Stem cells are resistant to TRAIL receptor‐mediated apoptosis

Abstract

New therapeutic approaches aim to eradicate tumours by expression of tumouricidal proteins in the tumour stroma. One such anti-neoplastic protein is tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) because it induces apoptosis in cancerous cells, but not in non-transformed cells. Stem cells can migrate to, survive and proliferate in tumours. We examined the suitability of bone marrow-derived adult mesenchymal stem cells (bmMSC), foetal-MSC and umbilical cord matrix stem cells (Wharton’s Jelly MSCs) as TRAIL-delivery vehicles. Although all MSC types expressed DR4 and/or DR5, none of them were sensitive to TRAIL-induced apoptosis. Selective activation of DR4 or DR5 with agonistic antibodies or DR5-selective TRAIL-mutant (D269H/E195R) revealed that the TRAIL receptors are inactive in MSCs. In fMSC DR5 was not fully inactivated, its activity however was minimal in comparison to the colon carcinoma cell, Colo205. The intracellular components of the TRAIL-apoptotic pathway, such as pro-caspase-8 and -9 were also expressed at very low; almost undetectable levels in all three MSC types. In conclusion, the MSC species examined are resistant to TRAIL and thus can be suitable tools for TRAIL delivery to tumours.

Complete Regression of Metastatic Renal Cell Carcinoma by Multiple Injections of Engineered Mesenchymal Stem Cells Expressing Dodecameric TRAIL and HSV-TK

“…Decreased MSC viability was unlikely to be caused by high levels of secreted TRAIL, as the extent of decrease in cell survival was comparable between MSC/ tTRAIL and MSC/dTRAIL despite the difference in their TRAIL induction. This result is supported by a previous observation that MSCs are resistant to TRAIL-mediated apoptosis (25). On the basis of these results, 50 MOI of rAd in the presence of Fe 3þ was determined to be the optimal condition for MSC transduction, which did not affect the phenotype of MSCs (Supplementary Fig.…”

Immunoregulatory Properties of Mouse Limbal Stem Cells

“…It has already been shown that human embryonic stem cells (ESCs) (34,35), rat ESC-like cells (36), or MSCs (20) are more resistant to cell-mediated lysis and immune rejection than adult cells. The enhanced resistance of LSCs to cell-mediated lysis might be due to the presence of the FasL molecule on LSCs or to the resistance of SCs to TRAIL receptor-mediated apoptosis (36,37). Because it has been demonstrated that FasL can protect rat ESCs from rejection in an allogeneic host (38), we measured the level of FasL mRNA in the LSC fraction and in other limbal cells.…”

Human Embryonic and Induced Pluripotent Stem Cells Express TRAIL Receptors and Can Be Sensitized to TRAIL-Induced Apoptosis

“…In addition to caspase-dependent apoptosis, under certain circumstances, death receptors can trigger a specific receptor-interacting protein (RIP)1/RIP3-dependent form of programmed necrosis called necroptosis [27,28]. Importantly, normal mesenchymal stem cells, progenitor cells, and terminally differentiated cells are resistant to death receptor-induced pro-death signaling [29][30][31]. In these cells, ligand-activated receptors may induce a number of other signaling events, for example, activation of the canonical NFkB pathway, mitogen-activated protein (MAP) and stress kinases, and the P3K/Akt axis, and can even enhance macroautophagy [32][33][34].…”