Article

Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits

1] Waisman Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA. [2] Department of Human Anatomy and Histology, Fudan University Shanghai Medical School, Shanghai, China.
Nature Biotechnology (Impact Factor: 41.51). 04/2013; DOI: 10.1038/nbt.2565
Source: PubMed

ABSTRACT

Dysfunction of basal forebrain cholinergic neurons (BFCNs) and γ-aminobutyric acid (GABA) interneurons, derived from medial ganglionic eminence (MGE), is implicated in disorders of learning and memory. Here we present a method for differentiating human embryonic stem cells (hESCs) to a nearly uniform population of NKX2.1(+) MGE-like progenitor cells. After transplantation into the hippocampus of mice in which BFCNs and some GABA neurons in the medial septum had been destroyed by mu P75-saporin, human MGE-like progenitors, but not ventral spinal progenitors, produced BFCNs that synaptically connected with endogenous neurons, whereas both progenitors generated similar populations of GABA neurons. Mice transplanted with MGE-like but not spinal progenitors showed improvements in learning and memory deficits. These results suggest that progeny of the MGE-like progenitors, particularly BFCNs, contributed to learning and memory. Our findings support the prospect of using human stem cell-derived MGE-like progenitors in developing therapies for neurological disorders of learning and memory.

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Available from: Huisheng Liu, Sep 09, 2014
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    • "The functional properties of human ESC-derived BFCNs have been investigated after transplantation into murine hippocampal slice cultures (Bissonnette et al., 2011) or into severe combined immunodeficiency mice with a destroyed medial septum by muP75-saporin but not into AD model mice (Liu et al., 2013). Thus, it remains unknown whether mouse or human ESCs can efficiently differentiate into BFCNs and whether mouse and human ESC-derived BFCNs can restore cholinergic function and alleviate cognitive deficits in AD transgenic mice. "
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    • "In a related study, this group reported the use of this method to successfully direct the differentiation of hESCs to medial ganglionic eminence progenitors and subsequently, GABA interneurons (Liu et al., 2013b). Interestingly, the transplantation of hESC-derived medial ganglionic eminence progenitors to the hippocampi of mice led to behavioural changes in learning and memory (Liu et al., 2013b). These findings show that in addition to the study of basic neurobiology, hiPSCs and hESCs can be also used to investigate behaviours associated with specific neuronal subtypes. "
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    • "This procedure also increase neutrotrophic factor levels and lead to behavioral improvement without changing the pathogenesis of AD, among these neurotrophic factors: brain-derived neurotrophic factor (BDNF) which is critically important in hippocampus & entorhinal cortex and nerve growth factor (NGF) which affect the function of cholinergic neurons in forebrain[81]. Also NSCs transplantation was found to elevate glial-derived neurotrophic factor (GDNF) in transgenic models of AD[82]. However, NSCs itself did not affect significantly the Aβ plaques of mice models But it was found to be helpful is replacing the cells and thus improve the course of AD[83]. "
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