title: Paclitaxel impairs adipose stem cell proliferation and differentiation.
abstract: BACKGROUND
  Cancer patients with chemotherapy-induced immunosuppression have poor surgical site wound healing. Prior literature supports the use of human adipose-derived stem cell (hASC) lipoinjection to improve wound healing. It has been established that multipotent hASCs facilitate neovascularization, accelerate epithelialization, and quicken wound closure in animal models. Although hASC wound therapy may benefit surgical cancer patients, the chemotherapeutic effects on hASCs are unknown. We hypothesized that paclitaxel, a chemotherapeutic agent, impairs hASC growth, multipotency, and induces apoptosis.
  
  
  METHODS
  hASCs were isolated and harvested from consented, chemotherapy and radiation naive patients. Growth curves, MTT (3-(4,5-Dimethylthiazol-2-Yl)-2,5-Diphenyltetrazolium Bromide), and EdU (5-ethynyl-2-deoxyguridine) assays measured cytotoxicity and proliferation. Oil Red O stain, Alizarin Red stain, matrigel tube formation assay, and quantitative polymerase chain reaction analyzed hASC differentiation. Annexin V assay measured apoptosis. Immunostaining and Western blot determined tumor necrosis factor α (TNF-α) expression.
  
  
  RESULTS
  hASCs were selectively more sensitive to paclitaxel (0.01-30 μM) than fibroblasts (P < 0.05). After 12 d, paclitaxel caused hASC growth arrest, whereas control hASCs proliferated (P = 0.006). Paclitaxel caused an 80.6% reduction in new DNA synthesis (P < 0.001). Paclitaxel severely inhibited endothelial differentiation and capillary-like tube formation. Differentiation markers, lipoprotein lipase (adipogenic), alkaline phosphatase (osteogenic), CD31, and van Willebrand factor (endothelial), were significantly decreased (all P < 0.05) confirming paclitaxel impaired differentiation. Paclitaxel was also found to induce apoptosis and TNF-α was upregulated in paclitaxel-treated hASCs (P < 0.001).
  
  
  CONCLUSIONS
  Paclitaxel is more cytotoxic to hASCs than fibroblasts. Paclitaxel inhibits hASC proliferation, differentiation, and induces apoptosis, possibly through the TNF-α pathway. Paclitaxel's severe inhibition of endothelial differentiation indicates neovascularization disruption, possibly causing poor wound healing in cancer patients receiving chemotherapy.
authors.affiliation: Department of Surgery, Cooper University Hospital, Camden, New Jersey. Electronic address: Rachel.Choron@gmail.com.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Choron
authors.affiliation: Department of Surgical Research, Cooper University Hospital, Camden, New Jersey.
authors.forename: Shaohua
authors.initials: S
authors.lastname: Chang
authors.affiliation: Department of Surgery, Cooper University Hospital, Camden, New Jersey.
authors.forename: Sophia
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Surgery, Cooper University Hospital, Camden, New Jersey.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Villalobos
authors.affiliation: Department of Surgical Research, Cooper University Hospital, Camden, New Jersey.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Cooper University Hospital, Camden, New Jersey.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Carpenter
authors.affiliation: Department of Surgical Research, Cooper University Hospital, Camden, New Jersey.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Tulenko
authors.affiliation: Department of Plastic Surgery, Cooper University Hospital, Camden, New Jersey.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000273:Adipose Tissue / Q000166:cytology; D053687:Adult Stem Cells / Q000187:drug effects* / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D042783:Endothelial Cells / Q000166:cytology; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D010012:Osteogenesis / Q000187:drug effects; D017239:Paclitaxel / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D014409:Tumor Necrosis Factor-alpha; D017239:Paclitaxel
keywords: Cancer therapy; Chronic wounds; Human adipose–derived stem cells; Neovascularization; Paclitaxel; Wound healing