Symmetry‐breaking in branching epithelia: cells on micro‐patterns under flow challenge the hypothesis of positive feedback by a secreted autocrine inhibitor of motility

Abstract

Branching morphogenesis of epithelia involves division of cells into leader (tip) and follower (stalk) cells. Published work on cell lines in culture has suggested that symmetry‐breaking takes place via a secreted autocrine inhibitor of motility, the inhibitor accumulating more in concave regions of the culture boundary, slowing advance of cells there, and less in convex areas, allowing advance and a further exaggeration of the concave/convex difference. Here we test this hypothesis using a two‐dimensional culture system that includes strong flow conditions to remove accumulating diffusible secretions. We find that, while motility does indeed follow boundary curvature in this system, flow makes no difference: this challenges the hypothesis of control by a diffusible secreted autocrine inhibitor.

Autocrine inhibition of cell motility can drive epithelial branching morphogenesis in absence of growth

“…At the same time, there are of course many observations that our model cannot explain and that will open up new perspectives for future modeling studies. In particular, observations of renal epithelial cells challenge the hypothesis of autocrine inhibition of motility studied in this work [35]. Renal epithelial cells grown on micropatterns of specific curved geometry exhibit curvature dependent protrusions.…”

“…These are potentially regulated by autocrinically secreted BMP7, a member of the TGF-β superfamily. To test this hypothesis, Martin et al [35] applied a flow to the culture medium that should flush away any diffusive signals potentially secreted by the cells. Surprisingly, this treatment did not affect the curvature-dependent protrusions.…”

“…Pavlovich et al [50] argued that the autocrine inhibition mechanism may uniquely apply to mammary epithelial patterning. An alternative explanation for the observations by Martin et al [35] may be that autocrinically secreted signals are bound to secreted extracellular matrix (ECM) proteins, which would prevent them from being flushed away. Such pericellular retention of signaling molecules has been observed for VEGF in endothelial cells [29].…”

Adaptive self‐organization in the embryo: its importance to adult anatomy and to tissue engineering

“…While the Nelson hypothesis described above is powerful, it should be noted that a recent attempt to explore it in two-dimensional culture of canine renal collecting duct cells, in which cells were cultured on shaped islands in the presence or absence of flow, confirmed that cells on convex curves are far more invasive than cells on straight edges and those on concave curves are particularly reluctant to move. Application of flow strong enough to sweep proteins away failed to alter this relationship; however, casting doubt on the hypothesis control by accumulation of a secreted inhibitor and suggesting that curvature itself may control invasion directly, for example by its effect on cytoskeletal tension (Martin et al 2017).…”

“…Application of flow strong enough to sweep proteins away failed to alter this relationship; however, casting doubt on the hypothesis control by accumulation of a secreted inhibitor and suggesting that curvature itself may control invasion directly, for example by its effect on cytoskeletal tension (Martin et al. ).…”