Hypoxia-Conditioned Mesenchymal Stem Cells in Tissue Regeneration Application

Mesenchymal stem cells (MSCs) have been demonstrated as promising cell sources for tissue regeneration due to their capability of self-regeneration, differentiation, and immunomodulation. MSCs also exert extensive paracrine effects through release of trophic factors and extracellular vesicles (EVs). However, despite extended exploration of MSCs in preclinical studies, the results are far from satisfactory due to the poor engraftment and low level of survival after implantation. Hypoxia preconditioning has been proposed as an engineering approach to improve the therapeutic potential of MSCs. During in vitro culture, hypoxic conditions can promote MSC proliferation, survival, and migration through various cellular responses to the reduction of oxygen tension. The multilineage differentiation potential of MSCs is altered under hypoxia, with consistent reports of enhanced chondrogenesis. Hypoxia also stimulates the paracrine activities of MSCs and increases the production of secretome both in terms of soluble factors as well as EVs. The secretome from hypoxia-preconditioned MSCs play important roles in promoting cell proliferation and migration, enhancing angiogenesis while inhibiting apoptosis and inflammation. In this review, we summarize current knowledge of hypoxia-induced changes in MSCs and discuss the application of hypoxia-preconditioned MSCs as well as hypoxic secretome in different kinds of disease models. Impact statement Mesenchymal stem cells (MSCs) have been applied in numerous cell-based and secretome-based therapies for tissue regeneration. Hypoxic conditions enhance the function of MSCs by increasing proliferation, survival, homing, differentiation, and paracrine activities. A timely up-to-date comprehensive overview of the effect of low oxygen tension to MSC, with emphasis on the influence and molecular mechanism of hypoxia preconditioning toward MSC's functionality is provided, including the therapeutic use of hypoxia-preconditioned MSC as well as hypoxic secretome in various prove-of-concept disease models. This knowledge would contribute to future engineering of MSC culture conditions for improved translational application.