The function of heparan sulfate during branching morphogenesis

Abstract

Branching morphogenesis is a fundamental process in the development of diverse epithelial organs such as the lung, kidney, liver, pancreas, prostate, salivary, lacrimal and mammary glands. A unifying theme during organogenesis is the importance of epithelial cell interactions with the extracellular matrix (ECM) and growth factors (GFs). The diverse developmental mechanisms giving rise to these epithelial organs involve many organ-specific GFs, but a unifying paradigm during organogenesis is the regulation of GF activity by heparan sulfates (HS) on the cell surface and in the ECM. This primarily involves the interactions of GFs with the sulfated side-chains of HS proteoglycans. HS is one of the most diverse biopolymers and modulates GF binding and signaling at the cell surface and in the ECM of all tissues. Here, we review what is known about how HS regulates branching morphogenesis of epithelial organs with emphasis on the developing salivary gland, which is a classic model to investigate epithelial-ECM interactions. We also address the structure, biosynthesis, turnover and function of HS during organogenesis. Understanding the regulatory mechanisms that control HS dynamics may aid in the development of therapeutic interventions for diseases and novel strategies for tissue engineering and regenerative medicine.

Proteoglycans as Immunomodulators of the Innate Immune Response to Lung Infection

“…The influence of HSPGs in lung development has been extensively reviewed. [8][9][10] In healthy adult human lungs, the total amounts of chondroitin sulfate/dermatan sulfate (CS/DS), HA, and HS were found to be equal. 11 Not as much is known about the importance of CS, DS, or keratan sulfate (KS) PGs in lung morphogenesis.…”

Novel Insights into the Pathogenesis of Monogenic Congenital Anomalies of the Kidney and Urinary Tract

“…43,93,100 Overall, the multitude of murine and human disease phenotypes that occur as result of disturbances in HSPG biosynthesis provides important insight into the mechanisms involved (Supplemental Figure 3, Supplemental Table 3). 117,118 However, although for some HS-relevant enzymes, there are strong loss-of-function phenotypes in animal models, mouse models for other HS-related ECM components (e.g., mouse models with a knockout of HPSE function) do not result in overt defects, thereby suggesting a redundancy of certain HS enzymes and HSPGs in the ECM that allow for a functional compensation. 96,119,120 This hypothesis, however, remains to be validated Table 4).…”

Epigenetic Regulation of the Biosynthesis & Enzymatic Modification of Heparan Sulfate Proteoglycans: Implications for Tumorigenesis and Cancer Biomarkers

“…HSPGs are involved in the development of the basement membrane barrier, providing a framework for epithelial support, regulating transport of solutes, and promoting the extravasation of cells during inflammatory responses [ 23 , 25 , 26 , 27 ]. HSPGs that are located at the cell surface are also involved in the establishment of morphogen and chemokine gradients important in WBC extravasation, but are also vital during development [ 28 , 29 , 30 ]. HSPGs located within secretory vesicles are involved in the packaging of vesicular contents, maintenance of protease activity, and regulating various activities upon secretion, such as host defense mechanisms and wound repair (e.g., [ 22 , 31 , 32 , 33 ]).…”