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Bcl2-expressing quiescent type B neural stem cells in the V-SVZ are resistant to concurrent temozolomide/X-irradiation


Cameron BD , Traver G , Roland JT , Brockman AA , Dean D , Johnson L , Boyd K , Ihrie RA , Freeman ML , . Stem cells (Dayton, Ohio). 2019 8 20; ().


The ventricular-subventricular zone (V-SVZ) of the mammalian brain is a site of adult neurogenesis. Within the V-SVZ reside type B neural stem cells (NSCs) and type A neuroblasts. The V-SVZ is also a primary site for very aggressive glioblastoma (GBM). Standard of care therapy for GBM consists of safe maximum resection, concurrent temozolomide (TMZ) and X-irradiation (XRT) followed by adjuvant TMZ therapy. The question of how this therapy impacts neurogenesis is not well understood and is of fundamental importance as normal tissue tolerance is a limiting factor. Here, we studied the effects of concurrent TMZ/XRT followed by adjuvant TMZ on type B stem cells and type A neuroblasts of the V-SVZ in C57BL/6 mice. We found that chemo-radiation induced an apoptotic response in type A neuroblasts, as marked by cleavage of Caspase-3, but not in NSCs, and that A cells within the V-SVZ were repopulated given sufficient recovery time. 53BP1 foci formation and resolution was used to assess repair of DNA double strand breaks. Remarkably, repair was the same in type B and A cells. While Bax expression was the same for type A or B cells, anti-apoptotic Bcl2 and Mcl1 expression was significantly greater in NSCs. Thus, the resistance of type B NSCs to TMZ/XRT appears to be due, in part, to high basal expression of anti-apoptotic proteins compared to type A cells. This preclinical research, demonstrating that murine NSCs residing in the V-SVZ are tolerant of standard chemoradiation therapy, supports a dose escalation strategy for treatment of GBM. SIGNIFICANCE STATEMENT: Evidence suggests that glioblastoma contacting the V-SVZ are resistant to concurrent temozolomide plus X-irradiation. An important question is whether therapeutic escalation of dose to counter aggressive glioblastoma can be limited by a failure of type B neural stem cells that reside in the V-SVZ to survive temozolomide plus X-irradiation and contribute to repair of treatment-induced injury. Studying the molecular responses to DNA damage in the intact in vivo microenvironment revealed that neural stem cells over express the anti-apoptotic proteins Bcl2 and and Mcl1 and do not undergo apoptosis in response to concurrent chemo-radiation therapy. Stem cell resistance sustains neurogenesis and suggests targeting the V-SVZ for the treatment of GBM would not result in unacceptable toxicity. © AlphaMed Press 2019.