Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • A live newborn with full

    2018-10-24

    A live newborn with full trisomy 12 was never reported, suggesting that it is embryonic lethal in humans. However, individuals carrying mosaic tetrasomy of 12p were reported showing a variety of abnormalities (Segel et al., 2006). This condition, known as Pallister-Killian mosaic syndrome, is extremely rare and has a range of developmental and behavioral outcomes (Kostanecka et al., 2012). Individuals carrying chromosome 21 trisomy also show a distinct set of abnormalities alongside intellectual disabilities, a condition known as Down syndrome (Patterson, 2009). With such an atypical in vivo development, we hypothesized that teratomas originating from cells carrying these mutations will show a more substantial differential gene expression. We suspected that the lack of significant changes originated from the small number of examined genes. While our 100-gene platform is sufficient for the TeratoScore analysis and defining a cell as pluripotent, it is not capable of identifying minor expression changes and tissue distribution between euploid and aneuploid cells. We therefore used another more sensitive bioinformatic strategy, establishing lists of the 200 most expressed genes in each tissue and looking for the ones most altered in chromosomally aberrant teratomas (Figure 4). In this analysis, trisomy 12-derived teratomas show a significant number of upregulated genes enriched for joint, spinal cord, brain, and fetal azilsartan medoxomil (p < 0.001) and a significant number of downregulated genes enriched for skeletal muscle, lung, small intestine, colon, fetal liver, and liver (p < 0.001) compared with normal karyotype teratomas. This wide set of gene expression alteration might suggest a pleiotropic effect of trisomy 12 on developmental patterns, contributing to its embryonic lethality. In contrast, teratomas initiated from cells with trisomy 21 show a more modest distortion of gene expression with a significant number of upregulated genes enriched for brain, fetal brain, and spinal cord (p < 0.001), as well as for joint, and a significant number of downregulated genes for skeletal muscle only compared with normal karyotype teratomas. The upregulation in brain genes in these teratomas is compatible with the neural phenotypes (such as mental impairment) observed in Down syndrome patients.
    Discussion Teratoma formation is the most abundant method to demonstrate hPSC differentiation capacity and a critical step when defining its potency (Müller et al., 2010). TeratoScore transforms this qualitative obligatory milestone into a quantitative tool. Although alternatives have been suggested to replace teratoma formation, they all suffer from imperfections. The computational method PluriTest has shown promising results identifying PSCs and differentiating them from cancer stem cells and cells that have underwent differentiation (Müller et al., 2011). While this method appears simpler than in vivo or in vitro differentiations, it can only determine a cell resemblance to PSCs in their undifferentiated state. The uniqueness of PSCs, however, is in their ability to transform from the pluripotent state to terminally differentiated cell types. These differentiation processes require master regulators that are not expressed in PSCs. A mutation in one of these genes will not be exposed using PluriTest, claiming that a cell is pluripotent even though it cannot differentiate toward all germ layers. Differentiation per se can be evaluated using directed and spontaneous in vitro protocols. Directed differentiation protocols toward many cell types and tissues have been published, ranging from neurons to pancreatic progenitors (reviewed in Schuldiner and Benvenisty, 2003; Tabar and Studer, 2014). Each protocol requires a set of specific factors and environment, presenting expensive and complex challenges to assess cell potency. Furthermore, there is no agreed-upon assembly of protocols which successful utilization is sufficient in determining cells’ pluripotency. In contrast, spontaneous differentiation is widely used and relatively simple to perform. EB formation has been suggested as a good replacement for teratoma formation. However, EBs do not always show complex differentiated structures and usually encapsulate a core of undifferentiated cells. When compared with teratomas, EBs show a lesser extant of mature tissue differentiation (Ozolek and Castro, 2011)—a difference that might provide a limited estimation of the differentiation capabilities. Teratoma formation enables differentiation to a wide variety of cells and tissues, presenting mature and complex structures. Although it is far from being a perfect assay, teratoma formation is still the best evaluator of pluripotent assessment.