Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts

Abstract

Transplantation of adult bone marrow-derived mesenchymal stem cells has been proposed as a strategy for cardiac repair following myocardial damage. However, poor cell viability associated with transplantation has limited the reparative capacity of these cells in vivo. In this study, we genetically engineered rat mesenchymal stem cells using ex vivo retroviral transduction to overexpress the prosurvival gene Akt1 (encoding the Akt protein). Transplantation of 5 x 10(6) cells overexpressing Akt into the ischemic rat myocardium inhibited the process of cardiac remodeling by reducing intramyocardial inflammation, collagen deposition and cardiac myocyte hypertrophy, regenerated 80-90% of lost myocardial volume, and completely normalized systolic and diastolic cardiac function. These observed effects were dose (cell number) dependent. Mesenchymal stem cells transduced with Akt1 restored fourfold greater myocardial volume than equal numbers of cells transduced with the reporter gene lacZ. Thus, mesenchymal stem cells genetically enhanced with Akt1 can repair infarcted myocardium, prevent remodeling and nearly normalize cardiac performance.

Epidermal growth factor receptor-transfected bone marrow stromal cells exhibit enhanced migratory response and therapeutic potential against murine brain tumors

“…Based on our in vitro data, it is thought that this superior migratory response of EGFR-MSC over primary MSCs in vivo resulted from several biological events that were induced by EGFR gene insertion: (1) direct enhancement of migration by interaction of EGFR and its ligands as demonstrated in vitro; (2) resistance to FasL-induced apoptosis, because FasL is known to be expressed in both normal and neoplastic CNS tissues, 44 Glioma gene therapy with EGFR-transfected MSCs H Sato et al mechanisms including activation of PI3-K. 45 Akt provides a powerful survival signal in many systems, 46 and a recent study has demonstrated that Akt-engineered MSCs are more resistant to apoptosis and can enhance cardiac repair after transplantation into the ischemic rat heart. 47 Indeed, both bulk and cloned EGFR-MSCs were maintained as a cell line over 30 passages, whereas primary MSCs died after three to four passages within a span of a month after their harvesting from bone marrow. Although the introduction of growth-stimulating receptor into a stem cell raises concern for potential tumorigenicity, our results demonstrated that EGFR-MSC were not tumorigenic.…”

Mesenchymal stem cells are superior to angiogenic growth factor genes for improving myocardial performance in the mouse model of acute myocardial infarction

“…The enhancement of cardiac function in MSCs therapy may be attributed to the ability of self-renewal of the MSCs and cytokines production of MSCs [23]. Prevention of apoptosis in ischemic myocardium may also represent another important mechanism for cardiomyocyte recovery by MSCs transplantation [24,25].…”

Anoikis: an emerging hallmark in health and diseases

“…Therefore, knowledge of molecules able to enhance the viability of the transplanted cells is crucial. Various strategies have been carried out to potentiate cell viability after transplantation: (a) pretreatment of the cells with growth factors or cytokines, including bFGF, insulin-like growth factor and bone morphogenic protein-2 in myocardial precursors [172] or adiponectin [173] and nitric oxide in mesoangioblasts [174]; (b) genetic modification to induce over-expression of pro-survival molecules, including Akt [175,176], bFGF [177], haem oxygenase-1 [178], VEGF [179] and Bcl-2 [180]. Hence, strategies that improve cell viability during transplantation, allowing cells to evade anoikis when circulating in the bloodstream until they reach the target organ, appear essential for the success of cell-based therapy.…”