Project ID CM-HD2023_13

ThemeCM-HD

Co Supervisor 1A CHAPS/BMB/FoLSMWebsite

Co Supervisor 1B Cardiovascular/FoLSMWebsite

The role of MSCs in modulating inflamm-aging in cardiovascular and ischemic diseases

Acute and chronic inflammation is damaging to all cell types and contributes to the pathogenesis of a number of diseases, including cardiovascular disease. “Inflamm-aging” is a chronic, sterile, systemic pro-inflammatory status that occurs during ageing. Senescent cells, which accumulate in tissues with ageing and disease, secrete pro-inflammatory senescence associated-secretory phenotype (SASP) factors contributing to inflamm-aging. Mesenchymal stromal cells or Medicinal signalling cells (MSCs) have a powerful immunomodulatory, anti-inflammatory and reparative/regenerative function.

We hypothesise that: MSCs can target and suppress inflammation and inflamm-aging, thus directly attenuate the damaging effects of inflammation to the cardiovascular system.

Objectives:
1. To elucidate whether MSCs attenuate the damaging systemic effects of inflamm-ageing on human cardiomyocytes and cardiac endothelial cells in vitro. Rotation project and Year 1
2. Characterising senescence and inflamm-aging in healthy and ischaemic muscle from patients with Chronic Limb Threatening Ischemia (CLTI). Year 2
3. To elucidate whether MSCs attenuate the damaging systemic effects of inflamm-ageing in an animal model of Chronic Limb Threatening Ischemia (CLTI). Year 3 and 4 (if 0+4).

Techniques and skills: The student will be trained in a range of cutting-edge in vitro and in vivo techniques. These include primary human cell isolation, generation and maintenance of human cells/iPSCs and iPSC-CMs in co-culture, cell phenotyping using multi-parameter flow cytometry, NGS, multiplex Luminex, immunostaining, confocal and light microscopy and image analysis, in vivo animal models. The student will use the laboratories of Dr. Patel and Prof. Ellison-Hughes as well as the BRC/KCL Core Facilities to carry out the work.

One representative publication from each co-supervisor:

• Zhu et al. (2021). Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms. Cell research, 31(12), 1244–1262. https://doi.org/10.1038/s41422-021-00573-y

• Patel AS, Smith A, Nucera S, Biziato D, Saha P, Attia RQ, Humphries J, Mattock K, Grover SP, Lyons OT, Guidotti LG, Siow R, Ivetic A, Egginton S, Waltham M, Naldini L, De Palma M, Modarai B. TIE2-expressing monocytes/macrophages regulate revascularization of the ischemic limb. EMBO Mol Med 2013 May 7. doi: 10.1002/emmm.201302752