Professor Ivana Barbaric
School of Biosciences
Professor of Stem Cell Biology
+44 114 222 3645
Full contact details
School of Biosciences
E225b
Alfred Denny Building
Western Bank
Sheffield
S10 2TN
- Profile
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- 2023 - present: Professor of Stem Cell Biology, Centre for Stem Cell Biology, School of Biosciences, University of Sheffield.
- 2019 – 2022: Senior Lecturer in Stem Cell Biology, Centre for Stem Cell Biology, School of Biosciences, University of Sheffield.
- 2014–2018: Lecturer in Stem Cell Biology, Centre for Stem Cell Biology, Department of Biomedical Science, University of Sheffield.
- 2013–2014: Research Fellow, Department of Materials Science and Tissue Engineering, University of Sheffield.
- 2006–2013: Post-doctoral Research Associate, Department of Biomedical Science, University of Sheffield. Research Advisor: Professor Peter Andrews.
- 2002–2006: DPhil, Wolfson College, University of Oxford. Supervisor: Professor Stephen Brown.
- Research interests
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Research in my group is focused on the genetic stability of human pluripotent stem cells (hPSCs) and implications of genetic changes arising in hPSCs for regenerative medicine applications. We also use hPSCs as a model for understanding the causes and consequences of aneuploidy on early human development. Finally, my lab is also using hPSCs for human disease modelling and therapeutic discovery.
Genetic stability of human pluripotent stem cells: implications for safety and efficacy of regenerative medicine applications
The ability of human pluripotent stem cells (hPSC) to self-renew and to differentiate into any cell type of the human body has led to the development of regenerative medicine strategies for treatment of previously incurable diseases and injuries. Clinical trials for regenerative medicine of various conditions, including macular degeneration, Parkinson’s disease and spinal cord injury using hPSC-derived differentiated cells are currently underway or on the horizon. However, a significant safety concern that stands to seriously jeopardise a successful translation of hPSC-based therapies is the takeover of cultures by genetically abnormal cells.
HPSCs can acquire genetic changes in culture, some of which increase their growth rate and cloning efficiency. The genetic changes observed during prolonged culture are mostly non-random, with the gain of material from chromosomes 1, 12, 17, 20 and X particularly frequent. The non-random nature of genetic changes implies that they confer the growth advantage to variant cells, by affecting the molecular mechanisms that control the balance between self-renewal, differentiation and apoptosis. However, the processes that lead to the generation of mutations and the subsequent selection of variant cells remain unclear. Our research aims to reveal the molecular mechanisms of genetic change in hPSCs and establish the processes that select for the growth of mutant cells. The results of these studies should pinpoint the mechanisms of genetic changes in hPSCs and instruct future hPSC maintenance to minimise the occurrence of variant cells.
The causes and consequences of aneuploidy in human pluripotent stem cells
Mammalian development requires multiple, rapid cell divisions in order to support the growth and morphogenesis of the developing embryo. Given the limited number of early embryonic cells within the embryo that give rise to all cells in the adult body, errors occurring during cell division (mitotic errors) in these cells could have devastating consequences, from congenital defects to embryonic lethality. Yet, despite the pivotal importance of preserving genome integrity during early embryogenesis, embryonic cells are particularly prone to mitotic errors. It remains unclear what makes early embryonic cells susceptible to mitotic errors and what is the fate of aneuploid cells during development.
Early human embryogenesis is experimentally inaccessible, but hPSCs represent a unique and powerful tool for studying otherwise intractable stages of development. We have recently demonstrated that the high frequency of mitotic errors characteristic of early embryos is also evident upon in vitro culture of hPSCs (Zhang et al., 2019 Stem Cell Reports 12:557; Halliwell et al., 2020 Stem Cell Reports 14:1009), indicating that the susceptibility to mitotic errors is an intrinsic property of early embryonic cells and that hPSC provide a good platform for determining the mechanistic basis of these errors. In our current work we are addressing the molecular mechanisms governing a high incidence of mitotic errors in hPSCs and are working to understand the impact of aneuploidy on the developmental potential of hPSCs.
HPSC-based disease modelling and therapeutic discovery
A significant bottleneck in disease modelling and drug discovery is the lack of suitable humanized models for sensitive and reliable assessment of disease phenotypes. The dual ability of hPSCs to self-renew and to differentiate makes them an ideal source of cells for disease modelling and drug discovery applications, whereby undifferentiated cells could be expanded and directed to differentiate into a cell type of interest. The advent of genome editing technologies, particularly CRISPR/Cas9, allows for the introduction and/or correction of disease-causing mutations in order to investigate the disease phenotype. We are using this approach to model diseases, in particular Charcot Marie Tooth Disease (CMT) and Osteogenesis imperfecta to study disease mechanisms. Our models also provide us with a platform for testing small molecules and gene therapy approaches in a human cell-based model in vitro.
