Description
- Abstract:
- The work in this thesis demonstrates that mesenchymal stem cell (MSC) function is influenced by aging and chemotherapy. Furthermore, these results illustrate that inherent differences exist among cell types. Examining the effects of environmental factors on different cell types and identifying mechanisms behind these responses is necessary to understand consequential tissue damage and optimize regenerative therapies. A literature review was conducted to examine differences among isolation, characterization, and chondrogenic differentiation procedures of various stem cell types. Techniques were predominantly stem cell- specific and varied widely across literature, preventing accurate comparisons. Revealing inherent differences among cell types and inconsistencies within the field are important to improve cartilage repair strategies. To understand how stem cell type influences sensitivity to adverse aging effects, regenerative properties were compared between young and old cells derived from muscle, bone marrow, and adipose tissue. MSCs were disparately affected by age. However, total metabolite production was comparable among old cells, indicating that MSCs from all three sources are potential candidates for regenerative therapies targeting older populations. The effects of chemotherapy on adipose derived stem cell (ASC) properties were also examined and compared with a normal human fibroblast (NHF) population. Treatment with several commonly used drugs in vitro impaired ASC and NHF proliferation. However, ASCs were more resistant than NHFs to methotrexate (MTX) and retained their multipotency after exposure. These results suggest that ASCs are a potential source to treat drug-induced tissue loss. Investigation into the mechanism behind normal cell response to MTX was conducted by overexpression and knockdown of dihydrofolate reductase (DHFR), the target of the drug. Overexpression and endogenous nucleoside delivery rescued normal cells from adverse effects, identifying DHFR as a resistance mechanism and potential target for MTX normal cell rescue therapies. When ASC MTX response was compared to other stem and non-stem cell populations, it was observed that undifferentiated MSCs were more resistant than differentiating and terminally differentiated cell types, suggesting that stemness could play a role in MTX resistance, as well.
- Notes:
- Thesis (Ph.D. -- Brown University (2016)
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Citation
Beane, Olivia S.,
"The Effects of Aging and Chemotherapeutics on Mesenchymal Stem Cell Regenerative Properties"
(2016).
Biomedical Engineering Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://doi.org/10.7301/Z0V1235D
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Biomedical Engineering Theses and Dissertations
Theses and Dissertations for the Biomedical Engineering department....