Surface Engineering to Control Embryonic Stem Cell Fate

Abstract

The niche established by supportive cells and the extracellular polymeric matrix (ECM) probably regulates stem cell fate through multiple, complimentary mechanisms, including the spatiotemporally defined presentation of immobilized signaling molecules, the modulation of matrix stiffness, the physicochemical characteristics of the environment, and the creation of cytokine gradients. In contrast to tissue-specific stem cells, embryonic stem (ES) cells are present only transiently in the developing embryo, and therefore, do not have a stable niche in vivo. ES cells also differ from tissue-specific stem cells in their ability to be readily expanded in culture over long time periods. However, the culture systems that have been used successfully for ES cell expansion suggest that ES cell self-renewal versus differentiation is regulated in a similar manner to tissue-specific stem cells, via interactions with other cells, ECM components, soluble factors, and the physicochemical environment (McDevitt & Palecek, 2008). ES cells commute between metastable states from the inner cell mass (ICM) to the epiblast stage, and these reversible states are associated with distinct differentiation potentials (Toyooka et al., 2008; Hayashi et al., 2008; Pelton et al., 2002). Thus, ES cells represent a highly dynamic, self-renewing population that responds to environmental cues to maintain its pluripotency or to differentiate. In ES cell cultures, these cues include growth factors in the culture medium surrounding the ES cell colonies or secreted by the colonies themselves, and signals arising from the ES cells’ adhesion to the substrate and the stiffness of the substrate (Discher et al., 2009). ES cells are anticipated to serve as an unlimited cell source for cell transplantation therapy. However, the most common techniques for controlling ES cell fate using soluble biochemical and biological factors (cytokines and growth/differentiation factors) in the growth medium are often inefficient, and the resulting cell population (either undifferentiated or differentiated) is not homogenous. The idea that ES cell populations are homogenous was first challenged by Cui et al., who observed differential spatial distributions of adhesion molecules within ES cell colonies (Cui et al., 2004), and more recently by the derivation of epiblast stem cells from ES cell (Brons et al., 2007) and the identification of ES cell subpopulations in mouse ES cell cultures (Toyooka et al., 2008).