Hydrogels pp 357-408 | Cite as

Stem Cell Culture on Polymer Hydrogels

  • Akon HiguchiEmail author
  • Hsing-Fen Li
  • S. Suresh Kumar
  • Abdullah A. Alarfaj
  • Murugan A. Munusamy
Part of the Gels Horizons: From Science to Smart Materials book series (GHFSSM)


The fate of stem cell differentiation is guided by several different factors of the stem cell microenvironment, such as cell culture biomaterial elasticity (physical cues) and cell–biomaterial interactions (biological cues). Mimicking the stem cell microenvironment using polymer hydrogels with optimal elasticities is an excellent strategy for stem cell expansion and differentiation. This chapter describes poly(vinyl alcohol) (PVA) hydrogels grafted with several nanosegments that are designed for the culture and differentiation of human hematopoietic and progenitor cells (hHSPCs), human amniotic fluid stem cells (hAFSCs), and human pluripotent stem cells (hPSCs). The elasticity of the cell culture hydrogels can regulate stem cell adhesion overall, as well as cell phenotype, focal adhesions, and morphology, especially in 2-D culture conditions. The mechano-sensing of cell culture biomaterials by stem cells is typically regulated by integrin-mediated focal adhesion signaling. PVA hydrogels having a storage modulus (E′) of 12–30 kPa were found to be efficient materials for ex vivo hHSPC expansion. We also developed PVA hydrogels grafted with oligopeptides derived from vitronectin (PVA-oligoVN hydrogels), which can be produced to have a variety of stiffnesses, for the xeno-free culture of hPSCs. The ideal stiffness of the PVA-oligoVN hydrogels for hPSC culture was found to be 25.3 kPa. A high concentration of oligoVN (500–1500 µg/mL) should be used to prepare the PVA-oligoVN hydrogels to achieve a sufficient oligoVN surface density to maintain hPSC pluripotency. Optimized stiffness (physical cues) and cell-binding moiety surface density (biological cues) are the key factors for designing hydrogel-based cell culture materials for supporting hPSC pluripotency in xeno-free culture conditions.


Hydrogels Stem cells Elasticity Differentiation Pluripotency Nanosegment Oligopeptide Poly(vinyl alcohol) 



This research was partially supported by the Ministry of Science and Technology, Taiwan, under grant number 104-2221-E-008-107-MY3. This work was also supported by the LandSeed Hospital project (NCU-LSH-105-A-001) and the Cathay General Hospital Project (105CGH-NCU-A3). A Grant-in-Aid for Scientific Research (15K06591) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan is also acknowledged. The Deanship of Scientific Research, College of Science Research Centre, King Saud University, Kingdom of Saudi Arabia, is also acknowledged.


  1. Brafman DA, Chang CW, Fernandez A, Willert K, Varghese S, Chien S (2010) Long-term human pluripotent stem cell self-renewal on synthetic polymer surfaces. Biomaterials 31:9135–9144CrossRefPubMedPubMedCentralGoogle Scholar
  2. Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425:841–846CrossRefGoogle Scholar
  3. Chang CW, Hwang Y, Brafman D, Hagan T, Phung C, Varghese S (2013) Engineering cell-material interfaces for long-term expansion of human pluripotent stem cells. Biomaterials 34:912–921CrossRefPubMedGoogle Scholar
