Tunable Supramolecular Hydrogels for Selection of Lineage-Guiding Metabolites in Stem Cell Cultures

被引：171

作者：

Alakpa, Enateri V. ^{[1
]}

Jayawarna, Vineetha ^{[2
,3
]}

Lampel, Ayala ^{[4
]}

Burgess, Karl V. ^{[5
]}

West, Christopher C. ^{[6
]}

Bakker, Sanne C. J. ^{[2
]}

Roy, Sangita ^{[2
]}

Javid, Nadeem ^{[2
]}

Fleming, Scott ^{[2
]}

Lamprou, Dimitris A. ^{[7
]}

Yang, Jingli ^{[1
]}

Miller, Angela ^{[1
]}

Urquhart, Andrew J. ^{[7
]}

Frederix, Pim W. J. M. ^{[2
,8
]}

Hunt, Neil T. ^{[8
]}

Peault, Bruno ^{[5
,9
]}

Ulijn, Rein V. ^{[2
,4
,10
,11
]}

Dalby, Matthew J. ^{[1
]}

机构：

[1] Univ Glasgow, Coll Med Vet & Life Sci, Inst Mol Cell & Syst, Ctr Cell Engn, Joseph Black Bldg, Glasgow G12 8QQ, Lanark, Scotland

[2] Univ Strathclyde, Dept Pure & Appl Chem, WestCHEM, 295 Cathedral St, Glasgow G1 1XL, Lanark, Scotland

[3] Biogelx Ltd, BioCity Scotland, Boness Rd, Newhouse LM1 5UH, Lanark, Scotland

[4] CUNY, ASRC, New York, NY 10031 USA

[5] Univ Glasgow, Coll Med Vet & Life Sci, Wolfson Wohl Canc Res Ctr, Sco Poly Facil, Garscube Estate, Glasgow G61 1QH, Lanark, Scotland

[6] Univ Edinburgh, Ctr Cardiovasc Sci, Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland

[7] Univ Strathclyde, SIPBS, Glasgow G4 0RE, Lanark, Scotland

[8] Univ Strathclyde, Dept Phys, SUPA, Glasgow G4 0NG, Lanark, Scotland

[9] Univ Calif Los Angeles, Dept Orthopaed Surg, Broad Stem Cell Res Ctr, Los Angeles, CA 90095 USA

[10] CUNY, Hunter Coll, Dept Chem, New York, NY 10065 USA

[11] CUNY, Grad Ctr, Program Chem, New York, NY 10016 USA

来源：

CHEM | 2016年 / 1卷 / 02期

基金：

英国工程与自然科学研究理事会; 英国生物技术与生命科学研究理事会;

关键词：

ATOMIC-FORCE MICROSCOPY; LYSOPHOSPHATIDIC ACID; CHOLESTEROL SULFATE; IN-VITRO; DIFFERENTIATION; PROLIFERATION; BIOMATERIALS; METABOLOMICS; CHONDROCYTES; ELASTICITY;

D O I：

10.1016/j.chempr.2016.07.001

中图分类号：

O6 [化学];

学科分类号：

070301 [无机化学];

摘要：

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.

引用

页码：298 / 319

页数：23

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