Smooth muscle: a stiff sculptor of epithelial shapes

Abstract

Smooth muscle is increasingly recognized as a key mechanical sculptor of epithelia during embryonic development. Smooth muscle is a mesenchymal tissue that surrounds the epithelia of organs including the gut, blood vessels, lungs, bladder, ureter, uterus, oviduct and epididymis. Smooth muscle is stiffer than its adjacent epithelium and often serves its morphogenetic function by physically constraining the growth of a proliferating epithelial layer. This constraint leads to mechanical instabilities and epithelial morphogenesis through buckling. Smooth muscle stiffness alone, without smooth muscle cell shortening, seems to be sufficient to drive epithelial morphogenesis. Fully understanding the development of organs that use smooth muscle stiffness as a driver of morphogenesis requires investigating how smooth muscle develops, a key aspect of which is distinguishing smooth muscle-like tissues from one another in vivo and in culture. This necessitates a comprehensive appreciation of the genetic, anatomical and functional markers that are used to distinguish the different subtypes of smooth muscle (for example, vascular versus visceral) from similar cell types (including myofibroblasts and myoepithelial cells). Here, we review how smooth muscle acts as a mechanical driver of morphogenesis and discuss ways of identifying smooth muscle, which is critical for understanding these morphogenetic events.This article is part of the Theo Murphy meeting issue 'Mechanics of Development'.

Keywords: buckling morphogenesis; differentiation markers; embryology; mechanical instability; mesenchyme.

Figure 1.

(a) The structure of a smooth muscle cell. The contractile apparatus of smooth muscle consists of a meshwork of actin and myosin fibres that undergo cross-bridge cycling upon activation of the cell. This meshwork is interconnected with the cytoskeletal network including intermediate filaments, cell–matrix and cell–cell adhesions. (b) Detailed view of these interconnections, focusing on structural proteins that are frequently used as markers of smooth muscle.

Figure 2.

(a) Three-dimensional structure of villi in the chick intestine. Grey plane indicates the location of the slice shown in (b). (b) Cross-section of the mature chick gut tube showing the mucosa and villi and their relationship to the smooth muscle layers in the gut. The thin muscularis mucosa separates the lamina propria (connective tissue just below the mucosal epithelium) from the submucosal connective tissue. The muscularis externa (also known as the muscularis propria) is the main muscle sheath and consists of an inner layer of fibres oriented circumferentially around the gut tube and an outer layer of fibres oriented along the length of the tube. (c) Progression of the structure of the gut epithelium as each of these muscle layers differentiates from the mesenchyme. Top: schematics, bottom: corresponding whole-mount microscopy images. Panel (c) is modified from [4]. Reprinted with permission from AAAS. muc, mucosa; sub muc., submucosa; circ, circular; long., longitudinal; ext., external; int., internal.

Figure 3.

(a) Schematic of an E12.5 mouse lung. Dashed box indicates one instance of epithelial bifurcation, detailed in (b). (b) Bifurcation of an epithelial bud as smooth muscle differentiates and mechanically drives the process. (c) Microscopy images of a bifurcating bud of lung epithelium corresponding to the schematics in (b). Ecad: green; α-SMA: red. (d) Structure of the mature mouse lung. Grey plane indicates the location of the cross-section shown in (e). (e) Cross-section of the adult bronchus showing the airway epithelium and its relation to the smooth muscle and connective tissue layers. Panels (b) and (c) modified from [6]. bronc., bronchus; Ecad, E-cadherin; α-SMA, α-smooth muscle actin.

Figure 4.

(a) Structure of the mature mouse uterus showing the location of the oviducts (also known as the fallopian tubes or uterine tubes) leading from the ovaries to the uterus. Grey plane indicates the location of the cross-section shown in (b). (b) Cross-section of the mature oviduct showing the relationship between the epithelium and smooth muscle. The undulating pattern of the epithelium develops through a process very similar to the first step of villus morphogenesis in the chicken. (c) The tortuous pattern of the mouse epididymis is created by compression of a growing epithelial tube by the surrounding stiff mesenchymal tissue between E15.5 and E18.5. Dashed arrows indicate the location of the cross-section shown in (d). (d) Cross-section of the mouse epididymis showing the relationship of the smooth muscle tissue to the epithelium. Panel (c) is modified from [8] under the CC BY licence (http://creativecommons.org/licenses/by/3.0/).