011).

    Article  CAS  Google Scholar 

  51. Trohatou, O. et al. Sox2 suppression by miR-21 governs human mesenchymal stem cell properties. Stem Cells Transl Med. 3, 54–68 (2014).

    Article  CAS  Google Scholar 

  52. Khetan, S. et al. Degradation-mediated cellular traction directs stem cell fate in covalently crosslinked three-dimensional hydrogels. Nat. Mater. 12, 458–465 (2013).

    Article  CAS  Google Scholar 

  53. Baker, B. M. et al. Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments. Nat. Mater. 14, 1262–1268 (2015).

    Article  CAS  Google Scholar 

  54. Tibbitt, M. W. & Anseth, K. S. Dynamic microenvironments: the fourth dimension. Sci. Transl Med. 4, 160–124 (2012).

    Article  CAS  Google Scholar 

  55. Watt, F. M. & Hogan, B. L. Out of Eden: stem cells and their niches. Science 287, 1427–1430 (2000).

    Article  CAS  Google Scholar 

  56. Kloxin, A. M., Kasko, A. M., Salinas, C. N. & Anseth, K. S. Photodegradable hydrogels for dynamic tuning of physical and chemical properties. Science 324, 59–63 (2009).

    Article  CAS  Google Scholar 

  57. DeForest, C. A. & Anseth, K. S. Photoreversible patterning of biomolecules within click-based hydrogels. Angew. Chem. Int. Ed. Engl. 51, 1816–1819 (2012).

    Article  CAS  Google Scholar 

  58. Chaudhuri, O. et al. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat. Mater. 15, 326–334 (2016).

    Article  CAS  Google Scholar 

  59. Rincon, E. et al. Mesenchymal stem cell carriers enhance antitumor efficacy of oncolytic adenoviruses in an immunocompetent mouse model. Oncotarget 11, 45415–45431 (2017).

    Google Scholar 

  60. Parker Kerrigan, B. C., Shimizu, Y., Andreeff, M. & Lang, F. F. Mesenchymal stromal cells for the delivery of oncolytic viruses in gliomas. Cytotherapy 19, 445–457 (2017).

    Article  CAS  Google Scholar 

  61. Yoshimatsu, G. et al. The co-transplantation of bone marrow derived mesenchymal stem cells reduced inflammation in intramuscular islet transplantation. PLoS ONE 10, e0117561 (2015).

    Article  CAS  Google Scholar 

  62. Ge, C., Xiao, G., Jiang, D. & Franceschi, R. T. Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J. Cell Biol. 176, 709–718 (2007).

    Article  CAS  Google Scholar 

  63. Ge, C. et al. Reciprocal control of osteogenic and adipogenic differentiation by ERK/MAP kinase phosphorylation of Runx2 and PPARgamma transcription factors. J. Cell. Physiol. 231, 587–596 (2016).

    Article  CAS  Google Scholar 

  64. Yanes, O. et al. Metabolic oxidation regulates embryonic stem cell differentiation. Nat. Chem. Biol. 6, 411–417 (2010).

    Article  CAS  Google Scholar 

  65. Seras-Franzoso, J. et al. Topographically targeted osteogenesis of mesenchymal stem cells stimulated by inclusion bodies attached to polycaprolactone surfaces. Nanomedicine 9, 207–220 (2014).

    Article  CAS  Google Scholar 

  66. Wilson, A. et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135, 1118–1129 (2008).

    Article  CAS  Google Scholar 

  67. Savatier, P., Huang, S., Szekely, L., Wiman, K. G. & Samarut, J. Contrasting patterns of retinoblastoma protein expression in mouse embryonic stem cells and embryonic fibroblasts. Oncogene 9, 809–818 (1994).

    CAS  Google Scholar 

  68. White, J. et al. Developmental activation of the Rb-E2F pathway and establishment of cell cycle-regulated cyclin-dependent kinase activity during embryonic stem cell differentiation. Mol. Biol. Cell 16, 2018–2027 (2005).

