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Title: Bone-resident mesenchymal stromal cells in healthy ageing and osteoarthritis : enumeration and gene expression analysis in uncultured cells
Author: Ganguly, Payal
ISNI:       0000 0004 9351 6953
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2019
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Ageing considerably reduces the quality of life with osteoarthritis (OA) being the most common age-related degenerative disorder. Whilst majority investigations have focussed on cartilage changes in OA, damage in the bone preceding cartilage damage, is increasingly being acknowledged. Bone and cartilage arise from progenitor cells called mesenchymal stromal cells (MSCs) resident in the bone marrow (BM). It was hypothesised that changes in BM MSCs contribute to OA development. It was aimed to investigate changes in BM MSCs in healthy ageing and then explore if these changes were aggravated in OA using flow cytometry for the CD45lowCD271+ phenotype and gene expression. Minimally-expanded/uncultured MSCs were used to avoid effects of in vitro ageing due to culture expansion. BM aspirates from 51 healthy donors (19-89 years old) were processed for MSC quantification using colony forming unit fibroblast (CFU-F) assay. For OA investigations, MSCs from donors with hip OA (56-83 years old) were recruited. Gene expression of MSC multipotentiality genes, genes associated with cell senescence and type 1 interferon (IFN1) pathway genes was compared between CD45lowCD271+ MSCs and donor-matched control CD45+CD271- haematopoietic lineage cells (HLCs). MSC numbers declined with advancing age as measured by both assays but a more prominent decline was noted using CFU-F assay. Colony size and integrated density significantly reduced in old donor MSCs indicating age-related decline in MSC proliferation. When cultured in media with old donor serum, young and old donor MSCs displayed lower proliferation. IL6 expression from old donors displayed 4-fold increase in both MSCs and HLCs. IFN1 genes displayed strikingly high expression but no age-related changes in MSCs. In OA, number of genes displayed significant differences including LepR, CXCL12 and IL6 as compared to healthy old donor MSCs. Surface marker expression of CD106 and CD295 were found to decline significantly in MSCs and a similar trend for CD295 decline was observed in HLCs. Age-related increase in IL6 expression was aggravated more notably in MSCs. In summary, age-related decline was observed in MSC number and proliferative capacity while gene and surface marker expression displayed non-significant differences as compared to donor-matched HLCs. These data indicate that BM MSCs are potentially more resistant to ageing stimuli in vivo compared to other BM resident hematopoietic lineage cells.
Supervisor: Jones, Elena ; Burska, Agata ; Giannoudis, Peter ; Ponchel, Frederique Sponsor: Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available