Abstract
Despite insights into the molecular pathways regulating hypoxia-induced gene expression, it is not known which cell types accomplish oxygen sensing during neo-vasculogenesis. We have developed a humanized mouse model of endothelial and mesenchymal progenitor co-transplantation to delineate the cellular compartments responsible for hypoxia response during vasculogenesis. Mesenchymal stem/progenitor cells (MSPCs) accumulated nuclear hypoxia-inducible transcription factor (HIF)-1α earlier and more sensitively than endothelial colony forming progenitor cells (ECFCs) in vitro and in vivo. Hypoxic ECFCs showed reduced function in vitro and underwent apoptosis within 24h in vivo when used without MSPCs. Surprisingly, only in MSPCs did pharmacologic or genetic inhibition of HIF-1α abrogate neo-vasculogenesis. HIF deletion in ECFCs caused no effect. ECFCs could be rescued from hypoxia-induced apoptosis by HIF-competent MSPCs resulting in the formation of patent perfused human vessels. Several angiogenic factors need to act in concert to partially substitute mesenchymal HIF-deficiency. Results demonstrate that ECFCs require HIF-competent vessel wall progenitors to initiate vasculogenesis in vivo and to bypass hypoxia-induced apoptosis. We describe a novel mechanistic role of MSPCs as oxygen sensors promoting vasculogenesis thus underscoring their importance for the development of advanced cellular therapies.
Highlights
Vascular homeostasis and regeneration play an essential role in development, health and disease [1,2]
To study the response to low oxygen more precisely at the single cell level over time, human endothelial colony forming progenitor cells (ECFCs) and Mesenchymal stem/progenitor cells (MSPCs) of different origin were exposed to reduced oxygen (5% O2 resembling the human venous oxygen level) and more severe hypoxia (1% O2) and compared to ambient air standard cell culture conditions (20% O2)
Approaches focusing on endothelial progenitors have been of limited efficiency in clinical trials, both for therapeutic vasculogenesis and for anti-angiogenic therapy [10]
Summary
Vascular homeostasis and regeneration play an essential role in development, health and disease [1,2]. Vessel remodeling and repair during postnatal life have long been viewed as occurring exclusively through proliferation and subsequent migration of mature ECs derived from pre-existing vessel walls, a process termed angiogenesis [3]. The isolation of EC progenitors from human blood changed that paradigm and introduced the concept of therapeutic vasculogenesis [4]. The discovery that vessel wallderived ECs rapidly proliferate because they contain a complete hierarchy of ECFCs supported the concept of the progenitordependence of vasculogenesis [5,6,7,8]. Therapeutic targets comprise cardiovascular diseases including stroke, myocardial infarction and peripheral artery disease as well as wound healing and vessel creation as the prerequisite for effective tissue engineering [10]
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