    Article  CAS  Google Scholar 

  69. Cortes, F., Debacker, C., Peault, B. & Labastie, M. C. Differential expression of KDR/VEGFR-2 and CD34 during mesoderm development of the early human embryo. Mechanisms Dev. 83, 161–164 (1999).

    Article  CAS  Google Scholar 

  70. Salomoni, P. & Calegari, F. Cell cycle control of mammalian neural stem cells: putting a speed limit on G1. Trends Cell Biol. 20, 233–243 (2010).

    Article  CAS  Google Scholar 

  71. Laurenti, E. et al. CDK6 levels regulate quiescence exit in human hematopoietic stem cells. Cell Stem Cell 16, 302–313 (2015).

    Article  CAS  Google Scholar 

  72. Ogasawara, T. et al. Bone morphogenetic protein 2-induced osteoblast differentiation requires smad-mediated down-regulation of Cdk6. Mol. Cell. Biol. 24, 6560–6568 (2004).

    Article  CAS  Google Scholar 

  73. Johnson, D. G., Schwarz, J. K., Cress, W. D. & Nevins, J. R. Expression of transcription factor E2F1 induces quiescent cells to enter S phase. Nature 365, 349–352 (1993).

    Article  CAS  Google Scholar 

  74. Chong, J. L. et al. E2f1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature 462, 930–934 (2009).

    Article  CAS  Google Scholar 

  75. Ranga, A. et al. 3D niche microarrays for systems-level analyses of cell fate. Nat. Commun. 5, 4324 (2014).

    Article  CAS  Google Scholar 

  76. Lutolf, M. P. & Blau, H. M. Artificial stem cell niches. Adv. Mater. 21, 3255–3268 (2009).

    Article  CAS  Google Scholar 

  77. Mei, Y. et al. Combinatorial development of biomaterials for clonal growth of human pluripotent stem cells. Nat. Mater. 9, 768–778 (2010).

    Article  CAS  Google Scholar 

  78. Curran, J. M. et al. Introducing dip pen nanolithography as a tool for controlling stem cell behaviour: unlocking the potential of the next generation of smart materials in regenerative medicine. Lab Chip 10, 1662–1670 (2010).

    Article  CAS  Google Scholar 

  79. Das, R. K., Gocheva, V., Hammink, R., Zouani, O. F. & Rowan, A. E. Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels. Nat. Mater. 15, 318–325 (2016).

    Article  CAS  Google Scholar 

  80. Gu, H., Yue, Z., Leong, W. S., Nugraha, B. & Tan, L. P. Control of in vitro neural differentiation of mesenchymal stem cells in 3D macroporous, cellulosic hydrogels. Regen. Med. 5, 245–253 (2010).

    Article  CAS  Google Scholar 

  81. Ehninger, A. & Trumpp, A. The bone marrow stem cell niche grows up: mesenchymal stem cells and macrophages move in. J. Exp. Med. 208, 421–428 (2011). This paper provides a good review of the cellular constituents of the bone marrow niche.

    Article  CAS  Google Scholar 

  82. Bianco, P. Bone and the hematopoietic niche: a tale of two stem cells. Blood 117, 5281–5288 (2011).

    Article  CAS  Google Scholar 

  83. Lewis, E. E. et al. A quiescent, regeneration-responsive tissue engineered mesenchymal stem cell bone marrow niche model via magnetic levitation. ACS Nano 10, 8346–8354 (2016). This paper shows a bioengineering approach to forming an in vitro MSC niche.

    Article  CAS  Google Scholar 

  84. Pennock, R. et al. Human cell dedifferentiation in mesenchymal condensates through controlled autophagy. Sci. Rep. 5, 13113 (2015).

    Article  CAS  Google Scholar 

  85. Lutolf, M. P., Gilbert, P. M. & Blau, H. M. Designing materials to direct stem-cell fate. Nature 462, 433–441 (2009).

    Article  CAS  Google Scholar 

  86. Yang, C. et al. Spatially patterned matrix elasticity directs stem cell fate. Proc. Natl Acad. Sci. USA 113, E4439–E4445 (2016).

