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Extracellular Matrix Regulation of Stem Cell Fate

  • Stem Cell Switches and Regulators (KK Hirschi, Section Editor)
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Abstract

Purpose of Review

The extracellular matrix (ECM) presents a complex myriad of biochemical and physical cues in the stem cell niche and is able to modulate stem cell fate and function. This review summarizes engineering approaches that have exploited natural and synthetic biomaterials to understand ECM regulation of stem cell fate. Specifically, we demonstrate how these studies have advanced our understanding of vascular maturation and mesenchymal lineage specification.

Recent Findings

ECM mechanics have emerged as a critical cue in stem cell lineage specification. With the introduction of mechanically dynamic materials, which mirror the non-linear elastic behavior of natural matrices, our understanding of differentiation behavior has evolved.

Summary

While studies using conventional culture employing rigid, two-dimensional surfaces have greatly advanced our understanding of stem cell differentiation, they overlook the complexity of ECM in the stem cell environment. Implementing defined analogs, through material science and tissue engineering approaches, will allow us to mirror the dynamic nature of ECM and fully elucidate how stem cells differentiate.

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References

Papers of particular interest, published recently, have been highlighted as:• Of importance •• Of major importance

  1. Ingber D. Extracellular matrix and cell shape: potential control points for inhibition of angiogenesis. J Cell Biochem. 1991;47(3):236–41. https://doi.org/10.1002/jcb.240470309.

    Article  CAS  PubMed  Google Scholar 

  2. Raab M, Swift J, Dingal PCD, Shah P, Shin J-W, Discher DE. Crawling from soft to stiff matrix polarizes the cytoskeleton and phosphoregulates myosin-II heavy chain. J Cell Biol. 2012;199(4):669–83. https://doi.org/10.1083/jcb.201205056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lo C-M, Wang H-B, Dembo M, Wang Y-L. Cell movement is guided by the rigidity of the substrate. Biophys J. 2000;79(1):144–52. https://doi.org/10.1016/S0006-3495(00)76279-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang N, Ingber DE. Control of cytoskeletal mechanics by extracellular matrix, cell shape, and mechanical tension. Biophys J. 1994;66(6):2181–9. https://doi.org/10.1016/S0006-3495(94)81014-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Prasain N, Lee MR, Vemula S, Meador JL, Yoshimoto M, Ferkowicz MJ, et al. Differentiation of human pluripotent stem cells to cells similar to cord-blood endothelial colony-forming cells. Nat Biotechnol. 2014;32(11):1151–7. https://doi.org/10.1038/nbt.3048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dickinson LE, Kusuma S, Gerecht S. Reconstructing the differentiation niche of embryonic stem cells using biomaterials. Macromol Biosci. 2011;11(1):36–49. https://doi.org/10.1002/mabi.201000245.

    Article  CAS  PubMed  Google Scholar 

  7. Levental I, Georges PC, Janmey PA. Soft biological materials and their impact on cell function. Soft Matter. 2007;3(3):299–306. https://doi.org/10.1039/B610522J.

    Article  CAS  Google Scholar 

  8. Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology. 2008;47(4):1394–400. https://doi.org/10.1002/hep.22193.

    Article  CAS  PubMed  Google Scholar 

  9. Kim IL, Mauck RL, Burdick JA. Hydrogel design for cartilage tissue engineering: a case study with hyaluronic acid. Biomaterials. 2011;32(34):8771–82. https://doi.org/10.1016/j.biomaterials.2011.08.073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Schaffler MB, Burr DB. Stiffness of compact bone: effects of porosity and density. J Biomech. 1988;21(1):13–6. https://doi.org/10.1016/0021-9290(88)90186-8.

    Article  CAS  PubMed  Google Scholar 

  11. Baldwin AD, Kiick KL. Polysaccharide-modified synthetic polymeric biomaterials. Pept Sci. 2010;94(1):128–40. https://doi.org/10.1002/bip.21334.

