title: Hypoxia-controlled EphA3 marks a human endometrium-derived multipotent mesenchymal stromal cell that supports vascular growth.
abstract: Eph and ephrin proteins are essential cell guidance cues that orchestrate cell navigation and control cell-cell interactions during developmental tissue patterning, organogenesis and vasculogenesis. They have been extensively studied in animal models of embryogenesis and adult tissue regeneration, but less is known about their expression and function during human tissue and organ regeneration. We discovered the hypoxia inducible factor (HIF)-1α-controlled expression of EphA3, an Eph family member with critical functions during human tumour progression, in the vascularised tissue of regenerating human endometrium and on isolated human endometrial multipotent mesenchymal stromal cells (eMSCs), but not in other highly vascularised human organs. EphA3 affinity-isolation from human biopsy tissue yielded multipotent CD29+/CD73+/CD90+/CD146+ eMSCs that can be clonally propagated and respond to EphA3 agonists with EphA3 phosphorylation, cell contraction, cell-cell segregation and directed cell migration. EphA3 silencing significantly inhibited the ability of transplanted eMSCs to support neovascularisation in immunocompromised mice. In accord with established roles of Eph receptors in mediating interactions between endothelial and perivascular stromal cells during mouse development, our findings suggest that HIF-1α-controlled expression of EphA3 on human MSCs functions during the hypoxia-initiated early stages of adult blood vessel formation.
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: To
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Rae H
authors.initials: RH
authors.lastname: Farnsworth
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Vail
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Chanly
authors.initials: C
authors.lastname: Chheang
authors.affiliation: MIMR-PHI Institute for Medical Research, Clayton, Victoria, Australia.
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Gargett
authors.affiliation: Ludwig Institute for Cancer Research, Olivia Newton-John Cancer & Wellness Centre, Melbourne, Victoria, Australia.
authors.forename: Carmel
authors.initials: C
authors.lastname: Murone
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Carmen
authors.initials: C
authors.lastname: Llerena
authors.affiliation: Department of Anatomy & Developmental Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Major
authors.affiliation: Ludwig Institute for Cancer Research, Olivia Newton-John Cancer & Wellness Centre, Melbourne, Victoria, Australia.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Janes
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Lackmann
mesh_terms: D000328:Adult; D000818:Animals; D015153:Blotting, Western; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004717:Endometrium / Q000166:cytology; D005260:Female; D015870:Gene Expression; D064593:Heterografts / Q000098:blood supply; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D039902:Multipotent Stem Cells / Q000378:metabolism* / Q000637:transplantation; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D036121:Receptor, EphA3 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D055815:Young Adult
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036121:Receptor, EphA3