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Review
. 2017 Jan:57-58:311-323.
doi: 10.1016/j.matbio.2016.09.004. Epub 2016 Sep 6.

The function of heparan sulfate during branching morphogenesis

Vaishali N Patel  1 , Dallas L Pineda  1 , Matthew P Hoffman  2
Affiliations
Review

The function of heparan sulfate during branching morphogenesis

Vaishali N Patel et al. Matrix Biol. 2017 Jan.

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.

Keywords: Branching morphogenesis; Extracellular matrix; FGF10; FGFR2b; Growth factors; Heparan sulfate; Heparan sulfate 3-O-sulfotransferase.

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Figures

Fig. 1
Fig. 1
The BM separates epithelial cells from mesenchyme during SMG branching morphogenesis and contains HS that binds growth factors and viral receptors. (A) Whole-mount staining of E14 SMG showing perlecan staining the BM (red) surrounding the branching epithelium, and nuclei (green). Images are 10 μm confocal projections. Scale bar: 100 μm. (B) Higher magnification of the SMG endbud shows that FGF10/rFGFR2b-Fc (LACE assay, green) binds the endogenous HS at the epithelial cell surface and colocalizes with perlecan (red) in BM. Images are single confocal sections. Scale bar: 10 μm. (C) The endbud HS also binds the viral receptor HSV-1 gD285 protein (green) at the epithelial cell surface and colocalizes with perlecan (red) in BM. Images are single 2 μm confocal sections. Scale bar: 10 μm.
Fig. 2
Fig. 2
HSPGs are differentially expressed during SMG branching morphogenesis. The epithelium and mesenchyme of E13 SMGs were separated by dispase, and the relative expression of HSPGs was compared in epithelium and mesenchyme by qPCR analysis. Gene expression was normalized to Rps29. Cdh1 and Fgf10 serve as controls for the separation of the epithelium and mesenchyme, respectively. Agrn, Col18a1, Gpc4 and Sdc4 are mainly expressed in the epithelium, whereas Gpc2, Gpc3, and Gpc6 are mainly expressed in the mesenchyme.
Fig. 3
Fig. 3
HS sulfotransferase isoform expression is developmentally regulated during SMG organogenesis. Graphs show the relative expression in arbitrary units (AU x 100) of sulfotransferase isoforms expressed in the SMG at 12 different stages from E11.5 to adult. Interestingly, Hs3st1, Hs3st3a1 and Hs3st3b1 expression peaks during stages when branching morphogenesis peaks. Gene expression was obtained using Agilent microarrays. Gene expression profiles are available online at http://sgmap.nidcr.nih.gov. AdtF, adult female; AdtM, adult male; E, embryonic day; D, postnatal day.
Fig. 4
Fig. 4
3-O-sulfated-HS increases FGF10-dependent epithelial morphogenesis by increasing proliferation. E13 SMG epithelia were cultured in a 3D laminin matrix and treated with FGF10 and either HS with low endogenous 3-O-sulfation or 3-O-sulfated-HS for 28 hr. Epithelia were were stained for K14 (red), K19 (green), and Ki67 (cyan). Images are confocal projections. Scale bars: 100 μm.
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