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  -