Wnt signaling pathway inhibitor promotes mesenchymal stem cells differentiation into cardiac progenitor cells in vitro and improves cardiomyopathy in vivo

by Selleckchem | Jan 04 2024

Background: Cardiovascular diseases particularly myocardial infarction (MI) are the leading cause of mortality and morbidity around the globe. As cardiac tissue possesses very limited regeneration potential, therefore use of a potent small molecule, inhibitor Wnt production-4 (IWP-4) for stem cell differentiation into cardiomyocytes could be a promising approach for cardiac regeneration. Wnt pathway inhibitors may help stem cells in their fate determination towards cardiomyogenic lineage and provide better homing and survival of cells in vivo. Mesenchymal stem cells (MSCs) derived from the human umbilical cord have the potential to regenerate cardiac tissue, as they are easy to isolate and possess multilineage differentiation capability. IWP-4 may promote the differentiation of MSCs into the cardiac lineage.

Aim: To evaluate the cardiac differentiation ability of IWP-4 and its subsequent in vivo effects.

Methods: Umbilical cord tissue of human origin was utilized to isolate the MSCs which were characterized by their morphology, immunophenotyping of surface markers specific to MSCs, as well as by tri-lineage differentiation capability. Cytotoxicity analysis was performed to identify the optimal concentration of IWP-4. MSCs were treated with 5 μM IWP-4 at two different time intervals. Differentiation of MSCs into cardiomyocytes was evaluated at DNA and protein levels. The MI rat model was developed. IWP-4 treated as well as untreated MSCs were implanted in the MI model, then the cardiac function was analyzed via echocardiography. MSCs were labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) dye for tracking, while the regeneration of infarcted myocardium was examined by histology and immunohistochemistry.

Results: MSCs were isolated and characterized. Cytotoxicity analysis showed that IWP-4 was non-cytotoxic at 5 μM concentration. Cardiac specific gene and protein expression analyses exhibited more remarkable results in fourteen days treated group that was eventually selected for in vivo transplantation. Cardiac function was restored in the IWP-4 treated group in comparison to the MI group. Immunohistochemical analysis confirmed the homing of pre-differentiated MSCs that were labeled with DiI cell labeling dye. Histological analysis confirmed the significant reduction in fibrotic area, and improved left ventricular wall thickness in IWP-4 treated MSC group.

Conclusion: Treatment of MSCs with IWP-4 inhibits Wnt pathway and promotes cardiac differentiation. These pre-conditioned MSCs transplanted in vivo improved cardiac function by cell homing, survival, and differentiation at the infarcted region, increased left ventricular wall thickness, and reduced infarct size.

Comments:

Looks like we're diving into some impressive medical research. The study you've outlined here is fascinating! It highlights the potential of IWP-4, a Wnt pathway inhibitor, in facilitating the differentiation of mesenchymal stem cells (MSCs) from human umbilical cord tissue into cardiomyocytes, ultimately aiding in cardiac tissue regeneration.

The methodology appears thorough, encompassing the isolation and characterization of MSCs, assessment of cytotoxicity for determining the optimal concentration of IWP-4, and subsequent evaluation of cardiac differentiation at both DNA and protein levels. Furthermore, the in vivo transplantation of these preconditioned MSCs into a myocardial infarction (MI) rat model demonstrates promising outcomes in terms of cardiac function restoration and myocardial regeneration.

The findings suggest that treating MSCs with IWP-4 enhances their ability to differentiate into cardiac lineage cells, thereby improving their therapeutic potential for cardiac regeneration. The observed improvements in cardiac function, reduced fibrotic area, and increased left ventricular wall thickness in the IWP-4 treated MSC group emphasize the potential clinical implications of this approach for treating myocardial infarction.

This research could significantly contribute to advancing regenerative medicine for cardiovascular diseases, offering a potential avenue for developing novel therapeutic strategies.