Increased adhesiveness of trisomy 21 cells and atrioventricular canal malformations in Down syndrome: a stochastic model.
Based on the finding that fetal trisomy 21 fibroblasts explanted from lungs and endocardial-cushion-derived structures appear more adhesive in vitro than those from normal control individuals, we present a stochastic model for atrioventricular (AV) canal malformations in Down syndrome (DS). Computer simulations were performed to model the normal anatomic sequences of cushion-to-cushion and cushion-to-septum fusion in AV canal development. In these simulations, random-walking endocardial cells were allowed to migrate, divide, and adhere with programmable probabilities. Low values of intercellular adhesiveness engendered simulations resembling normal AV canal development; higher values of adhesiveness yielded deficiencies of AV canal development as seen in DS. Moderately high levels of adhesiveness resulted in abnormalities in only a proportion of multiple, independently performed simulations. The model successfully predicts the temporospatial sequence of anatomic events in cushion-to-septum fusion, clinical variability among individuals with the same genotype based on chance alone, and amplified developmental instability as observed in individuals with DS.
Kurnit
D M
DM
Aldridge
J F
JF
Matsuoka
R
R
Matthysse
S
S
D002448:Cell Adhesion; D002465:Cell Movement; D003201:Computers; D004314:Down Syndrome / Q000473:pathology*; D004694:Endocardial Cushion Defects / Q000196:embryology / Q000473:pathology*; D005347:Fibroblasts / Q000473:pathology*; D006321:Heart / Q000196:embryology; D006343:Heart Septal Defects / Q000473:pathology*; D006345:Heart Septal Defects, Ventricular / Q000196:embryology / Q000473:pathology*; D006801:Humans; D008954:Models, Biological; D013269:Stochastic Processes