To exploit the full potential of human pluripotent stem (hPS) cells for regenerative medicine, developmental biology, and drug discovery, defined conditions for hPS cell propagation and differentiation must be reproducible and therefore chemically defined. To this end, the chemical cues that instruct hPS cells to make specific decisions must be determined. While strategies to identify the soluble cues are well established, an understanding of how insoluble signals guide cell fate decisions is lacking. Chemical synthesis provides access to well-defined surfaces and materials that vary in binding epitope identity, density, and in physicochemical properties. The three Specific Aims have been devised to leverage synthetic methods from chemistry and chemical biology to generate tailored materials and surfaces that promote hPS cell expansion or differentiation to desired cell types. In the past grant period, chemically defined peptide- substituted surfaces that promote hPS cell propagation were identified. The most effective substrates interact with hPS cell surface glycosaminoglycans. The experiments proposed in Aim 1 were conceived to test the hypothesis that engagement of hPS glycosaminoglycans contributes to pluripotency.
In Aim 2, we shall employ our surface array screen to identify insoluble signals (peptide- or small molecule-derived) that act in concert with soluble signals to direct hPS cell differentiation.
In Aim 3, we shall synthesize a series of biocompatible polymers that vary in cell binding groups, pore size, and elasticity to address how physicochemical cues influence cell fate decisions. A novel feature of the approach is the use of an array strategy to identify new surfaces that act on hPS cells to direct their proliferation and differentiation. The proposed experiments leverage this surface array screen not only to identify functional surfaces but also to devise and test novel hypotheses regarding the signaling pathways and molecular mechanisms that underlie hPS self-renewal and differentiation. Progress in understanding how hPS cells respond to distinct combinations of soluble, insoluble, and mechanical cues will be transformative: It will advance applications of hPS cells to human disease.

Public Health Relevance

Human pluripotent stem cells can be used to identify drugs for key human diseases, and they are promising potential sources of more specialized human cells (e.g., heart cells or brain cells) for treating disease. To obtain each desired type of specialized cell, the right combination of chemical cues must be given, such that hPS cells reproducibly differentiate into the specific cell type needed. The research proposed is designed to provide fundamental knowledge regarding how combinations of chemical cues influence hPS cell propagation and differentiation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Special Emphasis Panel (ZRG1-SBCA-U (02))
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Marino, Pamela
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University of Wisconsin Madison
Schools of Earth Sciences/Natur
United States
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Xu, Yongmei; Chandarajoti, Kasemsiri; Zhang, Xing et al. (2017) Synthetic oligosaccharides can replace animal-sourced low-molecular weight heparins. Sci Transl Med 9:
Hudson, Kieran L; Bartlett, Gail J; Diehl, Roger C et al. (2015) Carbohydrate-Aromatic Interactions in Proteins. J Am Chem Soc 137:15152-60
Bennett, Nitasha R; Zwick, Daniel B; Courtney, Adam H et al. (2015) Multivalent Antigens for Promoting B and T Cell Activation. ACS Chem Biol 10:1817-24
Wrighton, Paul J; Kiessling, Laura L (2015) Forces of Change: Mechanics Underlying Formation of Functional 3D Organ Buds. Cell Stem Cell 16:453-4
Wrighton, Paul J; Klim, Joseph R; Hernandez, Brandon A et al. (2014) Signals from the surface modulate differentiation of human pluripotent stem cells through glycosaminoglycans and integrins. Proc Natl Acad Sci U S A 111:18126-31
Sheridan, Rachael T C; Hudon, Jonathan; Hank, Jacquelyn A et al. (2014) Rhamnose glycoconjugates for the recruitment of endogenous anti-carbohydrate antibodies to tumor cells. Chembiochem 15:1393-8
Courtney, Adam H; Bennett, Nitasha R; Zwick, Daniel B et al. (2014) Synthetic antigens reveal dynamics of BCR endocytosis during inhibitory signaling. ACS Chem Biol 9:202-10
Musah, Samira; Wrighton, Paul J; Zaltsman, Yefim et al. (2014) Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification. Proc Natl Acad Sci U S A 111:13805-10
Fishman, Joshua M; Kiessling, Laura L (2013) Synthesis of functionalizable and degradable polymers by ring-opening metathesis polymerization. Angew Chem Int Ed Engl 52:5061-4
Kiessling, Laura L; Grim, Joseph C (2013) Glycopolymer probes of signal transduction. Chem Soc Rev 42:4476-91

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