    Article  CAS  Google Scholar 

  12. Davis GE, Camarillo CW. An α2β1 integrin-dependent pinocytic mechanism involving intracellular vacuole formation and coalescence regulates capillary lumen and tube formation in three-dimensional collagen matrix. Exp Cell Res. 1996;224(1):39–51. https://doi.org/10.1006/excr.1996.0109.

    Article  CAS  PubMed  Google Scholar 

  13. Bayless KJ, Davis GE. The Cdc42 and Rac1 GTPases are required for capillary lumen formation in three-dimensional extracellular matrices. J Cell Sci. 2002;115(6):1123–36.

    CAS  PubMed  Google Scholar 

  14. Davis GE, Bayless KJ, Mavila A. Molecular basis of endothelial cell morphogenesis in three-dimensional extracellular matrices. Anat Rec. 2002;268(3):252–75. https://doi.org/10.1002/ar.10159.

    Article  CAS  PubMed  Google Scholar 

  15. Davis GE, Black SM, Bayless KJ. Capillary morphogenesis during human endothelial cell invasion of three-dimensional collagen matrices. In Vitro Cellular & Developmental Biology—Animal. 2000;36(8):513–9. https://doi.org/10.1290/1071-2690(2000)036<0513:CMDHEC>2.0.CO;2.

    Article  CAS  Google Scholar 

  16. George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development. 1993;119(4):1079–91.

    CAS  PubMed  Google Scholar 

  17. Francis SE, Goh KL, Hodivala-Dilke K, Bader BL, Stark M, Davidson D, et al. Central roles of α5β1 integrin and fibronectin in vascular development in mouse embryos and embryoid bodies. Arterioscler Thromb Vasc Biol. 2002;22(6):927–33. https://doi.org/10.1161/01.ATV.0000016045.93313.F2.

    Article  CAS  PubMed  Google Scholar 

  18. Toole BP. Hyaluronan in morphogenesis. Semin Cell Dev Biol. 2001;12(2):79–87. https://doi.org/10.1006/scdb.2000.0244.

    Article  CAS  PubMed  Google Scholar 

  19. Davis GE, Senger DR. Extracellular matrix mediates a molecular balance between vascular morphogenesis and regression. Curr Opin Hematol. 2008;15(3):197–203. https://doi.org/10.1097/MOH.0b013e3282fcc321.

    Article  CAS  PubMed  Google Scholar 

  20. • Smith Q, Chan XY, Carmo AM, Trempel M, Saunders M, Gerecht S. Compliant substratum guides endothelial commitment from human pluripotent stem cells. Sci Adv. 2017;3(5):e1602883. Demonstration of the utility of polydimethylsiloxane (PDMS) substrates for controlling substrate stiffness and investigating mesodermal commitment of human induced pluripotent stem cells in chemcially defined media conditions. https://doi.org/10.1126/sciadv.1602883.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kusuma S, Smith Q, Facklam A, Gerecht S. Micropattern size-dependent endothelial differentiation from a human induced pluripotent stem cell line. Journal of Tissue Engineering and Regenerative Medicine. 2015.

  22. Dickinson LE, Moura ME, Gerecht S. Guiding endothelial progenitor cell tube formation using patterned fibronectin surfaces. Soft Matter. 2010;6(20):5109–19. https://doi.org/10.1039/c0sm00233j.

    Article  CAS  Google Scholar 

  23. Smith Q, Stukalin E, Kusuma S, Gerecht S, Sun SX. Stochasticity and spatial interaction govern stem cell differentiation dynamics. Sci Rep. 2015;5(1):12617. https://doi.org/10.1038/srep12617.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wanjare M, Kusuma S, Gerecht S. Defining differences among perivascular cells derived from human pluripotent stem cells. Stem Cell Reports. 2014;2(5):561–75. https://doi.org/10.1016/j.stemcr.2014.03.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kusuma S, Facklam A, Gerecht S. Characterizing human pluripotent-stem-cell-derived vascular cells for tissue engineering applications. Stem Cells Dev. 2015;24(4):451–8. https://doi.org/10.1089/scd.2014.0377.

