Dr Helle F Jørgensen

Atherosclerosis causes death by heart attack and stroke, and has vast socio-economic consequences. Targeting arterial cells to stabilise disease represents unexplored territory, that would complement current risk factor-reducing approaches. In particular, vascular smooth muscle cells (VSMCs) are enriched for coronary artery disease GWAS signals and generate the majority of cells in atherosclerotic lesions. The Jorgensen Team aims to identify mechanisms regulating VSMCs that can be leveraged for disease treatment and prevention.

Vascular smooth muscle cell diversity

Gene regulation

Vascular disease

Biography

Helle Jorgensen is an Associate Professor at the University of Cambridge. Her group studies how vascular smooth muscle cell (VSMC) plasticity and heterogeneity is regulated in vascular health and disease. Her team has demonstrated that a small number of pre-existing VSMC undergo extensive proliferative expansion to generate a large number of cell in atherosclerotic lesions and that similar clonal expansion is a hallmark of other vascular disease models. Using single cell transcriptome profiling, the group has revealed substantial VSMC heterogeneity both in lesions and in healthy arteries. These findings have implication for the understanding of VSMC behaviour and how selective targeting of disease-associated VSMC could be translated to the clinic.

Helle was awarded a PhD in molecular biology from Aarhus University in 2000 (Prof Brian Clarke). During her postdoctoral training she studied DNA-methylation-binding factors under the mentorship of Prof Sir Adrian Bird (University of Edinburgh) and investigated how transcription factors and epigenetic mechanisms control embryonic stem cell maintenance and cell fate choices (Prof Dame Amanda G Fisher, London Institute of Medical Research).

ORCID: 0000-0002-7909-2977

Research

The focus of the Jorgensen team is the regulation of cell plasticity in the cardiovascular system and the implications for vascular disease. In particular, we study vascular smooth muscle cells (VSMC) and how they contribute to the development of atherosclerosis, the disease underlying heart attack and stroke.

VSMCs exist in a contractile, quiescent state in healthy arteries, but can downregulate this phenotype in response to injury and inflammation. The resulting de-differentiated state is characterised by widespread changes in gene expression leading to perturbed extracellular matrix remodelling, proliferation and migration.

We study how these gene expression programs are regulated and impact on phenotypic plasticity in development, tissue homeostasis and disease models. The team has demonstrated that a small number of pre-existing VSMC undergo extensive proliferative expansion to generate a large number of cell in atherosclerotic lesions and that similar clonal expansion is a hallmark of other vascular disease models. Using single cell transcriptome profiling, the group has revealed substantial VSMC heterogeneity both in lesions and in healthy arteries. These findings have implication for the understanding of VSMC behaviour and how selective targeting of disease-associated VSMC could be translated to the clinic.

Publications

Key publications:

Taylor, J. C., Worssam, M. D., Oc, S., Lambert, J., Mahbubani, K. T., Foote, K., Finigan, A., Chan, Y.-H., Figg, N., Clarke, M. C. H., Bennett, M. R., & Jørgensen, H. F. (2024). Delineation of a thrombin receptor-stimulated vascular smooth muscle cell transition generating cells in the plaque-stabilising fibrous cap. BioRxiv, 2024.07.02.600985. https://doi.org/10.1101/2024.07.02.600985
Lambert, J.*/Oc, S.*, Worssam, M. D., Häußler, D., Figg, N. L., Baxter, R., Foote, K., Finigan, A., Mahbubani, K. T., Bennett, M. R., Krüger, A., Spivakov, M., & Jørgensen, H. F. (2024). Network-based prioritisation and validation of novel regulators of vascular smooth muscle cell proliferation in disease. Nature Cardiovas Res. https://www.nature.com/articles/s44161-024-00474-4. (deposited at BioRxiv https://doi.org/10.1101/2023.08.25.554834)
Worssam, M. D., Lambert, J., Oc, S., Taylor, J. C. K., Taylor, A. L., Dobnikar, L., Chappell, J., Harman, J. L., Figg, N. L., Finigan, A., Foote, K., Uryga, A. K., Bennett, M. R., Spivakov, M., & Jørgensen, H. F. (2022). Cellular mechanisms of oligoclonal vascular smooth muscle cell expansion in cardiovascular disease. Cardiovascular Research, 119(5), 1279–1294. https://doi.org/10.1093/cvr/cvac138
Harman, J. L., Dobnikar, L., Chappell, J., Stokell, B. G., Dalby, A., Foote, K., Finigan, A., Freire-Pritchett, P., Taylor, A. L., Worssam, M. D., Madsen, R. R., Loche, E., Uryga, A., Bennett, M. R., & Jørgensen, H. F. (2019). Epigenetic Regulation of Vascular Smooth Muscle Cells by Histone H3 Lysine 9 Dimethylation Attenuates Target Gene-Induction by Inflammatory Signaling. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(11), 2289–2302. https://doi.org/10.1161/atvbaha.119.312765
Dobnikar, L.*/Taylor, A. L.*, Chappell, J., Oldach, P., Harman, J. L., Oerton, E., Dzierzak, E., Bennett, M. R., Spivakov, M.*/Jørgensen, H. F.* (2018). Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels. Nature Communications, 9(1), 1-17 (4567). https://doi.org/10.1038/s41467-018-06891-x
Chappell, J., Harman, J. L., Narasimhan, V. M., Yu, H., Foote, K., Simons, B. D., Bennett, M. R., & Jørgensen, H. F. (2016). Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models. Circulation Research, 119(12), 1313–1323. https://doi.org/10.1161/circresaha.116.309799

