Director CIBUS Universidad de La Sabana Chia,CU, Cundinamarca, Colombia
Abstract: Pancreatic β cells derived from human induced pluripotent stem cells (hiPSCs) represent a promising therapeutic avenue in regenerative medicine for diabetes treatment. However, current differentiation protocols lack the specificity and efficiency required to reliably produce fully functional β cells, limiting their clinical applicability. Epigenetic barriers, such as histone modifications, may hinder proper differentiation and the acquisition of essential maturation markers in these cells. In this study, we investigated the role of the histone demethylase KDM4A in the differentiation of insulin-producing pancreatic β cells from hiPSCs. KDM4A specifically removes trimethyl groups from lysine residues H3K9 and H3K36, critical epigenetic marks associated with gene regulation. Modulation of KDM4A expression revealed its pivotal role in the epigenetic landscape of differentiation. The results showed that KD of KDM4A significantly reduced the expression of pancreatic differentiation genes, such as PDX1, NX6.1, and INS, compared to WT iPSCs differentiated under the same conditions. Similarly, glucose-stimulated insulin secretion was reduced by approximately 80%. Contrary to the KD results of KDM4A, its overexpression showed a high expression of pancreatic genes and an increase in glucose-stimulated insulin release. These findings underscore the importance of histone demethylation in optimizing differentiation protocols for hiPSC-derived β cells. Our results provide preliminary insights into the epigenetic mechanisms governing β-cell maturation, laying the groundwork for further exploration of histone demethylases as potential targets to enhance regenerative medicine strategies for diabetes treatment.
