CDH2 and CDH11 act as regulators of stem cell fate decisions

Abstract

Accumulating evidence suggests that the mechanical and biochemical signals originating from cell-cell adhesion are critical for stem cell lineage specification. In this review, we focus on the role of cadherin mediated signaling in development and stem cell differentiation, with emphasis on two well-known cadherins, cadherin-2 (CDH2) (N-cadherin) and cadherin-11 (CDH11) (OB-cadherin). We summarize the existing knowledge regarding the role of CDH2 and CDH11 during development and differentiation in vivo and in vitro. We also discuss engineering strategies to control stem cell fate decisions by fine-tuning the extent of cell-cell adhesion through surface chemistry and microtopology. These studies may be greatly facilitated by novel strategies that enable monitoring of stem cell specification in real time. We expect that better understanding of how intercellular adhesion signaling affects lineage specification may impact biomaterial and scaffold design to control stem cell fate decisions in three-dimensional context with potential implications for tissue engineering and regenerative medicine.

Figure 1. Schematic representation of cadherin structure and downstream signaling

Cadherins contain five extra cellular (EC) domains linked by Ca²⁺ binding sites and one intracellular domain. Classical cadherin partners include to β-catenin, which binds to α-catenin linking the AJ complex to the actin cytoskeleton, as well as p120 catenin, which regulates small GTPases such as Rho, Rac, and Cdc42. Ultimately, cadherin engagement regulates many cellular processes including proliferation, migration and stem cell differentiation.

Figure 2. Schematic representation of CDH2 and CDH11 expression during MSC lineage commitment

CDH2 and CDH11 expression levels during MSC commitment, differentiation and maturation towards (A) Osteogenic; (B) Chondrogenic; (C) Adipogenic; or (D) Myogenic Lineages. Upward or downward pointing arrows indicate increased or decreased expression, respectively.

Figure 3. CDH11 mediated AJ formation promotes MSC differentiation into SMC [9]

(A) Engagement of CDH11 activates the ROCK pathway, which in turn activates SRF leading to increased expression of SMC genes. (B) SRF controls the level of CDH11 expression through a positive feedback loop further promoting intercellular adhesion. (C) CDH11 engagement also increases TGF-β1 expression further promoting SMC differentiation (D) through a Smad2/3 independent pathway.