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).
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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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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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DOI: https://doi.org/10.1038/nbt.2565
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