  4. Chen LY, Chang Y, Shiao JS, Ling QD, Chang Y, Chen YH, Chen DC, Hsu ST, Lee HHC, Higuchi A (2012) Effect of the surface density of nanosegments immobilized on culture dishes on ex vivo expansion of hematopoietic stem and progenitor cells from umbilical cord blood. Acta Biomater 8:1749–1758CrossRefPubMedGoogle Scholar
  5. Chen X, Prowse AB, Jia Z, Tellier H, Munro TP, Gray PP, Monteiro MJ (2014) Thermoresponsive worms for expansion and release of human embryonic stem cells. Biomacromol 15:844–855CrossRefGoogle Scholar
  6. Chowdhury F, Li Y, Poh YC, Yokohama-Tamaki T, Wang N, Tanaka TS (2010) Soft substrates promote homogeneous self-renewal of embryonic stem cells via downregulating cell-matrix tractions. PLoS ONE 5:e15655CrossRefPubMedPubMedCentralGoogle Scholar
  7. Chua KN, Chai C, Lee PC, Ramakrishna S, Leong KW, Mao HQ (2007) Functional nanofiber scaffolds with different spacers modulate adhesion and expansion of cryopreserved umbilical cord blood hematopoietic stem/progenitor cells. Exp Hematol 35:771–781CrossRefPubMedPubMedCentralGoogle Scholar
  8. Chua KN, Chai C, Lee PC, Tang YN, Ramakrishna S, Leong KW, Mao HQ (2006) Surface-aminated electrospun nanofibers enhance adhesion and expansion of human umbilical cord blood hematopoietic stem/progenitor cells. Biomaterials 27:6043–6051CrossRefPubMedGoogle Scholar
  9. Copelan EA (2006) Hematopoietic stem-cell transplantation. New Eng J Med 354:1813–1826CrossRefPubMedGoogle Scholar
  10. De Coppi P, Bartsch G, Siddiqui MM, Xu T, Santos CC, Perin L, Mostoslavsky G, Serre AC, Snyder EY, Yoo JJ, Furth ME, Soker S, Atala A (2007) Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 25:100–106CrossRefPubMedGoogle Scholar
  11. Dellatore SM, Garcia AS, Miller WM (2008) Mimicking stem cell niches to increase stem cell expansion. Curr Opin Biotechnol 19:534–540CrossRefPubMedPubMedCentralGoogle Scholar
  12. Deng Y, Zhang X, Zhao X, Li Q, Ye Z, Li Z, Liu Y, Zhou Y, Ma H, Pan G, Pei D, Fang J, Wei S (2013) Long-term self-renewal of human pluripotent stem cells on peptide-decorated poly(OEGMA-co-HEMA) brushes under fully defined conditions. Acta Biomater 9:8840–8850CrossRefPubMedGoogle Scholar
  13. Di Maggio N, Piccinini E, Jaworski M, Trumpp A, Wendt DJ, Martin I (2011) Toward modeling the bone marrow niche using scaffold-based 3D culture systems. Biomaterials 32:321–329CrossRefPubMedGoogle Scholar
  14. Doran MR, Markway BD, Aird IA, Rowlands AS, George PA, Nielsen LK, Cooper-White JJ (2009) Surface-bound stem cell factor and the promotion of hematopoietic cell expansion. Biomaterials 30:4047–4052CrossRefPubMedGoogle Scholar
  15. Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126:677–689CrossRefGoogle Scholar
  16. Fan Y, Hsiung M, Cheng C, Tzanakakis ES (2014) Facile engineering of xeno-free microcarriers for the scalable cultivation of human pluripotent stem cells in stirred suspension. Tissue Eng Part A 20:588–599CrossRefPubMedGoogle Scholar
  17. Feng Q, Chai C, Jiang XS, Leong KW, Mao HQ (2006) Expansion of engrafting human hematopoietic stem/progenitor cells in three-dimensional scaffolds with surface-immobilized fibronectin. J Biom Mater Res A 78:781–791CrossRefGoogle Scholar
