Saudi Cultural Missions Theses & Dissertations
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Item Restricted Investigation of the molecular mechanisms of human mesenchymal stem cells and S. aureus interactions in osteomyelitis(University of Bristol, 2024-01-23) Alghuwainem, Ghannimah Y; Wael, Kafieneh; Darryl, HillOsteomyelitis (OM) is bone inflammation that typically arises due to bacterial infection. Current treatment strategies for eradicating this condition include surgical debridement and systemic and local antibiotics. Both strategies, however, come with limitations that impact the disease outcomes. New biological approaches that can reduce the bacterial burden and help regenerate damaged bone are being sought. The aims of this study were to identify the potential of ameliorating bone marrow mesenchymal stem cells (bmMSC) anti-inflammatory and anti-bacterial function for treating OM through modulating the Toll-like receptors (TLRs), the impact of bmMSC conditioned medium (MSC-CM) on osteogenic properties of osteoblasts and testing the therapeutic potential of MSCs in a 3D model of OM using a human ex vivo bone model. Stimulation of bmMSCs with TLR agonists (Pam3CK4 and PGN-SA) resulted in significant growth inhibition of S. aureus compared to the unstimulated control cells. Infected bmMSCs overexpressed indoleamine 2, 3-dioxygenase enzyme (IDO) after Pam3CSK4 stimulation. The inhibition correlated with IDO expression in response to PGN-SA but not Pam3CSk4 stimulation. The inflammatory cytokines, IL-6 and CCL2, were upregulated in MSCs stimulated with Pam3CK4 and PGN-SA, respectively. Upon administration of MSC-CM with infected osteoblasts revealed antibacterial properties of human bmMSCs on infected osteoblasts. Moreover, MSC-CM inhibited the growth of S. aureus using CM harvested from different cell densities of MSCs. An ex vivo model of OM infection was established by infecting bone explants from human femoral head with S. aureus. Studies using the model revealed differential expression of bone resorption marker including cathepsin K (CTSK), tartrate-resistant acid phosphatase (ACP5), extracellular matrix-degrading enzymes matrix metalloproteinase 1 and 13 (MMP-1 and MMP-13), and the inflammatory cytokines IL-6. The expression profile suggested alignment of the ex vivo model with the pathological profile of OM. The addition of MSC-CM to the infection model dampened the inflammatory and resorption response. There was significant downregulation of genes responsible for osteoclastic and inflammatory activities upon culture with MSC-CM. The results may suggest that MSC- CM should be investigated further to reveal its trophic composition and derive a biological treatment for OM.19 0Item Restricted In Vitro Assessment of Adipose-Derived Mesenchymal Stem Cell attachment to Injured Cartilage in Agarose Hydrogel Biomaterial(Saudi Digital Library, 2023-08-18) Sabah, Reem; Hall, AndrewArticular cartilage (AC) injuries are a prevalent problem leading to osteoarthritis (OA), which significantly impacts the quality of life of millions worldwide. Tissue engineering using mesenchymal stem cells (MSCs) holds potential as a promising therapeutic approach. This study aimed to investigate the attachment of adipose-derived MSCs (A-MSCs) to cartilage with four types of injuries: scraping, load, 3 mm biopsy punch, and scalpel cut. Injured explants and A-MSCs were placed inside 12 culture wells embedded in 2% agarose, one explant per well, hydrogel biomaterial to mimic native cartilage in vitro. The hypothesis was that A-MSCs would attach to the injured sites. Bovine cartilage explants (N=3) were subjected to the four injury types, totalling 56 explants, and the study was conducted over seven days, with attachment assessment on days 5 and 7 using confocal laser scanning microscopy (CLSM). The results revealed a decreased cartilage viability in both load and scraping injuries, with higher Propidium Iodide (PI)-labelled levels observed on CLSM. Additionally, the number of A-MSCs attachment was higher on these injuries compared to the 3mm biopsy punch and scalpel cut. Additionally, day 7 viability percentage was lower compared to day 5 across all injury samples. These findings suggest that injured areas show increased A-MSC attachment, indicating the potential of A-MSCs for promoting tissue repair. This study has implications for tissue engineering in developing a model to study A-MSCs behaviour to injured cartilage explants. Future recommendations include increasing the culture time to promote chondrogenesis and utilising a human model for a more clinically relevant approach. Understanding the attachment behaviour of A-MSCs to injured cartilage enhances the knowledge base in cartilage tissue engineering and contributes to future therapeutic advancements.4 0