title: Adipose-derived stem cells retain their regenerative potential after methotrexate treatment.
abstract: 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. In the current study, we investigated the effects of chemotherapeutics on adipose-derived stem cell (ASC) function to determine whether this cell source could be a candidate for repairing, or even preventing, chemotherapy-induced tissue damage. Dose-dependent proliferation rates of ASCs and normal human fibroblasts (NHFs) were quantified after treatment with cytarabine (CY), etoposide (ETO), methotrexate (MTX), and vincristine (VIN) using a fluorescence-based assay. The influence of MTX on the multipotency of ASCs and freshly isolated stromal vascular fraction (SVF) cells was also evaluated using lineage-specific stains and spectrophotometry. ASC and NHF proliferation were equally inhibited by exposure to CY and ETO; however, when treated with MTX and VIN, ASCs exhibited greater resistance. This was especially apparent for MTX-treated samples, with ASC proliferation showing no inhibition for clinically relevant MTX doses ranging from 0.1 to 50 μM. Additional experiments revealed that the differentiation potential of ASCs was not affected by MTX treatment and that upregulation of dihydrofolate reductase possibly contributed to this response. Moreover, SVF cells, which include ASCs, exhibited similar resistance to MTX impairment, with respect to cellular proliferation, clonogenicity, and differentiation capability. Therefore, we have shown that the regenerative properties of ASCs resist the cytotoxicity of MTX, identifying these cells as a potential key for repairing musculoskeletal damage in patients undergoing chemotherapy.
authors.affiliation: Center for Biomedical Engineering, Brown University, Providence, RI, USA.
authors.forename: Olivia S
authors.initials: OS
authors.lastname: Beane
authors.affiliation: Department of Molecular Pharmacology, Physiology, & Biotechnology, Brown University, Providence, RI, USA.
authors.forename: Vera C
authors.initials: VC
authors.lastname: Fonseca
authors.affiliation: Center for Biomedical Engineering, Brown University, Providence, RI, USA; Department of Molecular Pharmacology, Physiology, & Biotechnology, Brown University, Providence, RI, USA; Department of Orthopaedics, Brown University, Providence, RI, USA; School of Engineering, Brown University, Providence, RI, USA. Electronic address: Eric_Darling@brown.edu.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Darling
mesh_terms: D000273:Adipose Tissue / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D008875:Middle Aged; D039902:Multipotent Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate
keywords: Bone; Cell transplantation; Chemotherapy; Mesenchymal stem cell; Tissue regeneration