Peroxisome Proliferator-activated Receptor γ-mediated Regulation of Neural Stem Cell Proliferation and Differentiation

Abstract

Peroxisome proliferator-activated receptor ␥ (PPAR␥) plays an important role in insulin sensitivity, tissue homeostasis, and regulating cellular functions. We found high-level expression of PPAR␥ in embryo mouse brain and neural stem cells (NSCs), in contrast to extremely low levels in adult mouse brain. Here, we show that PPAR␥ mediates the proliferation and differentiation of murine NSCs via upregulation of the epidermal growth factor receptor and activation of the ERK pathway. Cell growth rates of NSCs prepared from heterozygous PPAR␥-deficient mouse brains, PPAR␥-RNA-silenced NSCs, and PPAR␥ dominant-negative NSCs were significantly decreased compared with those of wild-type NSCs. Physiological concentrations of PPAR␥ agonists, rosiglitazone and pioglitazone, stimulated NSC growth, whereas antagonists caused cell death in a concentration-dependent manner via activation of the caspase cascade. The stimulation of cell growth by PPAR␥ was associated with a rapid activation of the ERK pathway by phosphorylation and up-regulation of epidermal growth factor receptor and cyclin B protein levels. In contrast, activation of PPAR␥ by agonists inhibited the differentiation of NSCs into neurons. The inhibition of differentiation was associated with an activation of STAT3. These data indicate that PPAR␥ regulates the development of the central nervous system during early embryogenesis via control of NSC proliferation.It has recently been reported that peroxisome proliferator-activated receptor ␥ (PPAR␥) 3 and its related pathways play an important role in not only insulin sensitivity, but also in regulating other cellular functions and tissue homeostasis (1-3). We have previously reported that endogenous PPAR␥ provides anti-inflammatory activity against inflammatory bowel disease, ischemia-reperfusion injury, and rheumatoid arthritis (4, 5). We also reported an important role of PPAR␥ in the suppression of colon carcinogenesis and hepatocellular carcinoma (6). These reports suggest that the PPAR␥ pathway plays important roles in regulating cellular function and tissue homeostasis. The effects of PPAR␥ on cellular proliferation and differentiation are potentially important to tissues such as the central nervous system that are critically dependent upon an ability to exhibit regeneration postinjury. In the central nervous system, most self-renewal is dependent upon neural stem cells (NSCs) that can be isolated from embryonic brains. NSCs are multipotent and self-renewing progenitor cells that can differentiate into neurons and glial cells (7-9). As such, NSCs are expected to be of utility in the treatment of neurodegenerative disorders, such as Parkinson disease, Huntington disease, nerve injury, stroke, and multiple sclerosis. Likewise, NSCs are not only considered the main source of neurons but are also useful for investigating central nervous system development in vitro. Therefore, many studies have been performed regarding the mechanisms or factors involved in the proliferation and differentiation of NSCs (10 -12). How...

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