- Publications
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Show: Featured publications All publications
Featured publications
Journal articles
- Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition. Developmental Cell. View this article in WRRO
- Nucleosides rescue replication-mediated genome instability of human pluripotent stem cells. Stem Cell Reports, 14(6), 1009-1017. View this article in WRRO
- Anti-apoptotic Mutations Desensitize Human Pluripotent Stem Cells to Mitotic Stress and Enable Aneuploid Cell Survival. Stem Cell Reports, 12(3), 557-571. View this article in WRRO
- Identification and Single-Cell Functional Characterization of an Endodermally Biased Pluripotent Substate in Human Embryonic Stem Cells. Stem Cell Reports, 10(6), 1895-1907. View this article in WRRO
- Assessment of established techniques to determine developmental and malignant potential of human pluripotent stem cells. Nature Communications, 9. View this article in WRRO
- Detecting Genetic Mosaicism in Cultures of Human Pluripotent Stem Cells.. Stem Cell Reports, 7(5), 998-1012. View this article in WRRO
- Aneuploidy in pluripotent stem cells and implications for cancerous transformation.. Protein Cell, 5(8), 569-579. View this article in WRRO
- Time-Lapse Analysis of Human Embryonic Stem Cells Reveals Multiple Bottlenecks Restricting Colony Formation and Their Relief upon Culture Adaptation. Stem Cell Reports, 3(1), 142--155. View this article in WRRO
All publications
Journal articles
- Feeder-free culture of human pluripotent stem cells drives MDM4-mediated gain of chromosome 1q. Stem Cell Reports.
- A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations. Nature Communications, 15(1). View this article in WRRO
- Modeling the selective growth advantage of genetically variant human pluripotent stem cells to identify opportunities for manufacturing process control. Cytotherapy.
- ISSCR standards for the use of human stem cells in basic research. Stem Cell Reports, 18(9), 1744-1752.
- Abstract 3542: A stem cell model dissects detrimental effects of neuroblastoma-linked chromosomal aberrations on cell differentiation during neural crest development. Cancer Research, 83(7_Supplement), 3542-3542.
- The isochromosome 20q abnormality of pluripotent cells interrupts germ layer differentiation. Stem Cell Reports, 18(3), 782-797.
- The consequences of recurrent genetic and epigenetic variants in human pluripotent stem cells. Cell Stem Cell, 29(12), 1624-1636.
- Single nucleotide polymorphism (SNP) arrays and their sensitivity for detection of genetic changes in human pluripotent stem cell cultures. Current Protocols, 2(11).
- Assessing cell competition in human pluripotent stem cell (hPSC) cultures. Current Protocols, 2. View this article in WRRO
- DRP1 levels determine the apoptotic threshold during embryonic differentiation through a mitophagy-dependent mechanism.. Dev Cell.
- Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition. Developmental Cell. View this article in WRRO
- Fitness selection in human pluripotent stem cells and interspecies chimeras: Implications for human development and regenerative medicine.. Developmental Biology, 476, 209-217.
- Nanopore sequencing indicates that tandem amplification of chromosome 20q11.21 in human pluripotent stem cells is driven by break induced replication. Stem Cells and Development.
- Defining the signalling determinants of a posterior ventral spinal cord identity in human neuromesodermal progenitor derivatives. Development, 148(6). View this article in WRRO
- Low rates of mutation in clinical grade human pluripotent stem cells under different culture conditions. Nature Communications, 11(1). View this article in WRRO
- Generation and trapping of a mesoderm biased state of human pluripotency. Nature Communications, 11(1).
- Retinoic Acid Accelerates the Specification of Enteric Neural Progenitors from In-Vitro-Derived Neural Crest. Stem Cell Reports.
