Computational and in vitro validation of cardiogenic induction of quercetin on adipose‐derived mesenchymal stromal cells through the inhibition of Wnt and non‐Smad‐dependent TGF‐β pathways

Abstract

Exploiting human mesenchymal stem cells (hMSCs) was proposed as a promising therapeutic approach for cardiovascular disease due to their capacity to differentiate into cardiac cells. Though modulation of the intracellular signaling pathways dominantly WNT/β catenin and transforming growth factor-β (TGF-β) have been reported to promote differentiation of hMSCs into cardiomyocytes in the prevailing literature, a safe and reproducible system for their clinical application has not yet turned into reality. In the present study, the molecular docking-based strategy was first applied for evaluating the potency of some natural phenolic compounds in the modulation of Wnt and TGF-β signaling pathways using a vital class of crystallographic protein structures of WNT signaling regulators such as Frizzled, Disheveled, GSK3-β, β-catenin, LRP 5/6 extracellular domain, Tankyrase and their variety of active pockets. Then, the impacts of plant-derived chemical compounds on the regulation of the relevant signals for the differentiation of hMSCs into the definitive mesoderm lineage and cardiac progenitors were assessed in vitro. Data obtained revealed the synergistic activity of Wnt and TGF-β superfamily to direct cardiac differentiation in human cardiogenesis by comparing cardiac gene expression in the presence and absence of the TGF-β inhibitors. We found that the inhibitory effect of canonical Wnt/βcatenin is sufficient to cause proper cardiomyocyte differentiation, but the TGF-β pathway plays a vital role in enhancing the expression of the cardiomyocytespecific marker (cTnT). It was found that quercetin, a p38MAPK inhibitor with the high energy dock to the active pocket of Wnt receptors, promotes cardiac differentiation via the inhibition of both Wnt and non-Smad TGF-β pathways.Altogether, data presented here can contribute to the development of a feasible and efficient cardiac differentiation protocol as an "off-the-shelf" therapeutic source using novel natural agents for cardiac repair or regeneration.

Preparation of myocardial patches from DiI-labeled rat bone marrow mesenchymal stem cells and neonatal rat cardiomyocytes contact co-cultured on polycaprolactone film

“…With in-depth study of stem cell therapy, researchers gradually identified problems that have hindered further clinical applications. First, the efficiency of natural stem cell differentiation is very low in vitro, so researchers have attempted to improve the efficiency of BMSC differentiation into CMs [11][12][13]. At present, commonly used methods to induce differentiation in vitro include selection of appropriate inducers, contact co-culture, and other strategies [14].…”

Methicillin-Resistant Staphylococcus aureus: Docking-Based Virtual Screening and Molecular Dynamics Simulations to Identify Potential Penicillin-Binding Protein 2a Inhibitors from Natural Flavonoids

“…The lowest Glide score (dock score) for each ligand was considered the best-docked model. More details regarding settings in the Schrödinger Maestro docking software have been reported in a previous study by Azadian et al [ 26 ].…”

Exploring Cinnamic Acids as Potent Antimetastatic Agents for Cancer Therapy: Molecular Docking and Dynamic Simulation against MMP2

“…Within this context, docking values were computed, and the prime MM-GBSA procedure was employed to ascertain the relative binding energies of the compounds. Additional information regarding the confguration parameters in the Schrödinger Maestro docking tool has been documented in a prior investigation conducted by Azadian et al [45].…”