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.
Highlights
Mammalian tissue growth is controlled by oxygen and nutrient supply, where hypoxia inducible transcription factors (HIFs) respond to oxygen depletion by activating gene programs that initiate the formation and/or expansion of vascular networks [1, 2]
While their exact origin, phenotype and specific role in neovascularisation remain topics of active debate [4, 7, 15, 16], mesenchymal stromal cells (MSCs) have been described as multipotent stromal progenitor cells that are present in the perivascular region of nascent blood vessels and are involved in adult neovascularisation [17,18,19,20]
EphA3+eSC, endometrial stromal cells; TEC, tumour-derived endothelial cells; melanoma, AO9 melanoma cells; HEK293T cells used as control. (C) IP/Western blot of EphA3 protein in cells cultured in hypoxia or normoxia; 10x more lysate from EphA3+eSCs than from
Summary
Mammalian tissue growth is controlled by oxygen and nutrient supply, where hypoxia inducible transcription factors (HIFs) respond to oxygen depletion by activating gene programs that initiate the formation and/or expansion of vascular networks [1, 2]. Emerging studies indicate that in addition to driving neovascularisation, hypoxia may have a role in maintaining MSC stem cell properties [13, 14] While their exact origin, phenotype and specific role in neovascularisation remain topics of active debate [4, 7, 15, 16], MSCs have been described as multipotent stromal progenitor cells that are present in the perivascular region of nascent blood vessels and are involved in adult neovascularisation [17,18,19,20]
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