Human embryonic stem cell models of Huntington disease

Niclis, Jonathan C.; Trounson, Alan; Dottori, Mirella; Ellisdon, Andrew M.; Bottomley, Stephen P.; Verlinsky, Yuri; Cram, David S.

doi:10.1016/s1472-6483(10)60053-3

Cited by 69 publications

(54 citation statements)

References 40 publications

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“…These hESCs with genetic disease inheritance that have unlimited proliferating and self-renewing potential are unique sources to reproduce heredity of diseases in vitro [56,57]. However, only a few studies reported isolation of these cells so far [57][58][59][60][61].…”

Section: Isolation Of Pluripotent Hescs From Hd Embryosmentioning

confidence: 99%

“…The HD-hESCs isolated so far ( Table 1) can be considered primed hESCs according to the existing classification [43,62]. They express core pluripotency markers and present a normal karyotype [58][59][60][61]. Only one study demonstrated that HD-hESCs are able to form teratomas [59].…”

Section: Isolation Of Pluripotent Hescs From Hd Embryosmentioning

confidence: 99%

“…Only one study demonstrated that HD-hESCs are able to form teratomas [59]. In vitro, HD-hESCs are able to differentiate into neurons and astrocytes [58][59][60][61] through neurosphere formation by the cells positive for the neuroectodermal marker Pax6 [60]. Another study showed that HD-hESCs differentiate preferentially into astroglial cells [58].…”

Section: Isolation Of Pluripotent Hescs From Hd Embryosmentioning

confidence: 99%

“…The longer the repeats, the more severe the symptoms [66]. After differentiation, neuronal precursor populations derived from HD-hESCs do not present any alteration in the incidence of CAG repeats [58,60]. These findings indicate that the presence of Htt mutation does not prevent HD-hESCs from differentiating into neural cells in vitro [57,59,60], implying that HD-hESCs can be used as an in vitro model of HD.…”

Section: Isolation Of Pluripotent Hescs From Hd Embryosmentioning

confidence: 99%

“…After differentiation, neuronal precursor populations derived from HD-hESCs do not present any alteration in the incidence of CAG repeats [58,60]. These findings indicate that the presence of Htt mutation does not prevent HD-hESCs from differentiating into neural cells in vitro [57,59,60], implying that HD-hESCs can be used as an in vitro model of HD. This model has the potential to increase the understanding of the mechanisms of neurodegeneration and can be used for efficient screening for new anti-HD drugs, selecting only the most efficient for further testing in human clinical trials.…”

Section: Isolation Of Pluripotent Hescs From Hd Embryosmentioning

confidence: 99%

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Pluripotent Stem Cells to Model and Treat Huntington’s Disease

Wenceslau¹,

Kerkis²,

Pompéia³

et al. 2017

Huntington's Disease - Molecular Pathogenesis and Current Models

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Stem cell therapies hold considerable promise for the treatment of neurodegenerative diseases. Pluripotent stem cells (PSCs) have been of particular clinical interest because of their ability to generate neuronal cells and to be used in animal models of neurodegenerative disease as well as for testing new drugs. Several PSCs isolated from humans and animals that carry the genotype of Huntington's disease (HD) have been used in aforementioned studies. HD-PSCs obtained can produce in vitro neural progenitor cells (NPCs). These NPCs applied in HD models show several advantages: they engraft into the brain in animal models and differentiate into neuronal cells, thus promoting behavioral recovery and motor impairment. Although progress has been made using PSCs, additional tests should be done to overcome several limitations as, for example, tumorigenicity, before their clinical application. We focus this chapter on current knowledge regarding HD-PSC lines and their helpfulness as an in vitro model for basic research. Next, we discuss the advances of disease-free PSCs in preclinical HD models aiming to their potential application in patients. Additionally, we discuss their potential use as a test system for anti-HD drug screening by the pharmaceutical industry, especially considering HD patients' welfare.

