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STEM CELL GENETICS LAB

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GROUP LEADER:
PROF. IVANA BARBARIC

My lab is located in the Centre for Stem Cell Biology at the University of Sheffield. The main focus of our research is the biology of pluripotent stem cells and their applications in regenerative medicine and disease modelling.

LAB MEMBERS

FORMER MEMBERS

Dr Dylan Stavish Postdoctoral Researcher (Stem Cell Technologies, UK)

Dr Christopher Price Postdoctoral Researcher (Stem Cell Technologies, Canada)

Chiara Sander Research Assistant (SiTraN, Sheffield, UK)

RESEARCH

Stem Cell Genetics Lab, Dr Ivana Barbaric

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GENETIC CHANGES IN STEM CELLS

DISEASE MODELLING USING STEM CELLS

STEM CELL FATE CONTROL

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SELECTED RECENT PUBLICATIONS

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

Charcot Marie Tooth Disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain and loss of sensation in limbs. There are currently no treatments for this debilitating disease. To investigate disease mechanisms and facilitate treatment discovery, here we developed an in vitro model for CMT type 2A by introducing the patient-specific MFN2R94Q mutation into human embryonic stem cells (hESCs). Isogenic mutant and wild-type hESCs differentiated to spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in reduced numbers of mitochondria in distal parts of axons. Importantly, we showed that mitochondrial trafficking defects can be alleviated by treatment with an HDAC6 inhibitor. Chemical and genetic inhibition of HDAC6 also significantly rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a mutation-specific insight into CMT2A disease mechanism and confirms HDAC6 as a promising target for further therapeutic development.

doi: https://doi.org/10.1101/2022.07.05.498819

GENETICALLY VARIANT HUMAN PLURIPOTENT STEM CELLS SELECTIVELY ELIMINATE WILD-TYPE COUNTERPARTS THROUGH YAP-MEDIATED CELL COMPETITION

The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a concern for their use in research and regenerative medicine. Variant hPSCs that harbor recurrent culture-acquired aneuploidies display growth advantages over wild-type diploid cells, but the mechanisms that yield a drift from predominantly wild-type to variant cell populations remain poorly understood. Here, we show that the dominance of variant clones in mosaic cultures is enhanced through competitive interactions that result in the elimination of wild-type cells. This elimination occurs through corralling and mechanical compression by faster-growing variants, causing a redistribution of F-actin and sequestration of yes-associated protein (YAP) in the cytoplasm that induces apoptosis in wild-type cells. YAP overexpression or promotion of YAP nuclear localization in wild-type cells alleviates their "loser" phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues imposed by neighboring cells and reveal that hijacking this mechanism allows variants to achieve clonal dominance in cultures.

doi: 10.1016/j.devcel.2021.07.019

The changes that drive differentiation facilitate the emergence of abnormal cells that need to be removed before they contribute to further development or the germline. Consequently, in mice in the lead-up to gastrulation, ∼35% of embryonic cells are eliminated. This elimination is caused by hypersensitivity to apoptosis, but how it is regulated is poorly understood. Here, we show that upon exit of naive pluripotency, mouse embryonic stem cells lower their mitochondrial apoptotic threshold, and this increases their sensitivity to cell death. We demonstrate that this enhanced apoptotic response is induced by a decrease in mitochondrial fission due to a reduction in the activity of dynamin-related protein 1 (DRP1). Furthermore, we show that in naive pluripotent cells, DRP1 prevents apoptosis by promoting mitophagy. In contrast, during differentiation, reduced mitophagy levels facilitate apoptosis. Together, these results indicate that during early mammalian development, DRP1 regulation of mitophagy determines the apoptotic response.


DOI: 10.1016/j.devcel.2022.04.020

PLACEMENTS

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As a Year 12 Sixth Form student looking to study Biomedical Science at university, stem cell biology is a field that I find especially interesting. I wanted to expand my knowledge of stem cells and gain familiarity within a lab setting. I was given the opportunity to do some work experience for a week in Ivana’s lab, where I had the incredible chance to immerse myself in the ongoing stem cell research.

During my time in the lab, I learnt the importance of working in a sterile environment and shadowed PhD students undertaking their individual research projects.
Throughout the week I had the invaluable opportunity to work with hPSCs myself. I learnt how to work in a biosafety cabinet, how to perform media changes on stem cell cultures, coat a new flask ready for passaging and finally passaging stem cells. The hands on experience has taught me new skills such as aseptic technique and deepened my understanding of stem cell biology.
 
I thoroughly enjoyed my time in lab and I am grateful for the incredible opportunity.

Lauren H., Work Experience Student

Nina's Outreach Video: Extracting DNA from strawberries

For budding scientists and their teachers/ parents/ carers: have a go at extracting the DNA in your home- or school-based lab following the instructions in this video.

CONTACT DETAILS

Centre for Stem Cell Biology,
School of Biological Sciences
The University of Sheffield
Alfred Denny Building,
Sheffield, S10 2TN,
United Kingdom

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