Cell-penetrating anti-sense peptide nucleic acids targeting sulfatase 2 inhibit adipogenesis in human mesenchymal stem cells

Abstract

Targeting the genes regulate the lineage commitment of human mesenchymal stem cells (hMSCs) to adipocytes provides a promising strategy for addressing obesity. In this study, we investigated the therapeutic potential of cell-penetrating anti-sense peptide nucleic acids (PNAs) designed to enhance solubility and hybridization properties, specifically targeting sulfatase 2 (SULF2), a potential reciprocal regulator of adipocyte and osteoblast differentiation in hMSCs. Cell-penetrating modified PNA oligomers effectively inhibit SULF2 gene transcription, leading to significant reductions in adiponectin protein synthesis and intracellular lipid droplet accumulation during adipogenesis in human bone marrow-derived MSCs (hBM-MSCs). Notably, PNA oligomer compound 5 exhibited the most potent anti-adipogenic activity, with an IC₅₀ value of 0.28 μM. These findings show the potential of SULF2-targeting cell-penetrating PNA oligomers as novel therapeutic agents for obesity-related metabolic diseases.

Keywords: Adipogenesis; Anti-sense oligonucleotide; Binding affinity; Human bone marrow mesenchymal stem cells; Peptide nucleic acids; Sulfatase 2.