Stem cells in vivo reside in a complex microenvironment that presents them with numerous signaling factors that regulate their behavior and functions, and understanding how these factors influence stem cell fate is a major challenge of cell and developmental biology. Designing strategies to control cell behavior is therefore critical for both fundamental studies of stem cell biology from development through adulthood, as well as for applications of stem cells in tissue engineering and regeneration. The objective of this proposal is to design novel biomaterials that modulate and control stem cell behavior. Specifically, these well-defined, biomimetic ligands and surfaces will control the activation of signaling pathways that regulate the differentiation or proliferation of neural stem cells (NSCs). We have chosen NSCs as an effective cellular system to investigate the basic biological mechanisms of stem cell control, to explore their biomedical potential, and to evaluate the promise of hybrid biological-synthetic materials for controlling the multitude functions of a stem cell in culture. The NSC mitogen Sonic hedgehog and the Notch ligand Delta will be grafted onto both soluble liposomes and synthetic surfaces to modulate cell proliferation and differentiation. This proposal will explore the structure-activity relationships of these synthetic cellular effectors. The effects of effector valency, dimensions, fluidity, and dosage on receptor clustering, signal transduction, cell proliferation, and cell differentiation will be studied.
Our Specific Aims are: 1. To determine whether synthetic soluble liposome constructs displaying Sonic hedgehog or Delta can control NSC function. 2. To analyze whether biomimetic surfaces functionalized with Sonic hedgehog or Delta can effectively regulate NSC behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB007295-02
Application #
7685288
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Hunziker, Rosemarie
Project Start
2008-09-05
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
2
Fiscal Year
2009
Total Cost
$195,625
Indirect Cost
Name
Rensselaer Polytechnic Institute
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
002430742
City
Troy
State
NY
Country
United States
Zip Code
12180
Conway, Anthony; Schaffer, David V (2014) Biomaterial microenvironments to support the generation of new neurons in the adult brain. Stem Cells 32:1220-9
Conway, Anthony; Vazin, Tandis; Spelke, Dawn P et al. (2013) Multivalent ligands control stem cell behaviour in vitro and in vivo. Nat Nanotechnol 8:831-8
Pollock, Jacob F; Ashton, Randolph S; Rode, Nikhil A et al. (2012) Molecular characterization of multivalent bioconjugates by size-exclusion chromatography with multiangle laser light scattering. Bioconjug Chem 23:1794-801
Ashton, Randolph S; Conway, Anthony; Pangarkar, Chinmay et al. (2012) Astrocytes regulate adult hippocampal neurogenesis through ephrin-B signaling. Nat Neurosci 15:1399-406
Dickinson, Bryan C; Peltier, Joseph; Stone, Daniel et al. (2011) Nox2 redox signaling maintains essential cell populations in the brain. Nat Chem Biol 7:106-12
Ashton, Randolph S; Keung, Albert J; Peltier, Joseph et al. (2011) Progress and prospects for stem cell engineering. Annu Rev Chem Biomol Eng 2:479-502
Keung, Albert J; de Juan-Pardo, Elena M; Schaffer, David V et al. (2011) Rho GTPases mediate the mechanosensitive lineage commitment of neural stem cells. Stem Cells 29:1886-97
Peltier, Joseph; Conway, Anthony; Keung, Albert J et al. (2011) Akt increases sox2 expression in adult hippocampal neural progenitor cells, but increased sox2 does not promote proliferation. Stem Cells Dev 20:1153-61
Keung, Albert J; Kumar, Sanjay; Schaffer, David V (2010) Presentation counts: microenvironmental regulation of stem cells by biophysical and material cues. Annu Rev Cell Dev Biol 26:533-56
Kane, Ravi S (2010) Thermodynamics of multivalent interactions: influence of the linker. Langmuir 26:8636-40

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