    Article  CAS  Google Scholar 

  87. Li, L., Bennett, S. A. & Wang, L. Role of E-cadherin and other cell adhesion molecules in survival and differentiation of human pluripotent stem cells. Cell Adh. Migr. 6, 59–70 (2012).

    Article  Google Scholar 

  88. Xu, Y. et al. Revealing a core signaling regulatory mechanism for pluripotent stem cell survival and self-renewal by small molecules. Proc. Natl Acad. Sci. USA 107, 8129–8134 (2010).

    Article  CAS  Google Scholar 

  89. Rowland, T. J. et al. Roles of integrins in human induced pluripotent stem cell growth on Matrigel and vitronectin. Stem Cells Dev. 19, 1231–1240 (2010).

    Article  CAS  Google Scholar 

  90. Nagaoka, M., Si-Tayeb, K., Akaike, T. & Duncan, S. A. Culture of human pluripotent stem cells using completely defined conditions on a recombinant E-cadherin substratum. BMC Dev. Biol. 10, 60 (2010).

    Article  CAS  Google Scholar 

  91. Price, A. J., Huang, E. Y., Sebastiano, V. & Dunn, A. R. A semi-interpenetrating network of polyacrylamide and recombinant basement membrane allows pluripotent cell culture in a soft, ligand-rich microenvironment. Biomaterials 121, 179–192 (2017).

    Article  CAS  Google Scholar 

  92. Chen, W. et al. Nanotopography influences adhesion, spreading, and self-renewal of human embryonic stem cells. ACS Nano 6, 4094–4103 (2012).

    CAS  Google Scholar 

  93. Ji, L., LaPointe, V. L., Evans, N. D. & Stevens, M. M. Changes in embryonic stem cell colony morphology and early differentiation markers driven by colloidal crystal topographical cues. Eur. Cell. Mater. 23, 135–146 (2012).

    Article  CAS  Google Scholar 

  94. Schultz, G. S. & Wysocki, A. Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen. 17, 153–162 (2009).

    Article  Google Scholar 

  95. Kleinman, H. K., Philp, D. & Hoffman, M. P. Role of the extracellular matrix in morphogenesis. Curr. Opin. Biotechnol. 14, 526–532 (2003).

    Article  CAS  Google Scholar 

  96. Mitchell, A. C., Briquez, P. S., Hubbell, J. A. & Cochran, J. R. Engineering growth factors for regenerative medicine applications. Acta Biomater. 30, 1–12 (2016).

    Article  CAS  Google Scholar 

  97. Carragee, E. J., Hurwitz, E. L. & Weiner, B. K. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. Spine J. 11, 471–491 (2011).

    Article  Google Scholar 

  98. Yadin, D., Knaus, P. & Mueller, T. D. Structural insights into BMP receptors: specificity, activation and inhibition. Cytokine Growth Factor Rev. 27, 13–34 (2016).

    Article  CAS  Google Scholar 

  99. Nickel, J., Sebald, W., Groppe, J. C. & Mueller, T. D. Intricacies of BMP receptor assembly. Cytokine Growth Factor Rev. 20, 367–377 (2009).

    Article  CAS  Google Scholar 

  100. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  Google Scholar 

  101. Singh, M., Berkland, C. & Detamore, M. S. Strategies and applications for incorporating physical and chemical signal gradients in tissue engineering. Tissue Eng. Part B Rev. 14, 341–366 (2008).

    Article  CAS  Google Scholar 

  102. Liu, A. L. & Garcia, A. J. Methods for generating hydrogel particles for protein delivery. Ann. Biomed. Eng. 44, 1946–1958 (2016).

    Article  Google Scholar 

  103. Dingal, P. C. & Discher, D. E. Combining insoluble and soluble factors to steer stem cell fate. Nat. Mater. 13, 532–537 (2014).

    Article  CAS  Google Scholar 

  104. Rice, J. J. et al. Engineering the regenerative microenvironment with biomaterials. Adv. Healthc. Mater. 2, 57–71 (2013).

