IRX5 promotes adipogenesis of hMSCs by repressing glycolysis

Area of Science:

• Cell Biology
• Stem Cell Biology
• Molecular Biology

Background:

• Iroquois homeobox transcription factor 5 (IRX5) is known to influence extramedullary adipogenesis.
• The specific role of IRX5 in the adipogenesis of human bone marrow-derived mesenchymal stem cells (hMSCs) remains largely uncharacterized.

Purpose of the Study:

• To investigate the effect of IRX5 on the adipogenic differentiation of hMSCs.
• To elucidate the molecular mechanisms by which IRX5 regulates hMSC adipogenesis.

Main Methods:

• Quantitative PCR (qPCR) to assess IRX5 expression levels.
• Gain- and loss-of-function studies using lentiviral vectors to manipulate IRX5 levels in hMSCs.
• RNA sequencing (RNA-seq) and metabolomics to analyze global gene expression and metabolic changes.
• Dual-luciferase reporter assays to confirm transcriptional regulation.

Main Results:

• IRX5 expression was significantly upregulated during the adipogenic commitment of hMSCs.
• Overexpression of IRX5 enhanced hMSC adipogenesis, while IRX5 knockdown inhibited it.
• IRX5 overexpression led to the repression of glycolysis and transcriptional activation of peroxisome proliferator-activated receptor gamma coactivator (PGC-1α).
• Metformin and a PGC-1α inhibitor counteracted the effects of IRX5 overexpression on adipogenesis and glycolysis.

Conclusions:

• IRX5 acts as a positive regulator of adipogenic differentiation in hMSCs.
• IRX5 facilitates hMSC adipogenesis by transcriptionally activating PGC-1α and concurrently inhibiting glycolysis.
• IRX5 represents a potential therapeutic target for modulating bone marrow-derived mesenchymal stem cells (BMSCs) fate and maintaining bone homeostasis.