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

Nature Biotechnology volume 31, pages 440–447 (2013)Cite this article

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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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Figure 1: SHH-dependent specification of basal forebrain progenitors from hESCs.
Figure 2: Differentiation of basal forebrain progenitors to cholinergic neurons and GABAergic interneurons.
Figure 3: Survival, proliferation and differentiation of grafted cells in lesioned hippocampi.
Figure 4: Differentiation and integration of grafted GABA+ neurons.
Figure 5: Differentiation and integration of cholinergic neurons.
Figure 6: Transplantation of hESC-derived MGE progenitors contributes to functional recovery.

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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).

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Authors and 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.

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Correspondence to Su-Chun Zhang.

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Liu, Y., Weick, J., Liu, H. et al. Medial ganglionic eminence–like cells derived from human embryonic stem cells correct learning and memory deficits. Nat Biotechnol 31, 440–447 (2013). https://doi.org/10.1038/nbt.2565

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