Antimicrobial peptide LL-37 promotes proliferation of human bone marrow-derived mesenchymal stem cells

Human cathelicidin (LL-37), a pleiotropic host defense peptide, plays a pivotal role in orchestrating tissue repair, immunomodulation, and angiogenesis. It has been known to regulate the proliferation of mesenchymal stem cells (MSCs) derived from human adipose tissues, apical papilla, and dental pulp tissues, which are considered promising sources for bone regeneration. However, its effects on human bone marrow-derived MSCs (hBM-MSCs) and the underlying molecular mechanisms have not been fully investigated. This study evaluated the effects of LL-37 on hBM-MSCs proliferation and elucidated the transcriptomic landscape governing this response. The hBM-MSCs were isolated, cultured, and characterized based on their surface marker and multilineage differentiation potential. The cells were treated with various concentrations of LL-37 to evaluate proliferation. The results showed that LL-37 has a biphasic impact on hBM-MSCs kinetics, in which 2 µM of LL-37 markedly enhances proliferation, whereas supraphysiological levels (20 µM) cause cytotoxicity. RNA sequencing analysis suggested upregulation of proliferation-related genes in LL-37–treated hBM-MSCs, particularly AKT3 . Mechanistic validation through Western blotting confirmed that LL-37 treatment could enhance AKT3 expression and AKT phosphorylation. Inhibition of AKT phosphorylation by chemical inhibitors attenuated LL-37 induced cell proliferation. These findings indicate LL-37 as a potent bioactive modulator of hBM-MSCs proliferation, with mechanistic evidence suggesting the involvement of the AKT signalling pathway, and support its potential application in bone regeneration.