- Nucleosides rescue replication-mediated genome instability of human pluripotent stem cells. Stem Cell Reports, 14(6), 1009-1017. View this article in WRRO
- Anti-apoptotic Mutations Desensitize Human Pluripotent Stem Cells to Mitotic Stress and Enable Aneuploid Cell Survival. Stem Cell Reports, 12(3), 557-571. View this article in WRRO
- Rapid PCR Assay for Detecting Common Genetic Variants Arising in Human Pluripotent Stem Cell Cultures. Current Protocols in Stem Cell Biology. View this article in WRRO
- Stem cell culture conditions and stability: a joint workshop of the PluriMes Consortium and Pluripotent Stem Cell Platform. Regenerative medicine, 14(3), 243-255. View this article in WRRO
- Science-based assessment of source materials for cell-based medicines: report of a stakeholders workshop. Regenerative Medicine, 13(8), 935-944. View this article in WRRO
- Identification and Single-Cell Functional Characterization of an Endodermally Biased Pluripotent Substate in Human Embryonic Stem Cells. Stem Cell Reports, 10(6), 1895-1907. View this article in WRRO
- Assessment of established techniques to determine developmental and malignant potential of human pluripotent stem cells. Nature Communications, 9. View this article in WRRO
- Regenerative medicine: Advances from developmental to degenerative diseases. Advances in Experimental Medicine and Biology, 1007, 225-239. View this article in WRRO
- Erratum to: Loss of plakoglobin promotes cell-cell contact, increased invasion and breast cancer cell dissemination in vivo.. Breast Cancer Research, 19.
- Preclinical imaging methods for assessing the safety and efficacy of regenerative medicine therapies. npj Regenerative Medicine, 2(1). View this article in WRRO
- Detecting Genetic Mosaicism in Cultures of Human Pluripotent Stem Cells.. Stem Cell Reports, 7(5), 998-1012. View this article in WRRO
- Aneuploidy in pluripotent stem cells and implications for cancerous transformation.. Protein Cell, 5(8), 569-579. View this article in WRRO
- Time-Lapse Analysis of Human Embryonic Stem Cells Reveals Multiple Bottlenecks Restricting Colony Formation and Their Relief upon Culture Adaptation. Stem Cell Reports, 3(1), 142--155. View this article in WRRO
- Karyotypically abnormal human ESCs are sensitive to HDAC inhibitors and show altered regulation of genes linked to cancers and neurological diseases.. Stem Cell Res, 11(3), 1022-1036.
- Loss of plakoglobin promotes decreased cell-cell contact, increased invasion, and breast cancer cell dissemination in vivo.. Breast Cancer Res, 14(3), R86. View this article in WRRO
- Rediscovering pluripotency: from teratocarcinomas to embryonic stem cells. Cardiff, 10-12 October 2011.. Int J Dev Biol, 56(4), 197-206.
- Pinacidil enhances survival of cryopreserved human embryonic stem cells.. Cryobiology, 63(3), 298-305.
- High-content screening for chemical modulators of embryonal carcinoma cell differentiation and survival.. J Biomol Screen, 16(6), 603-617.
- High-content screening of small compounds on human embryonic stem cells.. Biochem Soc Trans, 38(4), 1046-1050.
- A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy.. PLoS Genet, 6(6), e1001000. View this article in WRRO
- Novel regulators of stem cell fates identified by a multivariate phenotype screen of small compounds on human embryonic stem cell colonies.. Stem Cell Res, 5(2), 104-119. View this article in WRRO
- Culture of murine embryonic stem cells.. Methods Mol Biol, 561, 161-184.
- An ENU-induced mutation in the Ankrd11 gene results in an osteopenia-like phenotype in the mouse mutant Yoda.. Physiol Genomics, 32(3), 311-321.
- Optimizing screening and mating strategies for phenotype-driven recessive N-ethyl-N-nitrosourea screens in mice.. J Am Assoc Lab Anim Sci, 46(6), 44-49.
- Appearances can be deceiving: phenotypes of knockout mice.. Brief Funct Genomic Proteomic, 6(2), 91-103.
- A new coat color mouse line for testing germline transmission of embryonic stem cells while retaining an inbred genetic background.. J Am Assoc Lab Anim Sci, 46(3), 37-40.
- Spectrum of ENU-induced mutations in phenotype-driven and gene-driven screens in the mouse.. Environ Mol Mutagen, 48(2), 124-142.
- Mutation at the Evi1 locus in Junbo mice causes susceptibility to otitis media.. PLoS Genet, 2(10), e149. View this article in WRRO
- Culture‐acquired genetic variation in human pluripotent stem cells: Twenty years on. BioEssays.
- Hyperspectral Mapping of Human Primary and Stem Cells at Cell–Matrix Interfaces. ACS Applied Materials & Interfaces.
- Acquired genetic changes in human pluripotent stem cells: origins and consequences. Nature Reviews Molecular Cell Biology.
- Human pluripotent stem cells as tools for high-throughput and high-content screening in drug discovery. International Journal of High Throughput Screening, 1-1. View this article in WRRO
Chapters
- Characterizing the Genetic Stability of Human Naïve and Primed Pluripotent Stem Cells In Rugg-Gunn P (Ed.), Human Naïve Pluripotent Stem Cells (pp. 267-284). Humana Press (part of Springer Nature)
- Human Embryonic Stem Cell Characterization: Similarities and Differences between Cell Lines and Sources, Stem Cells (pp. 1-22). WORLD SCIENTIFIC
- Human embryonic stem cell characterization: Similarities and differences between cell lines and sources, Stem Cells: From Bench to Bedside, Second Edition (pp. 1-22).
