Directed Differentiation of Embryonic Stem Cells into Motor Neurons

doi:10.1016/S0092-8674(02)00835-8

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Directed Differentiation of Embryonic Stem Cells into Motor Neurons

Journal Article•DOI•

Directed Differentiation of Embryonic Stem Cells into Motor Neurons

Hynek Wichterle¹, Ivo Lieberam¹, Jeffery A. Porter, Thomas M. Jessell¹•Institutions (1)

Howard Hughes Medical Institute¹

09 Aug 2002-Cell (Cell Press)-Vol. 110, Iss: 3, pp 385-397

TL;DR: It is shown that developmentally relevant signaling factors can induce mouse embryonic stem cells to differentiate into spinal progenitor cells, and subsequently into motor neurons, through a pathway recapitulating that used in vivo.

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About: This article is published in Cell.The article was published on 2002-08-09 and is currently open access. It has received 1763 citations till now. The article focuses on the topics: Motor neuron & Neurogenesis.

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Journal Article•DOI•

A ROCK inhibitor permits survival of dissociated human embryonic stem cells

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Kiichi Watanabe¹, Morio Ueno, Daisuke Kamiya, Ayaka Nishiyama, Michiru Matsumura, Takafumi Wataya², Jun Takahashi², Satomi Nishikawa, Shin-Ichi Nishikawa, Keiko Muguruma, Yoshiki Sasai - Show less +7 more•Institutions (2)

California Institute of Technology¹, Kyoto University²

27 May 2007-Nature Biotechnology

TL;DR: Application of a selective Rho-associated kinase (ROCK) inhibitor, Y-27632, to hES cells markedly diminishes dissociation-induced apoptosis, increases cloning efficiency and facilitates subcloning after gene transfer, and enables SFEB-cultured hES Cells to survive and differentiate into Bf1+ cortical and basal telencephalic progenitors.

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Abstract: Poor survival of human embryonic stem (hES) cells after cell dissociation is an obstacle to research, hindering manipulations such as subcloning. Here we show that application of a selective Rho-associated kinase (ROCK) inhibitor1,2, Y-27632, to hES cells markedly diminishes dissociation-induced apoptosis, increases cloning efficiency (from ∼1% to ∼27%) and facilitates subcloning after gene transfer. Furthermore, dissociated hES cells treated with Y-27632 are protected from apoptosis even in serum-free suspension (SFEB) culture3 and form floating aggregates. We demonstrate that the protective ability of Y-27632 enables SFEB-cultured hES cells to survive and differentiate into Bf1+ cortical and basal telencephalic progenitors, as do SFEB-cultured mouse ES cells.

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2,094 citations

Journal Article•DOI•

Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons.

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John T. Dimos¹, Kit T. Rodolfa¹, Kathy K. Niakan¹, Laurin M. Weisenthal¹, Hiroshi Mitsumoto², Wendy K. Chung³, Wendy K. Chung², Gist F. Croft², Genevieve Saphier¹, Rudy Leibel³, Robin Goland², Hynek Wichterle², Christopher E. Henderson², Kevin Eggan¹ - Show less +10 more•Institutions (3)

Harvard University¹, Columbia University Medical Center², Columbia University³

29 Aug 2008-Science

TL;DR: Induced pluripotent stem cells are generated from an 82-year-old woman diagnosed with a familial form of amyotrophic lateral sclerosis and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS.

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Abstract: The generation of pluripotent stem cells from an individual patient would enable the large-scale production of the cell types affected by that patient's disease. These cells could in turn be used for disease modeling, drug discovery, and eventually autologous cell replacement therapies. Although recent studies have demonstrated the reprogramming of human fibroblasts to a pluripotent state, it remains unclear whether these induced pluripotent stem (iPS) cells can be produced directly from elderly patients with chronic disease. We have generated iPS cells from an 82-year-old woman diagnosed with a familial form of amyotrophic lateral sclerosis (ALS). These patient-specific iPS cells possess properties of embryonic stem cells and were successfully directed to differentiate into motor neurons, the cell type destroyed in ALS.

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1,980 citations

Journal Article•DOI•

Differentiation of embryonic stem cells to clinically relevant populations: lessons from embryonic development.

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Charles E. Murry¹, Gordon Keller²•Institutions (2)

University of Washington¹, University Health Network²

22 Feb 2008-Cell

TL;DR: The potential to generate virtually any differentiated cell type from embryonic stem cells (ESCs) offers the possibility to establish new models of mammalian development and to create new sources of cells for regenerative medicine, but it is essential to be able to control ESC differentiation and to direct the development of these cells along specific pathways.

