Roles of Msx2 in exogen control: modulating the stem cell niche during the transition from hair shedding to regeneration

Introduction

The exogen phase of the hair follicle cycle, during which club hairs are shed and new hairs emerge, represents a critical transitional step involving distinct structural remodeling and adhesive changes. Despite its fundamental importance, the molecular mechanisms orchestrating exogen remain largely unknown.

Objective

To investigate the role of Msx2 in regulating hair anchoring, hair follicle stem cell (HFSC) lineage commitment, and extracellular matrix (ECM) remodeling during exogen.

Methods

We employed Msx2-knockout (KO) mice, bulk RNA sequencing, and late exogen transcriptome comparisons to identify differentially expressed genes (DEGs) and disrupted pathways. Additionally, protein interaction assays were conducted for functional studies.

Results

Msx2 deficiency mice still form new bulges containing HFSCs for subsequent hair cycles, but this resulted in the failed anchoring of older bulges and club hairs, leading to aberrant hair retention and accelerated hair shedding. Transcriptomic analysis revealed widespread transcriptional reprogramming, particularly in ECM-related genes, with significant overlap between Msx2-KO HFSCs and late exogen DEGs. Msx2-KO mice exhibited downregulated adhesion molecules, disrupted HFSC niche integrity, increased keratinization, and aberrant differentiation in HFSC and hair germ cells. Mechanistically, MSX2 directly interacts with SMAD proteins to regulate TGF-β signaling, thereby modulating ECM gene expression and suppressing HFSC trans-epidermal differentiation.

Conclusions

Our findings establish Msx2 as a master regulator of exogen control, orchestrating hair shedding, HFSC niche stability, and ECM remodeling. This study provides new insights into hair follicle cycling dynamics and identifies Msx2 as a potential therapeutic target for promoting hair regeneration and mitigating alopecia phenotypes.