Mesenchymal stem cells as endogenous regulators of leukocyte recruitment; the effects of differentiation

Munir, Hafsa (2016). Mesenchymal stem cells as endogenous regulators of leukocyte recruitment; the effects of differentiation. University of Birmingham. Ph.D.

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Abstract

Mesenchymal stem cells (MSC) are a tissue-resident stromal cell population that are able to regulate immune responses, in particular the capacity for endothelial cells (EC) to support leukocyte recruitment. In this thesis we examined the ability of MSC from different sources (bone marrow, Wharton’s jelly and trabecular bone) to regulate neutrophil recruitment to inflamed EC and how these responses are altered upon adipogenic differentiation of MSC. Using two flow based adhesion models with varying degrees of proximity between MSC and EC, we observed that all MSC populations suppressed neutrophil recruitment. IL-6 and TGFβ were identified as common bioactive agents found in all co-cultures. Upon differentiation, MSC exhibited a diminished capacity to suppress neutrophil, but not peripheral blood lymphocyte, recruitment. Loss of suppression by MSC-derived adipocytes was reversed by neutralising IL-6. Adipose tissue-derived mature adipocytes and culture differentiated pre-adipocytes did not recapitulate the effects of MSC-derived adipocytes. These data suggest that crosstalk between tissue-resident MSC and EC, dampens the endothelial response to cytokines and limits the aberrant infiltration of circulating leukocytes during inflammation. Upon adipogenic differentiation, MSC lose this regulatory capacity. This could impact on the beneficial effects of MSC in chronically inflamed sites where aberrant infiltration of leukocyte is a main driver of the disease.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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