Beta 1 integrin activation mediates adhesive differences between trisomy 21 and non‐trisomic fibroblasts on type VI collagen

Abstract

Trisomy 21 (Down syndrome) is a common genetic condition with a high incidence of congenital heart defects (CHD), particularly those involving abnormal development of the embryonic atrioventricular (AV) canal. Type VI collagen (Col VI) is expressed in the developing AV canal extracellular matrix, and has been associated with trisomy 21 AV canal defects in human genetic studies. Although the molecular mechanisms linking Col VI and trisomy 21 AV canal defects are not well understood, a computer model predicts increased cell adhesiveness is responsible for these CHD. We compared integrin-mediated cell adhesive properties for skin fibroblasts isolated from trisomy 21 and non-trisomic individuals on Col VI, fibronectin (FN) and type I collagen (Col I). Cell lines demonstrate similar adhesion profiles to FN and Col I, but all trisomy 21 cells display increased adhesive capacity for Col VI compared to non-trisomic fibroblasts. Cell adhesion to type VI collagen was shown to be GRGDS independent, but beta(1) integrin family dependent. Function-blocking antibodies identified alpha(3)beta(1) as the predominant integrin mediating trisomy 21 and non-trisomic skin fibroblast adhesion on Col VI. Trisomy 21 and non-trisomic fibroblasts display similar expression levels for each of the integrin receptors examined. A beta(1) integrin-activating antibody augments non-trisomic cell adhesion on Col VI, but has no effect upon trisomy 21 fibroblasts. These results demonstrate that beta(1) integrin family members mediate trisomy 21 and non-trisomic skin fibroblast adhesion for Col VI. Altered activation state of the beta(1) integrin is a mechanism responsible for increased trisomy 21 cell adhesion on Col VI.

Cell line differences in bacterially translocated ExoS ADP-ribosyltransferase substrate specificity

“…In comparing the efficiency of ExoS internalization in the two cell types, ExoS was found to be translocated as (or slightly more) efficiently in murine fibroblasts when compared to human epithelial cells, supporting that view that the TTS apparatus was functional in murine fibroblasts. Consistent with the translocation of ExoS through the membrane into cytosol via the TTS apparatus, levels of ExoS ADPRT activity and the efficiency of substrate modification were higher in membrane than cytoplasmic fractions of all cell lines, as has been recognized previously (Fraylick et al, 2001;Riese & Barbieri, 2002 (Govoni et al, 1996;Jongewaard et al, 2002). In assessing the role of viral or oncogenic transformation in ADPRT substrate modification, no alterations in patterns were detected in any of the cell lines in association with cellular transformation.…”

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.…”

Down's syndrome protects against breast cancer: Is a constitutional cell microenvironment the key?

“…Trisomy 21 fibroblasts have migration anomalies due to abnormal cell adhesivity and membrane fluidity anomalies. 15,16 Differences in the composition of connective tissue ECM have also been reported both in utero and after birth, particularly for Types I, II, V and VI collagen, for hyaluronan and for Type II interstitial metalloprotease. 17,18 These differences have been linked to the genes Col 6A 1 , Beta 2 integrin receptor, SOD 2 and IFN gamma that map to chromosome 21.…”