Date

2018

Department or Program

Biological Sciences

Primary Wellesley Thesis Advisor

Louise E.O. Darling

Additional Advisor(s)

Kimberly O’Donnell

Additional Advisor

Julie Roden

Additional Advisor

Jim Moyer

Abstract

Methotrexate (MTX) is a potent chemotherapeutic drug that inhibits cellular replication, reducing the proliferation of rapidly dividing cancer cells. Though effective, treatments using MTX have been found to be particularly detrimental for children with Acute Lymphoblastic leukemia, who have reported shorter stature, increases in bone fractures, and a higher risk of osteoporosis. It is believed that MTX harms bone marrow stem cells responsible for skeletal regeneration. Adipose derived stem cells (ASCs), multipotent cells which have the ability to differentiate into musculoskeletal tissues, have demonstrated a striking resistance to MTX. The mechanism through which ASCs are resistant to MTX is still unknown, however, one possible candidate may be reduced folate carrier protein-1 (RFC-1), encoded by the gene SLC19A1. This protein helps mediate the uptake of folate and MTX into the cell. To investigate the role of RFC-1 in MTX resistance, the expression level of RFC-1 can be modulated using siRNA knockdown and transient overexpression in resistant and non-resistant cell types. The present study focuses on the transient overexpression of RFC-1 in both ASCs and human embryonic kidney (HEK) cells, establishing the methodology needed to investigate the role of RFC-1. Initial findings suggest that ASC resistance against MTX may be patient-specific, but nonetheless understanding the mechanism these specific ASCs employ against MTX may be useful in mitigating the long-term skeletal side effects of ALL treatment. The resistance of ACSs will hopefully be used one day as a regenerative therapy for patients treated with high dosages of MTX in order to replace damaged bone marrow stem cells to avoid detrimental side effects on skeletal tissue.

Available for download on Tuesday, April 25, 2023

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