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.

Endometrial and Menstrual Blood Mesenchymal Stem/Stromal Cells: Biological Properties and Clinical Application

“…Mouse CD34 + KLF4 + and LRC cells are also represented by perivascular cells (yellow cytoplasm). Images reprinted with permission from: (A,E) Figures 1E , 4C from Oxford University Press ( Schwab et al, 2008 ), (B) Figure 4I from Oxford University Press ( Schwab and Gargett, 2007 ), (C) Figure 1A from Bioscientifica ( Yang et al, 2019 ), (D) Figure 4A from Oxford University Press ( Ulrich et al, 2014b ), (F) Figure 1A from Public Library of Science ( To et al, 2014 ), (G,H) Figures 5C,D from Mary Ann Liebert ( Sobiesiak et al, 2010 ), (I) Figure 5D from Public Library of Science ( Letouzey et al, 2015 ) and (K) Figure 2 from Wiley Online Library ( Darzi et al, 2016 ).…”

EPHA3 enhances macrophage autophagy and apoptosis by disrupting the mTOR signaling pathway in mice with endometriosis

“…Moreover, a previous study highlighted the association of deletion of EPHA3 protein expression with advanced tumor-node-metastasis (TNM) in clear renal cell carcinoma [24]. Furthermore, hypoxia-controlled EPHA3 has been demonstrated to mark a multipotent mesenchymal stromal cell derived from human endometrium, which facilitates vascular growth [25]. However, the exact function of EPHA3 in human endometriosis remains unclear.…”

Vascular Wall-Resident Multipotent Stem Cells within the Process of Vascular Remodelling

“…The basic molecular mechanism behind these cell-type-specific factors remains elusive at present. A prominent EphA3 expression in endometrial spiral arterioles and surrounding stroma, but not in other human tissues, suggests EphA3 as a unique marker of perivascular MSCs that are implicated in rapid neovascularization and vascular remodelling [129]. This selective EphA3 expression was further observed in actively growing rather than established blood vessels in the vascular microenvironment of solid tumours.…”