Mechanical Loading of Stem Cells for Improvement of Transplantation Outcome in a Model of Acute Myocardial Infarction: The Role of Loading History

Abstract

Stem cell therapy for tissue repair is a rapidly evolving field and the factors that dictate the physiological responsiveness of stem cells remain under intense investigation. In this study we hypothesized that the mechanical loading history of muscle-derived stem cells (MDSCs) would significantly impact MDSC survival, host tissue angiogenesis, and myocardial function after MDSC transplantation into acutely infarcted myocardium. Mice with acute myocardial infarction by permanent left coronary artery ligation were injected with either nonstimulated (NS) or mechanically stimulated (MS) MDSCs. Mechanical stimulation consisted of stretching the cells with equibiaxial stretch with a magnitude of 10% and frequency of 0.5 Hz. MS cell-transplanted hearts showed improved cardiac contractility, increased numbers of host CD31 + cells, and decreased fibrosis, in the peri-infarct region, compared to the hearts treated with NS MDSCs. MS MDSCs displayed higher vascular endothelial growth factor expression than NS cells in vitro. These findings highlight an important role for cyclic mechanical loading preconditioning of donor MDSCs in optimizing MDSC transplantation for myocardial repair.

Beneficial Effect of Mechanical Stimulation on the Regenerative Potential of Muscle-Derived Stem Cells Is Lost by Inhibiting Vascular Endothelial Growth Factor

“…Previous studies have shown a decrease in fibrosis and muscle necrosis with sustained VEGF secretion using gene or cell therapy40; however, when MS-MDSCs were transplanted into an infarcted heart they did not significantly affect fibrosis levels compared with the transplantation of NS-MDSCs 37. We examined collagen formation in muscles implanted with sFlt1-MDSCs, shRNA_VEGF-MDSCs, or lacZ-MDSCs and found increased fibrosis formation in all the groups where VEGF was blocked.…”

“…Mechanical stretch is a powerful stimulus for a broad spectrum of cellular responses, including growth, differentiation, motility, remodeling, and gene expression 29,35,36. Previous studies demonstrated that mechanically stimulated MDSCs expressed more VEGF and were able to repair the infarcted hearts of mice more effectively than nonmechanically stimulated MDSCs,37 which was attributed, at least in part, to an increase in angiogenesis in the peri-infarct area 37. In addition, blocking VEGF with sFlt1-MDSCs abrogated the benefits of MDSCs in both skeletal muscle regeneration and cardiac repair 21,22…”

Stem cells, angiogenesis and muscle healing: a potential role in massage therapies?

“…We have investigated whether in vitro mechanical stimulation has a beneficial effect on improving the transplantation capacity of MDSCs in cardiac muscle 47 52. We cultured MDSCs on flexible collagen-coated culture plates (Flexcell Intl Corp, Hillsborough, NC, USA).…”

“…At 2 weeks after cell implantation, the mice were sacrificed, and their hearts were harvested and stained for dystrophin expression. Infarcted hearts transplanted with stimulated MDSCs showed improved cardiac contractility, increased angiogenesis and decreased fibrosis compared with the hearts treated with non-stimulated MDSCs 52. Dystrophin-positive cells were counted for the largest engraftment area.…”

Synthetic Biology Approaches to Cell Therapy

“…They can also focus on coaxing immature cells toward more complex morphologies. Furthermore, these cellular preconditioning approaches can also be based on electrical [33] or mechanical stimuli [34]. Ideally, upon exposure to these preconditioning routines, cells will express phenotypes mirroring those in the native tissue, and will remodel the ECM to reproduce the complicated morphology of the tissue being replaced.…”