A mechanoresponsive PINCH ‐1‐Notch2 interaction regulates smooth muscle differentiation of human placental mesenchymal stem cells

This study shows that in response to mechanical cues from ECM, PINCH‐1 interaction with Notch2 is increased, which inhibits Notch2 degradation and consequently augments Notch2 signaling and smooth muscle differentiation. AbstractExtracellular matrix (ECM) stiffness plays an important role in the decision making process of smooth muscle differentiation of mesenchymal stem cells (MSCs) but the underlying mechanisms are incompletely understood. Here we show that a signaling axis consisting of PINCH ‐1 and Notch2 is critically involved in mediating the effect of ECM stiffness on smooth muscle differentiation of MSCs. Notch2 level is markedly increased in ECM stiffness‐induced smooth muscle differentiation of human placental MSCs. Knockdown of Notch2 from human placental MSCs effectively inh ibits ECM stiffness‐induced smooth muscle differentiation, whereas overexpression of North intracellular domain (NICD2) is sufficient to drive human placental MSC differentiation toward smooth muscle cells. At the molecular level, Notch2 directly interacts with PINCH‐1. The interaction of Notch2 with PINCH‐1 is significantly increased in response to ECM stiffness favoring smooth muscle differentiation. Furthermore, depletion of PINCH‐1 from human placental MSCs reduces Notch2 level and consequently suppresses ECM stiffness‐induced smooth muscle differentiation. Re‐expression of PIN CH‐1, but not that of a Notch2‐binding defective PINCH‐1 mutant, in PINCH‐1 knockdown h...
Source: Stem Cells - Category: Stem Cells Authors: Tags: ORIGINAL RESEARCH Source Type: research