Mechanobiology of Disease
Friday Speaker Abstracts
38
Mechanical Signalling in Embryonic Stem Cell Self-renewal and Differentiation
Kevin Chalut
.
University of Cambridge, Cambridge, CAMBS, United Kingdom.
Stem cell culture has been characterised using soluble signals on tissue culture plastic, providing
a biochemical foundation for self-renewal and differentiation. Nonetheless, most previous stem
cell research has overlooked the role of the extracellular matrix (ECM) and mechanical
signalling, despite increasing evidence that they both mediate self-renewal and differentiation.
To investigate the role of ECM and mechanical signalling, we have developed a novel hydrogel
protocol that can be mechanically tuned, ranging from embryo stiffness to skeletal stiffness,
while maintaining control of ECM density. We can now present any combination of ECM
molecules to cells with independent control over matrix density and stiffness. With our
hydrogels, we have explored mechanical and ECM signaling in both pluripotent stem cells and
oligodendrocyte progenitor cells (OPCs). We have shown, in both mouse and human, that we
can maintain optimal naïve pluripotency using soft substrates with high fibronectin density,
while forcing heterogeneity and differentiation on stiff substrates. We have also shown that we
can reverse the loss of function associated with ageing and neurodegeneration in OPCs using soft
substrates with high laminin density. We will present a number of functional studies to support
these conclusions, and I hope to present sequencing data revealing a quantitative analysis of how
stiffness drives stem cell identity (samples from both projects are currently being sequenced).
Using our hydrogel technology, we have also shown there to be significant actuation of Erk and
Stat3 signalling, which are important pathways for self-renewal and differentiation, with
mechanical stiffness independent of ECM composition and density. Ultimately, I will advance
the hypothesis that mechanical sensing acts as a switch to modulate growth factor signaling to
support either self-renewal or differentiation in stem cells.
Nuclear Mechano-genomics and Disease Diagnosis
G.V. Shivashankar
Mechanobiology Institute, National University of Singapore, Singapore
No Abstract