Growth factor priming of murine mesenchymal stem cells critically determines their functionality

Suresh, Shankar (2015). Growth factor priming of murine mesenchymal stem cells critically determines their functionality. University of Birmingham. Ph.D.

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Abstract

Mesenchymal stem cells (MSCs) are a subset of multipotent cells with a variety of trophic and immunosuppressive functions. Isolation of murine MSCs has traditionally been hampered by the presence of contaminating cells in culture. In this study, I prospectively isolate murine MSCs based on the co-expression of platelet-derived growth factor (PDGF) receptor alpha and stem cell antigen‐1 (PαS MSCs) and present novel data regarding their \(in\) \(vitro\) phenotype, karyotype and immunomodulatory functions. However, PαS MSCs undergo senescence after extended culture, resulting in a loss of function. Addition of fibroblast growth factor 2 (FGF2), PDGF‐BB or transforming growth factor-beta 1 (TGF-β1) was able to overcome senescence in MSC cultures. These factors also ‘lineage primed’ MSCs down specific fates at the genetic and phenotypic levels, with un‐supplemented MSCs primed towards bone, FGF2 or PDGF‐BB supplemented cells primed towards fat, and FGF2 supplemented cells primed towards cartilage. TGF‐β1 supplementation attenuated tri‐lineage differentiation of PαS MSCs but maintained their immunosuppressive functions. These findings were confirmed in a mouse model of inflammatory liver injury, with late‐passage TGF‐β1 MSCs improving liver injury compared to controls. In summary, these results have significant translational relevance as I reveal that culture conditions can functionally ‘prime’ MSCs down specific fates.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):