Role and mechanism of neural stem cells of the subventricular zone in glioblastoma

Table 1 Pre-clinical and clinical studies of interventions using subventricular zone/neural stem cells for glioblastoma treatment

Ref.	Experiment	Clinical	Interventions	Doses	Subjects	Outcomes	Mechanism
[87]	-	Yes	Adjuvant radiation therapy for the SVZ (NSCs)	Ipsilateral 48.7 Gy	Patients = 116	Improved PFS and OS in patients with GBM after GTR	-
[88]	Yes	-	Adjuvant TMZ/XRT of the SVZ (NSCs)	50-100 mg/kg TMZ, and 1-2 Gy	Mice, n = 6 per cohort	SVZ NSCs tolerated chemoradiation	-
[89]	-	Yes	Adjuvant chemoradiation therapy for the SVZ (NSCs)	Ipsilateral (High dose > 59.4 Gy)	Patients = 173	Improved PFS and OS in patients with high ipsilateral doses	-
[90]	-	Yes	Adjuvant radiation therapy for the SVZ (NSCs)	Ipsilateral High dose > 57.4 Gy	Patients = 50	Negatively impacted on OS in IDH wild type GBM	-
[91]	-	Yes	DWI evaluated before and after adjuvant chemoradiation	No data	Patients = 40	Increasing in ipsilesional ADCL associated with shorter PFS and OS	-
[96]	Yes	-	NSCs modified by IL-4	89 ng/5 × 105 cells per 48 h	Mice, n = 5-7 rats, n = 12-33 per group	Strong anti-tumor effects and long-term survival of animals	Produced IL-4
[97]	Yes	-	hNSCs overexpressed BMP4 (hNSCs-BMP4)	No data	Mice, n = 10 per group	Inhibited tumor growth and prolonged survival	BMP/Smad1 pathway
[99]	Yes	-	Modified iNSC with anticancer molecule TRAIL	7.5 × 105 cells per mouse	Mice, n = 12 per group	Decreased tumor growth and extended the survival	Secreted anticancer molecule TRAIL
[100]	Yes	-	h-iNSCTE transduced with TRAIL and TK	7.5 × 105 cells per mouse	Mice, n = 12 per group	Inhibited GBM growth and prolonged the median survival	Secreted cytotoxic molecules TRAIL and TK
[85]	Yes	-	HB1.F3.CD NSCs combined with intraperitoneal injection of 5-FC	1 × 104, 5 × 104, 1 × 105 cells per mouse, 500 mg/kg 5-FC	Mice, n = 12 per group	Inhibited GBM growth and prolonged the survival	Converted prodrug 5-FC to active 5-FU
[101]	-	Yes	HB1.F3.CD NSCs combined with oral administration of 5-FC	1 × 107, 5 × 107 cells, 75-150 mg/kg/day 5-FC	Patients = 15	Confirmed the safety and ability of NSCs to target brain tumors and locally produce chemotherapy	Convert prodrug 5-FC to active 5-FU
[102]	Yes	-	HB1.F3.CD NSCs-TRAIL combined with intraperitoneal injection of Lan C	2 × 105 cells, 1 mg/kg Lan C	Mice, n = 10 per group	Induced tumorregression	Lan C sensitized GBM to TRAIL
[105]	Yes	-	HB1.F3.CD NSCs loaded with CRAd-Survivin-pk7	5 × 105 cells, with 50 IU per cell of CRAd-S-pk7	Mice, n = 7 per group	Increased the median survival of mice	Overcame major limitations of OVs in vivo
[106]	Yes	-	HB1.F3.CD NSCs-CRAd-S-pk7 combined with intraperitoneal injection of NACA	4 × 105 cells, 250 mg/kg/day NACA	Mice, n = 6-7 per group	Extended the median survival of mice	Enhanced OVs production and distribution in vivo
[109]	Yes	-	Overexpressed CXCR4 in NSCs and loaded with CRAd-S-pk7	5 × 105 cells	Mice, n = 8 per group	Extended the survival	SDF-1/CXCR4 pathway
[110]	Yes	-	NSCs loaded CRAd-S-pK7 combined with intraperitoneal injection of MT	5 × 105 cells, 50 μg/g MT	Mice, n = 8 per group	Improved the survival of GBM-bearing mice	Prolonged thepersistence of NSCs in the nasal cavities
[114]	Yes	-	HB1.F3.CD NSCs loaded with MSN-Dox	2.5 × 105 cells	Mice, n = 4-8 per group	Prolonged the median survival of mice	Self-destructing mechanism
[116]	Yes	-	Scaffold GEMs/tNSCstk	1 × 106 cells per scaffold	Mice, n = 5 per group	Increased cell viability and improved the survival	Reduced residual tumor volumes
[117]	Yes	-	tNSC-TRAIL and/or tNSC–TK	7 × 105–1.4 × 106 cells	Mice, n = 4-13 per group	Inhibited tumor growth and survival	Secreted cytotoxic molecules TRAIL and/or TK

SVZ: Subventricular zone; NSCs: Neural stem cells; PFS: Progression free survival; OS: Overall survival; GTR: Gross total resection; TMZ: Temozolomide; XRT: X-irradiation; IDH: Isocitrate dehydrogenase; DWI: Diffusion-weighted imaging; ADC: Apparent diffusion coefficient; IL-4: Interleukin-4; BMP4: Bone morphogenetic protein 4; iNSC: Induced neural stem cell; TRAIL: Tumor necrosis factor-α-related apoptosis-inducing ligand; h-iNSC^TE: Human fibroblasts into tumor-homing early-stage induced neural stem cells; TK: Thymidine kinase; 5-FC: 5-fluorocytosine; 5-FU: 5-fluorouracil; Lan C: Lanatoside C; OV: Oncolytic adenovirus; CRAd-S-pk7: CRAd-Survivin-pk7; NACA: Novel antioxidant thiol, N-acetylcysteine amide; MT: Methimazole; MSN-Dox: Doxorubicin-loaded mesoporous silica nanoparticles; GEMs: Gelatin matrices; tNSC: Tumoricidal neural stem cells; tNSCs^tk: Engineered tNSCs to express the prodrug/enzyme thymidine kinase.