Background and Aim: Cardiovascular diseases and subsequent heartfailures are the leading causes of mortality and morbidity in adultsworldwide. Considering the Increasing number of heart problems versusdeficiency of donors, mesenchymal stem cells has recently introduced asa new tool for cell therapies in cardiology practices. However, most of theapproaches still suffer from low efficiency, high cost and the lack of safetydue to using growth factors and animal-derived materials. Therefore,using plant-derived chemical compounds to control mesenchymal cellfate and differentiating them into desired lineages would tackle theseconcerns. Here, we aimed to develop our strategy to differentiateadipose-derived mesenchymal stem cells into definitive mesoderm andfinally cardiomyocytes using plant deprived small molecules such asRutin, resveratrol and quercetin.Methods: Extraction of stem cells from the abdominal adipose tissueperformed by collagenase enzymatic method. Following characterizationusing flow cytometry, cells cultured in 24 well plates and treated witha various combination of growth factors such as Activin A, bFgF, AlK5inhibitor, rutin, resveratrol and quercetin. Moreover, crude extract ofSalix aegyptiaca also assessed in comparison with pure synthetic smallmolecules.Results: The current study showed that the addition of some smallmolecules could increase the efficiency of maintenance, propagationas well as directing differentiation of the mesenchymal stem cell intomesodermal cells followed by cardiac cells.Conclusion: The finding showed pharmacological activation of the WNTsignaling pathway and inhibition of the BMP signaling pathway usingsmall molecules have a crucial role in the differentiation of mesodermallineage. The data also showed that natural compounds or a crude extractof Salix have the same effect as synthetic chemicals. Our differentiationstrategy may help to overcome the current limitations to mesenchymalstem cell therapy that are faced in the field of cardiovascular disease.