Anti-Tumor Effects of Exosomes Derived from Drug-Incubated Permanently Growing Human MSC.

Catharina Melzer,Juliane Von Der Ohe,Ralf Hass

doi:10.3390/ijms21197311

Catharina Melzer, Juliane Von Der Ohe + Show 1 more

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https://doi.org/10.3390/ijms21197311

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Abstract

Similar to growth-limited human primary cultures of mesenchymal stroma/stem-like cells (MSC), the continuously proliferating human MSC544 cell line produced extracellular vesicles as characterized by expression of the tetraspanin molecules CD9, CD63, and CD81. Release of these particles was predominantly detectable during continuous cell growth of MSC544 in contrast to confluency-mediated transient growth arrest. For therapeutic use, these particles were isolated from proliferating MSC544 after taxol treatment and applied to different cancer cell cultures. A pronounced cytotoxicity of lung, ovarian, and breast cancer cells was observed primarily with taxol-loaded exosomes, similar to the effects displayed by application of taxol substance. While these findings suggested pronounced cancer cell targeting of MSC544 exosomes, a tumor therapeutic approach was performed using a mouse in vivo breast cancer model. Thus, intravenous injection of taxol-loaded MSC544 exosomes displayed superior tumor-reducing capabilities as compared to application of taxol exosomes by oral gavage. To broaden this therapeutic spectrum, epirubicin was applied to MSC544, and the derived exosomes likewise exhibited significant cytotoxic effects in different cancer cell cultures. These findings suggest an unlimited source for large-scale exosome production with reproducible quality to enable variable drug targeting of tumors or other diseases.

Highlights

Various clinical studies are using mesenchymal stroma/stem-like cells (MSC) for different clinical approaches, including hematological disease, graft-versus-host disease, organ transplantation, diabetes, inflammatory diseases, bone and cartilage, neurological, and skin diseases, among others [1,2,3,4]
The characteristics of MSC vary upon culture conditions and a changing environment by diverse stimuli in vitro, and may be different when compared to the corresponding tissue-originating MSC populations in vivo [2,9]
This work introduced the use of drug-loaded exosomes from MSC544 as a constant cell

Summary

Introduction

Various clinical studies are using mesenchymal stroma/stem-like cells (MSC) for different clinical approaches, including hematological disease, graft-versus-host disease, organ transplantation, diabetes, inflammatory diseases, bone and cartilage, neurological, and skin diseases, among others [1,2,3,4]. The use of human MSC for tissue replacement therapies or regenerative medicine is limited by eventual growth arrest and senescence due to a finite life span of primary MSC. This requires expansion of frequently new MSC populations and complicates reliability and reproducibility of the stem cell source, e.g., by donor heterogeneity. MSC heterogeneity is displayed by small subpopulations of stem-like cells and further special properties of other stromal subpopulations lacking stem-like features but displaying the minimal MSC characteristics which can be maintained during prolonged in vitro culture [8]. The characteristics of MSC vary upon culture conditions and a changing environment by diverse stimuli in vitro, and may be different when compared to the corresponding tissue-originating MSC populations in vivo [2,9]

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