Publications by authors named "Peter W Andrews"

Article Synopsis
  • Research on teratocarcinomas in laboratory mice paved the way for isolating human pluripotent stem cells (PSCs) through various studies by different teams.
  • The author emphasizes their work at the Wistar Institute in the 1980s, where they and colleagues identified one of the first clonal lines of human embryonal carcinoma cells, highlighting important characteristics like cell surface antigen markers.
  • The research was a collaborative effort across laboratories and often influenced by unexpected opportunities rather than a planned approach.
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Objective: Hirschsprung disease (HSCR) is a severe congenital disorder affecting 1:5000 live births. HSCR results from the failure of enteric nervous system (ENS) progenitors to fully colonise the gastrointestinal tract during embryonic development. This leads to aganglionosis in the distal bowel, resulting in disrupted motor activity and impaired peristalsis.

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Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ female human embryonic stem cell (hESC) differentiation and single-cell transcriptome and epigenome analysis to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB).

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The notion of using pluripotent stem cells (PSCs) as a source of differentiated cell types for replacement of disease or damaged tissues in regenerative medicine is now an active area of research, with approaches to treating eye diseases such as age-related macular degeneration or Parkinson's disease now on the horizon. But the foundations for this research lie in a quite different area of science, namely the role of genetics of cancer. In this review, we trace the evolution of ideas starting with the discovery that strain 129 mice are particularly subject to develop germ cell tumors, through the identification of embryonal carcinoma (EC) cells as the stem cells of the teratocarcinoma manifestation of these tumors, to the recognition of their relationship to pluripotent cells of the early embryo, and eventually their role in the derivation of embryonic stem cells, first from mouse embryos and then from primates including humans.

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The expression of one or more of a small number of molecules, typically cell surface-associated antigens, or transcription factors, is widely used for identifying pluripotent stem cells (PSCs) or for monitoring their differentiation. However, none of these marker molecules are uniquely expressed by PSCs and all are expressed by stem cells that have lost the ability to differentiate. Consequently, none are indicators of pluripotency, per se.

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Article Synopsis
  • The culture of human stem cells in labs aims to replicate a biological state for accurate research outcomes.
  • To ensure the reliability of results, standardized practices are necessary, but currently, no widely accepted guidelines exist for working with human pluripotent and tissue stem cells.
  • The International Society for Stem Cell Research has proposed recommendations for researchers, focusing on feasible reporting criteria to improve the reproducibility and rigor of stem cell studies.
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Article Synopsis
  • Human pluripotent stem cells (hPSCs) hold potential for medical applications, but they often acquire genetic changes that might pose safety risks during culture and therapy.
  • Specifically, about 20% of hPSC lines exhibit the amplification of 20q11.21, which provides a survival advantage but may lead to oncogenic risks that are not fully understood.
  • Research using human embryonic stem cells in mice shows that those with the 20q11.21 alteration had higher engraftment success and caused more severe lesions, highlighting the need for genetic screening of hPSCs prior to therapeutic use.
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Article Synopsis
  • Human pluripotent stem cells (hPSCs) can develop genetic and epigenetic changes when cultured in the lab, raising concerns about their quality control in research and therapy!
  • The International Society for Stem Cell Research emphasizes the necessity to reassess standards to maintain the genetic integrity of these stem cells as their usage grows!
  • The text discusses the detection methods for these changes and their impact on cell behavior, highlighting the unknown risks of contamination in cell therapies, pointing out the need for improved safety assessments!
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DPPA4 is essential for the pluripotent stem cell state, yet its function is poorly understood. DPPA4 is localized in the nucleus, where it is associated with active chromatin. We now report that it is also present in the cytosol, where it appears as diffused clouds, distinct foci and sometimes as spaghetti-like structures.

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Human embryonic stem cells and induced pluripotent stem cells, together denoted as pluripotent stem cells have opened up unprecedented opportunities for developments in human healthcare over the past 20 years. Although much about the properties and behaviour of these cells required to underpin their applications has been discovered over this time, a number of issues remain. This brief review considers the history of these developments and some of the underlying biology, pointing out some of the problems still to be resolved, particularly in relation to their genetic stability and possible malignancy.

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Article Synopsis
  • Copy number variants (CNVs) are changes in the number of copies of a particular gene or region in the genome, linked to various diseases, including cancer, and raise concerns for their presence in human pluripotent stem cells used in regenerative medicine.
  • The study focuses on a specific region on chromosome 20 (q11.21) where CNVs frequently occur, and the research utilizes long-read Nanopore sequencing to investigate two examples of these CNVs, which appear as duplications and triplications.
  • Results indicate that these CNVs are organized in a head-to-tail fashion and involve breakpoints characterized by microhomology sequences, suggesting that a process known as microhomology-mediated break-induced replication might be responsible for their
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The anteroposterior axial identity of motor neurons (MNs) determines their functionality and vulnerability to neurodegeneration. Thus, it is a crucial parameter in the design of strategies aiming to produce MNs from human pluripotent stem cells (hPSCs) for regenerative medicine/disease modelling applications. However, the generation of posterior MNs corresponding to the thoracic/lumbosacral spinal cord has been challenging.

