Roles of the mammalian subventricular zone in cell replacement after brain injury

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Abstract

The subventricular zones (SVZs) are essential sources of new cells in the developing brain and remnants of these germinal zones persist into adulthood. As these cells have the capacity to replenish neurons and glia that are turning over, many investigators have assessed the SVZ's role in replacing neural cells eliminated by brain injuries. A review of the literature reveals that the progenitors within the SVZs are vulnerable to chemical, radiation and ischemia-induced damage, whereas the neural stem cells are resilient. With moderate insults, the SVZ can recover, but it cannot recover after more severe injury. Thus, the vulnerability of these cells has important ramifications when considering therapeutic interventions for the treatment of brain tumors and for the prospect of recovery after ischemia. The cells of the perinatal and adult SVZ not only have the capacity to replenish their own numbers, but they also have the capacity to replace neurons and glia after ischemic and traumatic brain injuries. Moreover, the mechanisms underlying these regenerative responses are beginning to be revealed. By reviewing, comparing and contrasting the responses of the SVZs to different injuries, our goal is to provide a foundation from which current and future studies on the potential of the SVZs for cell replacement can be evaluated.

Introduction

The subventricular zones (SVZs) are cytoarchitectonically defined regions in the brain that are situated adjacent to the lateral ventricles. The cells of the SVZs are small and densely arranged, and they become readily identifiable during the latter third of embryonic development. This secondary proliferative population of precursors (the ventricular zone (VZ) comprising the primary proliferative population) is referred to by many names in the literature including the subependymal plate, subependymal layer, subependymal zone and the subventricular zone. In this review, we refer to both the prenatal and postnatal equivalents of this secondary proliferative population as the subventricular zone. We have chose to use this term for two reasons: (1) it appears that some VZ cells persist into postnatal development, thus it is appropriate to retain the SVZ designation for these cells (Staugaitis et al., 2001), and (2) this term is more commonly used by investigators actively studying the cells of these regions. In the human brain, the SVZs are quite large, especially in the third trimester, where it is referred to as the germinal matrix. This more general term, however, encompasses the precursor cells in both the VZ and SVZs. Over the last decade, the cells of the SVZs have been intensely studied as a consequence of the discovery that the SVZs harbor neural stem cells (NSCs). Through detailed studies we have come to appreciate the fact that the SVZs are comprised of a mosaic of immature cell types that include multipotential, bipotential, and unipotential stem cells as well as progenitors that are at different stages of lineage restriction (Brazel et al., in press-a, Brazel et al., in press-b; Brazel et al., 2003 ). We begin this review with a discussion of the relative vulnerability of the cells that comprise the SVZ to insult and then evaluate the roles of the SVZs in replacing cells after brain injury.

Section snippets

Effects of ionizing irradiation on the SVZ

The brain is exposed to ionizing irradiation during the management of specific disease states, particularly cancer. In the case of brain tumors, the amount or dose of irradiation that can be given is dictated to a large extent by the tolerance of the normal cells surrounding the tumor (Sheline et al., 1980). Radiation injury is manifold in character, involving damage to multiple regions and cell/tissue types, leading to a variety of structural and functional consequences. Sophisticated

Effects of chemotherapeutic agents on the SVZ

Chemotherapeutic agents are currently used in conjunction with local brain irradiation in the management of a number of neoplastic diseases. While the use of adjuvant chemotherapy has decreased mortality rates for a number of conditions, such as acute lymphoblastic leukemia, complications associated with the CNS have been reported (Lovblad et al., 1998). The character of such changes can be variable, and includes vascular and parenchymal changes. In addition, imaging studies have shown diffuse

Effects of cerebral ischemia on the SVZ

Cerebral hypoxia/ischemia (H/I) caused by an interruption of the blood supply to the brain has devastating consequences for both the very young and the adult brain. For the pre-term infant, H/I is regarded as the foremost cause of perinatal mortality and morbidity. In the United States alone, approximately 30,000 premature infants experience episodes of H/I which result in lifelong handicaps including learning disabilities, mental retardation, epilepsy and cerebral palsy (Robertson and Finer,

Effects of hypoxia on the SVZ

Cerebral hypoxia occurs when the brain receives an inadequate oxygen supply despite normal blood flow. It can result from drowning, carbon monoxide poisoning, strangulation, cardiac arrest, and suffocation, as well as from prolonged exposure to high altitudes. Symptoms, including inattentiveness, dizziness, loss of motor coordination, and memory impairment, are usually mild and may proceed undetected. Cerebral hypoxia is a common component of severe brain insults, including perinatal asphyxia

Mechanical brain injury and the SVZ

Mechanical injuries to the external regions of the brain including the cerebral cortex and other parts of the telencephalon are common yet relatively untreatable (Thurman, 1999). The predicament in recovery from brain injury is that the adult central nervous system is generally thought to be incapable of replacing dead neurons. As the SVZ is now known to be neurogenic and is in close proximity to the cerebral cortex and other functionally important forebrain nuclei, hope has risen that its

Conclusions

It is now evident that the cells in the SVZ that are essential for the development of the brain continue to produce new neurons and glia throughout life. While uncertainties remain regarding how injury develops in and around the SVZ, clearly this structure is sensitive to damage. Studies on the effects of irradiation, chemotherapy, and perinatal H/I all corroborate the relative vulnerability of the progenitors, whereas the neural stem cells are resilient to injury. With moderate insults, the

Acknowledgments

This work was supported by MH 59950 and HD 30705, awarded to SWL, by AHA #0215196U awarded to MJR, by NIH RO1 NS/AG42253-01 awarded to FGS and by R01 CA76141 and R21 NS40088 awarded to JRF. The authors gratefully acknowledge Heather VanGuilder for the editorial assistance.

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