Peter Zandstra

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Abstract for public lecture:

Intercellular (between cell) communication networks are an important component of the stem cell niche. These networks maintain homeostasis and coordinate regenerative and developmental cues in multicellular organisms. Despite the importance of intercellular networks in stem cell biology, their rules, structure and molecular components are poorly understood. We have been studying dynamic intercellular communication networks in defined pluripotent stem cell and human blood stem cell cultures. A fundamental limitation in all stem cell-driven culture systems is the rapid accumulation of fate-modifying endogenous signals. Although microengineering technologies can be used to prospectively control the initial levels and impact of endogenous signals, these technologies are typically unable to adapt to dynamic changes in the culture environment. We have developed a number of new tools to characterize and modulate these culture-generated soluble factor-mediated networks. In one example, we have used predictive microfluidic control of regulatory ligand trajectories in individual pluripotent cells to create spatial gradients of differentiation, and have demonstrated how convective fluid flow and local cell organization modulates the impact of endogenous signals. In a second example, we have used an integrated computational and experimental strategy to develop an automated “fed-batch” media dilution approach to control the levels and impact of inhibitory paracrine signaling factors, and have applied this technology to demonstrate a clinically-relevant 12-fold increase in the numbers of cultured human blood stem cells. These results demonstrate the impact of endogenously produced molecules on stem cell fate, and highlight the marked improvements that measurement and control of endogenous feedback signaling can offer stem cell culture. Emerging from this work are insights into the rules and mechanisms that govern developmental cellular dynamics in vitro and, ultimately, in vivo.

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