Mechanics in biology of progenitors: Spheroid growth modeling in silico and mechanical induction of human hepatic stem cell phenotype in vitro

Abstract

Stem cell biology is a collection of multivariate phenomena with strict regulatory mechanisms. These regulatory mechanisms assemble biological systems that coordinate growth and differentiation during development and remain in determined stem cells of adult tissues. In order to control these complex systems, biologists can, on the one hand, investigate how individual mechanisms affect global responses in stem cells, and on the other hand, explore how multiple mechanisms act in coordination to control the behavior of developing tissues. The types of stimuli traditionally studied in stem cell biology are biochemical; however, mechanics of stem cell environments also influence stem cell biology.

The objective of this thesis is to survey roles of mechanical variables in directing mechanisms of stem cell biology and growth of developing tissues. This inspection uses two approaches: an experimental system (in vitro ) that controls a small set of variables to reveal their roles in stem cell biology; and a biomathematical model (in silico) that defines a biological system to study the effects of interactions between multiple variables on growth of developing tissues. The in vitro model shows that the mechanical properties of threedimensional (3D) environments regulate phenotype of determined stem cells from the human liver. The in silico model reveals that growth of spheroids with properties of developing tissues exhibits two morphogenetic regimes, and explains quantitatively how expansion stops in growing spheroids that degrade their surroundings.

Each of these two models has strong implications for tissue engineering. Both models unveil paradigms of stem cell and developing tissue behavior, which researchers can use to optimize experimental conditions. Furthermore, this thesis evaluates stem cell biology from two distinct perspectives, which brings empirical and predictive aspects of tissue engineering one step closer to each other and creates useful models to close this gap.