title: Virtual-tissue computer simulations define the roles of cell adhesion and proliferation in the onset of kidney cystic disease.
abstract: In autosomal dominant polycystic kidney disease (ADPKD), cysts accumulate and progressively impair renal function. Mutations in PKD1 and PKD2 genes are causally linked to ADPKD, but how these mutations drive cell behaviors that underlie ADPKD pathogenesis is unknown. Human ADPKD cysts frequently express cadherin-8 (cad8), and expression of cad8 ectopically in vitro suffices to initiate cystogenesis. To explore cell behavioral mechanisms of cad8-driven cyst initiation, we developed a virtual-tissue computer model. Our simulations predicted that either reduced cell-cell adhesion or reduced contact inhibition of proliferation triggers cyst induction. To reproduce the full range of cyst morphologies observed in vivo, changes in both cell adhesion and proliferation are required. However, only loss-of-adhesion simulations produced morphologies matching in vitro cad8-induced cysts. Conversely, the saccular cysts described by others arise predominantly by decreased contact inhibition, that is, increased proliferation. In vitro experiments confirmed that cell-cell adhesion was reduced and proliferation was increased by ectopic cad8 expression. We conclude that adhesion loss due to cadherin type switching in ADPKD suffices to drive cystogenesis. Thus, control of cadherin type switching provides a new target for therapeutic intervention.
authors.affiliation: Biocomplexity Institute, Physics Department, Indiana University, Bloomington, IN 47405 rbacalla@iu.edu jmbelmon@indiana.edu.
authors.forename: Julio M
authors.initials: JM
authors.lastname: Belmonte
authors.affiliation: Biocomplexity Institute, Physics Department, Indiana University, Bloomington, IN 47405.
authors.forename: Sherry G
authors.initials: SG
authors.lastname: Clendenon
authors.affiliation: Biocomplexity Institute, Physics Department, Indiana University, Bloomington, IN 47405.
authors.forename: Guilherme M
authors.initials: GM
authors.lastname: Oliveira
authors.affiliation: Biocomplexity Institute, Physics Department, Indiana University, Bloomington, IN 47405.
authors.forename: Maciej H
authors.initials: MH
authors.lastname: Swat
authors.affiliation: Division of Nephrology, Richard L. Roudebush VA Medical Center, and Indiana University School of Medicine, Indianapolis, IN 46202.
authors.forename: Evan V
authors.initials: EV
authors.lastname: Greene
authors.affiliation: Biocomplexity Institute, Physics Department, Indiana University, Bloomington, IN 47405.
authors.forename: Srividhya
authors.initials: S
authors.lastname: Jeyaraman
authors.affiliation: Biocomplexity Institute, Physics Department, Indiana University, Bloomington, IN 47405.
authors.forename: James A
authors.initials: JA
authors.lastname: Glazier
authors.affiliation: Division of Nephrology, Richard L. Roudebush VA Medical Center, and Indiana University School of Medicine, Indianapolis, IN 46202 rbacalla@iu.edu jmbelmon@indiana.edu.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bacallao
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000502:physiology; D003198:Computer Simulation / Q000706:statistics & numerical data*; D003560:Cysts / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D009154:Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C112316:CDH8 protein, human; D015820:Cadherins