Other publications:

Jorgensen Team Publications

Lambert, J.*/Oc, S.*, Worssam, M. D., Häußler, D., Figg, N. L., Baxter, R., Foote, K., Finigan, A., Mahbubani, K. T., Bennett, M. R., Krüger, A., Spivakov, M., & Jørgensen, H. F. (2024). Network-based prioritisation and validation of novel regulators of vascular smooth muscle cell proliferation in disease. Nature Cardiovas Res. https://www.nature.com/articles/s44161-024-00474-4. (deposited at BioRxiv https://doi.org/10.1101/2023.08.25.554834)
Schoenmakers, E.*/Marelli, F.*/Jørgensen, H. F.*, Visser, W. E., Moran, C., Groeneweg, S., Avalos, C., Jurgens, S. J., Figg, N., Finigan, A., Wali, N., Agostini, M., Wardle-Jones, H., Lyons, G., Rusk, R., Gopalan, D., Twiss, P., Visser, J. J., Goddard, M., … Chatterjee, K. (2023). Selenoprotein deficiency disorder predisposes to aortic aneurysm formation. Nature Communications, 14(1), 7994. https://doi.org/10.1038/s41467-023-43851-6
Ćorović, A., Wall, C., Nus, M., Gopalan, D., Huang, Y., Imaz, M., Zulcinski, M., Peverelli, M., Uryga, A., Lambert, J., … Jørgensen, H.F. … Tarkin, J. M. (2023). Somatostatin Receptor PET/MR Imaging of Inflammation in Patients With Large Vessel Vasculitis and Atherosclerosis. Journal of the American College of Cardiology, 81(4), 336–354. https://doi.org/10.1016/j.jacc.2022.10.034
Johnson, R. T., Solanki, R., Wostear, F., Ahmed, S., Taylor, J. C. K., Rees, J., Abel, G., McColl, J., Jørgensen, H. F., Morris, C. J., Bidula, S., & Warren, D. T. (2023). Piezo1‐mediated regulation of smooth muscle cell volume in response to enhanced extracellular matrix rigidity. British Journal of Pharmacology. https://doi.org/10.1111/bph.16294
Winther, M. P. J. de, Bäck, M., Evans, P., Gomez, D., Goncalves, I., Jørgensen, H. F., Koenen, R. R., Lutgens, E., Norata, G. D., Osto, E., Dib, L., Simons, M., Stellos, K., Ylä-Herttuala, S., Winkels, H., Bochaton-Piallat, M.-L., & Monaco, C. (2022). Translational opportunities of single-cell biology in atherosclerosis. European Heart Journal, 44(14), 1216–1230. https://doi.org/10.1093/eurheartj/ehac686
Worssam, M. D., Lambert, J., Oc, S., Taylor, J. C. K., Taylor, A. L., Dobnikar, L., Chappell, J., Harman, J. L., Figg, N. L., Finigan, A., Foote, K., Uryga, A. K., Bennett, M. R., Spivakov, M., & Jørgensen, H. F. (2022). Cellular mechanisms of oligoclonal vascular smooth muscle cell expansion in cardiovascular disease. Cardiovascular Research, 119(5), 1279–1294. https://doi.org/10.1093/cvr/cvac138
Garrido, A. M., Kaistha, A., Uryga, A. K., Oc, S., Foote, K., Shah, A., Finigan, A., Figg, N., Dobnikar, L., Jørgensen, H., & Bennett, M. (2021). Efficacy and limitations of senolysis in atherosclerosis. Cardiovascular Research, 118(7), 1713–1727 (cvab208). https://doi.org/10.1093/cvr/cvab208
Lambert, J., & Jørgensen, H. F. (2021). Vascular smooth muscle cell phenotypic switching and plaque stability: a role for CHI3L1. Cardiovascular Research, 117(14), 2691–2693 (cvab099-).https://doi.org/10.1093/cvr/cvab099
Quiles-Jiménez, A., Gregersen, I., Segers, F. M., Skarpengland, T., Kroustallaki, P., … Jørgensen, H.F. … Halvorsen, B. (2021). DNA glycosylase Neil3 regulates vascular smooth muscle cell biology during atherosclerosis development. Atherosclerosis, 324, 123–132. https://doi.org/10.1016/j.atherosclerosis.2021.02.023
