Ionizing Radiation Enhances the Engraftment of Transplanted In Vitro–Derived Multipotent Astrocytic Stem Cells

Abstract

The subependymal zone (SEZ) is a region of persistent neurogenesis in the adult mammalian brain containing a neural stem cell (NSC) pool that continuously generates migratory neuroblasts that travel in chains through the rostral migratory stream (RMS) to the olfactory bulb (OB), where they differentiate and functionally integrate into existing neural circuitry. NSCs can be isolated from the SEZ and cultured to generate either neurospheres (NSs) or multipotent astrocytic stem cells (MASCs), with both possessing the stem cell characteristics of multipotency and self-renewal. NSs and MASCs home to the SEZ after transplantation into the lateral ventricle (LV) and contribute to neuroblast migration, with minimal engraftment into the OB observed in the adult mouse. Recent studies have compared the relatively uncharacterized NSC with the more established hematopoietic stem cell (HSC) in an effort to determine the level of stemness possessed by the NSC. Depletion of native HSCs in the bone marrow by lethal irradiation (LI) is necessary to maximize functional engraftment of donor HSCs. Our data show that the NSC pool and neuroblasts in the SEZ can be significantly and permanently depleted by exposure to LI. Attenuation of donor-derived migratory neuroblast engraftment into the OB is observed after transplantation of gfp + MASCs into the LV of LI animals, whereas engraftment is significantly enhanced after transplantation into animals exposed to sublethal levels of ionizing radiation. By increasing receptiveness of the NSC niche through depletion of indigenous cells, the adult SEZ-RMS-OB can be used as a model to further characterize the NSC. Stem Cells 2005;23:1276-1285

Growth hormone responsive neural precursor cells reside within the adult mammalian brain

“…As expected from previous reports5253 the number of neurosphere-forming cells in saline-infused mice was reduced to approximately 60% of normal (i.e. the number of cells present in non-irradiated (T0) animals), 24 hours following irradiation, rebounding to supra-control levels in the period following ablation (Fig.…”

“…We therefore adopted an in vivo ablation/regeneration approach to distinguish between these two possibilities. Ablation of the dividing cells within the SVZ can be achieved either by the infusion of anti-mitotic agents directly into the ventricle51 or by exposing the brain to ionizing or x-irradiation5253. Given their quiescent nature, NSCs are considered to be largely spared by this process2 as evidenced by efficient regeneration of the region post-irradiation.…”

“…neurosphere and N-CFCA assays) and in vivo assays (immunocytochemistry) as readouts of stem and progenitor cell activity. Based on earlier studies25253, we predicted that if GH was activating normally quiescent NSCs, these activated NSCs would be ablated by subsequent irradiation, resulting in fewer NSC-derived colonies, and a diminished regenerative response. Indeed, this was the case.…”

Stem Cell Therapies for the Resolution of Radiation Injury to the Brain

“…[51] and Marshall et al . [52], which noted the increased survived of neural stem cells transplanted into the brain and multipotent astrocytic stem cells transplanted into the lateral ventricle, respectively. Intramedullary transplantation of neural stem cells three months after local irradiation of the spinal cord were found to significantly ameliorate indications of myelopathy in a rat model [53].…”

Quiescent adult neural stem cells are exceptionally sensitive to cosmic radiation

“…It inhibits cell division and production of new neurons in the subventricular zone (SVZ) and the dentate gyrus (DG), the two main areas of persistent neurogenesis in the adult brain; moreover, suppressed levels of neurogenesis can be observed long after the exposure to radiation (Fike et al, 2007;Marshall et al, 2005;Mizumatsu et al, 2003;Monje et al, 2002;Rola et al, 2004). Given the link between adult neurogenesis and cognitive functions, the radiation-induced suppression of neurogenesis may be causally related to the cognitive deficits observed after radiation therapy; this possibility is now being recognized and countermeasures are being developed to prevent these therapyrelated side effects (Fike et al, 2007;Monje et al, 2003).…”