RESEARCH

Cell Response to External Stimuli

The overarching theme of our lab is elucidating cell responses to external stimuli toward the development of predictive links between input stimuli and output cell behavior. These predictive links will one day serve as powerful tools permitting the rational selection of input stimuli to achieve desired cell behavior. A range of fields will benefit from these tools, including guided stem cell differentiation and tissue engineering/regeneration.

To gain further insight into the concepts underlying our work, consider the figure above. At any given time, t, cell-state (phenotype) is a complex result of various external stimuli (mechanical forces, extracellular matrix (ECM), soluble regulators, cell-cell interactions) and initial cell state. Most connective tissue engineering studies focus on quantifying the effects of specific external stimuli on cell behavior by examining two primary outcomes: (1) ECM deposition and (2) markers indicative of cell differentiation. The broadest studies have included examination of pre-selected signaling pathways. However, these conventional tissue engineering analyses yield incomplete insight into the intracellular signaling underlying observed ECM synthesis or cell markers.

Although ECM production/organization and cell marker data are linked to input external stimuli, they are not uniquely linked (i.e., in a one-to-one fashion). This is because multiple cell signaling histories can result in the same observed ECM production/organization and cell markers and thus ECM analyses do not yield a unique signature for cell response to a particular stimulus. Without these one-to-one, input-output links, cell culture environment (external stimuli) cannot be selected in a rational way to produce desired tissue engineered outcomes.

To enable the development of predicative links between specific input stimuli and tissue engineering outcome, work in our laboratory focuses on transforming traditional tissue engineering experimental design via: (1) development of methods for controlled and uncoupled investigation of the impact of specific input stimuli on cell response and subsequent engineered tissue mechanical properties and (2) incorporation of more comprehensive cell-state analyses than are provided by conventional ECM deposition and cell marker analyses alone.