  18. Flores-Guzman P, Fernandez-Sanchez V, Valencia-Plata I, Arriaga-Pizano L, Alarcon-Santos G, Mayani H (2013) Comparative in vitro analysis of different hematopoietic cell populations from human cord blood: in search of the best option for clinically oriented ex vivo cell expansion. Transfusion 53:668–678CrossRefPubMedGoogle Scholar
  19. Franke K, Pompe T, Bornhauser M, Werner C (2007) Engineered matrix coatings to modulate the adhesion of CD133 + human hematopoietic progenitor cells. Biomaterials 28:836–843CrossRefPubMedGoogle Scholar
  20. Fujimoto N, Fujita S, Tsuji T, Toguchida J, Ida K, Suginami H, Iwata H (2007) Microencapsulated feeder cells as a source of soluble factors for expansion of CD34(+) hematopoietic stem cells. Biomaterials 28:4795–4805CrossRefPubMedGoogle Scholar
  21. Gilbert PM, Havenstrite KL, Magnusson KE, Sacco A, Leonardi NA, Kraft P, Nguyen NK, Thrun S, Lutolf MP, Blau HM (2010) Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture. Science 329:1078–1081CrossRefPubMedPubMedCentralGoogle Scholar
  22. Gori JL, Chandrasekaran D, Kowalski JP, Adair JE, Beard BC, D’Souza SL, Kiem HP (2012) Efficient generation, purification, and expansion of CD34(+) hematopoietic progenitor cells from nonhuman primate-induced pluripotent stem cells. Blood 120:e35–e44CrossRefPubMedPubMedCentralGoogle Scholar
  23. Higuchi A, Huang SC, Shen PY, Ling QD, Zhao JK, Chang Y, Wang HC, Bing JT, Hsu ST (2011a) Differentiation ability of amniotic fluid-derived stem cells cultured on extracellular matrix-immobilized surface. Curr Nanosci 7:893–901CrossRefGoogle Scholar
  24. Higuchi A, Kao SH, Ling QD, Chen YM, Li HF, Alarfaj AA, Munusamy MA, Murugan K, Chang SC, Lee HC, Hsu ST, Kumar SS, Umezawa A (2015a) Long-term xeno-free culture of human pluripotent stem cells on hydrogels with optimal elasticity Sci Rep 5:18136PubMedGoogle Scholar
  25. Higuchi A, Lin FL, Cheng YK, Kao TC, Kumar SS, Ling QD, Hou CH, Chen DC, Hsu ST, Wu GJ (2014a) Preparation of induced pluripotent stem cells on dishes grafted on oligopeptide under feeder-free conditions. J Taiwan Inst Chem Eng 45:295–301CrossRefGoogle Scholar
  26. Higuchi A, Ling QD, Chang Y, Hsu ST, Umezawa A (2013) Physical cues of biomaterials guide stem cell differentiation fate. Chem Rev 113:3297–3328CrossRefPubMedGoogle Scholar
  27. Higuchi A, Ling QD, Hsu ST, Umezawa A (2012) Biomimetic cell culture proteins as extracellular matrices for stem cell differentiation. Chem Rev 112:4507–4540CrossRefPubMedGoogle Scholar
  28. Higuchi A, Ling QD, Ko YA, Chang Y, Umezawa A (2011b) Biomaterials for the feeder-free culture of human embryonic stem cells and induced pluripotent stem cells. Chem Rev 111:3021–3035CrossRefPubMedGoogle Scholar
  29. Higuchi A, Ling QD, Kumar S, Munusamy M, Alarfajj AA, Umezawa A, Wu GJ (2014b) Design of polymeric materials for culturing human pluripotent stem cells: progress toward feeder-free and xeno-free culturing. Prog Polym Sci 39:1348–1374CrossRefGoogle Scholar
  30. Higuchi A, Ling QD, Kumar SS, Chang Y, Alarfaj AA, Munusamy MA, Murugan K, Hsu ST, Umezawa A (2015b) Physical cues of cell culture materials lead the direction of differentiation lineages of pluripotent stem cells. J Mater Chem B 3:8032–8058CrossRefGoogle Scholar
