TY  - JOUR
A1  - Kleefeldt, Florian
A1  - Upcin, Berin
A1  - Bömmel, Heike
A1  - Schulz, Christian
A1  - Eckner, Georg
A1  - Allmanritter, Jan
A1  - Bauer, Jochen
A1  - Braunger, Barbara
A1  - Rueckschloss, Uwe
A1  - Ergün, Süleyman
T1  - Bone marrow-independent adventitial macrophage progenitor cells contribute to angiogenesis
JF  - Cell Death & Disease
N2  - Pathological angiogenesis promotes tumor growth, metastasis, and atherosclerotic plaque rupture. Macrophages are key players in these processes. However, whether these macrophages differentiate from bone marrow-derived monocytes or from local vascular wall-resident stem and progenitor cells (VW-SCs) is an unresolved issue of angiogenesis. To answer this question, we analyzed vascular sprouting and alterations in aortic cell populations in mouse aortic ring assays (ARA). ARA culture leads to the generation of large numbers of macrophages, especially within the aortic adventitia. Using immunohistochemical fate-mapping and genetic in vivo-labeling approaches we show that 60% of these macrophages differentiate from bone marrow-independent Ly6c\(^{+}\)/Sca-1\(^{+}\) adventitial progenitor cells. Analysis of the NCX\(^{−/-}\) mouse model that genetically lacks embryonic circulation and yolk sac perfusion indicates that at least some of those progenitor cells arise yolk sac-independent. Macrophages represent the main source of VEGF in ARA that vice versa promotes the generation of additional macrophages thereby creating a pro-angiogenetic feedforward loop. Additionally, macrophage-derived VEGF activates CD34\(^{+}\) progenitor cells within the adventitial vasculogenic zone to differentiate into CD31\(^{+}\) endothelial cells. Consequently, depletion of macrophages and VEGFR2 antagonism drastically reduce vascular sprouting activity in ARA. In summary, we show that angiogenic activation induces differentiation of macrophages from bone marrow-derived as well as from bone marrow-independent VW-SCs. The latter ones are at least partially yolk sac-independent, too. Those VW-SC-derived macrophages critically contribute to angiogenesis, making them an attractive target to interfere with pathological angiogenesis in cancer and atherosclerosis as well as with regenerative angiogenesis in ischemic cardiovascular disorders.
KW  - macrophages
KW  - angiogenesis
KW  - bone marrow-derived monocytes
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299724
VL  - 13
IS  - 3
ER  - 
TY  - JOUR
A1  - Schmidt, Sven
A1  - Alt, Yvonne
A1  - Deoghare, Nikita
A1  - Krüger, Sarah
A1  - Kern, Anna
A1  - Rockel, Anna Frederike
A1  - Wagner, Nicole
A1  - Ergün, Süleyman
A1  - Wörsdörfer, Philipp
T1  - A blood vessel organoid model recapitulating aspects of vasculogenesis, angiogenesis and vessel wall maturation
JF  - Organoids
N2  - Blood vessel organoids are an important in vitro model to understand the underlying mechanisms of human blood vessel development and for toxicity testing or high throughput drug screening. Here we present a novel, cost-effective, and easy to manufacture vascular organoid model. To engineer the organoids, a defined number of human induced pluripotent stem cells are seeded in non-adhesive agarose coated wells of a 96-well plate and directed towards a lateral plate mesoderm fate by activation of Wnt and BMP4 signaling. We observe the formation of a circular layer of angioblasts around days 5–6. Induced by VEGF application, CD31\(^+\) vascular endothelial cells appear within this vasculogenic zone at approximately day 7 of organoid culture. These cells arrange to form a primitive vascular plexus from which angiogenic sprouting is observed after 10 days of culture. The differentiation outcome is highly reproducible, and the size of organoids is scalable depending on the number of starting cells. We observe that the initial vascular ring forms at the interface between two cell populations. The inner cellular compartment can be distinguished from the outer by the expression of GATA6, a marker of lateral plate mesoderm. Finally, 14-days-old organoids were transplanted on the chorioallantois membrane of chicken embryos resulting in a functional connection of the human vascular network to the chicken circulation. Perfusion of the vessels leads to vessel wall maturation and remodeling as indicated by the formation of a continuous layer of smooth muscle actin expressing cells enwrapping the endothelium. In summary, our organoid model recapitulates human vasculogenesis, angiogenesis as well as vessel wall maturation and therefore represents an easy and cost-effective tool to study all steps of blood vessel development and maturation directly in the human setting without animal experimentation.
KW  - organoid
KW  - blood vessel
KW  - vasculogenesis
KW  - angiogenesis
KW  - induced pluripotent stem cells
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284043
SN  - 2674-1172
VL  - 1
IS  - 1
SP  - 41
EP  - 53
ER  -