    Article  CAS  Google Scholar 

  105. Lee, K., Silva, E. A. & Mooney, D. J. Growth factor delivery-based tissue engineering: general approaches and a review of recent developments. J. R. Soc. Interface 8, 153–170 (2011).

    Article  CAS  Google Scholar 

  106. Hynes, R. O. The extracellular matrix: not just pretty fibrils. Science 326, 1216–1219 (2009).

    Article  CAS  Google Scholar 

  107. Migliorini, E., Valat, A., Picart, C. & Cavalcanti-Adam, E. A. Tuning cellular responses to BMP-2 with material surfaces. Cytokine Growth Factor Rev. 27, 43–54 (2016).

    Article  CAS  Google Scholar 

  108. Kuhl, P. R. & Griffith-Cima, L. G. Tethered epidermal growth factor as a paradigm for growth factor-induced stimulation from the solid phase. Nat. Med. 2, 1022–1027 (1996).

    Article  CAS  Google Scholar 

  109. Briquez, P. S., Hubbell, J. A. & Martino, M. M. Extracellular matrix-inspired growth factor delivery systems for skin wound healing. Adv. Wound Care 4, 479–489 (2015).

    Article  Google Scholar 

  110. Martino, M. M., Briquez, P. S., Maruyama, K. & Hubbell, J. A. Extracellular matrix-inspired growth factor delivery systems for bone regeneration. Adv. Drug Deliv. Rev. 94, 41–52 (2015).

    Article  CAS  Google Scholar 

  111. Briquez, P. S., Clegg, L. E., Martino, M. M., Mac Gabham, F. & Hubbell, J. A. Design principles for therapeutic angiogenic materials. Nat. Rev. Mater. 1, 15006 (2016).

    Article  CAS  Google Scholar 

  112. Cuatrecasas, P. Interaction of insulin with the cell membrane: the primary action of insulin. Proc. Natl Acad. Sci. USA 63, 450–457 (1969).

    Article  CAS  Google Scholar 

  113. Ito, Y., Zheng, J., Imanishi, Y., Yonezawa, K. & Kasuga, M. Protein-free cell culture on an artificial substrate with covalently immobilized insulin. Proc. Natl Acad. Sci. USA 93, 3598–3601 (1996).

    Article  CAS  Google Scholar 

  114. Davis, M. E. et al. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc. Natl Acad. Sci. USA 103, 8155–8160 (2006).

    Article  CAS  Google Scholar 

  115. Chen, T. T. et al. Anchorage of VEGF to the extracellular matrix conveys differential signaling responses to endothelial cells. J. Cell Biol. 188, 595–609 (2010).

    Article  CAS  Google Scholar 

  116. Fan, V. H. et al. Tethered epidermal growth factor provides a survival advantage to mesenchymal stem cells. Stem Cells 25, 1241–1251 (2007).

    Article  CAS  Google Scholar 

  117. Anderson, S. M., Siegman, S. N. & Segura, T. The effect of vascular endothelial growth factor (VEGF) presentation within fibrin matrices on endothelial cell branching. Biomaterials 32, 7432–7443 (2011).

    Article  CAS  Google Scholar 

  118. Schwab, E. H. et al. Nanoscale control of surface immobilized BMP-2: toward a quantitative assessment of BMP-mediated signaling events. Nano Lett. 15, 1526–1534 (2015).

    Article  CAS  Google Scholar 

  119. Hauff, K. et al. Matrix-immobilized BMP-2 on microcontact printed fibronectin as an in vitro tool to study BMP-mediated signaling and cell migration. Front. Bioeng. Biotechnol. 3, 62 (2015).

    Article  Google Scholar 

  120. Azevedo, H. S. & Pashkuleva, I. Biomimetic supramolecular designs for the controlled release of growth factors in bone regeneration. Adv. Drug Deliv. Rev. 94, 63–76 (2015).

