Journal of Bionic Engineering

, Volume 15, Issue 4, pp 682–692 | Cite as

Control of MSC Differentiation by Tuning the Alkyl Chain Length of Phenylboroinc Acid Based Low-molecular-weight Gelators

  • Jing He
  • Yalong Hu
  • Fang Wu
  • Bin He
  • Wenxia GaoEmail author


The physical environment plays a critical role in modulating stem cell differentiation into specific lineages. In this study, we designed and synthesized a series of low-molecular-weight gels (LMWGs) with different moduli based on phenylboronic acid derivatives. The moduli of the LMWGs were readily tuned by varying the alkyl chain without any chemical crosslinker. The cell responses to the gels were evaluated with mesenchymal stem cell (MSCs), in respect of cell morphology, proliferation and differentiation. The prepared gels were non-toxic to MSCs, suggesting good biocompatibility. The hydrogel stiffness exerted a striking modulation effect on MSC fate decisions, where MSCs were inclined to differentiate into osteoblasts in stiff LMWGs and into chondrocytes in soft LMWGs. The pivotal elastic modulus of the LMWGs to drive MSC differentiation into osteoblastic lineage and chondrocytic lineage were approximately 20 kPa – 40 kPa and 1 kPa – 10 kPa, respectively. Overall, our results demonstrated that the modification of hydrogel stiffness via tuning the alkyl chain was a simple but effective approach to regulate MSC differentiation into specific lineage, which might have important implications in the design of LMWGs for tissue engineering applications.


low-molecular-weight gels phenylboronic acid alkyl chain mesenchymal stem cell osteoblast differentiation chondrocytic differentiation 


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This work was supported by the Natural Science Foundation grants (Nos. 31600765 and 21672164), Natural Science Foundation of Zhejiang Province (No. LY15B020001), Sichuan Province Miaozi Project (No. 2016RZ0032), and Chinese Postdoctoral Science Foundation (2016M062690).

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Control of MSC Differentiation by Tuning the Alkyl Chain Length of Phenylboroinc Acid Based Low-molecular-weight Gelators


