UPenn Dept of ARCH745, Nonlinear Systems Biology & Design (Sabin & Jones)
Pablo Kohan, David Ettinger, Huishi Li
Normal human mammary epithelial cells (MCF-10A) cultured within a reconstituted extracellular matrix (ECM) form multi-cellular 3-D polarized acini, complete with a central lumen. These cells are enveloped by a continuous endogenous basement membrane. Apoptosis, or a programmed cell death, plays a crucial role in the formation and maintenance of luminal space in the mammary gland. The process of apoptosis begins when the cell's loss of contact to the basement membrane. This disconnect initiates the process of cell suicide. Upon proliferation of new cells within the layer of epithelial cell lining others are forced off the ECM, beginning the process of cell death. Healthy cells develop during gestation this way until the layer of epithelial cells reach a level of stasis in which there is no more cell death or proliferation. In the cancerous condition, proliferation of cells proceeds without the process of apoptosis, eventually filling the luminal cavity. It is this developmental process that we studied to understand the relationships between proliferation and apotosis' role in normal mammary gland health.
The first translations of our digital models to a physical form resulted in the discovery of a structural relevance of the seams created along the lines of collapse. The re-association of the parametric equation from a 2 dimensional surface to a 3 dimensional volume developed what could be a material and structural system that could deploy and adapt to specific spatial requirements that are programmed for. The relationship between the ECM and the layer of epithelial cells manifests in a double layered model of gradual difference responding to the luminal remodeling process which occurs in conjunction with apoptosis.
Jae-Won Shin, Jaeyoung Lee, Shuo Zhang
Studies of biological systems show that an organism is developed from a single stem cell, which is characterized by its ability to give rise to different types of cells in a self-regenerative manner
(‘self-renewal’). During embryonic development, this single cell undergoes a series of divisions to produce progenies which usually contain identical genetic codes. However, it is well established that cells produced from a single parent cell become different in terms of their phenotypes as well as ways their genetic codes are read – which eventually leads to approximately hundreds of cell types identified to date.
It is also striking that during development, cells can self-organize to form tissues and organs – this phenomenon is conserved within a given species and even across different species. This phenomenon can be replicated in vitro, where the 3D structure of mammary acini can be reproduced by seeding mammary epithelial cells into a gel-based 3D culture system . Since the discovery of DNA as a ‘blueprint’ of life, it was traditionally believed that programs required to undergo development of an organism are also encoded in DNA and ways genetic materials are read. However, discoveries that cells respond to signals from their environment via cell surface receptor proteins have broaden our understanding that both genetic codes (‘intrinsic’) and environmental factors (‘extrinsic’) can contribute to ways cells are organized. In order to better understand the contribution of extrinsic factors to self-organization of cells into tissue scaffolds, we motivated our study from previous observations made with Tenascin-C (TN-C).
To investigate the fundamental relationships between cells and their adjacent ECM in forming a
tissue scaffold, we developed a pipeline of investigations to understand and model two
phenomena in parallel – 1. Interactions between ECM and cells that can dictate the formation of
an overall tissue scaffold; 2. Alterations in scaffold dynamics as governed by cell packing behavior and receptor clustering.