    Article  CAS  Google Scholar 

  121. Delplace, V., Obermeyer, J. & Shoichet, M. S. Local affinity release. ACS Nano 10, 6433–6436 (2016).

    CAS  Google Scholar 

  122. Belair, D. G., Le, N. N. & Murphy, W. L. Design of growth factor sequestering biomaterials. Chem. Commun. 50, 15651–15668 (2014).

    Article  CAS  Google Scholar 

  123. Silva, J. M., Reis, R. L. & Mano, J. F. Biomimetic extracellular environment based on natural origin polyelectrolyte multilayers. Small 12, 4308–4342 (2016).

    Article  CAS  Google Scholar 

  124. Crouzier, T., Ren, K., Nicolas, C., Roy, C. & Picart, C. Layer-by-layer films as a biomimetic reservoir for rhBMP-2 delivery: controlled differentiation of myoblasts to osteoblasts. Small 5, 598–608 (2009).

    Article  CAS  Google Scholar 

  125. Crouzier, T., Fourel, L., Boudou, T., Albiges-Rizo, C. & Picart, C. Presentation of BMP-2 from a soft biopolymeric film unveils its activity on cell adhesion and migration. Adv. Mater. 23, H111–H118 (2011).

    Article  CAS  Google Scholar 

  126. Gilde, F. et al. Secondary structure of rhBMP-2 in a protective biopolymeric carrier material. Biomacromolecules 13, 3620–3626 (2012).

    Article  CAS  Google Scholar 

  127. Roca-Cusachs, P., Iskratsch, T. & Sheetz, M. P. Finding the weakest link: exploring integrin-mediated mechanical molecular pathways. J. Cell Sci. 125, 3025–3038 (2012).

    Article  CAS  Google Scholar 

  128. Zouani, O. F., Kalisky, J., Ibarboure, E. & Durrieu, M. C. Effect of BMP-2 from matrices of different stiffnesses for the modulation of stem cell fate. Biomaterials 34, 2157–2166 (2013).

    Article  CAS  Google Scholar 

  129. Mammoto, A. et al. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457, 1103–1108 (2009). This paper dissects biological mechanisms for stiffness and GF control of cell fate.

    Article  CAS  Google Scholar 

  130. Phelps, E. A., Landazuri, N., Thule, P. M., Taylor, W. R. & Garcia, A. J. Bioartificial matrices for therapeutic vascularization. Proc. Natl Acad. Sci. USA 107, 3323–3328 (2010).

    Article  CAS  Google Scholar 

  131. Shekaran, A. et al. Bone regeneration using an alpha 2 beta 1 integrin-specific hydrogel as a BMP-2 delivery vehicle. Biomaterials 35, 5453–5461 (2014).

    Article  CAS  Google Scholar 

  132. Comoglio, P. M., Boccaccio, C. & Trusolino, L. Interactions between growth factor receptors and adhesion molecules: breaking the rules. Curr. Opin. Cell Biol. 15, 565–571 (2003).

    Article  CAS  Google Scholar 

  133. Wang, F. et al. Reciprocal interactions between beta1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology. Proc. Natl Acad. Sci. USA 95, 14821–14826 (1998).

    Article  CAS  Google Scholar 

  134. Borges, E., Jan, Y. & Ruoslahti, E. Platelet-derived growth factor receptor beta and vascular endothelial growth factor receptor 2 bind to the beta 3 integrin through its extracellular domain. J. Biol. Chem. 275, 39867–39873 (2000).

    Article  CAS  Google Scholar 

  135. Schneller, M., Vuori, K. & Ruoslahti, E. Alphavbeta3 integrin associates with activated insulin and PDGFbeta receptors and potentiates the biological activity of PDGF. EMBO J. 16, 5600–5607 (1997).

    Article  CAS  Google Scholar 

  136. Soldi, R. et al. Role of alphavbeta3 integrin in the activation of vascular endothelial growth factor receptor-2. EMBO J. 18, 882–892 (1999).

    Article  CAS  Google Scholar 

  137. Streuli, C. H. & Akhtar, N. Signal co-operation between integrins and other receptor systems. Biochem. J. 418, 491–506 (2009).