  31. Higuchi A, Yang ST, Li PT, Chang Y, Tsai EM, Chen YH, Chen YJ, Wang HC, Hsu ST (2009) Polymeric materials for ex vivo expansion of hematopoietic progenitor and stem cells. Polym Rev 49:181–200CrossRefGoogle Scholar
  32. Higuchi A, Yang ST, Li PT, Tamai M, Tagawa Y, Chang Y, Chang Y, Ling QD, Hsu ST (2010) Direct ex vivo expansion of hematopoietic stem cells from umbilical cord blood on membranes. J Membr Sci 351:104–111CrossRefGoogle Scholar
  33. Holmes T, Yan F, Ko KH, Nordon R, Song E, O’Brien TA, Dolnikov A (2012) Ex vivo expansion of cord blood progenitors impairs their short-term and long-term repopulating activity associated with transcriptional dysregulation of signalling networks. Cell Prolif 45:266–278CrossRefPubMedGoogle Scholar
  34. Huebsch N, Arany PR, Mao AS, Shvartsman D, Ali OA, Bencherif SA, Rivera-Feliciano J, Mooney DJ (2010) Harnessing traction-mediated manipulation of the cell/matrix interface to control stem-cell fate. Nat Mater 9:518–526CrossRefPubMedPubMedCentralGoogle Scholar
  35. Irwin EF, Gupta R, Dashti DC, Healy KE (2011) Engineered polymer-media interfaces for the long-term self-renewal of human embryonic stem cells. Biomaterials 32:6912–6919CrossRefPubMedPubMedCentralGoogle Scholar
  36. Jiang XS, Chai C, Zhang Y, Zhuo RX, Mao HQ, Leong KW (2006) Surface-immobilization of adhesion peptides on substrate for ex vivo expansion of cryopreserved umbilical cord blood CD34 + cells. Biomaterials 27:2723–2732CrossRefPubMedPubMedCentralGoogle Scholar
  37. Jonas SJ, Alva HA, Richardson W, Sherman SP, Galic Z, Pyle AD, Dunn B (2013) A spatially and chemically defined platform for the uniform growth of human pluripotent stem cells. Mater Sci Eng, C 33:234–241CrossRefGoogle Scholar
  38. Keeney M, Chin-Yee I, Weir K, Popma J, Nayar R, Sutherland DR (1998) Single platform flow cytometric absolute CD34 + cell counts based on the ISHAGE guidelines. Cytometry 34:61–70CrossRefPubMedGoogle Scholar
  39. Kerst JM, Sanders JB, Slaper-Cortenbach IC, Doorakkers MC, Hooibrink B, van Oers RH, von dem Borne AE, van der Schoot CE (1993) Alpha 4 beta 1 and alpha 5 beta 1 are differentially expressed during myelopoiesis and mediate the adherence of human CD34 + cells to fibronectin in an activation-dependent way. Blood 81:344–351PubMedGoogle Scholar
  40. Kishore V, Eliason JF, Matthew HW (2011) Covalently immobilized glycosaminoglycans enhance megakaryocyte progenitor expansion and platelet release. J Biomed Mater Res A 96:682–692CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kumar SS, Hsiao JH, Ling QD, Dulinska-Molak I, Chen GP, Chang Y, Chang Y, Chen YH, Chen DC, Hsu ST, Higuchi A (2013) The combined influence of substrate elasticity and surface-grafted molecules on the ex vivo expansion of hematopoietic stem and progenitor cells. Biomaterials 34:7632–7644CrossRefPubMedGoogle Scholar
  42. Lanniel M, Huq E, Allen S, Buttery L, Williams PM, Alexander MR (2011) Substrate induced differentiation of human mesenchymal stem cells on hydrogels with modified surface chemistry and controlled modulus. Soft Matter 7:6501–6514CrossRefGoogle Scholar
  43. Lin PY, Hung SH, Yang YC, Liao LC, Hsieh YC, Yen HJ, Lu HE, Lee MS, Chu IM, Hwang SM (2014) A synthetic peptide-acrylate surface for production of insulin-producing cells from human embryonic stem cells. Stem Cells Dev 23:372–379CrossRefPubMedGoogle Scholar
