Impact of hydrogel stiffness on the induced neural stem cells modulation

Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) is the most common cancer to form brain metastases. Radiation treatment is standard-of-care, but recurrence is still observed in 40% of patients. An adjuvant treatment is desperately needed to track down and kill tumor remnants after radiation. Tumoritropic neural stem cells (NSCs) that can home to and deliver a cytotoxic payload offer potential as such an adjuvant treatment. Here we show the transdifferentiation of human fibroblasts into tumor-homing induced neural stem cells (hiNSCs) that secrete the cytotoxic protein TRAIL (hiNSC-TRAIL) and explore the use of hiNSC-TRAIL to treat NSCLC brain metastases. METHODS To determine the migratory capacity of hiNSCs, hiNSCs were infused intracerebroventricularly (ICV) into mice bearing established bilateral NSCLC H460 brain tumors. hiNSC accumulation at tumor foci was monitored using bioluminescent imaging and post-mortem fluorescent analysis. To determine synergistic effects of radiation with TRAIL on NSCLC, we performed in vitro co-culture assays and isobologram analysis. In vivo, efficacy was determined by tracking the progression and survival of mice bearing intracranial H460 treated with hiNSC-TRAIL alone or in combination with 2 Gy radiation. RESULTS/CONCLUSION Following ICV infusion, hiNSCs persisted in the brain for > 1 week and migrated from the ventricles to colocalize with bilateral tumor foci. In vitro, viability assays and isobologram analysis revealed the combination treatment of hiNSC-TRAIL and 2 Gy radiation induced synergistic killing (combination index=0.64). In vivo, hiNSC-TRAIL/radiation combination therapy reduced tumor volumes > 90% compared to control-treated animals while radiation-only and hiNSC-TRAIL-only treated mice showed 21% and 52% reduced volumes, respectively. Dual-treatment extended survival 40%, increasing survival from a median of 20 days in controls to 28 days in the treatment group. These results suggest hiNSC-TRAIL can improve radiation therapy for NSCLC brain metastases and could potentially improve outcomes for patients suffering from this aggressive form of cancer.

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Effect of stiffness change of transplanted induced neural stem cells after spinal cord injury using silk hydrogel

Journal of the Neurological Sciences ◽

10.1016/j.jns.2017.08.815 ◽

2017 ◽

Vol 381 ◽

pp. 286

Author(s):

G. Davaa ◽

J.Y. Hong ◽

J. Olmos Buitrago ◽

H.W. Kim ◽

J.K. Hyun

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Neural Stem Cells ◽

Cord Injury ◽

Induced Neural Stem Cells ◽

Silk Hydrogel

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Generation of Integration-free Induced Neural Stem Cells from Mouse Fibroblasts

Journal of Biological Chemistry ◽

10.1074/jbc.m115.713578 ◽

2016 ◽

Vol 291 (27) ◽

pp. 14199-14212 ◽

Cited By ~ 18

Author(s):

Sung Min Kim ◽

Jong-Wan Kim ◽

Tae Hwan Kwak ◽

Sang Woong Park ◽

Kee-Pyo Kim ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Mouse Fibroblasts ◽

Induced Neural Stem Cells

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Injection of next-generation directly-induced neural stem cells (iNSCs) induces recovery in a mouse model of multiple sclerosis

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2014.08.520 ◽

2014 ◽

Vol 275 (1-2) ◽

pp. 193 ◽

Cited By ~ 1

Author(s):

Luca Peruzzotti-jametti ◽

Giulia Mallucci ◽

Gillian Tannahill ◽

Bing Huang ◽

Yenal Bernard Lakes ◽

...

Keyword(s):

Multiple Sclerosis ◽

Stem Cells ◽

Mouse Model ◽

Neural Stem Cells ◽

Next Generation ◽

Induced Neural Stem Cells

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SCIDOT-22. INTRACEREBROVENTRICULAR DELIVERY OF TUMOR-HOMING CYTOTOXIC HUMAN INDUCED NEURAL STEM CELLS FOR TREATMENT OF BRAIN METASTASES

Neuro-Oncology ◽

10.1093/neuonc/noz175.1158 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi276-vi276

Author(s):

Wulin Jiang ◽

Alison Mercer-Smith ◽

Juli Bago ◽

Simon Khagi ◽

Carey Anders ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Brain Metastases ◽

Neural Stem Cells ◽

Tumor Homing ◽

Migration Assays ◽

Induced Neural Stem Cells ◽

First Time ◽

The Brain

Abstract INTRODUCTION Non-small cell lung cancer (NSCLC) and breast cancer are the most common cancers that metastasize to the brain. New therapies are needed to target and eradicate metastases. We have developed genetically-engineered induced neural stem cells (hiNSCs) derived from human fibroblasts that selectively home to tumors and release the cytotoxic protein TRAIL. Building on these results, we explored the efficacy of hiNSC therapy delivered via intracerebroventricular (ICV) injections for the treatment of metastatic foci in the brain for the first time. METHODS We performed in vitro efficacy and migration assays in conjunction with in vivo studies to determine the migration, persistence, and efficacy of therapeutic hiNSCs against H460 NSCLC and triple-negative breast cancer MB231-Br tumors in the brain. Following the establishment of tumors in the brains of nude mice, hiNSCs were injected directly into the tumor or the ventricle contralateral to the tumor. The migration and persistence of hiNSCs were investigated by following the bioluminescence of the hiNSCs. The therapeutic efficacy of the hiNSCs was determined by following the bioluminescence of the tumor. RESULTS/ CONCLUSION Co-culture results demonstrated that hiNSC therapy reduced the viability of H460 and MB231-Br up to 75% and 99.8% respectively compared to non-treated controls. In vitro migration assays showed significant directional migration toward both lung and breast cancer cells within 4 days. ICV-administered hiNSC serial imaging shows that cells persisted for >1 week in the brain. Fluorescent analysis of tissue sections showed that hiNSCs co-localized with lateral and contralateral tumors within 7 days. Using H460 and MB231-Br models, kinetic tracking of intracranial tumor volumes showed intratumoral or ICV-injected therapeutic hiNSCs suppressed the growth rate of brain tumors by 31-fold and 3-fold, respectively. This work demonstrates for the first time that we can effectively deliver personalized cytotoxic tumor-homing cells through the ventricles to target brain metastases.

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