Cell division in tissues enables macrophage infiltration

Abstract

Migration of cells through diverse tissues is essential for development, immune response and cancer metastasis. To reach their destination, cells must overcome the resistance imposed by complex microenvironments, composed of neighboring cells and extracellular matrix (ECM). While migration through pores and tracks in ECM has been well studied, little is known about cellular traversal into confining cell-dense tissues. Here by combining quantitative live imaging with genetic and optogenetic perturbations we identify a crucial role for cell division during cell migration into tissues. We find that normal embryonic invasion by Drosophila macrophages between the ectoderm and mesoderm absolutely requires division of an epithelial ectodermal cell at the site of entry. Dividing ectodermal cells disassemble ECM attachment formed by Integrin-mediated focal adhesions next to mesodermal cells, allowing macrophages to move their nuclei ahead and invade. Decreasing or increasing the frequency of ectodermal division correspondingly either hinders or promotes macrophage invasion. Reducing the levels of focal adhesion components in the ectoderm allows macrophage entry even in the absence of division. Our study demonstrates the critical importance of division at the entry site to enable in vivo cell invasion by relieving the steric impediment caused by focal adhesions. We thus provide a new perspective on the regulation of cellular movement into tissues

Mechanical stress driven by rigidity sensing governs epithelial stability

“…In vivo failure of adherens junctions 24 , 66 , polarity 67 , increased mechanical load 23 and post-apoptotic failure in sealing 68 , 69 leads to hole formation in tissues. During morphogenesis, hole formation is not only essential for Drosophila peripodium elongation 21 but is also crucial for macrophage invasion during Drosophila development 8 . In addition loss of epithelial integrity has been reported under pathophysiological conditions 70 , 71 , immune cell 72 and tumor extravasation 73 .…”

“…In response to these challenging environments, epithelia are subject to constant cell renewal and cell extrusions, whose balance is key for epithelia homeostasis while modifying their shape 5 . These morphological changes include the formation of holes between cells which are crucial for tissue development 6 , 7 but also in macrophage infiltration 8 or diseases such as diabetes 9 , asthma 10 and cancer 11 .…”

Mechanical stress driven by rigidity sensing governs epithelial stability

“…In vivo failure in adherens junctions 24,63 , increased mechanical load 23 and post-apoptotic failure in sealing 64,65 leads to hole formation in tissues. During morphogenesis, hole formation is not only essential for Drosophila peripodium elongation 21 , mouse embryogenesis 7 but is also crucial for macrophage invasion during Drosophila development 8 . In addition loss of epithelial integrity has been reported under pathophysiological conditions 66,67 , immune cell 68 and tumor extravasation 69 .…”

“…In response to these challenging environments, epithelia are subject to constant cell renewal and cell extrusions, whose balance is key for epithelia homeostasis but also modify their shapes 5 . These morphological changes include the formation of holes between cells which are crucial for tissue development 6,7 but also in macrophage infiltration 8 or diseases such as diabetes 9 , asthma 10 and cancer 11 .…”