  44. Liu L, Yoshioka M, Nakajima M, Ogasawara A, Liu J, Hasegawa K, Li S, Zou J, Nakatsuji N, Kamei K, Chen Y (2014) Nanofibrous gelatin substrates for long-term expansion of human pluripotent stem cells. Biomaterials 35:6259–6267CrossRefPubMedGoogle Scholar
  45. Lu HF, Chai C, Lim TC, Leong MF, Lim JK, Gao S, Lim KL, Wan AC (2014) A defined xeno-free and feeder-free culture system for the derivation, expansion and direct differentiation of transgene-free patient-specific induced pluripotent stem cells. Biomaterials 35:2816–2826CrossRefPubMedGoogle Scholar
  46. Melkoumian Z, Weber JL, Weber DM, Fadeev AG, Zhou Y, Dolley-Sonneville P, Yang J, Qiu L, Priest CA, Shogbon C, Martin AW, Nelson J, West P, Beltzer JP, Pal S, Brandenberger R (2010) Synthetic peptide-acrylate surfaces for long-term self-renewal and cardiomyocyte differentiation of human embryonic stem cells. Nat Biotech 28:606–610CrossRefGoogle Scholar
  47. Mendez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, Macarthur BD, Lira SA, Scadden DT, Ma’ayan A, Enikolopov GN, Frenette PS (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466:829–834CrossRefPubMedPubMedCentralGoogle Scholar
  48. Miyazaki T, Futaki S, Suemori H, Taniguchi Y, Yamada M, Kawasaki M, Hayashi M, Kumagai H, Nakatsuji N, Sekiguchi K, Kawase E (2012) Laminin E8 fragments support efficient adhesion and expansion of dissociated human pluripotent stem cells. Nat Commun 3:1236CrossRefPubMedPubMedCentralGoogle Scholar
  49. Mortera-Blanco T, Mantalaris A, Bismarck A, Aqel N, Panoskaltsis N (2011) Long-term cytokine-free expansion of cord blood mononuclear cells in three-dimensional scaffolds. Biomaterials 32:9263–9270CrossRefPubMedGoogle Scholar
  50. Murphy WL, McDevitt TC, Engler AJ (2014) Materials as stem cell regulators. Nat Mater 13:547–557CrossRefPubMedPubMedCentralGoogle Scholar
  51. Musah S, Morin SA, Wrighton PJ, Zwick DB, Jin S, Kiessling LL (2012) Glycosaminoglycan-binding hydrogels enable mechanical control of human pluripotent stem cell self-renewal. ACS Nano 6:10168–10177CrossRefPubMedPubMedCentralGoogle Scholar
  52. Nagaoka M, Si-Tayeb K, Akaike T, Duncan SA (2010) Culture of human pluripotent stem cells using completely defined conditions on a recombinant E-cadherin substratum. BMC Dev Biol 10:60CrossRefPubMedPubMedCentralGoogle Scholar
  53. Nandivada H, Villa-Diaz LG, O’Shea KS, Smith GD, Krebsbach PH, Lahann J (2011) Fabrication of synthetic polymer coatings and their use in feeder-free culture of human embryonic stem cells. Nat Protoc 6:1037–1043CrossRefPubMedPubMedCentralGoogle Scholar
  54. Park DH, Lee JH, Borlongan CV, Sanberg PR, Chung YG, Cho TH (2011a) Transplantation of umbilical cord blood stem cells for treating spinal cord injury. Stem Cell Rev 7:181–194CrossRefPubMedGoogle Scholar
  55. Park HJ, Yang K, Kim MJ, Jang J, Lee M, Kim DW, Lee H, Cho SW (2015) Bio-inspired oligovitronectin-grafted surface for enhanced self-renewal and long-term maintenance of human pluripotent stem cells under feeder-free conditions. Biomaterials 50:127–139CrossRefPubMedGoogle Scholar
