Stem Cells Engineered During Different Stages of Reprogramming Reveal Varying Therapeutic Efficacies.

Stem cells are emerging as promising treatment strategies for several brain disorders and pathologies. In this study, we explored the potential of creating induced pluripotent stem cell-derived neural stem cells (ipNSC) by using either unmodified or gene-modified somatic cells and tested their fate and therapeutic efficacies in vitro and in vivo. We show that cells engineered in somatic state lose transgene-expression during the neural induction process, which is partially restored by histone deacetylase inhibitor treatment whereas cells engineered at the ipNSC state have sustained expression of transgenes. In vivo, bimodal mouse and human ipNSCs engineered to express tumor specific death-receptor ligand and suicide-inducing therapeutic proteins have profound anti-tumor efficacy when encapsulated in synthetic extracellular matrix and transplanted in mouse models of resected-glioblastoma. This study provides insights into using somatic cells for treating CNS disorders and presents a receptor-targeted cancer therapeutic approach for brain tumors. Stem Cells 2018;36:932-942.

Morphological brain lesions of pediatric cerebellar tumor survivors correlate with inferior neurocognitive function but do not affect health-related quality of life.

PURPOSE: We aimed to determine whether extent of morphological brain injury in pediatric cerebellar tumor survivors correlates with neurocognitive function and health-related quality of life (HrQoL). METHODS: Seventeen cerebellar pilocytic astrocytoma (cPA) and 17 medulloblastoma (MB) survivors were examined for HrQoL, intelligence using the German version of the WISC-III, attention, working memory, and visual motor coordination. MRI scans were analyzed for extent of posterior fossa brain tissue loss. RESULTS: We found significant correlations between amount and extent morphological brain lesions of pediatric cerebellar tumor survivors and several cognitive impairments including intelligence and attention in both patient groups. These were in total more pronounced in MB patients when compared to cPA patients. Still, function loss and brain lesions detected on conventional MRI did not influence HrQoL. CONCLUSIONS: These findings support the notion that long-term neurocognitive deficits of pediatric posterior fossa tumor survivors significantly correlate with brain tissue damage. The cerebellum plays a role in regulating higher-order functions. On the contrary, the extent brain injury is not detected by HrQoL assessment.

Antiangiogenic variant of TSP-1 targets tumor cells in glioblastomas.

Three type-1 repeat (3TSR) domain of thrombospondin-1 is known to have anti-angiogenic effects by targeting tumor-associated endothelial cells, but its effect on tumor cells is unknown. This study explored the potential of 3TSR to target glioblastoma (GBM) cells in vitro and in vivo. We show that 3TSR upregulates death receptor (DR) 4/5 expression in a CD36-dependent manner and primes resistant GBMs to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced caspase-8/3/7 mediated apoptosis. We engineered human mesenchymal stem cells (MSC) for on-site delivery of 3TSR and a potent and secretable variant of TRAIL (S-TRAIL) in an effort to simultaneously target tumor cells and associated endothelial cells and circumvent issues of systemic delivery of drugs across the blood-brain barrier. We show that MSC-3TSR/S-TRAIL inhibits tumor growth in an expanded spectrum of GBMs. In vivo, a single administration of MSC-3TSR/S-TRAIL significantly targets both tumor cells and vascular component of GBMs, inhibits tumor progression, and extends survival of mice bearing highly vascularized GBM. The ability of 3TSR/S-TRAIL to simultaneously act on tumor cells and tumor-associated endothelial cells offers a great potential to target a broad spectrum of cancers and translate 3TSR/TRAIL therapies into clinics.