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Section: Isolation Of Pluripotent Hescs From Hd Embryosmentioning

confidence: 99%

Section: Isolation Of Pluripotent Hescs From Hd Embryosmentioning

confidence: 99%

Section: Isolation Of Pluripotent Hescs From Hd Embryosmentioning

confidence: 99%

Section: Isolation Of Pluripotent Hescs From Hd Embryosmentioning

confidence: 99%

Section: Isolation Of Pluripotent Hescs From Hd Embryosmentioning

confidence: 99%

See 3 more Smart Citations

Pluripotent Stem Cells to Model and Treat Huntington’s Disease

Wenceslau¹,

Kerkis²,

Pompéia³

et al. 2017

Huntington's Disease - Molecular Pathogenesis and Current Models

View full text Add to dashboard Cite

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Normal human embryonic stem cell lines were derived from microsurgical enucleated tripronuclear zygotes

Jiang

Cai

Huang

et al. 2013

J of Cellular Biochemistry

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A normal fertilized human zygote contains two pronuclei, but zygotes may also display one, three, or even more pronuclei resulting from irregular insemination or meiotic division. Today diploid and triploid human embryonic stem cell (hESC) lines have been derived from tripronuclear (3PN) triploid zygotes, and an in-vitro fertilization (IVF) baby was born from a rescued diploid zygote by removing the extra male pronucleus of the 3PN zygote. However, whether hESCs can be derived from a rescued 3PN zygote is still unknown. Here, by microsurgical pronuclear removal, we restored 61 diploid zygotes from 3PN zygotes donated by 35 couples, and 11 blastocysts developed with a blastocyst rate of 18.0%, which seems higher than that of nonrescued 3PN zygotes according to previous reports. After the whole zona pellucida free embryos were plated onto feeder cells to grow and passage, 2 hESC lines (CCRM-hESC-22 and CCRM-hESC-23) were generated and both carried normal karyotype (46, XY). The hESC lines were then characterized by morphology, expansion in vitro, and expression of specific markers of alkaline phosphatase, OCT4, SSEA4, TRA-1-60 and TRA-1-81. Furthermore, the pluripotency of these 2 hESC lines was confirmed by in vitro embryoid body formation and in vivo teratoma production. Our study indicates that depronucleared 3PN zygotes can improve the blastocysts formation rate, and normal hESC lines can be derived from those corrected 2PN embryos. Based on their multi-directional differentiation potential in vitro, the established hESC lines could be applied to the developmental risk assessment for IVF babies born from restored zygotes.

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Concise Review: Patient-Derived Stem Cell Research for Monogenic Disorders

Qin

Gao

2015

Stem Cells

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Monogenic disorders (MGDs) are caused by a single gene mutation and have a serious impact on human health. At present, there are no effective therapeutic methods for MGDs. Stem cell techniques provide insights into potential treatments for MGDs. With the development of patient-derived stem cells, we can begin to progressively understand the molecular mechanism of MGDs and identify new drugs for MGD treatment. Using powerful genome editing tools, such as zinc finger nucleases, transcriptional activator-like effector nucleases, and the clustered regulatory interspaced short palindromic repeat/Cas9 system, MGD-associated gene mutations can be corrected in MGD stem cells in vitro and then transplanted into MGD animal models to assess their safety and therapeutic effects. Despite the continued challenges surrounding potential pluripotent stem cell tumorigenicity and concerns regarding the genetic modification of stem cells, the extensive clinical application of MGD patient-specific stem cells will be pursued through further advances in basic research in the MGD field. In this review, we will summarize the latest progress in research into the use of patient-derived stem cells for the potential treatment of MGDs and provide predictions regarding the direction of future investigations. STEM CELLS 2016;34:44-54 SIGNIFICANCE STATEMENTMonogenic disorders (MGDs) are caused by a single gene mutation and have a serious impact on human health. At present, there are no effective therapeutic methods for MGDs. Stem cell techniques provide insights into potential treatments for MGDs. With the development of patient-derived stem cells, we can begin to progressively understand the molecular mechanism of MGDs and identify new drugs for MGD treatment. Using powerful genome editing tools, such as zinc finger nucleases (ZFNs), transcriptional activator-like effector nucleases (TALENs) and the clustered regulatory interspaced short palindromic repeat (CRISPR)/Cas9 system, MGD-associated gene mutations can be corrected in MGD stem cells in vitro and then transplanted into MGD animal models to assess their safety and therapeutic effects. Despite the continued challenges surrounding potential pluripotent stem cell tumorigenicity and concerns regarding the genetic modification of stem cells, the extensive clinical application of MGD patient-specific stem cells will be pursued through further advances in basic research in the MGD field. In this review, we will summarize the latest progress in research into the use of patient-derived stem cells for the potential treatment of MGDs and provide predictions regarding the direction of future investigations.

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Human embryonic stem cell models of Huntington disease

Cited by 69 publications

References 40 publications

Pluripotent Stem Cells to Model and Treat Huntington’s Disease

Pluripotent Stem Cells to Model and Treat Huntington’s Disease

Normal human embryonic stem cell lines were derived from microsurgical enucleated tripronuclear zygotes

Concise Review: Patient-Derived Stem Cell Research for Monogenic Disorders

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