Article

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

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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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Acknowledgements

We thank M.E. Andrzejewski and H. Mitchell for help in analyzing animal behavioral data. This study was supported in part by the US National Institute of Neurological Disorders and Stroke (NS045926) and the National Institute of Child Health and Human Development (P30 HD03352).

Author information

Affiliations

  1. Waisman Center, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.

    • Yan Liu
    • , Jason P Weick
    • , Huisheng Liu
    • , Robert Krencik
    • , Xiaoqing Zhang
    • , Lixiang Ma
    • , Melvin Ayala
    •  & Su-Chun Zhang
  2. Department of Human Anatomy and Histology, Fudan University Shanghai Medical School, Shanghai, China.

    • Yan Liu
    • , Lixiang Ma
    •  & Guo-min Zhou
  3. Neuroscience Training Program, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.

    • Robert Krencik
    •  & Su-Chun Zhang
  4. Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.

    • Su-Chun Zhang
  5. Department of Neurology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.

    • Su-Chun Zhang

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Contributions

Y.L. and S.-C.Z. designed the experiments and wrote the manuscript. Y.L., J.P.W., H.L., R.K., X.Z., L.M., G.Z. and M.A. performed the experiments. Y.L., J.P.W., H.L., R.K., X.Z., L.M., M.A. and S.-C.Z. analyzed the data.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Su-Chun Zhang.

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    Supplementary Text and Figures

    Supplementary Figures 1–5, Supplementary Tables 1–4