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    • In addition to PES pre treatment increasing HPC adhesion wit

    2018-11-06

    In addition to PES pre-treatment increasing HPC7 adhesion within the colon, it also concomitantly reduced pulmonary presence, thereby reducing non-specific retention in healthy tissues. Pulmonary entrapment is a major obstacle for systemic HSPC delivery for regenerative purposes both experimentally and clinically (Fischer et al., 2009). Indeed, patients receiving exogenous HSCs for haematologic disorders experience post-transplant pulmonary injury due to purchase Deferoxamine becoming trapped in lung capillaries. In addition to promoting lung damage, pulmonary entrapment significantly reduces the available pool of circulating transplanted cells available for recruitment to injured tissues. This study is the first to demonstrate that microparticle coating not only effectively enhanced recruitment into specific sites of tissue injury, but also concomitantly decreased their entrapment within lungs. This observation may simply be related to cell availability, i.e. enhanced intestinal recruitment means less cells are available for pulmonary entrapment and vice-versa. The mechanisms by which microparticles and activated platelet releasate may modify HPC7 adhesion appear to be similar to those we have previously seen with H2O2 (Kavanagh et al., 2013a). Although no change in the actual expression of HPC7 surface integrins was induced, the number of CD18 and/or CD49d clusters did increase. Evidence is emerging that the dynamic reorganisation of surface integrins into microclusters, through F-actin polymerisation, is the major mechanism regulating integrin binding strength and is a prerequisite for their activation and ligand binding (van Kooyk and Figdor, 2000). Hence, these observed changes in integrin clustering may play a major role in microparticle modification of HPC7 adhesion. Electron microscopic examination of the HPC7 surface also revealed that PMP/PES induced ruffling of the cell membrane and the extension of cellular protrusions, reminiscent of pseudopodia and filopodia. These phenotypic changes are often features of cellular activation. Indeed, macrophages have been shown to ‘ruffle’ following activation with lipopolysaccharide, but prior to antigen binding, suggesting that this is a direct cellular effect during activation (Patel and Harrison, 2008). Since cell migration requires the coordinated formation of filopodia at the cell front, the development of such structures prior to administration may enable HPC7 to increase their migratory responses to local chemokines and thus improve their subsequent adhesion. Ruffling could also be a means by which cells potentially regulate the clustering and positioning of cell surface receptors so as to enhance ligand binding (Lim and Hotchin, 2012). This may also contribute to the enhanced adhesion of HPC7 following PES/PMP pre-treatment. In conclusion, although evidence suggests that HSPCs are beneficial following tissue injury, the efficacy of such therapies is likely to be proportional to the degree of cell recruitment which can be achieved. Indeed, we have recently demonstrated that increasing the local presence of the same immortalised HSC-like line (HPC7) in the mouse small intestine was associated with significantly reduced neutrophil infiltration at 4h post-reperfusion injury (Kavanagh et al., 2013b). Hence a greater local presence of HPC7s was required for an anti-inflammatory benefit to be realised. Enhancing the effectiveness of regenerative processes, particularly in diseases where leukocytes are key players in mediating injury, may therefore depend on identifying and then modulating the adhesive mechanisms that underpin HSPC trafficking. This study demonstrated that HPC7 recruitment to different injuries of the colon is increased, but that this recruitment can only be increased further in colitis mice. This can be achieved by chemical and biological pre-treatment strategies in the form of H2O2, PMPs or platelet releasate. Observed enhanced adhesion was obtained by a short pre-treatment duration that may be translated into clinical settings as an adjuvant to cellular therapy. Our observations that individual pre-treatments are effective only in certain organs or diseases are novel as it highlights how a single universal approach may be difficult to identify. Previous studies have enhanced SC recruitment using genetically modified cells including the local introduction of genes which encode for the potent SC chemoattractant SDF-1α. However, the clinical applicability of such techniques is debatable and may be associated with aggravated tissue injury due to side effects such as SDF-1α-dependent lymphocyte recruitment. The current study offers the benefit of not requiring genetic manipulation and, crucially, does not require manipulation of host tissues to achieve enhanced recruitment. The data in this study may help in the design of future cellular therapies using haematopoietic progenitors. It is anticipated that enhancing their recruitment to injured organs may expedite the recovery process and encourage therapeutic success clinically in the field of regenerative medicine.