  1. [1]
    Kye E J, Kim S J, Park M H, Moon H J, Ryu K H, Jeong B. Differentiation of tonsil-tissue-derived mesenchymal stem cells controlled by surface-functionalized microspheres in PEG-polypeptide thermogels. Biomacromolecules, 2014, 15, 2180–2187.CrossRefGoogle Scholar
  2. [2]
    Subramony S D, Dargis B R, Castillo M, Azeloglu E U, Tracey M S, Su A, Lu H H. The guidance of stem cell differentiation by substrate alignment and mechanical stimulation. Biomaterials, 2013, 34, 1942–1953.CrossRefGoogle Scholar
  3. [3]
    Xu Y Y, Li Z Q, Li X F, Fan Z B, Liu Z G, Xie X Y, Guan J J. Regulating myogenic differentiation of mesenchymal stem cells using thermosensitive hydrogels. Acta Biomaterialia, 2015, 26, 23–33.CrossRefGoogle Scholar
  4. [4]
    Zhu J, Marchant R E. Design properties of hydrogel tissue engineering scaffolds. Expert Review of Medical Devices, 2011, 8, 607–626.CrossRefGoogle Scholar
  5. [5]
    Hoch A I, Mittal V, Mitra D, Vollmer N, Zikry C A, Leach J K. Cell-secreted matrices perpetuate the bone-forming phenotype of differentiated mesenchymal stem cells. Biomaterials, 2016, 74, 178–187.CrossRefGoogle Scholar
  6. [6]
    Burnsed O A, Schwartz Z, Marchand K O, Hyzy S L, Olivares-Navarrete R, Boyan B D. Hydeogels derived from cartilage matrices promote induction of human mesenchymal stem cell chondrogenic differentiation. Acta Biomaterialia, 2016, 43, 139–149.CrossRefGoogle Scholar
  7. [7]
    Chaudhuri O, Gu L, Klumpers D, Darnell M, Bencherif S A, Weaver J C, Huebsch N, Lee H, Lippens E, Duda G N, Mooney D J. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nature Materials, 2016, 15, 326–334.CrossRefGoogle Scholar
  8. [8]
    Thorpe A A, Boyes V L, Sammon C, Maitre C L. Thermally triggered injectable hydrogel, which induces mesenchymal stem cell differentiation to nucleus pulposus cells: Potential for regeneration of the intervertebral disc. Acta Biomaterialia, 2016, 36, 99–111.CrossRefGoogle Scholar
  9. [9]
    Mao A S, Shin J W, Mooney D J. Effects of substrate stiffness and cell-cell contact on mesenchymal stem cell differentiation. Biomaterials, 2016, 98, 184–191.CrossRefGoogle Scholar
  10. [10]
    Yuan H, Zhou Y, Lee M S, Zhang Y, Li W J. A newly identified mechanism involved in regulation of human mesenchymal stem cells by fibrous substrate stiffness. Acta Biomaterialia, 2016, 42, 247–257.CrossRefGoogle Scholar
  11. [11]
    Lee J H, Park H K, Kim K S. Intrinsic and extrinsic mechanical properties related to the differentiation of mesenchymal stem cells. Biochemical and Biophysical Research Communications, 2016, 473, 752–757.CrossRefGoogle Scholar
  12. [12]
    Engler A J, Sen S, Sweeney H L, Discher D E. Matrix elasticity directs stem cell lineage specification. Cell, 2006, 126, 677–689.CrossRefGoogle Scholar
  13. [13]
    Lin Y L, Chen C P, Lo C M, Wang H S. Stiffness-controlled three-dimensional collagen scaffolds for differentiation of human wharton’s jelly mesenchymal stem cells into cardiac progenitor cells. Journal of Biomedical Materials Research Part A, 2016, 104, 2234–2242.CrossRefGoogle Scholar
  14. [14]
    Park H J, Jin Y, Shin J, Yang K, Lee C, Yang H S, Cho S W. Catechol-functionalized hyaluronic acid hydrogels enhance angiogenesis and osteogenesis of human adipose-derived stem cells in critical tissue defects. Biomacromolecules, 2016, 17, 1939–1948.CrossRefGoogle Scholar
  15. [15]
    Lim H J, Mosley M C, Kurosu Y, Callahan L A S. Concentration dependent survival and neural differentiation of murine embryonic stem cells cultured on polyethylene glycol dimethacrylate hydrogels possessing a continuous concentration gradient of n-cadherin derived peptide His-Ala-Val-Asp-Lle. Acta Biomaterialia, 2017, 56, 153–160.CrossRefGoogle Scholar
  16. [16]
    Lin X, Shi Y, Cao Y, Liu W. Recent progress in stem cell differentiation directed by material and mechanical cues. Biomedical Materials, 2016, 11, 014109.CrossRefGoogle Scholar
  17. [17]
    Hopp I, Michelmore A, Smith L E, Robinson D E, Bachhuka A, Mierczynska A, Vasilev K. The influence of substrate stiffness gradients on primary human dermal fibroblasts. Biomaterials, 2013, 34, 5070–5077.CrossRefGoogle Scholar
  18. [18]
    Wang L S, Chung J E, Chan P P Y, Kurisawa M. Injectable biodegradable hydrogels with tunable mechanical properties for the stimulation of neurogenesic differentiation of human mesenchymal stem cells in 3D culture. Biomaterials, 2010, 31, 1148–1157.CrossRefGoogle Scholar
  19. [19]
    Kim T H, An D B, Oh S H, Kang M K, Song H H, Lee J H. Creating stiffness gradient polyvinyl alcohol hydrogel using a simple gradual freezing-thawing method to investigate stem cell differentiation behaviors. Biomaterials, 2015, 40, 51–60.CrossRefGoogle Scholar
  20. [20]
    Segarra-Maset M D, Nebot V J, Miravet J F, Escuder B. Control of molecular gelation by chemical stimuli. Chemical Society Review, 2013, 42, 7086–7098.CrossRefGoogle Scholar
  21. [21]
    Yu X, Chen L, Zhang M, Yi T. Low-molecular-mass gels responding to ultrasound and mechanical stress: Towards self-healing materials. Chemical Society Review, 2014, 43, 5346–5371.CrossRefGoogle Scholar
  22. [22]
    Tomasini C, Castellucci N. Peptides and peptidomimetics that behave as low molecular weight gelators. Chemical Society Review, 2013, 42, 156–172.CrossRefGoogle Scholar