    Article  CAS  PubMed  Google Scholar 

  26. Barreto-Ortiz SF, Zhang S, Davenport M, Fradkin J, Ginn B, Mao H-Q, et al. A novel in vitro model for microvasculature reveals regulation of circumferential ECM organization by curvature. PLoS One. 2013;8(11):e81061. https://doi.org/10.1371/journal.pone.0081061.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wanjare M, Kuo F, Gerecht S. Derivation and maturation of synthetic and contractile vascular smooth muscle cells from human pluripotent stem cells. Cardiovasc Res. 2013;97(2):321–30. https://doi.org/10.1093/cvr/cvs315.

    Article  CAS  PubMed  Google Scholar 

  28. Barreto-Ortiz SF, Fradkin J, Eoh J, Trivero J, Davenport M, Ginn B, et al. Fabrication of 3-dimensional multicellular microvascular structures. FASEB J. 2015;29(8):3302–14. https://doi.org/10.1096/fj.14-263343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kusuma S, Zhao S, Gerecht S. The extracellular matrix is a novel attribute of endothelial progenitors and of hypoxic mature endothelial cells. The FASEB J. 2012.

  30. Wanjare M, Agarwal N, Gerecht S. Biomechanical strain induces elastin and collagen production in human pluripotent stem cell-derived vascular smooth muscle cells. Am J Physiol Cell Physiol. 2015;309(4):C271–81. https://doi.org/10.1152/ajpcell.00366.2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Eoh JH, Shen N, Burke JA, Hinderer S, Xia Z, Schenke-Layland K, et al. Enhanced elastin synthesis and maturation in human vascular smooth muscle tissue derived from induced-pluripotent stem cells. Acta Biomater. 2017;52:49–59. https://doi.org/10.1016/j.actbio.2017.01.083.

    Article  CAS  PubMed  Google Scholar 

  32. Hanjaya-Putra D, Yee J, Ceci D, Truitt R, Yee D, Gerecht S. Vascular endothelial growth factor and substrate mechanics regulate in vitro tubulogenesis of endothelial progenitor cells. J Cell Mol Med. 2010;14(10):2436–47. https://doi.org/10.1111/j.1582-4934.2009.00981.x.

    Article  PubMed  Google Scholar 

  33. Hanjaya-Putra D, Bose V, Shen Y-I, Yee J, Khetan S, Fox-Talbot K, et al. Controlled activation of morphogenesis to generate a functional human microvasculature in a synthetic matrix. Blood. 2011;118(3):804–15. https://doi.org/10.1182/blood-2010-12-327338.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hanjaya-Putra D, Wong KT, Hirotsu K, Khetan S, Burdick JA, Gerecht S. Spatial control of cell-mediated degradation to regulate vasculogenesis and angiogenesis in hyaluronan hydrogels. Biomaterials. 2012;33(26):6123–31. https://doi.org/10.1016/j.biomaterials.2012.05.027.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kusuma S, Shen Y-I, Hanjaya-Putra D, Mali P, Cheng L, Gerecht S. Self-organized vascular networks from human pluripotent stem cells in a synthetic matrix. Proc Natl Acad Sci. 2013;110(31):12601–6. https://doi.org/10.1073/pnas.1306562110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Park KM, Gerecht S. Hypoxia-inducible hydrogels. Nature Communications. 2014;5.

  37. Blatchley M, Park KM, Gerecht S. Designer hydrogels for precision control of oxygen tension and mechanical properties. J Mater Chem B. 2015;3(40):7939–49. https://doi.org/10.1039/C5TB01038A.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chan XY, Black R, Dickerman K, Federico J, Lévesque M, Mumm J, et al. Three-dimensional vascular network assembly from diabetic patient-derived induced pluripotent stem cells. Arterioscler Thromb Vasc Biol. 2015;35(12):2677–85. https://doi.org/10.1161/ATVBAHA.115.306362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell. 2004;6(4):483–95. https://doi.org/10.1016/S1534-5807(04)00075-9.

