Naphthoquinones mediate differentiation of human umbilical cord derived mesenchymal stem cells into insulin producing cells through regulation of Wnt and BMP pathways
TL;DR
The regulatory role of lawsone and lapachol can be exploited for preconditioning of MSCs for improved pancreatic β-cell differentiation, as well as regulating downstream Wnt and BMP signaling.
Abstract
Introduction: Diabetes mellitus (DM) being a chronic metabolic disorder, causes a major concern for the healthcare system. Among different types, type 1 DM (T1DM) results in the destruction of insulin-producing pancreatic β cells, mediated by the immune system. Studies have demonstrated that human umbilical cord derived mesenchymal stem cells (hUMSCs) exhibit great potential to regenerate β-cells. Moreover, in order to enhance the regenerative potential of MSCs, several strategies are being utilized, including preconditioning with bioactive compounds. Among these, naphthoquinones can be used for MSC preconditioning in order to augment their therapeutic potential for β-cell regeneration, as these compounds possess anti‐inflammatory and anti-diabetic properties. Methods: hUMSCs were isolated, characterized, and treated with non-cytotoxic concentrations of lawsone, lapachol, or their combination. The preconditioned cells were subsequently analyzed for pancreatic β-cell differentiation at gene and protein levels. The study also explores the role of Wnt and BMP signaling pathways during the differentiation process through gene expression analysis. Binding patterns of these compounds with their respective receptors were analyzed using in silico studies. Results: Gene expression profiling showed overexpression of pancreatic β-cell–specific markers in the Law + hUMSC group, whereas downregulation of Neurogenin-3 (NGN3) was observed in all treatment groups. Immunocytochemical analysis also showed enhanced expression of insulin in Law + hUMSCs, relative to other groups. Transcriptional analysis of the wingless/integrated (Wnt) and bone morphogenetic protein (BMP) pathways showed increased Wnt and decreased BMP expression across all treatment groups. In silico analyses showed that the binding patterns of lawsone or lapachol with frizzled (FZD) and activin-like kinase 1 (ALK1) receptors share comparable sequence similarity, facilitating their binding to these receptors and regulating downstream Wnt and BMP signaling. Conclusion: The study concludes that the regulatory role of lawsone and lapachol can be exploited for preconditioning of MSCs for improved pancreatic β-cell differentiation.