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  • Journal article
    Lima A, Lubatti G, Burgstaller J, Hu D, Green AP, Di Gregorio A, Zawadzki T, Pernaute B, Mahammadov E, Perez-Montero S, Dore M, Sanchez JM, Bowling S, Sancho M, Kolbe T, Karimi MM, Carling D, Jones N, Srinivas S, Sciadldone A, Rodriguez Tet al., 2021,

    Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

    , Nature Metabolism, Vol: 3, Pages: 1091-1108, ISSN: 2522-5812

    Cell competition is emerging as a quality control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. In mice, 35% of epiblast cells are eliminated prior to gastrulation. Here we show that cells with mitochondrial defects are eliminated by cell competition during early mouse development. Using single cell transcriptional profiling of eliminated mouse epiblast cells we identify hallmarks of cell competition and mitochondrial defects. We go on to demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function triggers cell competition. In the mouse embryo, cell competition eliminates cells with sequence changes in mt-Rnr1 and mt-Rnr2, and that even non-pathological changes in mitochondrial DNA sequence can induce cell competition. Our results suggest that cell competition is a purifying selection that optimises mitochondrial performance prior to gastrulation.

  • Journal article
    Lawlor K, Marques-Torrejon MA, Dharmalingham G, El-Azhar Y, Schneider M, Pollard S, Rodríguez T, Rodriguez Tet al., 2020,

    Glioblastoma stem cells induce quiescence in surrounding neural stem cells via Notch signalling

    , Genes and Development, Vol: 34, Pages: 1599-1604, ISSN: 0890-9369

    There is increasing evidence demonstrating that adult neural stem cells (NSCs) are a cell of origin of glioblastoma. Here we analyzed the interaction between transformed and wild-type NSCs isolated from the adult mouse subventricular zone niche. We found that transformed NSCs are refractory to quiescence-inducing signals. Unexpectedly, we also demonstrated that these cells induce quiescence in surrounding wild-type NSCs in a cell–cell contact and Notch signaling-dependent manner. Our findings therefore suggest that oncogenic mutations are propagated in the stem cell niche not just through cell-intrinsic advantages, but also by outcompeting neighboring stem cells through repression of their proliferation.

  • Journal article
    Haltalli MLR, Watcham S, Wilson NK, Eilers K, Lipien A, Ang H, Birch F, Anton SG, Pirillo C, Ruivo N, Vainieri ML, Pospori C, Sinden RE, Luis TC, Langhorne J, Duffy KR, Gottgens B, Blagborough AM, Lo Celso Cet al., 2020,

    Manipulating niche composition limits damage to haematopoietic stem cells during Plasmodium infection

    , Nature Cell Biology, Vol: 22, Pages: 1399-1410, ISSN: 1465-7392

    Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches; however, what role the BM microenvironment plays in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single-cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over substantially faster than at steady-state and HSC function is drastically affected. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and—coupled with reactive oxygen species quenching—enables partial rescuing of HSC function.

  • Journal article
    Sory DR, Amin HD, Chapman D, Proud WG, Rankin SMet al., 2020,

    Replicating landmine blast loading in cellular <i>in Vitro</i> models

    , Physical Biology, Vol: 17, ISSN: 1478-3967

    Trauma arising from landmines and improvised explosive devices promotes heterotopic ossification, the formation of extra-skeletal bone in non-osseous tissue. To date, experimental platforms that can replicate the loading parameter space relevant to improvised explosive device and landmine blast wave exposure have not been available to study the effects of such non-physiological mechanical loading on cells. Here, we present the design and calibration of three distinct in vitro experimental loading platforms that allow us to replicate the spectrum of loading conditions recorded in near-field blast wave exposure. We subjected cells in suspension or in a three-dimensional hydrogel to strain rates up to 6000 s-1and pressure levels up to 45 MPa. Our results highlight that cellular activation is regulated in a non-linear fashion - not by a single mechanical parameter, it is the combined action of the applied mechanical pressure, rate of loading and loading impulse, along with the extracellular environment used to convey the pressure waves. Finally, our research indicates that PO MSCs are finely tuned to respond to mechanical stimuli that fall within defined ranges of loading.

