Abstract
IntroductionThe ability to predetermine the fate of transplanted neural progenitor cells (NPCs) and specifically to direct their maturation has the potential to enhance the efficiency of cell-transplantation therapy for neurodegenerative disease. We previously demonstrated that transient exposure of subventricular zone (SVZ)-derived adult NPCs to lithium chloride during in vitro proliferation alters differential fate in vitro and increases the proportion of cells expressing neuronal markers while reducing glial progeny. To extend these findings, we examined whether in vitro priming of adult SVZ-derived NPCs with lithium chloride before transplantation into the quinolinic acid (QA) lesion rat model of Huntington disease altered in vivo neuronal differentiation and sensorimotor function compared with nonprimed NPC transplants.MethodsNPCs were isolated from the SVZ of the adult rat brain and cultured for 2 weeks. Four days before transplantation into the QA-lesioned rat striatum, the cells were labeled with BrdU and primed with lithium chloride. The rats underwent regular evaluation of forelimb use and sensorimotor neglect to establish functional effects of NPC transplantation. Twelve weeks after transplantation, the brains were analyzed with immunohistochemistry to compare the differential fate of primed and nonprimed NPCs.ResultsWe observed that in vitro priming of adult NPCs with lithium chloride reduced gliogenesis and enhanced the occurrence of DARPP-32-positive neurons when compared with nonprimed cells 12 weeks after transplantation into the QA-lesioned striatum. Lithium chloride priming also augmented the formation of efferent projections from newly formed neurons in the damaged host striatum to the globus pallidus. This was associated with acceleration of sensorimotor function recovery in rats receiving transplants of lithium chloride-primed adult NPCs compared with nonprimed transplants.ConclusionsThese initial findings indicate that in vitro priming of adult NPCs with lithium chloride may augment transplant efficiency and accelerate sensorimotor function outcome in vivo.
Highlights
The ability to predetermine the fate of transplanted neural progenitor cells (NPCs) and to direct their maturation has the potential to enhance the efficiency of cell-transplantation therapy for neurodegenerative disease
With CldU and IdU co-labeling, we identified that the majority of subventricular zone (SVZ)-derived adult NPCs exhibit a cell cycle of 18 to 26 hours
Lithium chloride priming alone did not increase the overall proportion of mature neurons generated from transplanted adult NPCs, our results suggest that lithium chloride priming is able to enhance the phenotypic differentiation and/or maturation of regionally specific DARPP-32 neurons in the quinolinic acid (QA)-lesioned striatum
Summary
The ability to predetermine the fate of transplanted neural progenitor cells (NPCs) and to direct their maturation has the potential to enhance the efficiency of cell-transplantation therapy for neurodegenerative disease. We previously demonstrated that transient exposure of subventricular zone (SVZ)derived adult NPCs to lithium chloride during in vitro proliferation alters differential fate in vitro and increases the proportion of cells expressing neuronal markers while reducing glial progeny To extend these findings, we examined whether in vitro priming of adult SVZ-derived NPCs with lithium chloride before transplantation into the quinolinic acid (QA) lesion rat model of Huntington disease altered in vivo neuronal differentiation and sensorimotor function compared with nonprimed NPC transplants. The supply of human fetal tissue is limited and difficult to develop as a routine systematized source This has led to neural progenitor cell (NPC) populations being investigated as an alternative source of cells for transplantation therapy for HD. As limited neuronal differentiation of transplanted NPCs may result in incomplete functional recovery, it is necessary to develop an effective strategy by which the neuronal fate of NPCs can be predetermined before transplantation
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