title: Bone Marrow Stromal Cells Combined With Sodium Ferulate andn-Butylidenephthalide Promote the Effect of Therapeutic Angiogenesis via Advancing Astrocyte-Derived Trophic Factors After Ischemic Stroke.
abstract: Being a potential candidate for stroke treatment, bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) have been demonstrated to be able to enhance angiogenesis and proliferation of reactive astrocytes, which subsequently leads to the amelioration of neurological injury. Increasing evidence further indicates that combining BM-MSCs with certain agents, such as simvastatin, may improve therapeutic effects. Sodium ferulate (SF) and n-butylidenephthalide (BP), two main components of Radix Angelica Sinensis, are proven to be important regulators of stem cells in cell migration, differentiation, and pluripotency maintenance. This study aimed to investigate whether combining BM-MSCs with SF and BP had better therapeutic effect in the treatment of stroke, and the underlying molecular basis for the therapeutic effects was also investigated. The results showed that combination treatment notably reduced neurological injury after stroke and increased the expression of astrocyte-derived vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and von Willebrand factor-positive vascular density in the ischemic boundary zone as evaluated by immunofluorescence staining. After treatment with BM-MSCs plus SF and BP, astrocytes showed increased expression of VEGF and BDNF by upregulating protein kinase B/mammalian target of rapamycin (AKT/mTOR) expression in an oxygen- and glucose-deprived (OGD) environment. Human umbilical vein endothelial cells (HUVECs) incubated with the conditioned medium (CM) derived from OGD astrocytes treated with BM-MSCs plus SF and BP showed significantly increased migration and tube formation compared with those incubated with the CM derived from OGD astrocytes treated with BM-MSCs alone. These results demonstrate that combination treatment enhances the expression of astrocyte-derived VEGF and BDNF, which contribute to angiogenesis after cerebral ischemia, and the underlying mechanism is associated with activation of the astrocytic AKT/mTOR signaling pathway. Our study provides a potential therapeutic approach for ischemic stroke.
authors: Qian
authors: Q
authors: Zhang
authors: Zhen-Wei
authors: ZW
authors: Chen
authors: Yong-Hua
authors: YH
authors: Zhao
authors: Bo-Wen
authors: BW
authors: Liu
authors: Nai-Wei
authors: NW
authors: Liu
authors: Chien-Chih
authors: CC
authors: Ke
authors: Hong-Mei
authors: HM
authors: Tan
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology*; D002545:Brain Ischemia / Q000628:therapy*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D003373:Coumaric Acids / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010796:Phthalic Anhydrides / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000628:therapy*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D003373:Coumaric Acids; D010796:Phthalic Anhydrides; D042461:Vascular Endothelial Growth Factor A; D014841:von Willebrand Factor; C579455:BDNF protein, human; C004999:ferulic acid; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C026105:butylidenephthalide