Duffield Lab

FEATURED PUBLICATIONS

Fate Tracing Reveals the Pericyte and Not Epithelial Origin of Myofibroblasts in Kidney Fibrosis

Deficient Autophagy Results in Mitochondrial Dysfunction and FSGS

Cellular and Molecular Mechanisms in Kidney Fibrosis

Anti-microRNA-21 Oligonucleotides Prevent Alport Nephropathy Progression by Stimulating Metabolic Pathways

LRP-6 is a Coreceptor for Multiple Fibrogenic Signaling Pathways in Pericytes and Myofibroblasts That are Inhibited by DKK-1

Dicer1 Activity in the Stromal Compartment Regulates Nephron Differentiation and Vascular Patterning During Mammalian Kidney Organogenesis

Lab Publications

Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N-cadherin balance in mural cell-endothelial cell-regulated barrier function.

Three-dimensional biomimetic vascular model reveals a RhoA, Rac1, and N-cadherin balance in mural cell-endothelial cell-regulated barrier function.

Proc Natl Acad Sci U S A. 2017 08 15;114(33):8758-8763

Authors: Alimperti S, Mirabella T, Bajaj V, Polacheck W, Pirone DM, Duffield J, Eyckmans J, Assoian RK, Chen CS

Abstract
The integrity of the endothelial barrier between circulating blood and tissue is important for blood vessel function and, ultimately, for organ homeostasis. Here, we developed a vessel-on-a-chip with perfused endothelialized channels lined with human bone marrow stromal cells, which adopt a mural cell-like phenotype that recapitulates barrier function of the vasculature. In this model, barrier function is compromised upon exposure to inflammatory factors such as LPS, thrombin, and TNFα, as has been observed in vivo. Interestingly, we observed a rapid physical withdrawal of mural cells from the endothelium that was accompanied by an inhibition of endogenous Rac1 activity and increase in RhoA activity in the mural cells themselves upon inflammation. Using a system to chemically induce activity in exogenously expressed Rac1 or RhoA within minutes of stimulation, we demonstrated RhoA activation induced loss of mural cell coverage on the endothelium and reduced endothelial barrier function, and this effect was abrogated when Rac1 was simultaneously activated. We further showed that N-cadherin expression in mural cells plays a key role in barrier function, as CRISPR-mediated knockout of N-cadherin in the mural cells led to loss of barrier function, and overexpression of N-cadherin in CHO cells promoted barrier function. In summary, this bicellular model demonstrates the continuous and rapid modulation of adhesive interactions between endothelial and mural cells and its impact on vascular barrier function and highlights an in vitro platform to study the biology of perivascular-endothelial interactions.

PMID: 28765370 [PubMed - indexed for MEDLINE]