  23. [23]
    Yang C, Li D, Liu Z, Hong G, Zhang J, Kong D, Yang Z. Responsive small molecular hydrogels based on adamantane peptides for cell culture. Journal of Physical Chemistry B, 2012, 116, 633–638.CrossRefGoogle Scholar
  24. [24]
    Suzuki M, Hanabusa K. L-Lysine-based low-molecular-wei -ght gelators. Chemical Society Review, 2009, 38, 967–975.CrossRefGoogle Scholar
  25. [25]
    Suga T, Osada S, Narita T, Oishi Y, Kodama H. Promotion of cell adhesion by low-molecular-weight hydrogel by Lys based amphiphile. Materials Science & Engineering C, 2015, 47, 345–350.CrossRefGoogle Scholar
  26. [26]
    Skilling K J, Citossi F, Bradshaw T D, Ashford M, Kellam B, Marlow M. Insights into low molecular mass organic gelators: A focus on drug delivery and tissue engineering applications. Soft Matter, 2014, 10, 237–256.CrossRefGoogle Scholar
  27. [27]
    Latxague L, Ramin M A, Appavoo A, Berto P, Maisani M, Ehret C, Chassande O, Barthélémy P. Control of stem-cell behavior by fine tuning the supramolecular assemblies of low-molecular-weight gelators. Angewandte Chemie International Edition, 2015, 15, 4517–4521.CrossRefGoogle Scholar
  28. [28]
    He J, Meng G, Yao R, B. Jiang B, Y. Wu Y, F. Wu F. The essential role of inorganic substrate in the migration and osteoblastic differentiation of mesenchymal stem cells. Journal of the Mechanical Behavior Biomedical Materials, 2016, 59, 353–365.Google Scholar
  29. [29]
    He J, Wu F, Wang D, Yao R, Wu Y, Wu F. Modulation of cationicity of chitosan for tuning mesenchymal stem cell adhesion, proliferation, and differentiation. Biointerphases, 2015, 10, 04A304.CrossRefGoogle Scholar
  30. [30]
    Xu L, Hu Y L, Liu M C, Chen J X, Huang X B, Gao W X, Wu H Y. Gelation properties and glucose-sensitive behavior of phenylboronic acid based low-molecular-weight organogels. Tetrahedron, 2015, 71, 2079–2088.CrossRefGoogle Scholar
  31. [31]
    Zhou C Y, Gao W X, Yang K W, Xu L, Ding J C, Chen J X, Liu M C, Huang X B, Wang S, Wu H Y. A novel glucose/pH responsive low-molecular-weight organogel of easy recycling, Langmuir, 2013, 29, 13568–13575.CrossRefGoogle Scholar
  32. [32]
    Pati D, Kalva N, Das S, Kumaraswamy G, Gupta S S, Ambade A V. Multiple topologies from glycopolypeptidedendron conjugate self-assembly: Nanorods, micelles and organogels. Journal of the American Chemical Society, 2012, 134, 7796–7802.CrossRefGoogle Scholar
  33. [33]
    Svobodová H, Wimmer N Z, Kolehmainen E. Design, synthesis and stimuli responsive gelation of novel stigmasterol- amino acid conjugates. Journal of Colloid and Interface Science, 2011, 361, 587–593.CrossRefGoogle Scholar
  34. [34]
    Lee J, Kwon J E, You Y, Park S Y. Wholly p-conjugated low-molecular-weight organogelator that displays triplechannel responses to fluoride ions. Langmuir, 2014, 30, 2842–2851.CrossRefGoogle Scholar
  35. [35]
    Pan S F, Luo S, Li S, Lai Y S, Geng Y Y, He B, Gu Z W. Ultrasound accelerated gelation of novel L-lysine based hydrogelators. Chemical Communications, 2013, 49, 8045–8047.CrossRefGoogle Scholar
  36. [36]
    Qin J, Hua Y M. Effects of hydrogen sulfide on the expression of alkaline phosphatase, osteocalcin and collagen type I in human periodontal ligament cells induced by tension force stimulation. Molecular Medicine Reports, 2016, 14, 3871–3877.CrossRefGoogle Scholar
  37. [37]
    He J, Jiang B, Dai Y, Hao J Y, Zhou Z K, Tian Z L, Wu F, Gu Z W. Regulation of the osteoblastic and chondrocytic differentiation of stem cells by the extracellular matrix and subsequent bone formation. Biomaterials, 2013, 34, 6580–6588.CrossRefGoogle Scholar
  38. [38]
    Lei J, Trevino E, Temenoff J. Cell number and chondrogenesis in human mesenchymal stem cell aggregates is affected by the sulfation level of heparin as a cell coating. Journal of Biomedical Materials Research Part A, 2016, 104, 1817–1829.CrossRefGoogle Scholar
  39. [39]
    Nava M M, Raimondi M T, Pietrabissa R. Controlling self-renewal and differentiation of stem cells via mechanical cues. Journal of Biomedicine and Biotechnology, 2012, 2012, 797410.CrossRefGoogle Scholar
  40. [40]
    Wozniak M A, Chen C S. Mechanotransduction in development: A growing role for contractility. Nature Reviews Molecular Cell Biology, 2009, 10, 34–43.CrossRefGoogle Scholar
  41. [41]
    Ye K, Cao L P, Li S Y, Yu L, Ding L D. Interplay of matrix stiffness and cell-cell contact in regulating differentiation of stem cells. ACS Applied Materials & Interfaces, 2016, 8, 21903–21913.CrossRefGoogle Scholar
  42. [42]
    Huang C, Dai J, Zhang X A. Environmental physical cues determine the lineage specification of mesenchymal stem cells. Biochimica et Biophysica Acta-General Subjects, 2015, 1850, 1261–1266.CrossRefGoogle Scholar

Copyright information

© Jilin University 2018

Authors and Affiliations

  • Jing He
    • 1
  • Yalong Hu
    • 2
  • Fang Wu
    • 1
  • Bin He
    • 1
  • Wenxia Gao
    • 2
    Email author
  1. 1.National Engineering Research Centre for BiomaterialsSichuan UniversityChengduChina
  2. 2.College of Chemistry and Materials EngineeringWenzhou UniversityWenzhouChina

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