    Article  CAS  PubMed  Google Scholar 

  40. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126(4):677–89. https://doi.org/10.1016/j.cell.2006.06.044.

    Article  CAS  PubMed  Google Scholar 

  41. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, et al. Role of YAP/TAZ in mechanotransduction. Nature. 2011;474(7350):179–83. https://doi.org/10.1038/nature10137.

    Article  CAS  PubMed  Google Scholar 

  42. Azzolin L, Panciera T, Soligo S, Enzo E, Bicciato S, Dupont S, et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell. 2014;158(1):157–70. https://doi.org/10.1016/j.cell.2014.06.013.

    Article  CAS  PubMed  Google Scholar 

  43. Schwartz MA. Integrins and extracellular matrix in mechanotransduction. Cold Spring Harb Perspect Biol. 2010;2(12):a005066. https://doi.org/10.1101/cshperspect.a005066.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Cosgrove BD, Mui KL, Driscoll TP, Caliari SR, Mehta KD, Assoian RK, et al. N-cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells. Nature Materials. 2016.

  45. •• Yang C, Tibbitt MW, Basta L, Anseth KS. Mechanical memory and dosing influence stem cell fate. Nat Mater. 2014;13(6):645–52. Demonstration of photo-tunable poly(ethylene glycol) hydrogels for investigating temporal regulation of substrate stiffness, YAP/TAZ signaling, and downstream differentation of mesenchymal stem cells. https://doi.org/10.1038/nmat3889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang C, DelRio FW, Ma H, Killaars AR, Basta LP, Kyburz KA, et al. Spatially patterned matrix elasticity directs stem cell fate. Proc Natl Acad Sci U S A. 2016;113(31):E4439–45. https://doi.org/10.1073/pnas.1609731113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Trappmann B, Gautrot JE, Connelly JT, Strange DGT, Li Y, Oyen ML, et al. Extracellular-matrix tethering regulates stem-cell fate. Nat Mater. 2012;11(7):642–9. https://doi.org/10.1038/nmat3339.

    Article  CAS  PubMed  Google Scholar 

  48. Wen JH, Vincent LG, Fuhrmann A, Choi YS, Hribar KC, Taylor-Weiner H, et al. Interplay of matrix stiffness and protein tethering in stem cell differentiation 2014;13(10):979–87.

  49. •• Baker BM, Trappmann B, Wang WY, Sakar MS, Kim IL, Shenoy VB, et al. Cell-mediated fibre recruitment drives extracellular matrix mechanosensing in engineered fibrillar microenvironments. Nat Mater. 2015;14(12):1262–8. Tunable electrospun hydrogel fibers unveil new mechanistic insight into the mechanoresponse of mesenchymal stem cells in fibrillar microenvironments. Specifically, cells on soft fibrillar structures recruit neighboring fibers which lead to increased proliferation, spreading, and ligand density of adhesion domains. https://doi.org/10.1038/nmat4444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhang M, Nigwekar P, Castaneda B, Hoyt K, Joseph JV, di Sant'Agnese A, et al. Quantitative characterization of viscoelastic properties of human prostate correlated with histology. Ultrasound Med Biol. 2008;34(7):1033–42. https://doi.org/10.1016/j.ultrasmedbio.2007.11.024.

    Article  PubMed  Google Scholar 

  51. Hayes WC, Mockros LF. Viscoelastic properties of human articular cartilage. J Appl Physiol. 1971;31(4):562–8. https://doi.org/10.1152/jappl.1971.31.4.562.

    Article  CAS  PubMed  Google Scholar 

  52. Miller K, Chinzei K. Mechanical properties of brain tissue in tension. J Biomech. 2002;35(4):483–90. https://doi.org/10.1016/S0021-9290(01)00234-2.

