Anatomy and Neuroscience - Research Publications
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ItemPluripotent cell states and unexpected fates.(Elsevier BV, 2022-06-14)Pluripotent stem cells provide a powerful model for the study of human development and its disorders. Recent studies, including two in this issue of Stem Cell Reports, raise important questions concerning the developmental potential of human pluripotent stem cells, and how the behavior of these cells in vitro mirrors normal embryogenesis.
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ItemMessage from the Editor: Stem Cell Science in the Time of COVID-19.(Elsevier BV, 2020-04-14)
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ItemUpdates for contributors: Rigor and reproducibility in stem cell research.(Elsevier BV, 2021-07-13)
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ItemSelective elimination of pluripotent stem cells by PIKfyve specific inhibitors.(Elsevier BV, 2022-02-08)Inhibition of PIKfyve phosphoinositide kinase selectively kills autophagy-dependent cancer cells by disrupting lysosome homeostasis. Here, we show that PIKfyve inhibitors can also selectively eliminate pluripotent embryonal carcinoma cells (ECCs), embryonic stem cells, and induced pluripotent stem cells under conditions where differentiated cells remain viable. PIKfyve inhibitors prevented lysosome fission, induced autophagosome accumulation, and reduced cell proliferation in both pluripotent and differentiated cells, but they induced death only in pluripotent cells. The ability of PIKfyve inhibitors to distinguish between pluripotent and differentiated cells was confirmed with xenografts derived from ECCs. Pretreatment of ECCs with the PIKfyve specific inhibitor WX8 suppressed their ability to form teratocarcinomas in mice, and intraperitoneal injections of WX8 into mice harboring teratocarcinoma xenografts selectively eliminated pluripotent cells. Differentiated cells continued to proliferate, but at a reduced rate. These results provide a proof of principle that PIKfyve specific inhibitors can selectively eliminate pluripotent stem cells in vivo as well as in vitro.
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ItemA Splicing Mutation in Slc4a5 Results in Retinal Detachment and Retinal Pigment Epithelium Dysfunction.(MDPI AG, 2022-02-17)Fluid and solute transporters of the retinal pigment epithelium (RPE) are core components of the outer blood-retinal barrier. Characterizing these transporters and their role in retinal homeostasis may provide insights into ocular function and disease. Here, we describe RPE defects in tvrm77 mice, which exhibit hypopigmented patches in the central retina. Mapping and nucleotide sequencing of tvrm77 mice revealed a disrupted 5' splice donor sequence in Slc4a5, a sodium bicarbonate cotransporter gene. Slc4a5 expression was reduced 19.7-fold in tvrm77 RPE relative to controls, and alternative splice variants were detected. SLC4A5 was localized to the Golgi apparatus of cultured human RPE cells and in apical and basal membranes. Fundus imaging, optical coherence tomography, microscopy, and electroretinography (ERG) of tvrm77 mice revealed retinal detachment, hypopigmented patches corresponding to neovascular lesions, and retinal folds. Detachment worsened and outer nuclear layer thickness decreased with age. ERG a- and b-wave response amplitudes were initially normal but declined in older mice. The direct current ERG fast oscillation and light peak were reduced in amplitude at all ages, whereas other RPE-associated responses were unaffected. These results link a new Slc4a5 mutation to subretinal fluid accumulation and altered light-evoked RPE electrophysiological responses, suggesting that SLC4A5 functions at the outer blood-retinal barrier.
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ItemBiomedical and societal impacts of in vitro embryo models of mammalian development.(Elsevier BV, 2021-05-11)In recent years, a diverse array of in vitro cell-derived models of mammalian development have been described that hold immense potential for exploring fundamental questions in developmental biology, particularly in the case of the human embryo where ethical and technical limitations restrict research. These models open up new avenues toward biomedical advances in in vitro fertilization, clinical research, and drug screening with potential to impact wider society across many diverse fields. These technologies raise challenging questions with profound ethical, regulatory, and social implications that deserve due consideration. Here, we discuss the potential impacts of embryo-like models, and their biomedical potential and current limitations.