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1,695 citations

Cites background from "Directed Differentiation of Embryon..."

...Wichterle et al. (2002) were the first to derive a protocol for the directed differentiation of ESCs to a specific neural type, using induction with retinoic acid and a sonic hedgehog analog to induce transplantable murine spinal motor neurons (Wichterle et al., 2002)....
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Journal Article•DOI•

Spinal-cord injury

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John W. McDonald¹, Cristina L. Sadowsky¹•Institutions (1)

Washington University in St. Louis¹

02 Feb 2002-The Lancet

TL;DR: An overview of the newer therapeutic interventions employed in the care of the spinal cord injured individual and the theoretical rationale supporting them is presented.

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1,581 citations

Journal Article•DOI•

Induced pluripotent stem cells from a spinal muscular atrophy patient

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Allison D. Ebert¹, Junying Yu¹, Ferrill F. Rose², Virginia B. Mattis², Christian L. Lorson², James A. Thomson¹, Clive N. Svendsen - Show less +3 more•Institutions (2)

University of Wisconsin-Madison¹, University of Missouri²

15 Jan 2009-Nature

TL;DR: This is the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease and represents a promising resource to study disease mechanisms, screen new drug compounds and develop new therapies.

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Abstract: Spinal muscular atrophy is one of the most common inherited forms of neurological disease leading to infant mortality. Patients have selective loss of lower motor neurons resulting in muscle weakness, paralysis and often death. Although patient fibroblasts have been used extensively to study spinal muscular atrophy, motor neurons have a unique anatomy and physiology which may underlie their vulnerability to the disease process. Here we report the generation of induced pluripotent stem cells from skin fibroblast samples taken from a child with spinal muscular atrophy. These cells expanded robustly in culture, maintained the disease genotype and generated motor neurons that showed selective deficits compared to those derived from the child’s unaffected mother. This is the first study to show that human induced pluripotent stem cells can be used to model the specific pathology seen in a genetically inherited disease. As such, it represents a promising resource to study disease mechanisms, screen new drug compounds and develop new therapies. The inherited disease spinal muscular atrophy (SMA), one of the most common neurological disorders causing death in childhood, is caused by mutations in both copies of the SMN1 gene. Little is known about SMA pathogenesis, partly because it is unique to humans who have two versions of this gene — SMN1 and SMN2; rodents and other lab model candidates have just one. Now a new technique has been developed that creates a tool for studying SMA disease pathology at the cellular level. Skin fibroblasts from a child with SMA (and for comparison from his unaffected mother) were used to generate induced pluripotent stem (iPS) cell lines. They form neural progenitor cultures that can produce differentiated neural tissue and motor neurons that maintain the disease phenotype. The cultures also responded to drugs known to elevate the mutated protein associated with the disease. Similar iPS technology may be of value in the study of other genetic disorders such as Huntington's disease. This paper generates an iPS cell line from patients with spinal muscular atrophy, an autosomal recessive genetic disorder that is one of the most common inherited forms of neurological disease in children.

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1,495 citations

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References

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Journal Article•DOI•

Mammalian neural stem cells.

[...]

Fred H. Gage¹•Institutions (1)

Salk Institute for Biological Studies¹

25 Feb 2000-Science

TL;DR: Before the full potential of neural stem cells can be realized, the authors need to learn what controls their proliferation, as well as the various pathways of differentiation available to their daughter cells.

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Abstract: Neural stem cells exist not only in the developing mammalian nervous system but also in the adult nervous system of all mammalian organisms, including humans. Neural stem cells can also be derived from more primitive embryonic stem cells. The location of the adult stem cells and the brain regions to which their progeny migrate in order to differentiate remain unresolved, although the number of viable locations is limited in the adult. The mechanisms that regulate endogenous stem cells are poorly understood. Potential uses of stem cells in repair include transplantation to repair missing cells and the activation of endogenous cells to provide "self-repair. " Before the full potential of neural stem cells can be realized, we need to learn what controls their proliferation, as well as the various pathways of differentiation available to their daughter cells.