  • Journal article
    Sintou A, Mansfield C, Iacob A-O, Chowdhury RA, Narodden S, Rothery SM, Podoveo R, Sanchez Alonso JL, Ferraro E, Swiatlowska P, Harding S, Prasad S, Rosenthal N, Gorelik J, Sattler Set al., 2020,

    Mediastinal lymphadenopathy, class-switched auto-antibodies and myocardial immune-complexes during heart failure in rodents and humans

    , Frontiers in Cell and Developmental Biology, Vol: 8, Pages: 1-12, ISSN: 2296-634X

    Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemicheart failure pointing to an autoimmune response against the heart. T and B cell have beenconvincingly demonstrated to be activated after myocardial infarction, a prerequisite for thegeneration of mature auto-antibodies. Yet, little is known about the immunoglobulin isotyperepertoire thus pathological potential of anti-heart auto-antibodies during heart failure.We obtained human myocardial tissue from ischemic heart failure patients and inducedexperimental MI in rats. We found that anti-heart autoimmunity persists during heart failure.Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with matureisotype-switched IgG2a B cells. Mature IgG2a auto-antibodies specific for cardiac antigens arepresent in rat heart failure serum, and IgG and complement C3 deposits are evident in heartfailure tissue of both rats and human patients.Previously established myocardial inflammation, and the herein provided proof of B cellmaturation in lymph nodes and myocardial deposition of mature auto-antibodies, provide allthe hallmark signs of an established autoimmune response in chronic heart failure.

  • Journal article
    Constantinou C, Miranda Almeida A, Chaves Guerrero P, Bellahcene M, Massaia A, Cheng K, Samari S, Rothery S, Chandler A, Schwarz R, Harding S, Punjabi P, Schneider MD, Noseda Met al., 2020,

    Human pluripotent stem cell-derived cardiomyocytes as a targetplatform for paracrine protection by cardiac mesenchymal stromalcells

    , Scientific Reports, Vol: 10, ISSN: 2045-2322

    Ischemic heart disease remains the foremost cause of death globally, with survivors at risk for subsequent heart failure. Paradoxically, cell therapies to offset cardiomyocyte loss after ischemic injury improve long-term cardiac function despite a lack of durable engraftment. An evolving consensus, inferred preponderantly from non-human models, is that transplanted cells benefit the heart via early paracrinesignals. Here, we tested the impact of paracrine signals on human cardiomyocytes, using human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) as the target of mouse and human cardiac mesenchymal stromal cells (cMSC) with progenitor-like features. In co-culture and conditioned medium studies, cMSCs markedly inhibited human cardiomyocyte death. Little or no protection was conferred by mouse tail tip or human skin fibroblasts. Consistent with the results of transcriptomic profiling, functional analyses showed that the cMSC secretome suppressed apoptosis and and preserved cardiac mitochondrial transmembrane potential. Protection was independent of exosomes under the conditions tested. In mice, injecting cMSC-conditioned media into the infarct border zone reduced apoptotic cardiomyocytes >70% locally. Thus, hPSC-CMs provide an auspicious, relevant human platform to investigate extracellular signals for cardiac muscle survival, substantiating human cardioprotection by cMSCs, and suggesting the cMSC secretome or its components as potential cell-free therapeutic products.

  • Journal article
    Sparks H, Dvinskikh L, Firth J, Francis A, Harding S, Paterson C, MacLeod K, Dunsby Cet al., 2020,

    Development a flexible light-sheet fluorescence microscope for high-speed 3D imaging of calcium dynamics and 3D imaging of cellular microstructure