  56. Park JS, Chu JS, Tsou AD, Diop R, Tang ZY, Wang AJ, Li S (2011b) The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-beta. Biomaterials 32:3921–3930CrossRefPubMedPubMedCentralGoogle Scholar
  57. Pennington BO, Clegg DO, Melkoumian ZK, Hikita ST (2015) Defined culture of human embryonic stem cells and xeno-free derivation of retinal pigmented epithelial cells on a novel, synthetic substrate. Stem Cells Transl Med 4:165–177CrossRefPubMedPubMedCentralGoogle Scholar
  58. Qian X, Villa-Diaz LG, Kumar R, Lahann J, Krebsbach PH (2014) Enhancement of the propagation of human embryonic stem cells by modifications in the gel architecture of PMEDSAH polymer coatings. Biomaterials 35:9581–9590CrossRefPubMedPubMedCentralGoogle Scholar
  59. Remberger M, Mattsson J, Olsson R, Ringden O (2011) Second allogeneic hematopoietic stem cell transplantation: a treatment for graft failure. Clin Transplantation 25:E68–E76CrossRefGoogle Scholar
  60. Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, Jacobsen N, Ruutu T, de Lima M, Finke J, Frassoni F, Gluckman E (2004) Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. New Eng J Med 351:2276–2285CrossRefPubMedGoogle Scholar
  61. Rodin S, Domogatskaya A, Strom S, Hansson EM, Chien KR, Inzunza J, Hovatta O, Tryggvason K (2010) Long-term self-renewal of human pluripotent stem cells on human recombinant laminin-511. Nat Biotech 28:611–615CrossRefGoogle Scholar
  62. Rodriguez-Pardo VM, Vernot JP (2013) Mesenchymal stem cells promote a primitive phenotype CD34 + c-kit + in human cord blood-derived hematopoietic stem cells during ex vivo expansion. Cell Mol Biol Lett 18:11–33CrossRefPubMedGoogle Scholar
  63. Roy S, Tripathy M, Mathur N, Jain A, Mukhopadhyay A (2012) Hypoxia improves expansion potential of human cord blood-derived hematopoietic stem cells and marrow repopulation efficiency. Eur J Haematol 88:396–405CrossRefPubMedGoogle Scholar
  64. Saha K, Keung AJ, Irwin EF, Li Y, Little L, Schaffer DV, Healy KE (2008) Substrate modulus directs neural stem cell behavior. Biophy J 95:4426–4438CrossRefGoogle Scholar
  65. Salati S, Lisignoli G, Manferdini C, Pennucci V, Zini R, Bianchi E, Norfo R, Facchini A, Ferrari S, Manfredini R (2013) Co-culture of hematopoietic stem/progenitor cells with human osteblasts favours mono/macrophage differentiation at the expense of the erythroid lineage. PLoS ONE 8:e53496CrossRefPubMedPubMedCentralGoogle Scholar
  66. Stephenson E, Jacquet L, Miere C, Wood V, Kadeva N, Cornwell G, Codognotto S, Dajani Y, Braude P, Ilic D (2012) Derivation and propagation of human embryonic stem cell lines from frozen embryos in an animal product-free environment. Nat Protoc 7:1366–1381CrossRefPubMedGoogle Scholar
  67. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872CrossRefGoogle Scholar
  68. Trappmann B, Gautrot JE, Connelly JT, Strange DG, Li Y, Oyen ML, Cohen Stuart MA, Boehm H, Li B, Vogel V, Spatz JP, Watt FM, Huck WT (2012) Extracellular-matrix tethering regulates stem-cell fate. Nat Mater 11:642–649CrossRefPubMedGoogle Scholar
  69. Tse JR, Engler AJ (2011) Stiffness gradients mimicking in vivo tissue variation regulate mesenchymal stem cell fate. PLoS ONE 6:e15978CrossRefPubMedPubMedCentralGoogle Scholar
