TY  - JOUR
A1  - Trivanovic, Drenka
A1  - Volkmann, Noah
A1  - Stoeckl, Magdalena
A1  - Tertel, Tobias
A1  - Rudert, Maximilian
A1  - Giebel, Bernd
A1  - Herrmann, Marietta
T1  - Enhancement of immunosuppressive activity of mesenchymal stromal cells by platelet-derived factors is accompanied by apoptotic priming
JF  - Stem Cell Reviews and Reports
N2  - The pro-inflammatory phase of bone healing, initiated by platelet activation and eventually hematoma formation, impacts bone marrow mesenchymal stromal cells (MSCs) in unknown ways. Here, we created platelet-rich plasma (PRP) hydrogels to study how platelet-derived factors modulate functional properties of encapsulated MSCs in comparison to a non-inflammatory fibrin (FBR) hydrogel environment. MSCs were isolated from human bone marrow, while PRP was collected from pooled apheresis thrombocyte concentrates and used for hydrogel preparation. After their encapsulation in hydrogels for 72 h, retrieved MSCs were analyzed for immunomodulatory activities, apoptosis, stem cell properties, senescence, CD9\(^+\), CD63\(^+\) and CD81\(^+\) extracellular vesicle (EV) release, and metabolism-related changes. PRP-hydrogels stimulated immunosuppressive functions of MSCs, along with their upregulated susceptibility to cell death in communication with PBMCs and augmented caspase 3/7 activity. We found impaired clonal growth and cell cycle progression, and more pronounced β-galactosidase activity as well as accumulation of LC3-II-positive vacuoles in PRP-MSCs. Stimuli derived from PRP-hydrogels upregulated AKT and reduced mTOR phosphorylation in MSCs, which suggests an initiation of survival-related processes. Our results showed that PRP-hydrogels might represent a metabolically stressful environment, inducing acidification of MSCs, reducing polarization of the mitochondrial membrane and increasing lipid accumulation. These features were not detected in FBR-MSCs, which showed reduced CD63\(^+\) and CD81\(^+\) EV production and maintained clonogenicity. Our data revealed that PRP-derived hematoma components cause metabolic adaptation of MSCs followed by increased immune regulatory functions. For the first time, we showed that PRP stimuli represent a survival challenge and “apoptotic priming” that are detrimental for stem cell-like growth of MSCs and important for their therapeutic consideration.
KW  - hematoma
KW  - platelet-rich plasma
KW  - fibrin
KW  - mesenchymal stromal cells
KW  - immunomodulation
KW  - apoptosis
KW  - autophagy
KW  - senescence
KW  - extracellular vesicles
KW  - metabolism
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324669
VL  - 19
IS  - 3
ER  - 
TY  - JOUR
A1  - Muturi, Harrison T.
A1  - Dreesen, Janine D.
A1  - Nilewski, Elena
A1  - Jastrow, Holger
A1  - Giebel, Bernd
A1  - Ergun, Suleyman
A1  - Singer, Berhard B.
T1  - Tumor and Endothelial Cell-Derived Microvesicles Carry Distinct CEACAMs and Influence T-Cell Behavior
JF  - PLOS ONE
N2  - Normal and malignant cells release a variety of different vesicles into their extracellular environment. The most prominent vesicles are the microvesicles (MVs, 100-1 000 nm in diameter), which are shed of the plasma membrane, and the exosomes (70-120 nm in diameter), derivates of the endosomal system. MVs have been associated with intercellular communication processes and transport numerous proteins, lipids and RNAs. As essential component of immune-escape mechanisms tumor-derived MVs suppress immune responses. Additionally, tumor-derived MVs have been found to promote metastasis, tumor-stroma interactions and angiogenesis. Since members of the carcinoembryonic antigen related cell adhesion molecule (CEACAM)-family have been associated with similar processes, we studied the distribution and function of CEACAMs in MV fractions of different human epithelial tumor cells and of human and murine endothelial cells. Here we demonstrate that in association to their cell surface phenotype, MVs released from different human epithelial tumor cells contain CEACAM1, CEACAM5 and CEACAM6, while human and murine endothelial cells were positive for CEACAM1 only. Furthermore, MVs derived from CEACAM1 transfected CHO cells carried CEACAM1. In terms of their secretion kinetics, we show that MVs are permanently released in low doses, which are extensively increased upon cellular starvation stress. Although CEACAM1 did not transmit signals into MVs it served as ligand for CEACAM expressing cell types. We gained evidence that CEACAM1-positive MVs significantly increase the CD3 and CD3/CD28-induced T-cell proliferation. All together, our data demonstrate that MV-bound forms of CEACAMs play important roles in intercellular communication processes, which can modulate immune response, tumor progression, metastasis and angiogenesis.
KW  - carcinoembryonic anitgen family
KW  - biliary glycoprotein CD66A
KW  - adhesion molecule-1
KW  - epithelial cells
KW  - membrane vesicles
KW  - growth-factor
KW  - cancer
KW  - expression
KW  - proliferation
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128373
SN  - 1932-6203
VL  - 8
IS  - 9
ER  -