The Hippo-YAP/TAZ-TEAD axis promotes multipotency in bone marrow stromal cells

Area of Science:

• Stem cell biology
• Molecular and cellular biology

Background:

• Bone marrow stromal cells (BMSCs) possess multipotency, enabling differentiation into various cell types, but the underlying mechanisms maintaining this potential in vitro are not fully understood.
• Identifying the transcriptional regulators governing BMSC multipotency is critical for harnessing their therapeutic potential.

Approach:

• Paired single-nucleus multiomics was employed on freshly isolated BMSCs and those undergoing differentiation.
• Computational reconstruction of regulatory programs identified key transcription factors active during early expansion and differentiation stages.

Key Points:

• The TEAD family of transcription factors, normally inhibited by Hippo signaling, were found to be highly active in the multipotent state of BMSCs in vitro.
• Pharmacological inhibition of TEAD promoted osteogenic and adipogenic differentiation of BMSCs.
• TEAD activation maintained BMSCs in an undifferentiated state, suggesting a TEAD-controlled multipotent state upon isolation.

Conclusions:

• The Hippo signaling pathway and its regulation of TEAD transcription factors play a pivotal role in maintaining BMSC multipotency in vitro.
• The study provides a regulatory network of transcription factors and their targets, offering testable hypotheses for BMSC behavior.