    , Journal of Biophotonics, Vol: 13, ISSN: 1864-063X

    We report a flexible light‐sheet fluorescence microscope (LSFM) designed for studying dynamic events in cardiac tissue at high speed in 3D and the correlation of these events to cell microstructure. The system employs two illumination‐detection modes: the first uses angle‐dithering of a Gaussian light sheet combined with remote refocusing of the detection plane for video‐rate volumetric imaging; the second combines digitally‐scanned light‐sheet illumination with an axially‐swept light‐sheet waist and stage‐scanned acquisition for improved axial resolution compared to the first mode. We present a characterisation of the spatial resolution of the system in both modes. The first illumination‐detection mode achieves dual spectral‐channel imaging at 25 volumes per second with 1024 × 200 × 50 voxel volumes and is demonstrated by time‐lapse imaging of calcium dynamics in a live cardiomyocyte. The second illumination‐detection mode is demonstrated through the acquisition of a higher spatial resolution structural map of the t‐tubule network in a fixed cardiomyocyte cell.

  • Journal article
    Seong H, Higgins SG, Penders J, Armstrong JPK, Crowder SW, Moore AC, Sero JE, Becce M, Stevens MMet al., 2020,

    Size-tunable nanoneedle arrays for influencing stem cell morphology, gene expression and nuclear membrane curvature

    , ACS Nano, Vol: 14, Pages: 5371-5381, ISSN: 1936-0851

    High-aspect-ratio nanostructures have emerged as versatile platforms for intracellular sensing and biomolecule delivery. Here, we present a microfabrication approach in which a combination of reactive ion etching protocols was used to produce high-aspect-ratio, nondegradable silicon nanoneedle arrays with tip diameters that can be finely tuned between 20 and 700 nm. We used these arrays to guide the long-term culture of human mesenchymal stem cells (hMSCs). Notably, we used the nanoneedle tip diameter to control the morphology, nuclear size and F-actin alignment of interfaced hMSCs, and to regulate the expression of nuclear lamina genes, Yes-associated protein (YAP) target genes and focal adhesion genes. These topography-driven changes were attributed to signaling by Rho-family GTPase pathways, differences in the effective stiffness of the nanoneedle arrays and the degree of nuclear membrane impingement, with the latter clearly visualized using focused-ion beam scanning electron microscopy (FIB-SEM). Our approach to design high-aspect-ratio nanostructures will be broadly applicable to design biomaterials and biomedical devices used for long-term cell stimulation and monitoring.

  • Journal article
    Fellous TG, Redpath AN, Fleischer MM, Gandhi S, Hartner SE, Newton MD, Francois M, Wong S-P, Gowers KHC, Fahs AM, Possley DR, Bonnet D, Urquhart P, Nicolaou A, Baker KC, Rankin SMet al., 2020,

    Pharmacological tools to mobilise mesenchymal stromal cells into the blood promote bone formation after surgery

  • Journal article
    Nele V, Schutt CE, Wojciechowski J, Kit-Anan W, Doutch JJ, Armstrong J, Stevens Met al., 2020,

    Ultrasound-triggered enzymatic gelation

    , Advanced Materials, Vol: 32, Pages: 1-8, ISSN: 0935-9648

    Hydrogels are formed using various triggers, including light irradiation, pH adjustment, heating,cooling or chemical addition. In this report, a new method for forming hydrogels is introduced:ultrasound-triggered enzymatic gelation. Specifically, ultrasound is used as a stimulus to liberateliposomal calcium ions, which then trigger the enzymatic activity of transglutaminase. Theactivated enzyme catalyzes the formation of fibrinogen hydrogels through covalent intermolecularcrosslinking. The catalysis and gelation processes are monitored in real time and both the enzymekinetics and final hydrogel properties are controlled by varying the initial ultrasound exposure time.This technology is extended to microbubble-liposome conjugates, which exhibit a stronger responseto the applied acoustic field and are also used for ultrasound-triggered enzymatic hydrogelation. Tothe best of our knowledge, these results are the first instance in which ultrasound has been used as atrigger for either enzyme catalysis or enzymatic hydrogelation. This approach is highly versatile and Peer reviewed version of the manuscript published in final form at Advanced Materials (2020)2could be readily applied to different ion-dependent enzymes or gelation systems. Moreover, thiswork paves the way for the use of ultrasound as a remote trigger for in vivo hydrogelation.

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