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

Abstract

We have created a novel cellular vehicle for gene therapy of malignant gliomas by transfection of murine bone marrow stroma cells (MSCs) with a cDNA encoding epidermal growth factor receptor (EGFR). These cells (EGFR-MSCs) demonstrate enhanced migratory responses toward glioma-conditioned media in comparison to primary MSCs in vitro. Enhanced migration of EGFR-MSC was at least partially dependent on EGF-EGFR, PI3-, MAP kinase kinase, and MAP kinases, protein kinase C, and actin polymerization. Unlike primary MSCs, EGFR-MSCs were resistant to FasL-mediated cytotoxicity and were capable of stimulating allogeneic mixed lymphocyte reaction, suggesting EGFR-MSCs possess suitable characteristics as vehicles for brain tumor immuno-gene therapy. Following injection at various sites, including the contralateral hemisphere in the brain of syngeneic mice, EGFR-MSCs were able to migrate toward GL261 gliomas or B16 melanoma in vivo. Finally, intratumoral injection with EGFR-MSC adenovirally engineered to secrete interferon-a to intracranial GL261 resulted in significantly prolonged survival in comparison to controls. These data indicate that EGFR-MSCs may serve as attractive vehicles for infiltrating brain malignancies such as malignant gliomas.

Tethered Epidermal Growth Factor Provides a Survival Advantage to Mesenchymal Stem Cells

“…These data agree with various studies implicating ERK in survival [78], as well as specific reports showing that ERK can block FasL-mediated apoptosis [79]. These data are also in agreement with a previous report that primary murine MSC transfected with EGFR show enhanced resistance to FasL-mediated apoptosis [80]. The involvement of FasL in MSC biology is likely to be physiologically important, as is the possible antagonism between FasL and EGF-like repeat-containing ECM proteins in the wound-healing milieu.…”

Knockdown of p21Cip1/Waf1 enhances proliferation, the expression of stemness markers, and osteogenic potential in human mesenchymal stem cells

“…It has been demonstrated that MSCs derived from Fas-deficient mice increased in the ability to escape activated T cells-induced apoptosis (Yamaza et al, 2008). Moreover, epidermal growth factor receptor (EGFR)-transfected MSCs are negative for Fas and do not respond to Fas ligand-mediated apoptotic signals (Sato et al, 2005). Thus, the increase in Fas in late-passage MSCs is speculated to inhibit MSCs to resist the assault of cytotoxic T cells or Fas ligand-mediated apoptosis.…”

Gene Therapy and Stem Cell Therapy to Improve the Outcome of Human Islet Transplantation

“…Generally, the lack of co-stimulatory factors (CD80 and CD86) led to an immature antigen presenting to the Th cells and subsequent immune tolerance [151]. Despite that some groups showed that BMSCs expressed FasL and promoted the apoptosis of T cells through direct contact [146,152], our BMSCs were negative for FasL (Figure 6-2), which was supported by the results from other groups [55,153] and confirmed by the MLR that BMSCs did not promote the apoptosis of T cells (data not shown). The expression of HLA class II on the surface of BMSCs is still unclear.…”