The histone deacetylase inhibitor MS-275 enhances the matrix mineralization of dental pulp stem cells by inducing fibronectin expression

Tissue engineering approaches for dental pulp regeneration: The development of novel bioactive materials using pharmacological epigenetic inhibitors

“…TSA is a potent pan-HDAC isoform inhibitor, non-selectively targeting various HDACs, which has garnered significant attention within dental pulp regenerative contexts [ 346 ]. TSA demonstrates significant anti-proliferative effects in primary DPCs when applied at 100 nM and 400 nM without affecting cell viability [ 347 , 348 ], reflecting previous reports using TSA at much lower concentrations [ 349 , 350 ]. Notably, TSA-induced caspase-3 and -9 cleavage were observed in DPSCs, a process associated with apoptosis [ 351 ].…”

“…However, without osteogenic induction media, TSA at all concentrations failed to replicate this effect in culture systems [ 353 ]. Notably, Suzuki et al [ 350 ] determined that induced TSA-treated cells fail to enhance DPSC mineralisation, though this result is significantly influenced by methodological limitations discussed later in this review. The different cellular responses of primary cells and transformed cell lines, the type and concentration of HDACi employed, and the presence or absence of osteogenic induction in studies likely account for the discrepancies observed.…”

“…This may result from the protracted residence time of MS-275 on HDAC2 (743 m) [ 360 ]. Similarly, DMP-1, RUNX2, ALP, BCL-2 and DSPP were upregulated at all concentrations of MS-275, with notable enhancements at 5–10 nM accelerating DPSC differentiation with no apoptotic effects, though concentrations above 5 μM demonstrate anti-proliferative impacts [ 350 , 362 ]. When comparing its effects on odontogenic differentiation to TSA, it was revealed that mineralised deposits are significantly increased in MS-275-treated cells; however, the monolayer of both control and TSA-treated cells had detached, altering the interpretation of results [ 350 ].…”

“…Similarly, DMP-1, RUNX2, ALP, BCL-2 and DSPP were upregulated at all concentrations of MS-275, with notable enhancements at 5–10 nM accelerating DPSC differentiation with no apoptotic effects, though concentrations above 5 μM demonstrate anti-proliferative impacts [ 350 , 362 ]. When comparing its effects on odontogenic differentiation to TSA, it was revealed that mineralised deposits are significantly increased in MS-275-treated cells; however, the monolayer of both control and TSA-treated cells had detached, altering the interpretation of results [ 350 ]. Despite the promise of MS-275, the trends observed in both this compound and VPA reinforce that significant inhibition of HDAC2 may not be well-suited to the goals of dental pulp regeneration as previously described; however, further experimentation in primary DPCs in 3D models and in vivo analyses are required to elucidate the effectiveness of this modality properly.…”