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4,608 citations

"Directed Differentiation of Embryon..." refers background in this paper

...ES cells have been reported to gen-tissue (Alvarez-Buylla et al., 2001; Gage, 2000; Uchida erate cells with some of the molecular characteristicset al., 2000), nonneural progenitor cells derived from of MNs (Renoncourt et al., 1998), but neither the pathwayother tissues and organs (Brazelton et…...
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...Studies of the neurogenic potential of progenitor cells have focused on three major classes of cells: neural progenitors derived from embryonic or adult nervous tissue (Alvarez-Buylla et al., 2001; Gage, 2000; Uchida et al., 2000), nonneural progenitor cells derived from other tissues and organs (Brazelton et al....
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Journal Article•DOI•

Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.

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Chin Chiang¹, Ying Litingtung¹, Eric Lee, Keith E. Young¹, Jeffrey L Corden¹, Heiner Westphal, Philip A. Beachy¹ - Show less +3 more•Institutions (1)

Johns Hopkins University School of Medicine¹

03 Oct 1996-Nature

TL;DR: Targeted gene disruption in the mouse shows that the Sonic hedgehog(Shh) gene plays a critical role in patterning of vertebrate embryonic tissues, including the brain and spinal cord, the axial skeleton and the limbs.

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Abstract: Targeted gene disruption in the mouse shows that the Sonic hedgehog (Shh) gene plays a critical role in patterning of vertebrate embryonic tissues, including the brain and spinal cord, the axial skeleton and the limbs. Early defects are observed in the establishment or maintenance of midline structures, such as the notochord and the floorplate, and later defects include absence of distal limb structures, cyclopia, absence of ventral cell types within the neural tube, and absence of the spinal column and most of the ribs. Defects in all tissues extend beyond the normal sites of Shh transcription, confirming the proposed role of Shh proteins as an extracellular signal required for the tissue-organizing properties of several vertebrate patterning centres.

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3,084 citations

"Directed Differentiation of Embryon..." refers background in this paper

...MN generation from ES cellderived spinal progenitors, as in vivo (Chiang et al., 1996), is completely dependent on Hh signaling....
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...Recent studies have suggested a role for inhibition of BMP signaling in neural induction in ESES cell-derived spinal progenitors, as in vivo (Chiang et al., 1996), is completely dependent on Hh signaling. cells (Gratsch and O’Shea, 2002; Tropepe et al., 2001), but additional studies are needed to…...
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Journal Article•DOI•

Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion

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Naohiro Terada¹, Takashi Hamazaki¹, Masahiro Oka¹, Masanori Hoki¹, Diana M. Mastalerz¹, Yuka Nakano¹, Edwin M. Meyer¹, Laurence Morel¹, Bryon E. Petersen¹, Edward W. Scott¹ - Show less +6 more•Institutions (1)

University of Florida¹

04 Apr 2002-Nature

TL;DR: It is demonstrated that mouse bone marrow cells can fuse spontaneously with embryonic stem cells in culture in vitro that contains interleukin-3, which, without detailed genetic analysis, might be interpreted as ‘dedifferentiation’ or transdifferentiation.

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Abstract: Recent studies have demonstrated that transplanted bone marrow cells can turn into unexpected lineages including myocytes, hepatocytes, neurons and many others. A potential problem, however, is that reports discussing such 'transdifferentiation' in vivo tend to conclude donor origin of transdifferentiated cells on the basis of the existence of donor-specific genes such as Y-chromosome markers. Here we demonstrate that mouse bone marrow cells can fuse spontaneously with embryonic stem cells in culture in vitro that contains interleukin-3. Moreover, spontaneously fused bone marrow cells can subsequently adopt the phenotype of the recipient cells, which, without detailed genetic analysis, might be interpreted as 'dedifferentiation' or transdifferentiation.

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2,071 citations

"Directed Differentiation of Embryon..." refers background in this paper

...Analysis of the Certain cell populations have been reported to undergo fusion with somatic cells (Terada et al., 2002; Ying pattern of peripheral projections of eGFP motor axons in stage 27 embryos revealed that HBG3 ES cell-derived et al., 2002) prompting us to test the possibility that HBG3 ES cell-derived eGFP /HB9 MNs might have MNs grafted at rostral cervical levels projected to axial musculature (data not shown), MNs grafted at thoracic formed somatic hybrids with chick neurons....
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...…progenitor cells derived from of MNs (Renoncourt et al., 1998), but neither the pathwayother tissues and organs (Brazelton et al., 2000; Mezey of generation of these neurons nor their developmentalet al., 2000; Terada et al., 2002; Ying et al., 2002), and potential in vivo have been explored....
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..., 1998), but neither the pathway other tissues and organs (Brazelton et al., 2000; Mezey of generation of these neurons nor their developmental et al., 2000; Terada et al., 2002; Ying et al., 2002), and potential in vivo have been explored....
[...]
...Analysis of theCertain cell populations have been reported to un- dergo fusion with somatic cells (Terada et al., 2002; Ying pattern of peripheral projections of eGFP motor axons in stage 27 embryos revealed that HBG3 ES cell-derivedet al., 2002) prompting us to test the possibility that HBG3 ES…...
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Journal Article•DOI•

