Tunable supramolecular hydrogels for selection of lineage-guiding metabolites in stem cell cultures

Enateri V. Alakpa, Vineetha Jayawarna, Ayala Lampel, Karl V. Burgess, Christopher C. West, Sanne C.J. Bakker, Sangita Roy, Nadeem Javid, Scott Fleming, Dimitris A. Lamprou, Jingli Yang, Angela Miller, Andrew J. Urquhart, Pim W.J.M. Frederix, Neil T. Hunt, Bruno Péault, Rein V. Ulijn, Matthew J. Dalby

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Abstract

Stem cells are known to differentiate in response to the chemical and mechanical properties of the substrates on which they are cultured. Thus, supramolecular biomaterials with tunable properties are well suited for the study of stem cell differentiation. In this report, we exploited this phenomenon by combining stem cell differentiation in hydrogels with variable stiffness and metabolomics analysis to identify specific bioactive lipids that are uniquely used up during differentiation. To achieve this, we cultured perivascular stem cells on supramolecular peptide gels of different stiffness, and metabolite depletion followed. On soft (1 kPa), stiff (13 kPa), and rigid (32 kPa) gels, we observed neuronal, chondrogenic, and osteogenic differentiation, respectively, showing that these stem cells undergo stiffness-directed fate selection. By analyzing concentration variances of >600 metabolites during differentiation on the stiff and rigid gels (and focusing on chondrogenesis and osteogenesis as regenerative targets, respectively), we identified that specific lipids (lysophosphatidic acid and cholesterol sulfate, respectively), were significantly depleted. We propose that these metabolites are therefore involved in the differentiation process. In order to unequivocally demonstrate that the lipid metabolites that we identified play key roles in driving differentiation, we subsequently demonstrated that these individual lipids can, when fed to standard stem cell cultures, induce differentiation toward chondrocyte and osteoblast phenotypes. Our concept exploits the design of supramolecular biomaterials as a strategy for discovering cell-directing bioactive metabolites of therapeutic relevance.

Original languageEnglish
Pages (from-to)298-319
Number of pages22
JournalChem
Volume1
Issue number2
Early online date27 Jul 2016
DOIs
Publication statusPublished - 11 Aug 2016

Fingerprint

Hydrogels
Metabolites
Stem cells
Cell culture
metabolite
Stem Cells
Cell Culture Techniques
Lipids
Gels
lipid
Stiffness
Biocompatible Materials
stiffness
Biomaterials
gel
Cell Differentiation
stem
Chondrogenesis
Metabolomics
Cholesterol

Keywords

  • stem cells
  • metabolites
  • biomaterials

Cite this

Alakpa, E. V., Jayawarna, V., Lampel, A., Burgess, K. V., West, C. C., Bakker, S. C. J., ... Dalby, M. J. (2016). Tunable supramolecular hydrogels for selection of lineage-guiding metabolites in stem cell cultures. Chem, 1(2), 298-319. https://doi.org/10.1016/j.chempr.2016.07.001
Alakpa, Enateri V. ; Jayawarna, Vineetha ; Lampel, Ayala ; Burgess, Karl V. ; West, Christopher C. ; Bakker, Sanne C.J. ; Roy, Sangita ; Javid, Nadeem ; Fleming, Scott ; Lamprou, Dimitris A. ; Yang, Jingli ; Miller, Angela ; Urquhart, Andrew J. ; Frederix, Pim W.J.M. ; Hunt, Neil T. ; Péault, Bruno ; Ulijn, Rein V. ; Dalby, Matthew J. / Tunable supramolecular hydrogels for selection of lineage-guiding metabolites in stem cell cultures. In: Chem. 2016 ; Vol. 1, No. 2. pp. 298-319.
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Alakpa, EV, Jayawarna, V, Lampel, A, Burgess, KV, West, CC, Bakker, SCJ, Roy, S, Javid, N, Fleming, S, Lamprou, DA, Yang, J, Miller, A, Urquhart, AJ, Frederix, PWJM, Hunt, NT, Péault, B, Ulijn, RV & Dalby, MJ 2016, 'Tunable supramolecular hydrogels for selection of lineage-guiding metabolites in stem cell cultures', Chem, vol. 1, no. 2, pp. 298-319. https://doi.org/10.1016/j.chempr.2016.07.001

Tunable supramolecular hydrogels for selection of lineage-guiding metabolites in stem cell cultures. / Alakpa, Enateri V.; Jayawarna, Vineetha; Lampel, Ayala; Burgess, Karl V.; West, Christopher C.; Bakker, Sanne C.J.; Roy, Sangita; Javid, Nadeem; Fleming, Scott; Lamprou, Dimitris A.; Yang, Jingli; Miller, Angela; Urquhart, Andrew J.; Frederix, Pim W.J.M.; Hunt, Neil T.; Péault, Bruno; Ulijn, Rein V.; Dalby, Matthew J.

In: Chem, Vol. 1, No. 2, 11.08.2016, p. 298-319.

Research output: Contribution to journalArticle

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AU - Alakpa, Enateri V.

AU - Jayawarna, Vineetha

AU - Lampel, Ayala

AU - Burgess, Karl V.

AU - West, Christopher C.

AU - Bakker, Sanne C.J.

AU - Roy, Sangita

AU - Javid, Nadeem

AU - Fleming, Scott

AU - Lamprou, Dimitris A.

AU - Yang, Jingli

AU - Miller, Angela

AU - Urquhart, Andrew J.

AU - Frederix, Pim W.J.M.

AU - Hunt, Neil T.

AU - Péault, Bruno

AU - Ulijn, Rein V.

AU - Dalby, Matthew J.

PY - 2016/8/11

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N2 - Stem cells are known to differentiate in response to the chemical and mechanical properties of the substrates on which they are cultured. Thus, supramolecular biomaterials with tunable properties are well suited for the study of stem cell differentiation. In this report, we exploited this phenomenon by combining stem cell differentiation in hydrogels with variable stiffness and metabolomics analysis to identify specific bioactive lipids that are uniquely used up during differentiation. To achieve this, we cultured perivascular stem cells on supramolecular peptide gels of different stiffness, and metabolite depletion followed. On soft (1 kPa), stiff (13 kPa), and rigid (32 kPa) gels, we observed neuronal, chondrogenic, and osteogenic differentiation, respectively, showing that these stem cells undergo stiffness-directed fate selection. By analyzing concentration variances of >600 metabolites during differentiation on the stiff and rigid gels (and focusing on chondrogenesis and osteogenesis as regenerative targets, respectively), we identified that specific lipids (lysophosphatidic acid and cholesterol sulfate, respectively), were significantly depleted. We propose that these metabolites are therefore involved in the differentiation process. In order to unequivocally demonstrate that the lipid metabolites that we identified play key roles in driving differentiation, we subsequently demonstrated that these individual lipids can, when fed to standard stem cell cultures, induce differentiation toward chondrocyte and osteoblast phenotypes. Our concept exploits the design of supramolecular biomaterials as a strategy for discovering cell-directing bioactive metabolites of therapeutic relevance.

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Alakpa EV, Jayawarna V, Lampel A, Burgess KV, West CC, Bakker SCJ et al. Tunable supramolecular hydrogels for selection of lineage-guiding metabolites in stem cell cultures. Chem. 2016 Aug 11;1(2):298-319. https://doi.org/10.1016/j.chempr.2016.07.001