New insights into the pathobiology of Down syndrome – hyaluronan synthase‐2 overexpression is regulated by collagen VI α2 chain

Abstract

Down syndrome (DS) is a common birth defect characterized by the trisomy of chromosome 21. DS-affected umbilical cords (UCs) of fetuses show altered architecture of the extracellular matrix. Overexpression of the chromosome 21 genes encoding the collagen type VI (COLVI) chains a1 (VI) and a2(VI), COL6A1 and COL6A2, respectively, has also reported to occur in the nuchal skin of DS fetuses. The aim of this study was therefore to evaluate the COLVI content in euploid and DS-affected UCs and human skin fibroblasts, and to investigate the relationships between COL-VI and hyaluronan (HA) and HA synthase-2 (HAS2). We found that the UCs of DS fetuses showed denser staining of COLVI and increased COL6A2 expression at both early and term gestational ages. In vitro expression studies in DS-derived fibroblasts showed similarly increased amounts of a1(VI) and a2(VI) chains at the protein and transcriptional level, supporting the hypothesis of the gene dosage effect. Furthermore, increased levels of HA and HAS2 were also found in DS-derived skin fibroblast cultures. Notably, silencing of COL6A2 in DS-derived cells resulted in downregulation of HAS2, with a simultaneous decrease in secreted HA. Exogenous addition of COLVI to normal fibroblasts did not have any effect on HAS2 expression. In conclusion, UCs and skin fibroblasts in DS show significant increases in COLVI and HA; the overexpression of COL6A2 in DS tissue and cells is closely related to the increased expression of HAS2. These data may explain the DS phenotypes and their effects in organ tissue maturation.

Extracellular Matrix and Dermal Fibroblast Function in the Healing Wound

“…Interestingly, dermal fibroblasts isolated from patients with trisomy 21 show increased expression of collagen VI, greater adherence to collagen VI, and also increased hyaluronan (HA) synthase correlated to the overexpression of collagen VI. 77,78 These facts, coupled with the progeroid skin aging and sometimes impaired healing of surgical wounds characteristic of trisomy 21, could provide future avenues of study. 79 Collagen VII has been shown to support dermal fibroblast migration and, in addition, regulates cytokine expression in wound-infiltrating macrophages.…”

Collagen VI and Hyaluronan: The Common Role in Breast Cancer

“…In addition, overexpression of COL6A1 and COL6A2 and higher synthesis of collagen VI have been observed in the umbilical cord and the ECM of the skin fibroblasts from foetuses and individuals, respectively, affected with trisomy 21 [57, 58]. As it will be discussed below, alterations in collagen VI and especially ETP peptide demonstrate a crucial role in breast cancer progression [59, 60].…”

Disseminate Recurrent Folliculitis and Hidradenitis Suppurativa Are Associated Conditions: Results From a Retrospective Study of 131 Patients With Down Syndrome and a Cohort of 12,351 Pediatric Controls

“…In fact, in the HS+ control group a female-to-male ratio of 1 [24,25]. Type VI collagen is an extracellular matrix molecule abundantly expressed in the dermis, which plays a key role in the processes of hair follicle cycling and wound healing, tissue repair through the regulation of the dermal matrix assembly, and fibroblastic motility [24,26]. It has a heterotrimeric structure, consisting of 3 distinct polypeptide chains: α1, α2, and α3.…”