Cadherin-11 is a novel regulator of extracellular matrix synthesis and tissue mechanics

Abstract

We discovered that Cadherin-11 (CDH11) regulates collagen and elastin synthesis, both affecting the mechanical properties and contractile function of animal tissues. Using a Cdh11-null mouse model, we observed a significant reduction in the mechanical properties [Youngs' modulus and ultimate tensile strength (UTS)] of Cdh11 −/− as compared to wild-type (WT) mouse tissues, such as the aorta, bladder and skin. The deterioration of mechanical properties (Youngs' modulus and UTS) was accompanied by reduced collagen and elastin content in Cdh11 −/− mouse tissues as well as in cells in culture. Similarly, knocking down CDH11 abolished collagen and elastin synthesis in human cells, and consequently reduced their ability to generate force. Conversely, engagement of CDH11 through homophilic interactions, led to swift activation of the TGF-β and ROCK pathways as evidenced by phosphorylation of downstream effectors. Subsequently, activation of the key transcription factors, MRTF-A (also known as MKL1) and MYOCD led to significant upregulation of collagen and elastin genes. Taken together, our results demonstrate a novel role of adherens junctions in regulating extracellular matrix (ECM) synthesis with implications for many important biological processes, including maintenance of tissue integrity, wound healing and tissue regeneration.

Cadherin‐11 binds to PDGFRβ and enhances cell proliferation and tissue regeneration via the PDGFR‐AKT signaling axis

“…Specifically, gene expression of CyclinD1 increased by 3400‐fold, cyclin dependent kinases, CDK4, and CDK6 increased by 8‐ and 15‐fold, and transcription factors c‐MYC and E2F1 increased by 10‐ and 20‐fold, respectively (n = 3, P < .05). Interestingly, PDGFRβ gene expression increased by ~15‐fold and CDH11 by ~35‐fold upon CDH11 engagement, in agreement with previous work from our laboratory …”

“…Recently we reported that deficiency of CDH11 results in impaired ECM synthesis by skin fibroblasts in vitro and in vivo . When we examined skin tissues from Cdh11 knockout ( Cdh11 −/− ) and WT mice, we found that the thickness of the dermis was significantly reduced in Cdh11 −/− mice (59 ± 8%, n = 4, P < .05) as compared to their WT counterparts (Figure A,B).…”

“…Mice were euthanized in a standard CO2 chamber and all tissues were immediately harvested and fixed in 10% neutral-buffered formalin for immunohistochemistry as described previously. 22…”

“…Human neonatal foreskin dermal fibroblasts and mouse dermal fibroblasts (mDFs) were isolated from tissues as reported elsewhere. 22 L-cell was received as a gift from Dr. Hazan. All cells were cultured in Dulbecco's Modified eagle medium (DMEM; Thermo Fisher Scientific, Grand Island, NY) supplemented with 1% (v/v) Antibiotic-antimycotic cocktail (Thermo Fisher Scientific) and 10% (v/v) fetal bovine serum (Atlanta Biologicals, Norcross, GA).…”

“…19,20 Fibroblasts play a critical role in wound closure through its contractile function as well as synthesis and remodeling of extracellular matrix (ECM), mainly collagen. Interestingly, loss of CDH11 diminished several key biological functions in smooth muscle, hair follicle, and fibroblast cells, including contractility, 21 migration capacity, 12 and ECM synthesis, 22 ultimately compromising the tissue mechanical properties. CDH11 was also reported to play a role in the response of fibroblasts to inflammatory mediators such as TNF-α.…”