OXI-SCENARIO aim was to improve the functional properties of human mesenchymal stem cells (MSC) by in vitro targeting the oxygen-responsive mechanisms and evaluate the therapeutic potential of modulated cells in a pre-clinical mouse model of myocardial infarction (MI).
While MSC have a native potential to repair injured tissues and are the focus of intensive efforts for developing cell-based therapies for a wide range of diseases, increasing evidence points towards a rather abnormal and non-effective behavior of cultured MSCs. One possible explanation is the translocation of these cells from a low oxygen environment, where they normally reside in vivo, into an atmospheric oxygen environment for in vitro proliferation before therapeutic use.
In this context, we hypothesized that modulating the culture conditions so as to better mimic the in vivo environment might produce MSC with superior functionality and therapeutic potential. To assess our hypothesis, three specific objectives are envisioned: (i) Assessing the effector functions (pro-angiogenic, anti-inflammatory and immunomodulatory) of MSC cultured for up to three passages in an hypoxic environment; (ii) Functional dissection of MSC to undercover the way by which hypoxamiRs (hypoxia-induced microRNAs) interfere in the functional properties; (iii) Evaluate the migration efficacy and regenerative capacity of modified human MSCs in a clinically-relevant animal model of MI.
The importance of this project resides in its potential to yield new advances with regard to the molecular mechanisms that mediate the hypoxia-responsive pathways in human MSCs, which might help the development of many effective therapies.