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.

journal_name

Mol Biol Cell

authors

Belmonte JM,Clendenon SG,Oliveira GM,Swat MH,Greene EV,Jeyaraman S,Glazier JA,Bacallao RL

doi

10.1091/mbc.E16-01-0059

subject

Has Abstract

pub_date

2016-11-07 00:00:00

pages

3673-3685

issue

22

eissn

1059-1524

issn

1939-4586

pii

mbc.E16-01-0059

journal_volume

27

pub_type

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