Neuronal specification in the spinal cord: inductive signals and transcriptional codes

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Thomas M. Jessell¹•Institutions (1)

Howard Hughes Medical Institute¹

01 Oct 2000-Nature Reviews Genetics

TL;DR: The mechanisms that specify the identity of neural cells have been examined in many regions of the nervous system and reveal a high degree of conservation in the specification of cell fate by key signalling molecules.

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Abstract: Neural circuits are assembled with remarkable precision during embryonic development, and the selectivity inherent in their formation helps to define the behavioural repertoire of the mature organism. In the vertebrate central nervous system, this developmental program begins with the differentiation of distinct classes of neurons from progenitor cells located at defined positions within the neural tube. The mechanisms that specify the identity of neural cells have been examined in many regions of the nervous system and reveal a high degree of conservation in the specification of cell fate by key signalling molecules.

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2,060 citations

"Directed Differentiation of Embryon..." refers background in this paper

...The specification of MN fate in vivo can be considered in three sequential steps: (1) the primary neuralization of ectodermal cells, (2) the secondary caudalization of neural cells, and (3) the ventralization of caudalized neural cells (Jessell, 2000; Wilson and Edlund, 2001)....
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...Spinal motor neurons (MNs) represent one CNS neuronal subtype for which pathways of neuronal specification have been defined (Jessell, 2000; Lee and Pfaff, 2001)....
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...New York, New York 10032 Spinal motor neurons (MNs) represent one CNS neu2 Curis, Inc. ronal subtype for which pathways of neuronal specifica61 South Moulton Street tion have been defined (Jessell, 2000; Lee and Pfaff, Cambridge, Massachusetts 02138 2001)....
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...Surviving MNs maintain expression of eGFP (G). neural cells, and (3) the ventralization of caudalized neu(H and I) Most FACS-sorted ES cell-derived MNs cultured without ral cells (Jessell, 2000; Wilson and Edlund, 2001)....
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Journal Article•DOI•

In vitro differentiation of transplantable neural precursors from human embryonic stem cells

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Su-Chun Zhang¹, Marius Wernig², Ian D. Duncan¹, Oliver Brüstle², James A. Thomson¹ - Show less +1 more•Institutions (2)

University of Wisconsin-Madison¹, University of Bonn²

01 Dec 2001-Nature Biotechnology

TL;DR: In vitro differentiation, enrichment, and transplantation of neural precursor cells from human ES cells are described, depicting humanES cells as a source of transplantable neural precursors for possible nervous system repair.

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Abstract: The remarkable developmental potential and replicative capacity of human embryonic stem (ES) cells promise an almost unlimited supply of specific cell types for transplantation therapies. Here we describe the in vitro differentiation, enrichment, and transplantation of neural precursor cells from human ES cells. Upon aggregation to embryoid bodies, differentiating ES cells formed large numbers of neural tube-like structures in the presence of fibroblast growth factor 2 (FGF-2). Neural precursors within these formations were isolated by selective enzymatic digestion and further purified on the basis of differential adhesion. Following withdrawal of FGF-2, they differentiated into neurons, astrocytes, and oligodendrocytes. After transplantation into the neonatal mouse brain, human ES cell-derived neural precursors were incorporated into a variety of brain regions, where they differentiated into both neurons and astrocytes. No teratoma formation was observed in the transplant recipients. These results depict human ES cells as a source of transplantable neural precursors for possible nervous system repair.

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1,982 citations

"Directed Differentiation of Embryon..." refers background in this paper

...In this study, weembryonic stem (ES) cells (Bain et al., 1995; Reubinoff have examined whether the signaling factors that oper-et al., 2001; Zhang et al., 2001; Rathjen et al., 2002)....
[...]
...In this study, we embryonic stem (ES) cells (Bain et al., 1995; Reubinoff have examined whether the signaling factors that operet al., 2001; Zhang et al., 2001; Rathjen et al., 2002)....
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