Confounding effects of macromolecular crowding and extracellular matrix on fibroblast proliferation

Jenna Graham^a, Nikhil Jain^a, Viola Vogel^a, Denis Wirtz^b^,^c^,^d

^aLaboratory of Applied Mechanobiology, Department of Health Sciences and Technology, ETH Zurich, Vladimir-Prelog-Weg, 4, Zürich, Switzerland

^bJohns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins Univeristy, Baltimore, MD

^cDepartment of Chemical and Biomolecular Engineering, National university of Singapore

^dDepartment of Oncology, Johns Hopkins Univeristy School of Medicine, Baltimore, MD

Proceedings of New Advances in Probing Cell-ECM Interactions (CellMatrix)

Berlin, Germany, 2016 October 20th - 21st

Organizers: Ovijit Chaudhuri, Allen Liu and Sapun Parekh

Poster, Jenna Graham, 048
Publication date: 25th July 2016

The fluid surrounding cells in vivo is densely crowded with soluble macromolecules, however this is poorly mimicked by in vitro cell culture experiments. Significant work in the field of biophysics has shown that macromolecular crowding has profound and complex effects on interactions between molecules, impacting protein conformation, supramolecular assembly, diffusion, and binding interactions. Since the function of cells in our body depends entirely on molecular interactions, it easily follows that crowding should impact cell functions too. Though the tissue engineering community has shown that the addition of crowding agents into cell culture media significantly enhances self-assembly of extracellular matrix, there is very little understanding of how macromolecular crowding directly interacts with cells to alter their function. We have found that adding neutral, inert macromolecules to primary human fibroblast culture significantly reduces proliferation within 24 hours. This effect develops slowly, lasts for several days, is dose dependent, and is partially reversible upon removal of the crowding agents. Further analysis of cell morphology has shown little change in cell and nuclear geometry, cytoskeletal architecture, and cell volume, suggesting that macromolecular crowding impacts the cell through molecular signaling pathways rather than significant mechanical changes to the cell. Consistent with previous literature, the introduction of macromolecular crowding in our system enhances cell production of fibronectin and collagen. As the extracellular matrix is known to impact cell proliferation, we propose a complex system whereby crowding effects the proliferation behavior directly through molecular interactions at the membrane and indirectly through the matrix. Since most cells are known to be quiescent in vivo, this observed state of reduced proliferation is very relevant to normal biology. Our developing understanding will lend insights into the role of extracellular crowding in vivo and may show that adding artificial crowders to cell culture is a simple way to better recapitulate in vivo biology using in vitro approaches.

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