Biology subjects

Erguen, S.

Publications and source records attributed to Erguen, S..

3 recordsLinked to original sources

bioRxiv2022

Taxanes act as vascular disrupting agents and increase rate of metastasis when combined with anti-angiogenic therapy

Taxanes are known to have a profound effect on endothelial cells and the vasculature even at low doses. Here, we show that taxanes, rather than being anti-angiogenic, function more as vascular disrupting agents (VDAs), although they exert a different mechanism of vascular permeabilization when compared to traditional VDAs such as combretastatins. In the tumor context, this VDA-effect leads to a rapid vascular collapse and acute hypoxia. Concomitant treatment with anti-VEGF drugs aggravates hypoxia by blocking vasculogenic rescue mechanisms. While this results in a strong growth-suppressing effect on the tumor, it also increases its invasiveness and metastatic potential. We demonstrate that combination of anti-angiogenic drugs with taxanes blocks tumor reperfusion, intensifies intravasation of circulating tumor cells (CTCs) and strongly increases metastasis. Anti-VEGF drugs are commonly applied in combination with cytotoxic drugs including taxanes. Our findings have significant implications for the clinical use of this drug combination.

cancer biology↗

bioRxiv2022

Human neuro-mesodermal assembloids recapitulate aspects of peripheral nervous system development in vitro

Here we describe a novel neuro-mesodermal assembloid model which recapitulates aspects of peripheral nervous system (PNS) development such as neural crest cell (NCC) induction, delamination, migration and sensory as well as sympathetic ganglion formation. The ganglia send neuronal projections to the mesodermal as well as the neural compartment. Axons in the mesodermal part are associated with Schwann cells. In addition, peripheral ganglia as well as nerve fibers interact with the co-developing vascular plexus, forming a neurovascular niche. Finally, developing sensory ganglia show response to capsaicin treatment indicating their functionality. The presented assembloid model could help to uncover mechanisms of NCC delamination, migration and PNS development in the human tissue context. Moreover, the model could be used for toxicity screenings or drug testing. The co-development of mesodermal and neuroectodermal tissues and of a well-organized vascular plexus along with a peripheral nervous system allows to investigate the crosstalk between neuroectoderm and mesoderm and between peripheral neurons/neuroblasts and endothelial cells. Such interactions influence NCC delamination and migration, sensory neuron differentiation and rearrangement of the primitive vascular plexus in the embryo.

developmental biology↗

bioRxiv2021

Human iPSC-derived mesodermal progenitor cells preserve their vasculogenesis potential after extrusion and form hierarchically organized blood vessels

Post-fabrication formation of a proper vasculature remains an unresolved challenge in bioprinting. Established strategies focus on the supply of the fabricated structure with nutrients and oxygen and either rely on the mere formation of a channel system using fugitive inks, or additionally use mature endothelial cells and/or peri-endothelial cells such as smooth muscle cells for the formation of blood vessels in vitro. Functional vessels, however, exhibit a hierarchical organization and multilayered wall structure that is important for their function. Human induced pluripotent stem cell-derived mesodermal progenitor cells (hiMPCs) have been shown to possess the capacity to form blood vessels in vitro, but have so far not been assessed for their applicability in bioprinting processes. Here, we demonstrate that hiMPCs, after formulation into an alginate / collagen type 1 bioink and subsequent extrusion, retain their ability to give rise to the formation of complex vessels that display a hierarchical network in a process that mimicks the embryonic steps of vessel formation by vasculogenesis. Histological evaluations at different time points of extrusion revealed initial formation of spheres, followed by lumen formation and further structural maturation as evidenced by building a multilayered vessel wall and a vascular network. These findings are supported by immunostainings for endothelial and peri-endothelial cell markers as well as electron microscopic analyses at the ultrastructural level. Moreover, capillary-like vessel structures deposited a basement membrane-like matrix structure at the basal side between the vessel wall and the alginate-collagen matrix. These results evidence the applicability and great potential of hiMPCs for the bioprinting of vascular structures mimicking the basic morphogenetic steps of de novo vessel formation during embryogenesis.

bioengineering↗