Entschlüsselung der Rolle von Galektinen in der durch extrazelluläre Vesikel von mesenchymalen Stroma/Stammzellen vermittelte Immunmodulation
Tanja Jasmin Kutzner (Essen / DE), Tobias Tertel (Essen / DE), Yanis Mouloud (Essen / DE), Bernd Giebel (Essen / DE)
Mesenchymal stromal/stem cells (MSCs) hold immense therapeutic potentials due to their ability to modulate immune responses and promote regeneration, primarily through paracrine signaling, especially extracellular vesicles (EVs). The concrete mechanism of how MSC-EVs exert their therapeutic function remains spars.
Galectins are crucial players in various physiological and pathological processes. By recognizing and bridging glycans on plasma membranes they have been shown to control various immune responses. Since selected galectins, especially galectins 1, 3, and 9, are expressed in MSCs and their function has been linked to EV biology, they might essentially contribute to the therapeutic function of MSC-EVs.
In our effort in effectively translating MSC-EVs as a new proregenerative agent into the clinics, we have established clonally immortalized MSCs (ciMSCs). In addition to enable the scaled production of MSC-EV products for the clinical setting, these cells can be effectively genetically manipulated. Thus, they provide an ideal platform for dissecting the MSC-EVs" Mechanism of Action, which is crucial for developing surrogate methods providing insights into the therapeutic potency of the EV products. Here, we used the CRISPR/Cas-9 technology to delete the coding regions of the galectins 1, 3, and 9 in ciMSCs and explored the impacts of the deletion on biological properties of the cells and the immunomodulatory function of resulting EV products.
In our ongoing experiments, deletion of galectin-1 did neither recognizably alter cell biological properties of the genetically engineered ciMSCs nor of their EV products. Currently, we explore impacts of the Galectin 3 and 9 knock outs. Moreover, the generation of various galectin knockout combinations will be explored in the future.
The function of Galectin-1 is dispensable for the immunomodulatory properties of ciMSC-EV products that result in the reduction of the activated T cell pool within the mdMLR assay. Further experiments are required to finally determine the role of Galectins in the immunomodulatory potential of MSC-EVs and to understand whether and how they contribute to the mechanism of action of ciMSC-EVs.
BG is a scientific advisory board member of Innovex Therapeutics SL, Mursla Ltd, ReNeuron Ltd. and PL BioScience. He is a founding director of Exosla Ltd. All other authors report no conflicts of interest.