Bcl2-Expressing Quiescent Type B Neural Stem Cells in the Ventricular-Subventricular Zone Are Resistant to Concurrent Temozolomide/X-Irradiation

Stem Cells. 2019 Dec;37(12):1629-1639. doi: 10.1002/stem.3081. Epub 2019 Oct 17.


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 chemoradiation 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 the repair of DNA double-strand breaks. Remarkably, the repair was the same in type B and type A cells. While Bax expression was the same for type A or B cells, antiapoptotic 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 antiapoptotic proteins compared with 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. Stem Cells 2019;37:1629-1639.

Keywords: Apoptosis; Glioblastoma; Ionizing radiation; Neural stem cells; Subventricular zone; Temozolomide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / adverse effects
  • Antineoplastic Agents, Alkylating / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Chemoradiotherapy / adverse effects*
  • Chemoradiotherapy / methods
  • DNA Breaks, Double-Stranded
  • DNA Repair / genetics
  • Disease Models, Animal
  • Drug Resistance / physiology
  • Female
  • Glioblastoma / pathology
  • Glioblastoma / therapy
  • Lateral Ventricles / cytology*
  • Lateral Ventricles / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Stem Cells / metabolism*
  • Neurogenesis / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Temozolomide / adverse effects*
  • Temozolomide / pharmacology
  • X-Ray Therapy / adverse effects*
  • X-Ray Therapy / methods


  • Antineoplastic Agents, Alkylating
  • Proto-Oncogene Proteins c-bcl-2
  • Bcl2 protein, mouse
  • Temozolomide