Uptake and Metabolism of Folate Among Dental Pulp-Derived Stem Cells

Objectives: Folic acid (FA) participates in many cellular pathways required for growth and survival among mesenchymal stem cells, although few studies have evaluated dental pulp stem cells (DPSC). Recent studies from this group have suggested that FA administration may increase both viability and proliferation among DPSC, although the pathways and mechanisms associated with these observations were not elucidated. The main objectives of this study were to evaluate the potential mechanisms associated with intake of FA among DPSC, as well as to determine any changes to pathways involving cellular FA metabolism.
Methods: Using previously isolated and characterized DPSC isolates, FA was administered within the normal human physiologic range of 1-400 uM to assess the effects on cellular phenotypes (growth, viability). RNA was isolated from DPSC isolates under FA administration to evaluate the pathways involved with FA intake and metabolism.

Results: Preliminary results demonstrated that the potocytotic FA carrier caveolin may be strongly up-regulated by FA administration in a dose-dependent manner. Although the compensatory intake mechanism human reduced folate carrier (hRFC) is normally down-regulated by increased caveolin activity, no hRFC reduction was observed – which may explain (in part) the increased responsiveness of DPSC to FA administration. In addition, RT-PCR screening of DPSC mRNA revealed a significant increase in thymidylate synthetase (TS) and dihydrofolate reductase (DHFR), enzymes involved in FA metabolism and biosynthethic pathways.

Conclusions: This study may be among the first to demonstrate that DPSC can significantly increase FA uptake via caveolin up-regulation without corresponding down-regulation of hRFC. In addition, both metabolic and biosynthetic pathways associated with FA may be directly influenced by FA administration, suggesting an additional consideration for future studies that strive to develop or differentiate DPSC for therapeutic or clinical treatments in the future.