Extracellular matrix dynamics in tubulogenesis

Abstract

Biological tubes form in a variety of shapes and sizes. Tubular topology of cells and tissues is a widely recognizable histological feature of multicellular life. Fluid secretion, storage, transport, absorption, exchange, and elimination-processes central to metazoans-hinge on the exquisite tubular architectures of cells, tissues, and organs. In general, the apparent structural and functional complexity of tubular tissues and organs parallels the architectural and biophysical properties of their constitution, i.e., cells and the extracellular matrix (ECM). Together, cellular and ECM dynamics determine the developmental trajectory, topological characteristics, and functional efficacy of biological tubes. In this review of tubulogenesis, we highlight the multifarious roles of ECM dynamics-the less recognized and poorly understood morphogenetic counterpart of cellular dynamics. The ECM is a dynamic, tripartite composite spanning the luminal, abluminal, and interstitial space within the tubulogenic realm. The critical role of ECM dynamics in the determination of shape, size, and function of tubes is evinced by developmental studies across multiple levels-from morphological through molecular-in model tubular organs.

Keywords: Branching morphogenesis; Development; Embryo; Extracellular matrix; Lumen; Tubulogenesis.

Figure 1:. Common tubular forms in the metazoan; and the tripartite extracellular matrix in the tubulogenic realm.

(A) Cross-sectional topologies of common metazoan tube types, viz., multicellular, unicellular, and subcellular tubes. The en face plane of multicellular and unicellular tubes highlight intercellular and autocellular adherens junctions (orange), respectively. Subcellular tubes occur as cytoplasmic extensions of unicellular tubes, and they lack adherens junctions; thus, they are also referred to as seamless tubes. (B) A generic monolayered epithelial tube depicting the tripartite ECM—luminal ECM (red), abluminal ECM (sepia), and the interstitial ECM (khaki).

Figure 2:. Luminal ECM dynamics and tubulogenesis

(A) The Drosophila trachea spans the entire three dimensional embryonic space. All ten metameric tube units from one side of the embryo are shown. Inset: A hemisegment from the ninth metameric unit composed of one unit of the dorsal trunk and the dorsal branch highlights the various tubular architectures—a multicellular tubule with intercellular junctions, a unicellular tubule with autocellular junctions, and a subcellular (seamless) tubule devoid of cell junctions. (B) The chitin-rich luminal matrix regulates the size along both the axial and diametric (circumferential) dimensions of tracheal tubules. (C) Drosophila embryonic salivary gland morphology is determined by the luminal ECM. The secreted luminal ECM contains a fibrillar component that keeps the apical membranes of opposing cells from contacting each other thus preventing luminal space constriction. The secreted metalloprotease ADAMTS-A cleaves the apical/luminal ECM, hence, untethering it from the apical membrane and forestalling impedance to collective cell migration. (D) Drosophila hindgut is composed of an expansive small intestinal tubular wall and a narrow large intestinal tubular wall. The difference in tubular architecture manifested by small and large intestinal segments is a consequence of hydrostatic pressure differentials between the two tubular structures (walls)—which are, in turn, the result of concentration differences in the secreted luminal glycoprotein, Tenectin; High Tenectin concentration allows expansion of the small intestine, and its low concentration limits the free expansion of large intestinal wall.

Figure 3:. Luminal ECM dynamics and tubulogenesis (continued...)

(A) The ommatidium of the Drosophila compound eye consists of a lumen called the interrhabdomeric space. Its luminal expansion, and the consequent rhabdomeric separation motion depend on Eyes shut, a proteoglycan, which is a component of the luminal extracellular matrix, secreted by the surrounding epithelial cells. (B) Heart lumen expansion is facilitated by multiplexin, the Drosophila ortholog of mammalian collagen-XV/XVIII, by its synergistic action with Slit-Robo signaling at the cardioblast apical membrane. (C) Left: The unicellular tubule components of the C. elegans excretory system: The H-shaped canal cell; the duct cell; and the pore cells. Right: Pore cell swapping, anchored/mediated by the luminal ECM (red), occurs during excretory organ development. To highlight the tubular cell connectivity in the cartoon, the canal cell arms have been truncated, and the excretory gland cell connection at the canal-duct junction is not shown.

Figure 4:. Abluminal ECM dynamics and tubulogenesis

(A) Top: Drosophila renal (Malpighian) tubules are anchored distally to the hindgut, and proximally to the A3/A4 segment-alary muscle (anterior tubule) and the hindgut visceral nerve (posterior tubule); only two out of four tubules are shown for clarity. Bottom: Tube elongation by cell intercalation occurs over the hemocyte-deposited abluminal ECM. Inset: Tube pathfinding and positioning by the tip cell is facilitated by selective denudement of its abluminal ECM. Note the absence of abluminal ECM around the tip cell basal membrane. (B) Xenopus intestine metamorphosis depends on abluminal ECM dynamics (remodeling). The replacement of the larval epithelial layer by the stem cell-derived nascent adult cells is determined by thyroid hormone (T3) and MMP-dependent thickening of abluminal ECM. (C) Adult Drosophila midgut homeostatic epithelial remodeling occurs via a basal-to-apical polarity acquisition by nascent enteric epithelial cells—a process that relies on continuous cellular contact with the abluminal ECM. The new epithelial cells traverse towards the lumen to replace the damaged enteric epithelial cells while acquiring basement membrane adhesion-dependent apicobasal polarity.

Figure 5:. Interstitial ECM dynamics (signaling) and tubulogenesis

(A) Mouse submandibular gland form is sculpted by fibronectin-dependent regulation of epithelial morphology. Insets: Cleft formation is orchestrated by the local enrichment of fibronectin, which leads to the downregulation of E-cadherin. Low E-cadherin levels allow the labile epithelial cells to accommodate clefting. (B) Mouse lung alveolarization occurs following the growth factor-dependent early branching morphogenesis mediated by the interstitial ECM. Inset: Sacculation, which marks the development of alveolar sacs in association with the pulmonary vasculature, is shaped largely by an elastin-rich interstitial matrix crest that forms an organized network at the alveolar ridges. (C) Branching morphogenesis of the ureteric bud leads to mouse kidney assembly, and is driven by glial cell line-derived neurotrophic factor (GDNF) signaling; The interstitial extracellular matrix hosts remodeling factors and facilitates cell-cell and cell-matrix morphogenetic signaling. (D) Mammary gland duct branching morphogenesis is mediated by the collagen-rich interstitial ECM—the major component of the fat pad mesenchyme.

Figure 6:. Interstitial ECM dynamics (motion & cavitation) and tubulogenesis

(A) Avian heart tube is shaped by the convective tissue-scale motion of fibronectin and fibrillin-rich interstitial ECM, coordinated with the movement of cardiac precursor cells, within the primary heart fields towards the midline. (B) Convective tissue-scale motion involving interstitial ECM and the endothelial cells, within the expanding splanchnopleural ECM, is critical for the establishment of the primary vasculature during avian embryogenesis. Insets: Tissue (interstitial ECM plus endothelial cell) motion convects endothelial cords during the initial stages of vasculogenesis (no lumen). Vascular drift, concomitant with the condensation of the primary polygonal network (lumen present), occurs during the final stages. Arrows indicate the direction of tissue motion, within the region of interest beneath the embryonic heart, to establish connectivity between the omphalomesenteric vein and the sinus venosus. C) Interstitial fluid pressure-induced cavitation may be critical for the development of primary body cavities circumscribed by the interstitial ECM.