    Article  PubMed  Google Scholar 

  53. Cameron AR, Frith JE, Cooper-White JJ. The influence of substrate creep on mesenchymal stem cell behaviour and phenotype. Biomaterials. 2011;32(26):5979–93. https://doi.org/10.1016/j.biomaterials.2011.04.003.

    Article  CAS  PubMed  Google Scholar 

  54. •• Chaudhuri O, Gu L, Klumpers D, Darnell M, Bencherif SA, Weaver JC, et al. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat Mater. 2016;15(3):326–34. Using alginate hydrogels, osteogenic differentiation of mesenchymal stem cells was found to be dependent on the rate of stress relaxation of the material. In particular, with faster stress-relaxation substratum, osteogenic differentiaton was enhanced via YAP-mediated signaling resulting from enhanced RGD clustering and actomyosin activity. https://doi.org/10.1038/nmat4489.

    Article  CAS  PubMed  Google Scholar 

  55. Flaim CJ, Chien S, Bhatia SN. An extracellular matrix microarray for probing cellular differentiation. Nat Meth. 2005;2(2):119–25. https://doi.org/10.1038/nmeth736.

    Article  CAS  Google Scholar 

  56. Brafman DA, Phung C, Kumar N, Willert K. Regulation of endodermal differentiation of human embryonic stem cells through integrin-ECM interactions. Cell Death Differ. 2013;20(3):369–81. https://doi.org/10.1038/cdd.2012.138.

    Article  CAS  PubMed  Google Scholar 

  57. Hou L, Kim JJ, Wanjare M, Patlolla B, Coller J, Natu V, et al. Combinatorial extracellular matrix microenvironments for probing endothelial differentiation of human pluripotent stem cells. Sci Rep. 2017;7(1):6551. https://doi.org/10.1038/s41598-017-06986-3.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Tsai Y, Cutts J, Kimura A, Varun D, Brafman DA. A chemically defined substrate for the expansion and neuronal differentiation of human pluripotent stem cell-derived neural progenitor cells. Stem Cell Res. 2015;15(1):75–87. https://doi.org/10.1016/j.scr.2015.05.002.

    Article  CAS  PubMed  Google Scholar 

  59. •• Nguyen EH, Daly WT, Le NNT, Farnoodian M, Belair DG, Schwartz MP, et al. Versatile synthetic alternatives to Matrigel for vascular toxicity screening and stem cell expansion. 2017;1:0096. An array of synthetic hydrogel formulations, ranging in stiffness, degradability, and RGD composition, were used in tandem with varied media conditions to probe optimal chemically defined conditions that support human pluripotent stem cell culture and expansion.

    Google Scholar 

  60. Rosales AM, Anseth KS. The design of reversible hydrogels to capture extracellular matrix dynamics. 2016;1:15012.

  61. Das RK, Gocheva V, Hammink R, Zouani OF, Rowan AE. Stress-stiffening-mediated stem-cell commitment switch in soft responsive hydrogels. Nat Mater. 2016;15(3):318–25. https://doi.org/10.1038/nmat4483.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to give thanks and recognition to the institutions who provided funding for the mentioned studies from our lab including the National Institute of Health, National Science Foundation, Maryland Stem Cell Fund and American Heart Association.

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Authors and Affiliations

  1. Department of Chemical and Biomolecular Engineering, Physical Sciences-Oncology Center and the Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA

    Quinton Smith & Sharon Gerecht

  2. Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA

    Sharon Gerecht

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  1. Quinton Smith
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Correspondence to Sharon Gerecht.

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Quinton Smith and Sharon Gerecht declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Stem Cell Switches and Regulators

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Smith, Q., Gerecht, S. Extracellular Matrix Regulation of Stem Cell Fate. Curr Stem Cell Rep 4, 13–21 (2018). https://doi.org/10.1007/s40778-018-0111-2

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