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


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.

Download full-text


Available from: Huisheng Liu, Sep 09, 2014
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Degeneration of basal forebrain cholinergic neurons (BFCNs) is associated with cognitive impairments of Alzheimer's disease (AD), implying that BFCNs hold potentials in exploring stem cell-based replacement therapy for AD. However, studies on derivation of BFCNs from embryonic stem cells (ESCs) are limited, and the application of ESC-derived BFCNs remains to be determined. Here, we report on differentiation approaches for directing both mouse and human ESCs into mature BFCNs. These ESC-derived BFCNs exhibit features similar to those of their in vivo counterparts and acquire appropriate functional properties. After transplantation into the basal forebrain of AD model mice, ESC-derived BFCN progenitors predominantly differentiate into mature cholinergic neurons that functionally integrate into the endogenous basal forebrain cholinergic projection system. The AD mice grafted with mouse or human BFCNs exhibit improvements in learning and memory performances. Our findings suggest a promising perspective of ESC-derived BFCNs in the development of stem cell-based therapies for treatment of AD.
    Full-text · Article · Oct 2015 · Stem Cell Reports
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over recent years tremendous progress has been made towards understanding the molecular and cellular mechanism by which estrogens exert enhancing effects on cognition, and how they act as a neuroprotective or neurotrophic agent in disease. Currently, much of this work has been carried out in animal models with only a limited number of studies using native human tissue or cells. Recent advances in stem cell technology now make it possible to reprogram somatic cells from humans into induced pluripotent stem cells (iPSCs), which can subsequently be differentiated in neurons of specific lineages. Importantly, the reprogramming of cells allows for the generation of iPSCs that retains the genetic "makeup" of the donor. Therefore, it is possible to generate iPSC-derived neurons from patients diagnosed with specific diseases, that harbor the complex genetic background associated with the disorder. Here, we review the iPSC technology and how its currently being used to model neural development and neurological diseases. Furthermore, we explore whether this cellular system could be used to understand the role of estrogens in human neurons, and present preliminary data in support of this. We further suggest that the use of iPSC technology offers a novel system in which to not only further understand estrogens' effects in human cells, but in which to investigate the mechanism by which estrogens are beneficial in disease. Developing a greater understanding of these mechanisms in native human cells will also aid in the development of safer and more effective estrogen-based therapeutics. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Hormones and Behavior
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroregeneration (NR) is a long-sought medical dream which has intrigued vast research in the past decades. A traditional physiologic dogma that central nervous system does not regenerate has been strongly challenged in the recent years since the advent of the stem cell era. Stem cell research in the regenerative field passes through three main stages. The first stage is the in-vitro experiments which studies the exact molecular and cellular mechanisms underlying stem cell-mediated NR. The second stage is the application of these data in experimental animal settings to provide "proof of concept" of stem cell therapy in animal models. The final step is the translation of these data in pilot clinical trials. In this review, we will try to gather the different data of stem cell-mediated NR from various experimental and clinical researches.
    Full-text · Article · Jun 2015
Show more