Ischemia-Induced Neurogenesis: Role of Growth Factors
Section snippets
Growth factors and neurogenesis
Neurogenesis involves the proliferation, differentiation, and maturation of neural progenitor/stem cells into different types of cells in the brain and the integration of the resulting cells into the brain circuitry. Although several growth factors promote neurogenesis by stimulating the proliferation and inducing the differentiation of neural progenitor/stem cells [4], [10], the exact sequence of events that stimulates differentiation after proliferation in vivo is not clear. Most growth
Stroke-induced neurogenesis
Ischemia-induced neurogenesis has been well studied in a variety of animals and stroke models [12], [13]. The progenitor cells in the subventricular zone and the dentate gyrus proliferate in response to cerebral ischemia. Neurogenesis after ischemic damage may be attributable to the release of endogenous growth factors or chemokines by the ischemic tissue. Gene expression analysis using DNA microarrays identified the differential regulation of several genes after ischemia [12]. The transcripts
Brain-derived neurotrophic factor
BDNF, a member of nerve growth factor (NGF) family of neurotrophic factors, is required for the proliferation, differentiation, and survival of specific neurons in the brain. In the adult brain, ischemia increases the expression of BDNF [15] and its receptor, trk B, [16] to enhance neuroprotection and neurogenesis [17]. Consistent with this observation, BDNF knockout mice produced larger infarcts [18], whereas blockade of endogenous BDNF decreased the survival of neurons after an ischemic
Glial cell line–derived neurotrophic factor
GDNF is a potent neurotrophic factor belonging to the transforming growth factor-β superfamily, which is involved in the survival and differentiation of neurons [25]. Cerebral ischemia has been shown to upregulate the GDNF content [26], [27] and induce neuroprotection in the ischemic brain [26], [28]. Conflicting studies have shown that long-term treatment with GDNF may increase the infarct size after ischemia, however [29]. In addition, pretreatment with GDNF was shown to enhance the death of
Epidermal growth factor
EGF is a mitogen known to be involved in the proliferation of adult neural progenitor/stem cells. Previous studies using exogenous EGF in ischemic animals have demonstrated replacement of 20% of the interneurons that would have died after ischemia, suggesting the potential to use EGF for manipulating endogenous neurogenesis and to promote brain repair [32]. Heparin-binding epidermal growth factor–like growth factor (HB-EGF-GF) is a hypoxia-inducible protein involved in neurogenesis. Studies
Fibroblast growth factor-2 or basic fibroblast growth factor
FGF2 or bFGF is a heparin-binding protein involved in the regulation of neurogenesis in the brain [5], [37]. In normal rat brain, deletion of the FGF2 gene reduces the progenitor cell population by 50% in the anterior subventricular zone (SVZa), supporting a role for FGF2 in neural progenitor proliferation [38]. Previous studies have shown upregulated expression of FGF2 in the brain after ischemic injury [39]. Deletion of the FGF2 gene decreased the total number of newborn cells in the dentate
Insulin-like growth factor-I
IGF-I plays a major role in the growth and development of the brain [7], [10]. Although IGF-I is primarily produced in the liver, the brain can also synthesize this peptide [46], implicating a role for endogenous IGF-I in neurogenesis. Several studies have shown that administration of IGF-I reduced neuronal loss [47] and enhanced neurogenesis [8], [48] after cerebral ischemia. In contrast, an earlier study demonstrated the lack of neuroprotection by IGF-I and implicated the disruption of the
Platelet-derived growth factors
Platelet-derived growth factors (PDGFs) are a family of dimeric ligands composed of four polypeptide chains (PDGF-A, PDGF-B, PDGF-C, and PDGF-D) that bind to their receptors PDGFR-α and PDGFR-β. PDGF-B and its receptor, PDGF-β, are highly expressed in the neurons of the central nervous system, however, which are implicated in nerve regeneration and glial cell proliferation [57], [58]. Thus, a role for PDGF in neuroprotection was proposed [59]. These studies are supported by a recent report
Summary
The neurogenic response in ischemic brain to growth factors is the net result of cell division and cell survival in specific regions of the brain. To increase the cell number, these physiologic processes should be active. Hence, when growth factors are infused into the brain, they might stimulate survival, cell division, or both to enhance neurogenesis. It should be noted that the withdrawal of growth factors (mitogens) in vitro leads to the differentiation of progenitor cells. Because the
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This work was supported by National Institutes of Health grant 5RO1NS045143 (R.J. Dempsey) and the Department of Neurological Surgery, University of Wisconsin.