Human Embryonic Stem Cells as Models for Aneuploid Chromosomal Syndromes

Biancotti, Juan-Carlos; Narwani, Kavita; Buehler, N.; Mandefro, Berhan; Golan‐Lev, Tamar; Yanuka, Ofra; Clark, Amander T.; Hill, Dottie; Benvenisty, Nissim; Lavon, Neta

doi:10.1002/stem.483

Cited by 83 publications

(56 citation statements)

References 30 publications

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“…Both Ts21 iPSC lines (DS1 and DS4) displayed a preferential increase in expression of HSA21 genes compared with genes on other chromosomes (Fig. S2A), consistent with gene expression in Ts21 human ES cells (21). Changes in HSA21 genes seemed evenly distributed across HSA21 (Fig.…”

Section: Resultssupporting

confidence: 70%

Deficits in human trisomy 21 iPSCs and neurons

Weick

Held

Bonadurer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

179

214

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Down syndrome (trisomy 21) is the most common genetic cause of intellectual disability, but the precise molecular mechanisms underlying impaired cognition remain unclear. Elucidation of these mechanisms has been hindered by the lack of a model system that contains full trisomy of chromosome 21 (Ts21) in a human genome that enables normal gene regulation. To overcome this limitation, we created Ts21-induced pluripotent stem cells (iPSCs) from two sets of Ts21 human fibroblasts. One of the fibroblast lines had low level mosaicism for Ts21 and yielded Ts21 iPSCs and an isogenic control that is disomic for human chromosome 21 (HSA21). Differentiation of all Ts21 iPSCs yielded similar numbers of neurons expressing markers characteristic of dorsal forebrain neurons that were functionally similar to controls. Expression profiling of Ts21 iPSCs and their neuronal derivatives revealed changes in HSA21 genes consistent with the presence of 50% more genetic material as well as changes in non-HSA21 genes that suggested compensatory responses to oxidative stress. Ts21 neurons displayed reduced synaptic activity, affecting excitatory and inhibitory synapses equally. Thus, Ts21 iPSCs and neurons display unique developmental defects that are consistent with cognitive deficits in individuals with Down syndrome and may enable discovery of the underlying causes of and treatments for this disorder.cerebral cortex | developmental disorders D own syndrome (DS) is the most frequent single cause of human birth defects and intellectual disability (ID) (1). DS is caused by trisomy of chromosome 21 (Ts21) (2), resulting in the triplication of over 400 genes (3-5), which makes elucidation of the precise mechanisms underlying ID in DS a significant challenge. Confounding this difficulty is the relative inaccessibility of human tissue and incomplete human Ts21 in the context of mouse models. Despite these shortcomings, studies using mouse models containing trisomy of parts of syntenic chromosome 21 (HSA21) have put forth several critical hypotheses on the cellular and molecular mechanisms underlying DS features. It is essential, however, to test these hypotheses in human cells with full triplication of HSA21 in a context that allows for normal gene regulation. Here, we used Ts21-induced pluripotent stem cells (iPSCs) to test hypotheses of the underlying causes of ID in DS, with specific regard to neuropathophysiology. ResultsIsogenic Human Ts21 iPSCs. Fibroblasts from two individuals diagnosed with DS were reprogrammed to iPSCs. FISH for HSA21 in one fibroblast line showed mosaicism, where ∼90% of cells carried Ts21, whereas ∼10% were euploid (Fig. 1A). Reprogramming of the mosaic fibroblasts by retrovirus (6) resulted in three viable iPSC clones, two clones that carried Ts21 and one euploid (Fig. 1B). Mosaicism in DS individuals is rare, occurring in ∼1-3% of DS cases (7), but it can also emerge in vitro (8), potentially because of nondisjunction events during cell division.

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Section: Resultssupporting

confidence: 70%

Deficits in human trisomy 21 iPSCs and neurons

Weick

Held

Bonadurer

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

179

214

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“…Based on the variable extent and quality of in vitro differentiation reported for human pluripotent cell clones and potential differences between ES and iPS cells, we examined lines of diverse origins to minimize these challenges (Table S1). Accordingly, we have analyzed independently derived disomic and trisomic hES (CSES2 and CSES13) and iPS (DS2-iPS1, DS2-iPS10, DS1-iPS4, MRC5-IPS7) cell lines (14,15), as well as disomic and trisomic iPS subclones that are isogenic except for the presence of an additional chromosome 21 (detailed below).…”

Section: Resultsmentioning

confidence: 99%

Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells

MacLean

Menne

Guo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

134

140

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Trisomy 21 is associated with hematopoietic abnormalities in the fetal liver, a preleukemic condition termed transient myeloproliferative disorder, and increased incidence of acute megakaryoblastic leukemia. Human trisomy 21 pluripotent cells of various origins, human embryionic stem (hES), and induced pluripotent stem (iPS) cells, were differentiated in vitro as a model to recapitulate the effects of trisomy on hematopoiesis. To mitigate clonal variation, we isolated disomic and trisomic subclones from the same parental iPS line, thereby generating subclones isogenic except for chromosome 21. Under differentiation conditions favoring development of fetal liver-like, γ-globin expressing, definitive hematopoiesis, we found that trisomic cells of hES, iPS, or isogenic origins exhibited a two-to fivefold increase in a population of CD43 + (Leukosialin)/ CD235 + (Glycophorin A) hematopoietic cells, accompanied by increased multilineage colony-forming potential in colony-forming assays. These findings establish an intrinsic disturbance of multilineage myeloid hematopoiesis in trisomy 21 at the fetal liver stage.

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“…However, brain development differs in mice and humans. 48 Although some human ES cells with trisomy 21 have been generated, 49 the establishment of human ES cells from patients with DS remains ethically challenging.…”

Section: Somatic Mosaicism In Dsmentioning

confidence: 99%

Perspectives for Induced Pluripotent Stem Cell Technology

Nagata

Yamanaka

2014

Circulation Research

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Induced pluripotent stem cell technology makes in vitro reprogramming of somatic cells from individualswith various genetic backgrounds possible. By applying this technology, it is possible to produce pluripotent stem cells from biopsy samples of arbitrarily selected individuals with various genetic backgrounds and to subsequently maintain, expand, and stock these cells. From these induced pluripotent stem cells, target cells and tissues can be generated after certain differentiation processes. These target cells/tissues are expected to be useful in regenerative medicine, disease modeling, drug screening, toxicology testing, and proof-of-concept studies in drug development. Therefore, the number of publications concerning induced pluripotent stem cells has recently been increasing rapidly, demonstrating that this technology has begun to infiltrate many aspects of stem cell biology and medical applications. In this review, we discuss the perspectives of induced pluripotent stem cell technology for modeling human diseases. In particular, we focus on the cloning event occurring through the reprogramming process and its ability to let us analyze the development of complex disease-harboring somatic mosaicism. (Circ Res. 2014;114:505-510.)

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Human Embryonic Stem Cells as Models for Aneuploid Chromosomal Syndromes

Cited by 83 publications

References 30 publications

Deficits in human trisomy 21 iPSCs and neurons

Deficits in human trisomy 21 iPSCs and neurons

Altered hematopoiesis in trisomy 21 as revealed through in vitro differentiation of isogenic human pluripotent cells

Perspectives for Induced Pluripotent Stem Cell Technology

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