Abstract
Whilst demonstrated extensively in vitro, the control of cell behaviour via modulation of substrate compliance in live tissues has not been accomplished to date. Here we propose that stem cells can be regulated solely through in situ modulation of tissue biomechanics. By first establishing, via high-resolution Brillouin spectro-microscopy, that the outer edge (limbus) of live human corneas has a substantially lower bulk modulus compared to their centre, we then demonstrate that this difference is associated with limbal epithelial stem cell (LESC) residence and YAP-dependent mechanotransduction. This phenotype-through-biomechanics correlation is further explored in vivo using a rabbit alkali burn model. Specifically, we show that treating the burnt surface of the cornea with collagenase effectively restores the tissue’s mechanical properties and its capacity to support LESCs through mechanisms involving YAP suppression. Overall, these findings have extended implications for understanding stem cell niche biomechanics and its impact on tissue regeneration.
Highlights
Whilst demonstrated extensively in vitro, the control of cell behaviour via modulation of substrate compliance in live tissues has not been accomplished to date
We start by using Brillouin spectro-microscopy (BSM), a technique based on the interaction of light with spontaneous acoustic phonons in the GHz frequency range, to characterise the mechanical properties of live human corneas in a true non-contact, penetrating, non-destructive mode
The limbal epithelium ranging 40–60 μm depth (Fig. 1d) and 6.34 ± 0.14 GHz was followed by matrix with significantly lower frequency shift (6.24 ± 0.09 GHz), which in turn was followed by tissue exhibiting slightly higher shifts (6.40 ± 0.14 GHz, respectively; Fig. 1e), probably corresponding to the continuation of the corneal stroma under the limbus (Fig. 1b)[28]
Summary
Whilst demonstrated extensively in vitro, the control of cell behaviour via modulation of substrate compliance in live tissues has not been accomplished to date. Via high-resolution Brillouin spectro-microscopy, that the outer edge (limbus) of live human corneas has a substantially lower bulk modulus compared to their centre, we demonstrate that this difference is associated with limbal epithelial stem cell (LESC) residence and YAP-dependent mechanotransduction This phenotype-through-biomechanics correlation is further explored in vivo using a rabbit alkali burn model. We use the accuracy of this method to identify critical biomechanical differences between the (softer) limbus and the (stiffer) central cornea, and establish a correlation between tissue biomechanics and corneal epithelial cell phenotype This data supports our hypothesis that epithelial cell differentiation across the corneal surface is controlled by changes in substrate stiffness, via the activation of YAP-
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