    Article  CAS  Google Scholar 

  138. Veevers-Lowe, J., Ball, S. G., Shuttleworth, A. & Kielty, C. M. Mesenchymal stem cell migration is regulated by fibronectin through alpha5beta1-integrin-mediated activation of PDGFR-beta and potentiation of growth factor signals. J. Cell Sci. 124, 1288–1300 (2011).

    Article  CAS  Google Scholar 

  139. Cascone, I., Napione, L., Maniero, F., Serini, G. & Bussolino, F. Stable interaction between alpha5beta1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1. J. Cell Biol. 170, 993–1004 (2005).

    Article  CAS  Google Scholar 

  140. Ivaska, J. & Heino, J. Cooperation between integrins and growth factor receptors in signaling and endocytosis. Annu. Rev. Cell Dev. Biol. 27, 291–320 (2011).

    Article  CAS  Google Scholar 

  141. Brizzi, M. F., Tarone, G. & Defilippi, P. Extracellular matrix, integrins, and growth factors as tailors of the stem cell niche. Curr. Opin. Cell Biol. 24, 645–651 (2012).

    Article  CAS  Google Scholar 

  142. Martino, M. M. & Hubbell, J. A. The 12th-14th type III repeats of fibronectin function as a highly promiscuous growth factor-binding domain. FASEB J. 24, 4711–4721 (2010).

    Article  CAS  Google Scholar 

  143. Wijelath, E. S. et al. Heparin-II domain of fibronectin is a vascular endothelial growth factor-binding domain: enhancement of VEGF biological activity by a singular growth factor/matrix protein synergism. Circ. Res. 99, 853–860 (2006).

    Article  CAS  Google Scholar 

  144. Martino, M. M. et al. Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing. Sci. Transl Med. 3, 100–189 (2011). This paper demonstrates the engineering of materials for synergistic integrin and GF signalling through the use of recombinant fragments of fibronectin.

    Article  CAS  Google Scholar 

  145. Pankov, R. & Yamada, K. M. Fibronectin at a glance. J. Cell Sci. 115, 3861–3863 (2002).

    Article  CAS  Google Scholar 

  146. Mao, Y. & Schwarzbauer, J. E. Fibronectin fibrillogenesis, a cell-mediated matrix assembly process. Matrix Biol. 24, 389–399 (2005).

    Article  CAS  Google Scholar 

  147. Schwarzbauer, J. E. & DeSimone, D. W. Fibronectins, their fibrillogenesis, and in vivo functions. Cold Spring Harb. Perspect. Biol. 3, a005041 (2011).

    Article  CAS  Google Scholar 

  148. Garcia, A. J., Vega, M. D. & Boettiger, D. Modulation of cell proliferation and differentiation through substrate-dependent changes in fibronectin conformation. Mol. Biol. Cell 10, 785–798 (1999).

    Article  CAS  Google Scholar 

  149. Keselowsky, B. G., Collard, D. M. & Garcia, A. J. Integrin binding specificity regulates biomaterial surface chemistry effects on cell differentiation. Proc. Natl Acad. Sci. USA 102, 5953–5957 (2005).

    Article  CAS  Google Scholar 

  150. Cantini, M., Gonzalez-Garcia, C., Llopis-Hernandez, V. & Salmeron-Sanchez, M. in Proteins at Interfaces III: State of the Art (eds Horbett, T., Brash, J. L. & Norde, W. ) 471–496 (American Chemical Society, 2012).

    Google Scholar 

  151. Llopis-Hernandez, V., Cantini, M., Gonzalez-Garcia, C. & Salmeron-Sanchez, M. Material-based strategies to engineer fibronectin matrices for regenerative medicine. Int. Mater. Rev. 60, 245–263 (2015).

    Article  CAS  Google Scholar 

  152. Salmerón-Sánchez, M. et al. Role of material-driveen fibronectin fibrillogenesis in cell differentiation. Biomaterials 32, 2099–2105 (2010).