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ItemThe genetic basis of inter-individual variation in recovery from traumatic brain injury(NATURE RESEARCH, 2021-01-21)Traumatic brain injury (TBI) is one of the leading causes of death among young people, and is increasingly prevalent in the aging population. Survivors of TBI face a spectrum of outcomes from short-term non-incapacitating injuries to long-lasting serious and deteriorating sequelae. TBI is a highly complex condition to treat; many variables can account for the observed heterogeneity in patient outcome. The limited success of neuroprotection strategies in the clinic has led to a new emphasis on neurorestorative approaches. In TBI, it is well recognized clinically that patients with similar lesions, age, and health status often display differences in recovery of function after injury. Despite this heterogeneity of outcomes in TBI, restorative treatment has remained generic. There is now a new emphasis on developing a personalized medicine approach in TBI, and this will require an improved understanding of how genetics impacts on long-term outcomes. Studies in animal model systems indicate clearly that the genetic background plays a role in determining the extent of recovery following an insult. A candidate gene approach in human studies has led to the identification of factors that can influence recovery. Here we review studies of the genetic basis for individual differences in functional recovery in the CNS in animals and man. The application of in vitro modeling with human cells and organoid cultures, along with whole-organism studies, will help to identify genes and networks that account for individual variation in recovery from brain injury, and will point the way towards the development of new therapeutic approaches.
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ItemComparison of defined culture systems for feeder cell free propagation of human embryonic stem cells(SPRINGER, 2010-04)There are many reports of defined culture systems for the propagation of human embryonic stem cells in the absence of feeder cell support, but no previous study has undertaken a multi-laboratory comparison of these diverse methodologies. In this study, five separate laboratories, each with experience in human embryonic stem cell culture, used a panel of ten embryonic stem cell lines (including WA09 as an index cell line common to all laboratories) to assess eight cell culture methods, with propagation in the presence of Knockout Serum Replacer, FGF-2, and mouse embryonic fibroblast feeder cell layers serving as a positive control. The cultures were assessed for up to ten passages for attachment, death, and differentiated morphology by phase contrast microscopy, for growth by serial cell counts, and for maintenance of stem cell surface marker expression by flow cytometry. Of the eight culture systems, only the control and those based on two commercial media, mTeSR1 and STEMPRO, supported maintenance of most cell lines for ten passages. Cultures grown in the remaining media failed before this point due to lack of attachment, cell death, or overt cell differentiation. Possible explanations for relative success of the commercial formulations in this study, and the lack of success with other formulations from academic groups compared to previously published results, include: the complex combination of growth factors present in the commercial preparations; improved development, manufacture, and quality control in the commercial products; differences in epigenetic adaptation to culture in vitro between different ES cell lines grown in different laboratories.
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ItemEXCEPTIONAL SENSITIVITY OF TESTICULAR GERM-CELL TUMOR-CELL LINES TO THE NEW ANTICANCER AGENT, TEMOZOLOMIDE(NATURE PUBLISHING GROUP, 1995-05)Metastatic testicular germ cell tumours are cured in approximately 85% of patients using cisplatin-based combination chemotherapy. Patients who fail to respond have a poor prognosis, and there is a need for more effective treatments for cisplatin-resistant disease. In this study, it is shown that two of four cell lines derived from human non-seminomatous testicular germ cell tumours are exceptionally sensitive to temozolomide, a new imidazotetrazine which can cross the blood-brain barrier in mice. In addition, three pairs of cisplatin-resistant sublines show little cross-resistance to temozolomide. These data suggest that temozolomide might have activity against non-seminomatous testicular germ cell tumours which have relapsed following cisplatin-containing chemotherapy, and could have a role in the treatment of patients with metastatic lesions in the brain.