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Principal Investigator: Allen Po-Chih Liu
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2024
Award: $15,175
Funding agency: National Institute of Biomedical Imaging and Bioengineering
Project summary
Our abilities to engineer synthetic cell systems that can communicate with living cells remain
limited. The long-term goal is to engineer cell-like systems with increasingly complex biomimetic
functions that can serve as cell replacements or augment functions of natural cells. The
objective of this proposal is to develop a mechanosensitive synthetic cell that can respond to an
increase in shear stress, which is most prevalent in the cardiovascular system, and secrete
bioactive molecules to affect living cells. Cells in our bodies constantly sense and respond to
microenvironmental stimuli, including passive and active physical stimuli, such as extracellular
matrix rigidity, adhesive ligand density, tension, compression, and fluid shear flow. The rationale
underlying this proposal is that completion will result in a novel biomimetic cell-like system as a
novel shear stress-responsive ‘material’ that can interface with natural living cells. Most
engineered biomaterials respond to differences in the biochemical environment (e.g. differences
in redox, pH, and enzyme composition) between normal and diseased tissues. By comparison,
there has been relatively less effort in exploiting forces for stimulus-responsive behaviors. The
synthetic cell idea is inspired by natural platelets’ ability to bind and respond to elevated shear
stress and secrete granule contents when bound to a surface. The proposed work consists of
three specific aims: 1) Characterize the shear stress response of mechanosensing vesicles, 2)
Couple mechanosensing with exocytosis in synthetic cells, and 3) Test intercellular
communication of shear stress-activated synthetic cells with endothelial cells in vitro. We will
pursue these aims using an innovative approach of repurposing mechanosensitive channels for
shear stress sensing and using peptide-based membrane fusion. Our lab was the first group to
demonstrate mechanosensing synthetic cells and we have significant expertise in bottom-up
synthetic biology. The proposed research is significant because it will be the first synthetic cell
system developed to communicate with mammalian cells using calcium-triggered secretion. The
work will develop fundamental strategies for coupling mechanosensing to a biochemical
response in synthetic cells. This will open new avenues for other researchers interested in
developing more complex cell-like systems. The results will have an important positive impact
immediately because it will support the idea that mechanosensitive channels can sense lateral
membrane tension due to shear stress and long-term because they lay the groundwork of
engineering synthetic cells with other sensing abilities.
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