Yes-associated protein 1 regulates proliferation of mesenchymal stem cells by regulating the β-catenin signaling pathway

Abstract

Objectives: The
placenta and umbilical cord are preeminent candidate sources of mesenchymal
stem cells (MSCs). However, placenta-derived MSCs (P-MSCs) showed greater proliferation
capacity than umbilical cord-derived MSCs (UC-MSCs) in our study. We
investigated the drivers of this proliferation difference and elucidated the
mechanisms of proliferation regulation.

Materials and Methods: Proteomic profiling and Gene Ontology (GO)
functional enrichment were conducted to identify candidate proteins that may
influence proliferation. Using lentiviral or small interfering RNA infection,
we established overexpression and knockdown models and observed changes in cell
proliferation to examine whether a relationship exists between the candidate
proteins and proliferation capacity. Real-time quantitative polymerase chain
reaction, western blotting, and immunofluorescence assays were conducted to
elucidate the mechanisms underlying proliferation.

Results: Six candidate proteins were selected based on the results of proteomic profiling
and GO functional enrichment. Through further validation, Yes-associated
protein 1 (YAP1) and β-catenin were confirmed to affect MSC proliferation
rates. YAP1 and β-catenin showed increased nuclear co-localization
during cell expansion. YAP1 overexpression significantly enhanced proliferation capacity and upregulated
the expression of both β-catenin and the transcriptional targets of Wnt signaling,
CCND1 and c-MYC, whereas silencing β-catenin attenuated this effect. We found
that YAP1 directly interacts with β-catenin in the nucleus to form a
transcriptional YAP/β-catenin/TCF4 complex.

Conclusions: Our
study revealed that YAP1 and β-catenin cause the different proliferation
capacities of P-MSCs and UC-MSCs. Mechanism analysis showed that YAP1
stabilized the nuclear β-catenin protein, and also triggered the Wnt/β-catenin
pathway, promoting proliferation.