title: Estradiol promotes neural stem cell differentiation into endothelial lineage and angiogenesis in injured peripheral nerve.
abstract: Neural stem cells (NSCs) differentiate into endothelial cells (ECs) and neuronal cells. Estradiol (E2) is known to exhibit proangiogenic effects on ischemic tissues via EC activation. Therefore, we hypothesized that E2 can promote the therapeutic potential of NSC transplantation for injured nerve repair via the differentiation of NSCs into ECs during neovascularization. NSCs isolated from newborn mouse brains were transplanted into injured sciatic nerves with (NSC/E2 group) or without E2-conjugated gelatin hydrogel (E2 group). The NSC/E2 group exhibited the greatest recovery in motor nerve conduction velocity, voltage amplitude, and exercise tolerance. Histological analyses revealed increased intraneural vascularity and blood perfusion as well as striking NSC recruitment to the neovasculature in the injured nerves in the NSC/E2 group. In vitro, E2 enhanced the NSC migration and proliferation inhibiting apoptosis. Fluorescence-activated cell sorting analysis also revealed that E2 significantly increased the percentage of CD31 in NSCs, and the effect of E2 was completely neutralized by the estrogen receptor antagonist ICI. The combination of E2 administration and NSC transplantation cooperatively improved the functional recovery of injured peripheral nerves, at least in part, via E2-associated NSC differentiation into ECs. These findings provide a novel mechanistic insight into both NSC biology and the biological effects of endogenous E2.
authors.affiliation: Feinberg Cardiovascular Research Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Haruki
authors.initials: H
authors.lastname: Sekiguchi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ii
authors.forename: Kentaro
authors.initials: K
authors.lastname: Jujo
authors.forename: Tina
authors.initials: T
authors.lastname: Thorne
authors.forename: Aiko
authors.initials: A
authors.lastname: Ito
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Klyachko
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Hamada
authors.forename: John A
authors.initials: JA
authors.lastname: Kessler
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Kawana
authors.forename: Michio
authors.initials: M
authors.lastname: Asahi
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Hagiwara
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects; D004958:Estradiol / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D019344:Lactic Acid / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009409:Nerve Crush; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000637:transplantation; D059348:Peripheral Nerve Injuries / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology / Q000628:therapy*; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D020127:Recovery of Function / Q000187:drug effects; D012584:Sciatic Nerve / Q000187:drug effects / Q000293:injuries / Q000473:pathology / Q000503:physiopathology; D033581:Stem Cell Transplantation
chemical_list: D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004958:Estradiol