  70. Tsutsui H, Valamehr B, Hindoyan A, Qiao R, Ding X, Guo S, Witte ON, Liu X, Ho CM, Wu H (2011) An optimized small molecule inhibitor cocktail supports long-term maintenance of human embryonic stem cells. Nat Commun 2:167CrossRefPubMedPubMedCentralGoogle Scholar
  71. Villa-Diaz LG, Nandivada H, Ding J, Nogueira-de-Souza NC, Krebsbach PH, O’Shea KS, Lahann J, Smith GD (2010) Synthetic polymer coatings for long-term growth of human embryonic stem cells. Nat Biotech 28:581–583CrossRefGoogle Scholar
  72. Wang PY, Lee HHC, Higuchi A, Ling QD, Lin HR, Li HF, Kumar SS, Chang Y, Alarfaj AA, Munusamy MA, Chen DC, Hsu ST, Wang HC, Hsiao HY, Wu GJ (2015) Pluripotency maintenance of amniotic fluid-derived stem cells cultured on biomaterials. J Mater Chem B 3:3858–3869CrossRefGoogle Scholar
  73. Wen JH, Vincent LG, Fuhrmann A, Choi YS, Hribar KC, Taylor-Weiner H, Chen S, Engler AJ (2014) Interplay of matrix stiffness and protein tethering in stem cell differentiation. Nat Mater 13:979–987CrossRefPubMedPubMedCentralGoogle Scholar
  74. Winer JP, Janmey PA, McCormick ME, Funaki M (2009) Bone marrow-derived human mesenchymal stem cells become quiescent on soft substrates but remain responsive to chemical or mechanical stimuli. Tissue Eng Part A 15:147–154CrossRefPubMedGoogle Scholar
  75. Wu S, Johansson J, Damdimopoulou P, Shahsavani M, Falk A, Hovatta O, Rising A (2014) Spider silk for xeno-free long-term self-renewal and differentiation of human pluripotent stem cells. Biomaterials 35:8496–8502CrossRefPubMedGoogle Scholar
  76. Xie Y, Yin T, Wiegraebe W, He XC, Miller D, Stark D, Perko K, Alexander R, Schwartz J, Grindley JC, Park J, Haug JS, Wunderlich JP, Li H, Zhang S, Johnson T, Feldman RA, Li L (2009) Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457:97–101CrossRefPubMedGoogle Scholar
  77. Yamamoto S, Ikeda H, Toyama D, Hayashi M, Akiyama K, Suzuki M, Tanaka Y, Watanabe T, Fujimoto Y, Hosaki I, Nishihira H, Isoyama K (2011) Quality of long-term cryopreserved umbilical cord blood units for hematopoietic cell transplantation. Int J Hematol 93:99–105CrossRefPubMedGoogle Scholar
  78. Zhang R, Mjoseng HK, Hoeve MA, Bauer NG, Pells S, Besseling R, Velugotla S, Tourniaire G, Kishen RE, Tsenkina Y, Armit C, Duffy CR, Helfen M, Edenhofer F, de Sousa PA, Bradley M (2013) A thermoresponsive and chemically defined hydrogel for long-term culture of human embryonic stem cells. Nat Commun 4:1335CrossRefPubMedPubMedCentralGoogle Scholar
  79. Zheng YB, Gao ZL, Xie C, Zhu HP, Peng L, Chen JH, Chong YT (2008) Characterization and hepatogenic differentiation of mesenchymal stem cells from human amniotic fluid and human bone marrow: a comparative study. Cell Biol Int 32:1439–1448CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Akon Higuchi
    • 1
    • 2
    • 3
    Email author
  • Hsing-Fen Li
    • 1
  • S. Suresh Kumar
    • 4
  • Abdullah A. Alarfaj
    • 3
  • Murugan A. Munusamy
    • 3
  1. 1.Department of Chemical and Materials EngineeringNational Central UniversityTaoyuanTaiwan
  2. 2.Nano Medical Engineering LaboratoryRIKENWako, SaitamaJapan
  3. 3.Department of Botany and Microbiology, College of ScienceKing Saud UniversityRiyadhSaudi Arabia
  4. 4.Department of Medical Microbiology and ParasitologyUniversities Putra MalaysiaSerdangMalaysia

Personalised recommendations