1: Brain Res. 2006 Jan 30; [Epub ahead of print] Links

Induction of neuronal differentiation of adult human olfactory neuroepithelial-derived progenitors.

Zhang X, Klueber KM, Guo Z, Cai J, Lu C, Winstead WI, Qiu M, Roisen FJ.

Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, 500 South Preston Street, Louisville, KY 40202, USA.

Neurosphere forming cells (NSFCs) have been established from cultures of adult olfactory neuroepithelium obtained from patients and cadavers as described previously. They remained undifferentiated in serum or defined media with or without neurotrophic factors. Many factors affect the differentiation of stem cells along a neuronal pathway. Retinoic acid (RA), forskolin (FN), and sonic hedgehog (Shh) have been reported to act as growth promoters during neurogenesis of embryonic CNS in vivo. The effect of RA, FN, and Shh on NSFCs' neuronal lineage restriction has not been described. The application of RA, FN, and Shh to NSFCs induced the expression of motoneuronal transcription factors, tyrosine hydroxylase, an indicator of dopamine production, and neurite formation. These studies further heighten the potential for using olfactory neuroepithelial progenitors for future autologous cell replacement strategies in neurodegenerative conditions and trauma as well as for use in diagnostic evaluation.

Stem Cells. 2006 Feb 2;

Activin A maintains self-renewal and regulates FGF, Wnt and BMP pathways in human embryonic stem cells.

Xiao L, Yuan X, Sharkis SJ.

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Human embryonic stem cells (hESCs) self-renew indefinitely while maintaining pluripotency. The molecular mechanism underlying hESCs self-renewal and pluripotency is poorly understood. In order to identify the signaling pathway molecules that maintain the proliferation of hESCs, we performed a microarray analysis comparing an aneuploid H1 hESC line (named H1T) versus euploid H1 hESC line because the H1T hESC line demonstrates a self-renewal advantage while maintaining pluripotency. We find differential gene expression for the Nodal/Activin, FGF, Wnt and Hedgehog signaling pathways in the H1T line which implicates each of these molecules in maintaining the undifferentiated state; whereas the BMP and Notch pathways could promote hESCs differentiation. Experimentally, Activin A we find is necessary and sufficient for the maintenance of self-renewal and pluripotency of hESCs and supports longterm feeder and serum free growth of hESCs. We show Activin A induced the expression of Oct4, Nanog, Nodal, Wnt3, bFGF and FGF8 and suppressed the BMP signal. Our data indicates Activin A is a key regulator in maintenance of the stemness in hESCs. This finding will help elucidate the complex signaling network which maintains the hESC phenotype and function.

Curr Alzheimer Res. 2006 Feb;3(1):5-10. Related Articles, Links

Small molecule approaches for promoting neurogenesis.

Longo FM, Yang T, Xie Y, Massa SM.

Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. longof@neurology.unc.edu.

The discovery of small molecules capable of promoting neurogenesis will contribute to the elucidation of the physiological roles of neurogenesis and to novel therapeutic approaches. Small molecule development can be targeted to the promotion of precursor proliferation, survival, migration or maturation and might be applied to augmenting physiological neurogenesis already present in the dentate gyrus or subventricular zone/olfactory bulb or to normally non-neurogenic regions relevant to neuropathological states. Current small molecule discovery can be assessed from the perspective of the following categories: compounds modulating physiological signaling pathways regulating neurogenesis including the sonic hedgehog, bone morphogenic protein Wnt/,-catenin, Notch and chemokine systems; growth factor mimetics; protein tyrosine phosphatase inhibitors; existing drugs including antidepressants, lithium, valproate, sidenafil and statins; hormones, steroids and peptides; and neurotransmitter receptor agonists and antagonists. Unbiased, high throughput screening will likely lead to the discovery of additional active compounds and the recognition of novel mechanisms regulating neurogenesis. A major therapeutic challenge will consist of the identification of molecular targets and mechanisms relatively specific for precursor cells of interest.

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