Uryga, A. K., Grootaert, M. O. J., Garrido, A. M., Oc, S., Foote, K., Chappell, J., Finigan, A., Rossiello, F., Fagagna, F. d’Adda di, Aravani, D., Jorgensen, H. F., & Bennett, M. R. (2021). Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury. Communications Biology, 4(1), 1-16 (611). https://doi.org/10.1038/s42003-021-02123-z
Worssam, M. D., & Jørgensen, H. F. (2021). Mechanisms of vascular smooth muscle cell investment and phenotypic diversification in vascular diseases. Biochemical Society Transactions, 49(5), 2101–2111. https://doi.org/10.1042/bst20210138
Jørgensen, H. F., & Bennett, M. R. (2020). PCSK6-Mediated Regulation of Vascular Remodeling. Circulation Research, 126(5), 586–588. https://doi.org/10.1161/circresaha.120.316612
Basatemur, G. L., Jørgensen, H. F., Clarke, M. C. H., Bennett, M. R., & Mallat, Z. (2019). Vascular smooth muscle cells in atherosclerosis. Nature Reviews Cardiology, 16(12), 727–744. https://doi.org/10.1038/s41569-019-0227-9
Clément, M.*/Chappell, J.*, Raffort, J., Lareyre, F., Vandestienne, M., Taylor, A. L., Finigan, A., Harrison, J., Bennett, M. R., Bruneval, P., Taleb, S., Jørgensen, H. F.*/Mallat, Z.* (2019). Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(6), 1149–1159. https://doi.org/10.1161/atvbaha.118.311727
Harman, J. L., Dobnikar, L., Chappell, J., Stokell, B. G., Dalby, A., Foote, K., Finigan, A., Freire-Pritchett, P., Taylor, A. L., Worssam, M. D., Madsen, R. R., Loche, E., Uryga, A., Bennett, M. R., & Jørgensen, H. F.(2019). Epigenetic Regulation of Vascular Smooth Muscle Cells by Histone H3 Lysine 9 Dimethylation Attenuates Target Gene-Induction by Inflammatory Signaling. Arteriosclerosis, Thrombosis, and Vascular Biology, 39(11), 2289–2302. https://doi.org/10.1161/atvbaha.119.312765
Harman, J. L., & Jørgensen, H. F. (2019). The role of smooth muscle cells in plaque stability: Therapeutic targeting potential. British Journal of Pharmacology, 176(19), 3741–3753. https://doi.org/10.1111/bph.14779
Rana, B. M. J., Jou, E., Barlow, J. L., Rodriguez-Rodriguez, N., Walker, J. A., Knox, C., Jolin, H. E., … Jørgensen, H.F. …, Vidal-Puig, A., & McKenzie, A. N. J. (2019). A stromal cell niche sustains ILC2-mediated type-2 conditioning in adipose tissue. Journal of Experimental Medicine, 216(9), 1999–2009. https://doi.org/10.1084/jem.20190689
Dobnikar, L.*/Taylor, A. L.*, Chappell, J., Oldach, P., Harman, J. L., Oerton, E., Dzierzak, E., Bennett, M. R., Spivakov, M.*/Jørgensen, H. F.* (2018). Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels. Nature Communications, 9(1), 1-17 (4567). https://doi.org/10.1038/s41467-018-06891-x
Tomaz, R. A., Harman, J. L., Karimlou, D., Weavers, L., Fritsch, L., Bou-Kheir, T., Bell, E., Torres, I. del V., Niakan, K. K., Fisher, C., Joshi, O., Stunnenberg, H. G., Curry, E., Ait-Si-Ali, S., Jørgensen, H. F., & Azuara, V. (2017). Jmjd2c facilitates the assembly of essential enhancer-protein complexes at the onset of embryonic stem cell differentiation. Development, 144(4), 567–579. https://doi.org/10.1242/dev.142489
Chappell, J., Harman, J. L., Narasimhan, V. M., Yu, H., Foote, K., Simons, B. D., Bennett, M. R., & Jørgensen, H. F. (2016). Extensive Proliferation of a Subset of Differentiated, yet Plastic, Medial Vascular Smooth Muscle Cells Contributes to Neointimal Formation in Mouse Injury and Atherosclerosis Models. Circulation Research, 119(12), 1313–1323. https://doi.org/10.1161/circresaha.116.309799