Mobilization of Neural Stem Cells and Generation of New Neurons in 6-OHDA–lesioned Rats by Intracerebroventricular Infusion of Liver Growth Factor

Abstract

S U M M A R Y Neural stem cells with self-renewal and multilineage potential persist in the subventricular zone of the adult mammalian forebrain. These cells remain relatively quiescent but, under certain conditions, can be stimulated, giving rise to new neurons. Liver growth factor (LGF) is a mitogen for liver cells that shows biological activity in extrahepatic sites and is useful for neuroregenerative therapies. The aim of this study was to investigate the potential neurogenic activity of LGF in the 6-hydroxydopamine rat model of Parkinson's disease. Proliferation was significantly increased in the subventricular zone and denervated striatum of rats receiving ICV LGF infusions, and 25% of the proliferating cells were doublecortin-positive neurons. Doublecortin-positive cells with the morphology of migrating neuroblasts were also observed in the dorsal and ventral regions of the striatum of LGF-infused animals. Moreover, some newly generated cells were neuronal nuclei-positive mature neurons.LGF also stimulated microglia and induced astrogliosis, both phenomena associated with generation and migration of new neurons in the adult brain. In summary, our study shows that LGF stimulates neurogenesis when applied intraventricularly in 6-hydroxydopamine-lesioned rats. Considering that this factor also promotes neuronal migration into damaged tissue, we propose LGF as a novel factor useful for neuronal replacement in neurodegenerative diseases. (J Histochem Cytochem 57:491-502, 2009)

Liver growth factor treatment restores cell-extracellular matrix balance in resistance arteries and improves left ventricular hypertrophy in SHR

“…LGF was also able to increase endothelial cell number, as previously described in intraparenquimal cerebral vessels from rats treated with LGF (35). All these data suggest that LGF acts as mitogen for vascular cells, and it is able to normalize the imbalance between decreased cell number-excessive ECM production in the vascular wall.…”

“…We have previously demonstrated that the excessive ECM deposition by VSMC from SHR is related to a cellular defect in SHR, consisting of defective proliferation, but enhanced cell survival of hypertrophied diploid cells, which keep producing ECM, without normal turnover (7). On the other hand, the regenerative actions of LGF in several biological systems have been linked to its mitogenic effects (26,27,35,52). In our previous study, we also reported that LGF was able to improve the reduced VSMC density and abnormally high ploidy in carotid arteries from SHR.…”

“…The aim of the present study has been to gain further insight in the regenerative cardiovascular actions of LGF treatment in SHR, assessing its effects on intramyocardial and mesenteric resistance arteries (MRA) and LVH. Furthermore, we have investigated if the restoration of arterial cell/ECM disbalance by this factor is linked to a mitogenic effect on vascular smooth muscle cells (VSMC), as previously described in other cell types (26,35,52). …”

“…The chemical analysis of LGF obtained from human and rat plasma has revealed that it is a covalently bound albumin-bilirubin complex (24,25). The regenerative effects of LGF, initially described in hepato-biliary disorders (22,23,26), have been recently extended to other diseases, such as Parkinson's disease (35,52), testicular degeneration (51), and pulmonary fibrosis (47).…”

Liver growth factor treatment reverses emphysema previously established in a cigarette smoke exposure mouse model

“…In view of the results obtained in this study, what seems clear is that LGF treatment promotes tissue regeneration, probably by promoting cell proliferation (7,18,39,42) of the lung parenchyma. Maybe the LGF stimulates cellular antioxidant response (8,9) or decreases cellular apoptotic processes (13).…”