» Articles » PMID: 23543894

Genome-Scale Mapping of MicroRNA Signatures in Human Embryonic Stem Cell Neurogenesis

Overview
Journal Mol Med Ther
Date 2013 Apr 2
PMID 23543894
Citations 13
Authors
Affiliations
Soon will be listed here.
Abstract

To date, lacking of a clinically-suitable source of engraftable human stem/progenitor cells with adequate neurogenic potential has been the major setback in developing effective cell-based therapies against a wide range of neurological disorders. Derivation of human embryonic stem cells (hESCs) provides a powerful tool to investigate the molecular controls in human embryonic neurogenesis as well as an unlimited source to generate the diversity of human neuronal cell types in the developing CNS for repair. However, realizing the developmental and therapeutic potential of hESCs has been hindered by conventional multi-lineage differentiation of pluripotent cells, which is uncontrollable, inefficient, highly variable, difficult to reproduce and scale-up. We recently identified retinoic acid (RA) as sufficient to induce the specification of neuroectoderm direct from the pluripotent state of hESCs under defined platform and trigger progression to human neuronal progenitors (hESC-I hNuPs) and neurons (hESC-I hNus) in the developing CNS with high efficiency, which enables hESC neuronal lineage-specific differentiation and opens the door to investigate human embryonic neurogenesis using the hESC model system. In this study, genome-scale profiling of microRNA (miRNA) differential expression patterns in hESC neuronal lineage-specific progression was used to identify molecular signatures of human embryonic neurogenesis. These in vitro neuroectoderm-derived human neuronal cells have acquired a neuron al identity by down-regulating pluripotence-associated miRNAs and inducing the expression of miRNAs linked to regulating human CNS development to high levels in a stage-specific manner, including silencing of the prominent pluripotence-associated hsa-miR-302 family and drastic expression increases of the Hox hsa-miR-10 and let-7 miRNAs. Following transplantation, hESC-I hNuPs engrafted and yielded well-integrated neurons at a high prevalence within neurogenic regions of the brain. In 3D culture, these hESC-I hNuPs proceeded to express subtype neuronal markers, such as dopaminergic and motor neurons, demonstrating their therapeutic potential for CNS repair. Our study provides critical insight into molecular neurogenesis in human embryonic development as well as offers an adequate human neurogenic cell source in high purity and large quantity for scale-up CNS regeneration.

Citing Articles

BMPRII neural precursor cells isolated and characterized from organotypic neurospheres: an model of human fetal spinal cord development.

Weible Ii M, Lovelace M, Mundell H, Pang T, Chan-Ling T Neural Regen Res. 2023; 19(2):447-457.

PMID: 37488910 PMC: 10503628. DOI: 10.4103/1673-5374.373669.


The Essential Function of miR-5739 in Embryonic Muscle Development.

Lee J, Kim M, Lee J, Lee D, Park C, Lee D Int J Stem Cells. 2023; 16(2):145-155.

PMID: 36823980 PMC: 10226859. DOI: 10.15283/ijsc22187.


Nutraceutical regulation of miRNAs involved in neurodegenerative diseases and brain cancers.

Ghosh S, Kumar V, Mukherjee H, Lahiri D, Roy P Heliyon. 2021; 7(6):e07262.

PMID: 34195404 PMC: 8225984. DOI: 10.1016/j.heliyon.2021.e07262.


Retinoic acid and microRNA.

Wang L, Rohatgi A, Wan Y Methods Enzymol. 2020; 637:283-308.

PMID: 32359650 PMC: 7445077. DOI: 10.1016/bs.mie.2020.02.009.


High content image analysis reveals function of miR-124 upstream of Vimentin in regulating motor neuron mitochondria.

Yardeni T, Fine R, Joshi Y, Gradus-Pery T, Kozer N, Reichenstein I Sci Rep. 2018; 8(1):59.

PMID: 29311649 PMC: 5758812. DOI: 10.1038/s41598-017-17878-x.


References
1.
Parsons X, Teng Y, Parsons J, Snyder E, Smotrich D, Moore D . Efficient derivation of human neuronal progenitors and neurons from pluripotent human embryonic stem cells with small molecule induction. J Vis Exp. 2011; (56):e3273. PMC: 3227216. DOI: 10.3791/3273. View

2.
Roy N, Cleren C, Singh S, Yang L, Beal M, Goldman S . Functional engraftment of human ES cell-derived dopaminergic neurons enriched by coculture with telomerase-immortalized midbrain astrocytes. Nat Med. 2006; 12(11):1259-68. DOI: 10.1038/nm1495. View

3.
Aubry L, Bugi A, Lefort N, Rousseau F, Peschanski M, Perrier A . Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc Natl Acad Sci U S A. 2008; 105(43):16707-12. PMC: 2575484. DOI: 10.1073/pnas.0808488105. View

4.
Thomson J, Itskovitz-Eldor J, Shapiro S, Waknitz M, Swiergiel J, Marshall V . Embryonic stem cell lines derived from human blastocysts. Science. 1998; 282(5391):1145-7. DOI: 10.1126/science.282.5391.1145. View

5.
Mikkelsen T, Ku M, Jaffe D, Issac B, Lieberman E, Giannoukos G . Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007; 448(7153):553-60. PMC: 2921165. DOI: 10.1038/nature06008. View