Abstract

Stemness Influences the Regenerative Potential of Cells Exposed to Chemotherapy

Eric Darling, Associate Professor of Medical Science, Engineering, and Orthopaedics, Brown University

In musculoskeletal tissues like bone, chemotherapy can impair progenitor cell differentiation and proliferation, resulting in decreased bone growth and mineralization throughout a patient’s lifetime. The current study examined the effects of chemotherapy on mesenchymal stem cell (MSC) regenerative characteristics compared to non-stem cells. The proliferation of stem and non-stem cell types could be used as an in vitro measure of susceptibility to common chemotherapeutic drugs. Interestingly, MSCs showed no susceptibility to the highly prevalent drug methotrexate (MTX), retaining both sustained proliferation and multipotency capabilities after exposure. Investigation into the mechanism behind cell response to MTX involved overexpression and knockdown of dihydrofolate reductase (DHFR), the target of the drug. Overexpression and endogenous nucleoside + amino acid delivery rescued non-stem cell types from adverse effects, identifying DHFR as one resistance mechanism and potential means of protecting beneficial cells exposed to MTX. Furthermore, it was observed that undifferentiated MSCs were more resistant than differentiating and terminally differentiated cell types, suggesting that stemness could play a role in chemotherapeutic resistance as well.