Our group seeks to answer the following fundamental questions: How are the final architectures of tissues and organs determined? Specifically, how do individual cells -- the building blocks of these materials -- integrate complex biological signals (both biochemical and mechanical) dynamically and spatially within tissues to direct the development of organs?

The answers to these questions have broad ramifications, from understanding the fundamental mechanisms of development, to delineating the developmental control processes that are circumvented by cancer and other diseases, to elucidating new paradigms required for successful therapeutic approaches in regenerative medicine and tissue engineering. Because of the complexity of the interacting pathways and three-dimensional (3D) nature of developing tissues, this problem requires an interdisciplinary approach, combining expertise from the cell biology, developmental biology, and engineering communities. Our group works at the interface of these disciplines, developing tools to engineer organotypic culture models that mimic tissue development, enabling rigorous quantitative analysis and computational predictions of the dynamics of morphogenesis. Our current focus is on understanding the branching morphogenesis process that builds the mammary gland and vertebrate lung.

Biochemical and mechanical signal integration
What signals determine final tissue geometry? Long-range communication between individual cells within a tissue is critical for determining pattern formation during morphogenesis. We have shown that pattern formation and symmetry breaking are determined in part by long-range transmission of mechanical stresses and autocrine morphogen gradients; these gradients are determined by the structure of the tissue, forming a feedback system during morphogenesis. We use experimental and computational approaches to determine the relative roles of morphogen and mechanical gradients during tissue development. Our recent studies have also started to reveal the chemical signaling that underlies mechanical regulation of branching morphogenesis.

Cellular cooperation within 3D tissues
How do cells cooperate and integrate to build complex tissue geometries, such as the branching architectures of the lung, kidney, and mammary gland? The most straightforward way to address this question would be to manipulate individual cells at specific locations within a tissue at will -- reproducibly and with high precision. We accomplish this by using microfabrication approaches to recreate 3D vertebrate tissue architecture in culture. Current challenges include: (1) understanding the dynamics of individual cells during morphogenesis; (2) understanding the roles of different cell types within an organ during development; (3) defining the role of the cellular microenvironment in normal development and neoplastic progression.

Nelson Group, Department of Chemical & Biological Engineering, Princeton University

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