Regulation of Stem Cell Functions by Micro-Patterned Structures

  • Guoping ChenEmail author
  • Naoki Kawazoe
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1250)


Micro-patterned surfaces have been broadly used to control the morphology of stem cells for investigation of the influence of physiochemical and biological cues on stem cell functions. Different structures of micro-patterned surfaces can be prepared by photolithography through designing the photomask features. Cell spreading area, geometry, aspect ratio, and alignment can be regulated by the micro-patterned structures. Their influences on adipogenic, osteogenic, and smooth muscle differentiation of the human bone marrow-derived mesenchymal stem cells are compared and investigated in details. Variation of cell morphology can trigger rearrangement of cytoskeleton, generating cytoskeletal mechanical stimulation and consequently inducing differentiation of mesenchymal stem cells into different lineages. This chapter summarizes the latest development of regulation of mesenchymal stem cell morphology by micro-patterns and the influence on the behaviors and differentiation of the mesenchymal stem cells.


Micro-patterned surface Mesenchymal stem cell Cell morphology Cell function Differentiation 



This work was supported by JSPS KAKENHI Grant Number 18K19947, 18K19945 and 19H04475.


  1. 1.
    Cook D, Genever P (2013) Regulation of mesenchymal stem cell differentiation. In: Hime G, Abud H (eds) Transcriptional and translational regulation of stem cells, Advances in experimental medicine and biology, vol 786. Springer, Dordrecht, pp 213–229Google Scholar
  2. 2.
    Pittenger MF, Mackay AM, Beck SC et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedPubMedCentralGoogle Scholar
  3. 3.
    Jiang YH, Jahagirdar BN, Reinhardt RL et al (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49PubMedPubMedCentralGoogle Scholar
  4. 4.
    Lane SW, Williams DA, Watt FM (2014) Modulating the stem cell niche for tissue regeneration. Nat Biotechnol 32:795–803PubMedPubMedCentralGoogle Scholar
  5. 5.
    Thery M (2010) Micro-patterning as a tool to decipher cell morphogenesis and functions. J Cell Sci 123:4201–4213PubMedGoogle Scholar
  6. 6.
    Versaevel M, Grevesse T, Gabriele S (2012) Spatial coordination between cell and nuclear shape within micro-patterned endothelial cells. Nat Commun 3:671–681PubMedGoogle Scholar
  7. 7.
    Downing TL, Soto J, Morez C (2013) Biophysical regulation of epigenetic state and cell reprogramming. Nat Mater 12:1154–1162PubMedGoogle Scholar
  8. 8.
    Ermis M, Antmen E, Hasirci V (2018) Micro and nanofabrication methods to control cell-substrate interactions and cell behavior: a review from the tissue engineering perspective. Bioact Mater 3:355–369PubMedPubMedCentralGoogle Scholar
  9. 9.
    Lim JY, Donahue HJ (2007) Cell sensing and response to micro- and nanostructured surfaces produced by chemical and topographic patterning. Tissue Eng 13:1879–1891PubMedGoogle Scholar
  10. 10.
    Jiang XY, Bruzewicz DA, Wong AP et al (2005) Directing cell migration with asymmetric micro-patterns. Proc Natl Acad Sci U S A 102:975–978PubMedPubMedCentralGoogle Scholar
  11. 11.
    Thakar RG, Cheng Q, Patel S et al (2009) Cell-shape regulation of smooth muscle cell proliferation. Biophys J 96:3423–3432PubMedPubMedCentralGoogle Scholar
  12. 12.
    Thery M, Racine V, Piel M et al (2006) Anisotropy of cell adhesive microenvironment governs cell internal organization and orientation of polarity. Proc Natl Acad Sci U S A 103:19771–19776PubMedPubMedCentralGoogle Scholar
  13. 13.
    Song W, Lu H, Kawazoe N et al (2011) Adipogenic differentiation of individual mesenchymal stem cell on different geometric micro-patterns. Langmuir 27:6155–6162PubMedGoogle Scholar
  14. 14.
    Song W, Kawazoe N, Chen G (2011) Dependence of spreading and differentiation of mesenchymal stem cells on micro-patterned surface area. J Nanomater 2011:9Google Scholar
  15. 15.
    Song W, Wang X, Lu H et al (2012) Exploring adipogenic differentiation of a single stem cell on poly(acrylic acid) and polystyrene micro-patterns. Soft Matter 8:8429–8437Google Scholar
  16. 16.
    Wang X, Song W, Kawazoe N et al (2013) The osteogenic differentiation of mesenchymal stem cells by controlled cell-cell interaction on micro-patterned surfaces. J Biomed Mater Res A 101:3388–3395PubMedGoogle Scholar
  17. 17.
    Wang X, Song W, Kawazoe N et al (2013) Influence of cell protrusion and spreading on adipogenic differentiation of mesenchymal stem cells on micro-patterned surfaces. Soft Matter 9:4160–4166Google Scholar
  18. 18.
    Nakamoto T, Wang X, Kawazoe NP et al (2014) Influence of micro-pattern width on differentiation of human mesenchymal stem cells to vascular smooth muscle cells. Colloid Surf B-Biointerfaces 122:316–323Google Scholar
  19. 19.
    Wang X, Nakamoto T, Dulinska-Molak I et al (2016) Regulating the stemness of mesenchymal stem cells by tuning micro-pattern features. J Mater Chem B 4:37–45PubMedGoogle Scholar
  20. 20.
    Wang X, Hu X, Kawazoe N et al (2016) Manipulating cell nanomechanics using micro-patterns. Adv Funct Mater 26:7634–7643Google Scholar
