WHAT WE SEEK TO UNDERSTAND
How does the physical shape of an organ emerge from the collective activity of its constituents - microscopic fluctuating biological cells? To what extent is shape programmed by genes or is it self-organized through biomechanical feedback loops? What is needed to engineer tissues into complex 3D shapes?
To address these questions, we develop robust human stem-cell systems that undergo complex shape changes in response to controlled biochemical and mechanical cues. We further use physical frameworks - such as the theories of thin sheets and fluids - to develop a quantitative and predictive understanding of organ formation.
Bioengineering 3D human stem-cell systems
To gain insight into embryonic development, we develop 3D stem-cell systems which capture key aspects of organ morphogenesis. For this purpose, we combine advanced microfabrication and microfluidic tools with tailored stem-cell differentiation protocols. We have recently developed a human stem-cell system that self-organizes into a neural tube in a dish. Our system offers quantitative control over experimental parameters, and a unique opportunity to understand the biomechanics of human neural tube formation in health and disease.
Biomechanics of tubular organ formation
Tubular organs form through mechanical deformations of embryonic tissues, which behave like thin fluidic sheets. For example, the spinal cord forms by folding an embryonic neural tissue, followed by seamless fusion into a closed tube. This shape transformation requires a combination of elastic-like and fluid-like properties, which cannot be achieved in non-living materials. We use stem-cell systems to study the mechanical properties of tissues and how they are biologically regulated to drive organ morphogenesis.
Human Birth Defects
Birth defects arise from a combination of genetic and environmental factors, which are often not well understood. Failures in neural tube folding are among the most common birth defects, affecting 1:1000 pregnancies. Neural tube defects result in severe disabilities and lethality shortly after birth. Surprisingly, some genetic mutations associated with neural tube defects in humans do not lead to defects in mice. Thus, new model systems are required to advance our understanding of human disease. Our stem-cell platform offers a unique opportunity to study how neural tube morphogenesis is regulated by the human genome and to understand its evolution across species.
Organ shape information is encoded in genetic networks and in the boundary and initial conditions of the tissue. Our 3D stem-cell sheets are a clean slate on which we can quantitatively explore this idea. We will study how tissue geometry, mechanical environment, and positioning of morphogens control tissue morphogenesis. We aim to reveal morphogenetic motifs which will allow us to design new synthetic organ forms.