Spermidine Boosts Bone Stem Cell Regeneration by Rewiring Epigenetic Autophagy

Bone loss driven by chronic jaw inflammation is a significant clinical problem, often stemming from impaired osteogenic (bone-forming) capacity in bone marrow mesenchymal stem cells (BMSCs). Understanding what metabolic disruptions underlie this impairment is key to developing new treatments.

This study used comprehensive targeted metabolomics to compare BMSC metabolism during osteogenic differentiation under normal versus lipopolysaccharide (LPS)-induced inflammatory conditions. A striking finding was the significant downregulation of spermidine (SPD), a naturally occurring polyamine found in foods like wheat germ, soybeans, and aged cheese, along with methylated purines and pyrimidines, in the inflammatory environment.

When exogenous SPD was supplemented, it rescued osteogenic differentiation and increased N6-methyladenosine (m6A) RNA methylation — an important epigenetic modification regulating gene expression. Mechanistically, SPD elevated levels of S-adenosylmethionine (SAM), the primary methyl donor in cells, and upregulated the RNA methyltransferases METTL3 and METTL14. Betaine, a known promoter of SAM synthesis, produced similar effects. Conversely, blocking METTL3/METTL14 with S-adenosylhomocysteine (SAH) reduced m6A methylation and abolished SPD's osteogenic benefits. SPD also activated autophagy in BMSCs, and this autophagy induction was likewise blocked by SAH but rescued by rapamycin, establishing a clear m6A methylation-autophagy axis.

In vivo experiments using a rat model of inflammatory mandibular bone defects confirmed that SPD supplementation enhanced m6A methylation and accelerated bone regeneration.

These findings position spermidine as a metabolic regulator of epigenetic and autophagic processes critical for bone repair. Caveats include reliance on LPS-induced inflammation as a simplified model and the preclinical nature of in vivo data, requiring human validation before clinical translation.