Therapeutisches Potenzial von extrazellulären Vesikeln aus mesenchymalen Stamm- bzw. Stromazellen

Zusammenfassung

Seit der Beschreibung, dass sich mesenchymale Stamm- bzw. Stromazellen (MSC) des Menschen in verschiedene Zelltypen differenzieren können bzw. immunmodulierende Effekte vermitteln, sind sie in mehr als 500 beim NIH registrierten Studien zur Behandlung verschiedenster Erkrankungen eingesetzt worden. Allem Anschein nach erzielen sie ihre therapeutische Wirkung jedoch nicht wie lange angenommen durch die Integration in betroffene Gewebe, sondern durch die Freisetzung parakriner Faktoren, insbesondere durch extrazelluläre Vesikel (EV) wie Exosomen und Mikrovesikel. EV stellen extrazelluläre Organellen dar, die sehr spezifisch interzelluläre Kommunikation auch über größere Distanzen hinweg vermitteln, von verschiedensten Zellen abgegeben werden und in sämtlichen Körperflüssigkeiten nachweisbar sind. Sie besitzen einen heterogenen Gehalt an Lipiden, Proteinen und nicht kodierenden RNA-Molekülen. Als nicht selbstreplizierende Einheiten, die sich steril filtrieren lassen, weisen sie für therapeutische Anwendungen prinzipiell nennenswerte Vorteile gegenüber Zellen auf. Neben verschiedenen präklinischen Modellen wurden aus MSC-Kulturüberständen gewonnene EV bereits in einem ersten individuellen Heilversuch zur Behandlung einer steroidrefraktären Graft-versus-Host-Disease (GvHD)-Patientin eingesetzt. Sowohl in den bislang durchgeführten präklinischen Versuchen als auch in der behandelten GvHD-Patientin ließen sich nach MSC-EV-Applikation vielversprechende therapeutische Effekte beobachten, ohne erkennbare Nebenwirkungen hervorzurufen. MSC-EV erfüllen somit allem Anschein nach wichtige Voraussetzungen, um als neues Behandlungsmittel in der Immuntherapie und der regenerativen Medizin in Betracht gezogen zu werden.

Summary

Following the discoveries that human mesenchymal stem or stromal cells (MSC) contain multilineage differentiation potentials and can modulate immune responses, more than 500 clinical trials have been registered at the NIH to test for the therapeutic potentials of MSC in various diseases. In contrast to the initial hypothesis that MSCs mediate their therapeutic effects by intercalating into affected tissues, novel results suggest that they exert their therapeutic impacts in a paracrine rather than in a cellular manner. To this end, extracellular vesicles (EV), like exosomes and microvesicles, have been found to mediate at least a proportion of the MSCsʼ therapeutic functions. EV are considered to be extracellular organelles which mediate intercellular communication processes very specifically, also between cells at distance sites. EV are formed by almost all cell types and have been detected in all body liquids. Depending on their origin, they contain specific mixtures of lipids, proteins and non-coding RNAs. As non-self-replicating units which can be sterilized by filtration, EVs provide a number of advantages over cellular therapeutics. In addition to a variety of different preclinical models, EVs harvested from MSC-conditioned media have been administered in an individual treatment attempt to a steroid-refractory Graft-versus-Host Disease (GvHD) patient. Positive therapeutic effects, but no side effects were observed in all preclinical models tested so far as well as in the GvHD patient. Thus, MSC-EVs appear to be a promising new tool in immune therapy and in regenerative medicine.

Schlüsselwörter

MSC - Stammzelltherapie - extrazelluläre Vesikel - Exosomen - Immunmodulation - zellfreie Therapie

Key words

MSC - stem cell therapy - extracellular vesicles - exosomes - immunomodulation - cell-free therapy

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