  21. 21.
    Wang X, Hu X, Dulińska-Molak I et al (2016) Discriminating the independent influence of cell adhesion and spreading area on stem cell fate determination using micro-patterned surfaces. Sci Rep 6:28708PubMedPubMedCentralGoogle Scholar
  22. 22.
    Wang X, Hu XH, Li J et al (2016) Influence of cell size on cellular uptake of gold nanoparticles. Biomater Sci 4:970–978PubMedGoogle Scholar
  23. 23.
    Yang Y, Wang X, Huang T et al (2018) Regulation of mesenchymal stem cell functions by micro-nano hybrid patterned surfaces. J Mater Chem B 6:5424–5434PubMedGoogle Scholar
  24. 24.
    Yang Y, Wang X, Wang Y et al (2019) Influence of cell spreading area on the osteogenic commitment and phenotype maintenance of mesenchymal stem cells. Sci Rep 9:6891PubMedPubMedCentralGoogle Scholar
  25. 25.
    Yang Y, Wang X, Hu X et al (2019) Influence of cell morphology on mesenchymal stem cell transfection. ACS Appl Mater Interfaces 11:1932–1941PubMedGoogle Scholar
  26. 26.
    Denitsa D, Florian H, Matthias S (2008) Mesenchymal stem cells and their cell surface receptors. Curr Rheumatol Rev 4:155–160Google Scholar
  27. 27.
    Majumdar MK, Keane-Moore M, Buyaner D et al (2003) Characterization and functionality of cell surface molecules on human mesenchymal stem cells. J Biomed Sci 10:228–241PubMedGoogle Scholar
  28. 28.
    Dominici M, Le Blanc K, Mueller I et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317PubMedPubMedCentralGoogle Scholar
  29. 29.
    Bhadriraju K, Hansen LK (2002) Extracellular matrix- and cytoskeleton-dependent changes in cell shape and stiffness. Exp Cell Res 278:92–100PubMedGoogle Scholar
  30. 30.
    Szabo E, Feng TS, Dziak E et al (2009) Cell adhesion and spreading affect adipogenesis from embryonic stem cells: the role of calreticulin. Stem Cells 27:2092–2102PubMedGoogle Scholar
  31. 31.
    Falconnet D, Csucs G, Grandin HM et al (2006) Surface engineering approaches to micro-patternsurfaces for cell-based assays. Biomaterials 27:3044–3063PubMedGoogle Scholar
  32. 32.
    Zhang D, Sun MB, Lee JM et al (2016) Cell shape and the presentation of adhesion ligands guide smooth muscle myogenesis. J Biomed Mater Res A 104:1212–1220PubMedGoogle Scholar
  33. 33.
    Zhao Y, Zeng HS, Nam J et al (2009) Fabrication of skeletal muscle constructs by topographic activation of cell alignment. Biotechnol Bioeng 102:624–631PubMedGoogle Scholar
  34. 34.
    Wang PY, Yu HT, Tsai WB (2010) Modulation of alignment and differentiation of skeletal myoblasts by submicron ridges/grooves surface structure. Biotechnol Bioeng 106:285–294PubMedGoogle Scholar
  35. 35.
    Hoehme S, Brulport M, Bauer A et al (2010) Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci U S A 107:10371–10376PubMedPubMedCentralGoogle Scholar
  36. 36.
    Xu CY, Inai R, Kotaki M et al (2004) Aligned biodegradable nanofibrous structure: a potential scaffold for blood vessel engineering. Biomaterials 25:877–886PubMedGoogle Scholar
  37. 37.
    Aubin H, Nichol JW, Hutson CB et al (2010) Directed 3D cell alignment and elongation in microengineered hydrogels. Biomaterials 31:6941–6951PubMedPubMedCentralGoogle Scholar
  38. 38.
    Wang PY, Yu J, Lin JH et al (2011) Modulation of alignment, elongation and contraction of cardiomyocytes through a combination of nanotopography and rigidity of substrates. Acta Biomater 7:3285–3293PubMedGoogle Scholar
  39. 39.
    Owens GK, Kumar MS, Wamhoff BR (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84:767–801PubMedGoogle Scholar
  40. 40.
    Park JS, Chu JS, Tsou AD et al (2011) The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-β. Biomaterials 32:3921–3930PubMedPubMedCentralGoogle Scholar
  41. 41.
    Floren M, Bonani W, Dharmarajan A et al (2016) Human mesenchymal stem cells cultured on silk hydrogels with variable stiffness and growth factor differentiate into mature smooth muscle cell phenotype. Acta Biomater 31:156–166PubMedGoogle Scholar
  42. 42.
    Parandakh A, Anbarlou A, Tafazzoli-Shadpour M et al (2019) Substrate topography interacts with substrate stiffness and culture time to regulate mechanical properties and smooth muscle differentiation of mesenchymal stem cells. Colloids Surf B Biointerfaces 173:194–201PubMedGoogle Scholar
  43. 43.
    Huang NF, Lee RJ, Li S (2010) Engineering of aligned skeletal muscle by micro-patterning. Am J Transl Res 2:43–55PubMedPubMedCentralGoogle Scholar
  44. 44.
    Tay CY, Pal M, Yu HY et al (2011) Bio-inspired micro-patterned platform to steer stem cell differentiation. Small 7:1416–1421PubMedGoogle Scholar
  45. 45.
    Khetan S, Burdick JA (2010) Patterning network structure to spatially control cellular remodeling and stem cell fate within 3-dimensional hydrogels. Biomaterials 31:8228–8234PubMedGoogle Scholar
  46. 46.
    Solway J, Seltzer J, Samaha FF et al (1995) Structure and expression of a smooth-muscle cell-specific gene, SM22α. J Biol Chem 270:13460–13469PubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2020

Authors and Affiliations

  1. 1.Research Center for Functional MaterialsNational Institute for Materials ScienceTsukubaJapan

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