Enhancing haematopoeitic stem cell recruitment to injured murine colon

Yemm, Adrian Ian (2014). Enhancing haematopoeitic stem cell recruitment to injured murine colon. University of Birmingham. Ph.D.

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Abstract

Haematopoietic stem cells (HSCs) have been described as potential therapeutic agents for the repair of several inflammatory injuries including inflammatory bowel diseases (IBDs). However, their efficacy within clinics has been poor. This has been partially attributed to poor recruitment to sites of injury. Thus identifying the mechanisms by which HSCs are recruited to inflamed bowel, and developing strategies to enhance this recruitment, may increase their clinical efficacy. Critical adhesive mechanisms and several pre-treatment strategies to enhance adhesion to chronically (DSS induced colitis) and acutely (IR) injured murine colon were investigated in vitro and in vivo. It was found that recruitment to IR injured colon was mediated by CD49d, whereas recruitment to colitic colon was mediated by both CD18 and CD49d. In vitro investigation revealed that both hydrogen peroxide (H2O2) and platelet derived pre-treatments, such as coating HSCs with platelet microparticles (PMPs), could enhance adhesion to colon endothelial cells, immobilised endothelial counterligands ICAM-1 and VCAM-1 and frozen tissue sections. Furthermore, pre-treatment of HSCs with PMPs significantly enhanced their adhesion to chronically injured colon in vivo. These increases in adhesion were likely to be attributed to the altered distribution of integrins on the HSC surface as determined confocally. Furthermore, electron micrscopy showed that pre-treatment also resulted in overt HSC morphological changes reminiscent of activated macrophages. Overall, these investigations describe a two-component recruitment mechanism for pre-treated cells in which enhanced recruitment is dependent on both activation of stem cells and also vascular endothelium. These studies provide novel evidence that pre-treatment of HSCs can result in their increased recruitment to injured colon, a finding that may allow for stem cell therapy for IBDs to be fully realised.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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