Hemicentin-1 is an essential extracellular matrix component of the dermal\u2013epidermal and myotendinous junctions

Daniela Welcker,Sabine A Eming,Joy Armistead,Jin-Li Zhang,Jens C Brüning,Steffen Lütke,Cornelia Stein,Anja Niehoff,Matthias Hammerschmidt,Natalia Martins Feitosa,Andre Kleinridders,Wilhelm Bloch,Gerhard Sengle

doi:10.1038/s41598-021-96824-4

Abstract

The extracellular matrix architecture is composed of supramolecular fibrillar networks that define tissue specific cellular microenvironments. Hemicentins (Hmcn1 and Hmcn2) are ancient and very large members (> 600 kDa) of the fibulin family, whose short members are known to guide proper morphology and functional behavior of specialized cell types predominantly in elastic tissues. However, the tissue distribution and function of Hemicentins within the cellular microenvironment of connective tissues has remained largely unknown. Performing in situ hybridization and immunofluorescence analyses, we found that mouse Hmcn1 and Hmcn2 show a complementary distribution throughout different tissues and developmental stages. In postnatal dermal–epidermal junctions (DEJ) and myotendinous junctions (MTJ), Hmcn1 is primarily produced by mesenchymal cells (fibroblasts, tenocytes), Hmcn2 by cells of epithelial origin (keratinocytes, myocytes). Hmcn1−/− mice are viable and show no overt phenotypes in tissue tensile strength and locomotion tests. However, transmission electron microscopy revealed ultrastructural basement membrane (BM) alterations at the DEJ and MTJ of Hmcn1−/− mice, pointing to a thus far unknown role of Hmcn1 for BM and connective tissue boundary integrity.

Highlights

The extracellular matrix architecture is composed of supramolecular fibrillar networks that define tissue specific cellular microenvironments
The fibulin family of extracellular matrix (ECM) proteins is of particular interest in this regard since they surround cells in close proximity to basement membranes (BMs) and the elastic fiber network, thereby guiding proper morphology and functional behavior of specialized cell types[1,2,3,4]
More recent studies using planarians as a highly regenerative and long-lived organism, nicely demonstrated that hmcn made by muscle cells as the main source of ECM proteins is required for BM integrity

Summary

Introduction

The extracellular matrix architecture is composed of supramolecular fibrillar networks that define tissue specific cellular microenvironments. Most functional investigations have been carried out in the nematode C. elegans where only one hemicentin (hmcn) gene is known, referred to as him-46–8 These studies point to pleiotropic roles of hmcn in transient cell contacts that are required for cell migration and basement membrane invasion, as well as in stable contacts at hemidesmosome-mediated cell junctions and elastic fiber-like s tructures[6,7]. Synergistic enhancement with specific antisense morpholino oligonucleotides (MOs) further showed that neither the hmcn[1] nor the fbn[2] MO-mediated knock-down alone elicited a phenotype at low MO doses, when combined, they generated fin blisters similar to hmcn[1] mutants These data strongly suggest that hmcn[1] and fbn[2] functionally interact during zebrafish fin development in vivo to allow proper fin DEJ formation and tissue linkage[14]. Hmcn2/fbln[1] double knock-down fish displayed impaired migration of fin mesenchymal cells into the fin folds, pointing to a crucial role of hmcn[2] and fbln[1] to remodel the ECM in the interepidermal space of the fin fold as a prerequisite for fibroblast ingrowth

Methods

Results

Conclusion