| Descript |
196 p |
| Note |
Source: Dissertation Abstracts International, Volume: 73-09, Section: B, page: |
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Adviser: Laura L. Kiessling |
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Thesis (Ph.D.)--The University of Wisconsin - Madison, 2012 |
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Human embryonic and induced pluripotent stem cells, collectively known as hPS cells, hold great promise for the fields of regenerative medicine, developmental biology, and drug discovery. Elucidating the molecular mechanisms underlying their proliferation and differentiation is vital for realizing their potential. My research has focused on defining the molecular interactions that mediate hPS cell adhesion and self- renewal. To accomplish this goal, we assayed surfaces that mimic soluble signaling factors, mediate cell-cell interactions, or display peptides derived from extracellular matrix (ECM) proteins. I focused initially on the adhesion receptor E-cadherin, but my latter work used surfaces displaying synthetic peptides to engage other cell surface molecules. A key feature of these tailored surfaces is our ability to attribute cellular responses to the specific interactions between the cell and underlying substratum |
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The major accomplishment of this research was the development of a synthetic substrate for hPS cell propagation. The effective substrates displayed heparin-binding peptides that can interact with cell surface glycosaminoglycans (GAGs). My results also reveal that adhesion is not the sole prerequisite for self-renewal; integrin-binding surfaces did not maintain hPS cells in their pluripotent state. The chemically defined substratum highlights the utility of engaging cell surface GAGs and provides the foundation for investigating the influence of cellular adhesion on cell fate |
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To complement this work, I expanded our tailored surface strategy to target differentiated cells. In principle, surfaces modified with synthetic peptides can support adhesion by mimicking the ECM, but synthetic peptides typically lack affinity or selectivity for specific adhesion receptors. In contrast, organic chemistry can afford compounds that are highly selective. We hypothesized that selective small molecule integrin antagonists, when immobilized, would support adhesion and activate signaling. Indeed, surfaces decorated with a selective alphavbeta3 integrin-targeting molecule promoted both cellular adhesion and integrin activation. I anticipate that peptidomimetics will add to our arsenal of building blocks for generating tailored surfaces. Surfaces displaying highly selective ligands can illuminate the contributions of specific adhesion receptors to signaling cascades and perhaps even control stem cell differentiation. In conclusion, my research has afforded new, practical methods for propagating and manipulating pluripotent cells and their derivatives |
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School code: 0262 |
| Host Item |
Dissertation Abstracts International 73-09B
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| Subject |
Biology, Molecular
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Biology, Cell
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Chemistry, Biochemistry
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0307
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0379
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0487
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| Alt Author |
The University of Wisconsin - Madison. Cellular & Molecular Bio - AG
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