Conference proceedings papers
- The implications of genetic variants on human pluripotent stem cell characteristics. HUMAN GENE THERAPY, Vol. 30(8) (pp A18-A18)
- Mechanisms that lead to genetic instability in human pluripotent stem cells. HUMAN GENE THERAPY, Vol. 30(8) (pp A18-A19)
- Mechanisms of selective advantage in cultures of human pluripotent stem cells. HUMAN GENE THERAPY, Vol. 30(8) (pp A27-A27)
- Genetic changes in human pluripotent stem cells: implications for basic biology and regenerative medicine. HUMAN GENE THERAPY, Vol. 28(8) (pp A8-A9) View this article in WRRO
- Genetic models of bone disease using ENU mutagenesis. BONE, Vol. 44 (pp S19-S19)
Preprints
- Chromosome X Dosage Modulates Development of Aneuploidy in Genetically Diverse Mouse Embryonic Stem Cells, Cold Spring Harbor Laboratory.
- Aberrant Wnt activation in recurrent genetically variant human pluripotent stem cells impairs cardiomyocyte differentiation and phenotype, Cold Spring Harbor Laboratory.
- Cytogenetic resource enables mechanistic resolution of changing trends in human pluripotent stem cell aberrations linked to feeder-free culture, Cold Spring Harbor Laboratory.
- Neuroblastoma-associated chromosomal aberrations drive cell identity loss in human neural crest via disruption of developmental regulators, Cold Spring Harbor Laboratory.
- HDAC6 inhibition partially alleviates mitochondrial trafficking defects and restores motor function in human motor neuron and zebrafish models of Charcot-Marie-Tooth Disease Type 2A, Cold Spring Harbor Laboratory.
- Template switching mechanism drives the tandem amplification of chromosome 20q11.21 in human pluripotent stem cells, Cold Spring Harbor Laboratory.
- Defining the signalling determinants of a posterior ventral spinal cord identity in human neuromesodermal progenitor derivatives.
- Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition.
- Nucleosides rescue replication-mediated genome instability of human pluripotent stem cells, Cold Spring Harbor Laboratory. View this article in WRRO
- DRP1-mediated regulation of mitochondrial dynamics determines the apoptotic response upon embryonic differentiation, Cold Spring Harbor Laboratory.
- Retinoic acid accelerates the specification of enteric neural progenitors from in vitro-derived neural crest.
- Generation and Trapping of a Mesoderm Biased State of Human Pluripotency, Cold Spring Harbor Laboratory.
- Genetically Variant Human Pluripotent Stem Cells Selectively Eliminate Wild-Type Counterparts Through YAP-Mediated Cell Competition.
- Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition. Developmental Cell. View this article in WRRO
- Grants
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- Medical Research Council
- UK Regenerative Medicine Platform
- Muscular Dystrophy UK
- EU Horizon2020
- The Royal Society
- Sheffield Children's NHS Trust
- Canadian Institute for Health Research
- Teaching activities
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Undergraduate and postgraduate taught modules:
Level 3:- BMS354 Principles of Regenerative Medicine and Tissue Engineering (Coordinator)
- BMS382 Stem Cell Biology
- Practical and Dissertation Modules (BIS303)
Masters (MSc):
- BMS6398 Principles of Regenerative Medicine and Tissue Engineering (Coordinator)
- BMS6056 Stem Cell Biology
- Practical and Dissertation Modules (BIS404-401, BMS51005-BMS61006)
- Professional activities and memberships
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- Member of the MRC Molecular and Cellular Medicine Board (2022)
- Co-chair of the Working group on Genomic characterisation of hPSC within the ISSCR Task Force on Standards in Stem Cell Research (2021 – present)
- Member of the Steering Committee of the International Stem Cell Initiative (2021 – present)
- Board member of the British Society for Cell and Gene Therapy (2019 – present) and the BSGCT EDI lead (2022 – present)
- Member of the Executive Team of the Pluripotent and Engineered Stem Cell Hub (2018 –present)
- Member of the EuroGCT Consortium (2020 – present)
- Co-lead for the Mechanistic Neurobiology theme within the Neuroscience Institute Executive Team at the University of Sheffield (2020 – present)
- Co-Director of the INSIGNEO Biomechanics, Biomaterials and Cell Engineering theme (2022 – present)
- Member of the Scientific Advisory Board for WiCell (USA) (2022 – present)
- Member of the Scientific Advisory Board for Broken Strings Ltd (UK) (2021 – present)