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We postulate that exit from pluripotency involves intermediates that retain pluripotency while simultaneously exhibiting lineage-bias. Using a MIXL1 reporter, we explore mesoderm lineage-bias within the human pluripotent stem cell compartment. We identify a substate, which at the single cell level coexpresses pluripotent and mesodermal gene expression programmes.

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In the 20 years since human embryonic stem cells, and subsequently induced pluripotent stem cells, were first described, it has become apparent that during long-term culture these cells (collectively referred to as 'pluripotent stem cells' (PSCs)) can acquire genetic changes, which commonly include gains or losses of particular chromosomal regions, or mutations in certain cancer-associated genes, especially TP53. Such changes raise concerns for the safety of PSC-derived cellular therapies for regenerative medicine. Although acquired genetic changes may not be present in a cell line at the start of a research programme, the low sensitivity of current detection methods means that mutations may be difficult to detect if they arise but are present in only a small proportion of the cells.

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The enteric nervous system (ENS) is derived primarily from the vagal neural crest, a migratory multipotent cell population emerging from the dorsal neural tube between somites 1 and 7. Defects in the development and function of the ENS cause a range of enteric neuropathies, including Hirschsprung disease. Little is known about the signals that specify early ENS progenitors, limiting progress in the generation of enteric neurons from human pluripotent stem cells (hPSCs) to provide tools for disease modeling and regenerative medicine for enteric neuropathies.

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Testicular germ cell tumours (TGCTs) appear as different histological subtypes or mixtures of these. They show similar, multiple DNA copy number changes, where gain of 12p is pathognomonic. However, few high-resolution analyses have been performed and focal DNA copy number changes with corresponding candidate target genes remain poorly described for individual subtypes.

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Human pluripotent stem cells (PSCs) are subject to the appearance of recurrent genetic variants on prolonged culture. We have now found that, compared with isogenic differentiated cells, PSCs exhibit evidence of considerably more DNA damage during the S phase of the cell cycle, apparently as a consequence of DNA replication stress marked by slower progression of DNA replication, activation of latent origins of replication, and collapse of replication forks. As in many cancers, which, like PSCs, exhibit a shortened G1 phase and DNA replication stress, the resulting DNA damage may underlie the higher incidence of abnormal and abortive mitoses in PSCs, resulting in chromosomal non-dysjunction or cell death.

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The occurrence of repetitive genomic changes that provide a selective growth advantage in pluripotent stem cells is of concern for their clinical application. However, the effect of different culture conditions on the underlying mutation rate is unknown. Here we show that the mutation rate in two human embryonic stem cell lines derived and banked for clinical application is low and not substantially affected by culture with Rho Kinase inhibitor, commonly used in their routine maintenance.

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Article Synopsis
  • - The neural crest is a crucial embryonic tissue that forms at the neural plate's edge and migrates throughout the embryo, contributing to various tissues and being linked to disorders known as neurocristopathies, like cancers and facial malformations.
  • - Developing human pluripotent stem cells (hPSCs) into neural crest cells can aid in studying neural crest growth, modeling neurocristopathies, and exploring drug discovery and cell replacement therapies.
  • - A new method for producing neural crest cells from hPSCs that avoids animal-derived components has been created, employing a "top-down inhibition" (TDi) system to address differentiation efficiency issues caused by variability in BMP expression without the use of serum.
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Human stem cells have the potential to transform medicine. However, hurdles remain to ensure that manufacturing processes produce safe and effective products. A thorough understanding of the biological processes occurring during manufacture is fundamental to assuring these qualities and thus, their acceptability to regulators and clinicians.

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Human pluripotent stem cells (hPSCs) are susceptible to numerical and structural chromosomal alterations during long-term culture. We show that mitotic errors occur frequently in hPSCs and that prometaphase arrest leads to very rapid apoptosis in undifferentiated but not in differentiated cells. hPSCs express high levels of proapoptotic protein NOXA in undifferentiated state.

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The neural crest (NC) is a multipotent embryonic cell population that generates distinct cell types in an axial position-dependent manner. The production of NC cells from human pluripotent stem cells (hPSCs) is a valuable approach to study human NC biology. However, the origin of human trunk NC remains undefined and current in vitro differentiation strategies induce only a modest yield of trunk NC cells.

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Human embryonic stem cells (hESCs) display substantial heterogeneity in gene expression, implying the existence of discrete substates within the stem cell compartment. To determine whether these substates impact fate decisions of hESCs we used a GFP reporter line to investigate the properties of fractions of putative undifferentiated cells defined by their differential expression of the endoderm transcription factor, GATA6, together with the hESC surface marker, SSEA3. By single-cell cloning, we confirmed that substates characterized by expression of GATA6 and SSEA3 include pluripotent stem cells capable of long-term self-renewal.

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