Provisional matrix: A role for versican and hyaluronan

Abstract

Hyaluronan and versican are extracellular matrix (ECM) components that are enriched in the provisional matrices that form during the early stages of development and disease. These two molecules interact to create pericellular "coats" and "open space" that facilitate cell sorting, proliferation, migration, and survival. Such complexes also impact the recruitment of leukocytes during development and in the early stages of disease. Once thought to be inert components of the ECM that help hold cells together, it is now quite clear that they play important roles in controlling cell phenotype, shaping tissue response to injury and maintaining tissue homeostasis. Conversion of hyaluronan-/versican-enriched provisional matrix to collagen-rich matrix is a "hallmark" of tissue fibrosis. Targeting the hyaluronan and versican content of provisional matrices in a variety of diseases including, cardiovascular disease and cancer, is becoming an attractive strategy for intervention.

Keywords: Development; Extracellular matrix; Glycocaylx; Hyaluronan; Leukocytes; Remodeling; Versican.

Figure 1

ECM transitions in the pericellular matrix required for cell shape changes in r cell proliferation and migration. Growth factors such as PDGF and/or TGF-β stimulate arterial smooth muscle cells to produce hyaluronan and versican which interact and expand the tissue space by entrapping water. Reprinted from Advanced Drug Delivery Reviews, Volume 59, Evanko SP, Tammi, MI, Tammi, RH, Wight, TN. Hyaluronan-dependent pericellular matrix, pages 1351–65, Copyright 2007, with permission from Elsevier.

Figure 2

(A) Pericellular hyaluronan cables. Recombinant G1 domain of versican (red) was added to cultured human dermal fibroblasts and the cultures stained for hyaluronan (green). The G1 domain bound to the hyaluronan strands causing them to aggregate (yellow). These cable-like strands were observed connecting adjacent cells in a perinuclear distribution. (B) Pericellular hyaluronan/versican cables bind leukocytes. Adhesion of T lymphocytes (purple) to a hyaluronan (red)/versican (green)-enriched cable in the pericellular matrix of fibroblasts. Panel A is reprinted from Merrilees MJ, Zuo N, Evanko SP, Day AJ, Wight TN. G1 domain of versican regulates hyaluronan organization and the phenotype of cultured human dermal fibroblasts. J Histochem Cytochem. 64:353–363, 2016. Panel B is reprinted from Biochimica et Biophysica Acta (BBA) - General Subjects, Vol. 1840, Issue 8, Wight TN, Kinsella MG, Evanko SP, Potter-Perigo S, Merrilees MJ. Versican and the regulation of cell phenotype in disease, pages 2441–2451, Copyright 2014, with permission from Elsevier.

Figure 3

Video microscopic images of migrating (A, B, C) and dividing (D-G) human vascular smooth muscle cells treated with PDGF. Fixed red blood cells (particles) have been added to the living culture and are being excluded from the pericellular matrix by the viscoelastic versican/hyaluronan matrix. The formation of this matrix facilitates cell shape change and is permissive for cell proliferation and migration. Reprinted from Chemistry and Biology of Hyaluronan, Garg HG, Hales CA, eds. Wight TN, Evanko S, Kolodgie F, Farb A, Virmani R, Chapter 14, Hyaluronan in atherosclerosis and restenosis, pages 307–321, Copyright 2004, with permission from Elsevier.

Figure 4

Hyaluronan accumulates in blood vessels following balloon angioplasty. Rat carotid artery stained for hyaluronan (red) and proliferative cell nuclear antigen (brown). (A) Uninjured. Hyaluronan is confined to the adventitia with little to no staining for PCNA. (B) 3 days after balloon injury, positive PCNA staining appears in the media surrounded by hyaluronan staining (red). (C) By 7 days, a neointima has formed consisting of PCNA-positive cells in a “sea” of hyaluronan (red). Versican is also present with hyaluronan, but little to no collagen or elastic fibers are present. (D) A section of a human coronary restenotic lesion retrieved 3 months after angioplasty and doubled stained for PCNA (brown) and hyaluronan (red). This myxoid ECM is also enriched in versican (not shown) with little to no collagen or elastic fibers present. Originally published in Circulation. Riessen R, Wight TN, Pastore C, Henley C, Isner JM. Distribution of hyaluronan during extracellular remodeling in human restenotic arteries and balloon-injured rat carotid arteries. Circulation. 1996; 93:1141–1147. Wolters Kluwer Health Lippincott Williams & Wilkins©.

Figure 5

Versican in tumor provisional matrix. (A) Section of normal human myometrium stained for versican showing no staining. (B) Grade 2 leiomyosarcoma stained for versican (brown) showing extensive immunostaining. (C) Northern blot analyses showing enrichment for the versican signal in the tumor compared to control. (D–F) Leiomyosarcoma smooth muscle (LMS) cells in culture treated with fixed red blood cells to image the pericellular matrix. (D) The LMS cells exhibit extensive pericellular coats. E. Pericellular matrix of the LMS cells after treatment with siRNA to versican. (F) LMS pericellular coat 24 hours after adding back versican to cells shown in B. (G) Tumor growth in a mouse model of LMS using LMS cells treated or not treated with siRNA to versican. This figure shows reduced tumor growth in the animals receiving siRNA versican LMS cells. This research was originally published in Journal of Biological Chemistry. Keire PA, Bressler SL, Lemire JM, Edris B, Rubin BP, Rahmani M, McManus BM, van de Rijn M, Wight TN. A role for versican in the development of leiomyosarcoma. J Biol Chem. 2014; 289:34089–103. © by the American Society for Biochemistry and Molecular Biology.

Figure 6

Impact of hyaluronan on synthesis and accumulation of fibronectin and collagen. TGFβ1-treated myofibroblasts were left untreated (A) or treated with 4-MU (B), hyaluronan oligosaccharides (C) or Streptomyces hyaluronidase (D) for 4 days. Cultures were stained for fibronectin (red) and hyaluronan (green). Parallel cultures undergoing the same treatments were evaluated for collagen I (E) and fibronectin (F) gene expression using qRT-PCR. Results indicate that chronic removal of HA from TGF-β1-treated myofibroblasts increases their fibrotic response by promoting collagen and fibronectin synthesis and accumulation. Reprinted from Matrix Biology, Vol. 42, Evanko SP, Potter-Perigo S, Petty LJ, Workman GA, Wight TN, Hyaluronan controls the deposition of fibronectin and collagen and modulates TGF-β1 induction of lung myofibroblasts, Pages 74–92, Copyright (2015), with permission from Elsevier.