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

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.

Differentiation of hypothalamic-like neurons from human pluripotent stem cells

“…The hypothalamus develops from the ventral diencephalon, where NKX2.1 is highly expressed. High-dose SHH(C24II) treatment efficiently induces the expression of NKX2.1 in human ESCs (23,24). The timing of SHH exposure influ-ences the development of the ventral neuron population in the mouse hypothalamus: early Shh-expressing progenitors contribute to neurons and astrocytes of the tuberal region, while late Shh-expressing progenitors almost exclusively generate astrocytes in mouse hypothalamus development (2).…”

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer׳s and Parkinson׳s diseases

“…Hence, generation of MGE-and LGE-like progenitors from hESCs and hiPSCs through directed differentiation approaches is critical. The methods to generate MGE-like cells from hESCs and hiPSCs are already available Maroof et al, 2013;Liu et al, 2013aLiu et al, , 2013bNicholas et al, 2013). Fig.…”

“…The various steps involved in the generation of gamma-amino butyric acid positive (GABAergic) progenitors from human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) and the utility of these GABA-ergic progenitors for treating conditions such as schizophrenia, Parkinson's disease, Alzheimer's disease and neuropathic pain. As described by Liu et al (2013aLiu et al ( , 2013b, the pluripotent stem cells (PSCs) are first expanded as embryoid bodies in a suspension culture using a chemically defined medium (A, B). The embryoid bodies are next treated with neural induction medium to obtain neural rossettes, which are then lifted and grown in suspension cultures with high doses of sonic hedgehog (Shh) to obtain neurospheres of cells expressing markers of medial ganglionic eminence progenitor cells (NK×2.1+ cells).…”

Regulation of ECM degradation and axon guidance by growth cone invadosomes

“…Human neurons were differentiated from iPSCs as previously described (Gamm et al, 2008;Hu and Zhang, 2009;Liu et al, 2013;Pankratz et al, 2007). Neurospheres were plated onto glass coverslips coated with poly-Dlysine (PDL) and laminin (PDL-LN) and cultured in neural basal media with B27 supplements (Gibco).…”