Regulation of endogenous neural stem/progenitor cells for neural repair—factors that promote neurogenesis and gliogenesis in the normal and damaged brain

Abstract

Neural stem/precursor cells in the adult brain reside in the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus. These cells primarily generate neuroblasts that normally migrate to the olfactory bulb (OB) and the dentate granule cell layer respectively. Following brain damage, such as traumatic brain injury, ischemic stroke or in degenerative disease models, neural precursor cells from the SVZ in particular, can migrate from their normal route along the rostral migratory stream (RMS) to the site of neural damage. This neural precursor cell response to neural damage is mediated by release of endogenous factors, including cytokines and chemokines produced by the inflammatory response at the injury site, and by the production of growth and neurotrophic factors. Endogenous hippocampal neurogenesis is frequently also directly or indirectly affected by neural damage. Administration of a variety of factors that regulate different aspects of neural stem/precursor biology often leads to improved functional motor and/or behavioral outcomes. Such factors can target neural stem/precursor proliferation, survival, migration and differentiation into appropriate neuronal or glial lineages. Newborn cells also need to subsequently survive and functionally integrate into extant neural circuitry, which may be the major bottleneck to the current therapeutic potential of neural stem/precursor cells. This review will cover the effects of a range of intrinsic and extrinsic factors that regulate neural stem/precursor cell functions. In particular it focuses on factors that may be harnessed to enhance the endogenous neural stem/precursor cell response to neural damage, highlighting those that have already shown evidence of preclinical effectiveness and discussing others that warrant further preclinical investigation.

Selective lesion of the hippocampus increases the differentiation of immature neurons in the monkey amygdala

“…Additionally, although a number of cellular mechanisms involved in the regulation of postnatal neurogenesis in neurogenic brain regions have been identified (16), the specific factors that may induce the differentiation of immature neurons in nonneurogenic regions are largely unknown. Among general factors that impact cell proliferation in neurogenic regions (17), focal brain lesions may also influence the differentiation of immature neurons in the postnatal monkey amygdala.…”

Transplantation of Cryopreserved Human Umbilical Cord Blood Mononuclear Cells Does Not Induce Sustained Recovery after Experimental Stroke in Spontaneously Hypertensive Rats

“…23 While the regulation of ischemia-induced neurogenesis is poorly understood, various growth factors are known to be implicated in precursor cell proliferation in the subventricular zone as well as in chemotaxis toward the sites of injury and survival of neuroblasts in the ischemic border zone. 24 In this context, the ability of HUCB MNC to increase local growth factor levels after stroke, either by direct secretion or by inducing host expression, 9 is supposed to be a major mediator of the reported beneficial effects. In this study, we found a rapid increase of endogenous BDNF, nerve growth factor, and basic fibroblast growth factor mRNA after the ischemic injury; however, HUCB MNC treatment did not further augment these levels within 48 hours after stroke.…”

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell Replacement Therapy for either Huntington’s or Parkinson’s Disease

“…Specific functions that rely upon neurogenesis include new learning for the hippocampus [69], and rich olfactory sensory experience for the olfactory bulb [70]. As this occurs regularly in an activity-dependent manner already, it stands to reason that neuronal precursors transplanted into these regions would be more likely to receive signals encouraging their incorporation into either the hippocampus or the olfactory bulb, and in fact, this seems to be the case [71,72]. Yet in other regions such as the striatum (the main input structure of the basal ganglia), the capacity of endogenous neuronal progenitors to become neurons seems reduced compared to exogenous transplantations [73].…”