    Article  CAS  Google Scholar 

  153. Gugutkov, D. et al. Biological activity of the substrate-induced fibronectin network: insight into the third dimension through electrospun fibers. Langmuir 25, 10893–10900 (2009).

    Article  CAS  Google Scholar 

  154. Llopis-Hernandez, V. et al. Material-driven fibronectin assembly for high-efficiency presentation of growth factors. Sci. Adv. 2, e1600188 (2016). This paper demonstrates a simple engineering approach for synergistic integrin and GF signalling.

    Article  CAS  Google Scholar 

  155. Moulisova, V. et al. Engineered microenvironments for synergistic VEGF — integrin signalling during vascularization. Biomaterials 126, 61–74 (2017).

    Article  CAS  Google Scholar 

  156. Martino, M. M. et al. Growth factors engineered for super-affinity to the extracellular matrix enhance tissue healing. Science 343, 885–888 (2014). This paper shows that GFs have better potential when bound to the ECM than when administered as soluble factors.

    Article  CAS  Google Scholar 

  157. Unadkat, H. V. et al. An algorithm-based topographical biomaterials library to instruct cell fate. Proc. Natl Acad. Sci. USA 108, 16565–16570 (2011).

    Article  CAS  Google Scholar 

  158. Reimer, A. et al. Scalable topographies to support proliferation and Oct4 expression by human induced pluripotent stem cells. Sci. Rep. 6, 18948 (2016).

    Article  CAS  Google Scholar 

  159. Gobaa, S. et al. Artificial niche microarrays for probing single stem cell fate in high throughput. Nat. Methods 8, 949–955 (2011).

    Article  CAS  Google Scholar 

  160. Chiappini, C. et al. Biodegradable nanoneedles for localized delivery of nanoparticles in vivo: exploring the biointerface. ACS Nano 9, 5500–5509 (2015).

    CAS  Google Scholar 

  161. Chiappini, C. et al. Biodegradable silicon nanoneedles delivering nucleic acids intracellularly induce localized in vivo neovascularization. Nat. Mater. 14, 532–539 (2015).

    Article  CAS  Google Scholar 

  162. Passier, R., van Laake, L. W. & Mummery, C. L. Stem-cell-based therapy and lessons from the heart. Nature 453, 322–329 (2008).

    Article  CAS  Google Scholar 

  163. Mosiewicz, K. A. et al. In situ cell manipulation through enzymatic hydrogel photopatterning. Nat. Mater. 12, 1072–1078 (2013).

    Article  CAS  Google Scholar 

  164. Fonseca, K. B. et al. Injectable MMP-sensitive alginate hydrogels as hMSC delivery systems. Biomacromolecules 15, 380–390 (2014).

    Article  CAS  Google Scholar 

  165. Huebsch, N. et al. Matrix elasticity of void-forming hydrogels controls transplanted-stem-cell-mediated bone formation. Nat. Mater. 14, 1269–1277 (2015).

    Article  CAS  Google Scholar 

  166. Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

    Article  CAS  Google Scholar 

  167. Wang, Y., Chen, X., Cao, W. & Shi, Y. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat. Immunol. 15, 1009–1016 (2014).

    Article  CAS  Google Scholar 

  168. Ayenehdeh, J. M. et al. Immunomodulatory and protective effects of adipose tissue-derived mesenchymal stem cells in an allograft islet composite transplantation for experimental autoimmune type 1 diabetes. Immunol. Lett. 188, 21–31 (2017).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank the UK Medical Research Council, the UK Engineering and Physical Sciences Research Council and the UK Biotechnology and Biological Sciences Research Council for grants MR/L022710/1, EP/P001114/1 and BB/N018419/1, respectively. The authors thank A. Rodrigo-Navarro for the design of the illustrations.

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Dalby, M., García, A. & Salmeron-Sanchez, M. Receptor control in mesenchymal stem cell engineering. Nat Rev Mater 3, 17091 (2018). https://doi.org/10.1038/natrevmats.2017.91

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