Therapeutic Properties of Mesenchymal Stromal/Stem Cells: The Need of Cell Priming for Cell-Free Therapies in Regenerative Medicine

Abstract

Mesenchymal stromal/stem cells (MSCs) are multipotent adult stem cells that support homeostasis during tissue regeneration. In the last decade, cell therapies based on the use of MSCs have emerged as a promising strategy in the field of regenerative medicine. Although these cells possess robust therapeutic properties that can be applied in the treatment of different diseases, variables in preclinical and clinical trials lead to inconsistent outcomes. MSC therapeutic effects result from the secretion of bioactive molecules affected by either local microenvironment or MSC culture conditions. Hence, MSC paracrine action is currently being explored in several clinical settings either using a conditioned medium (CM) or MSC-derived exosomes (EXOs), where these products modulate tissue responses in different types of injuries. In this scenario, MSC paracrine mechanisms provide a promising framework for enhancing MSC therapeutic benefits, where the composition of secretome can be modulated by priming of the MSCs. In this review, we examine the literature on the priming of MSCs as a tool to enhance their therapeutic properties applicable to the main processes involved in tissue regeneration, including the reduction of fibrosis, the immunomodulation, the stimulation of angiogenesis, and the stimulation of resident progenitor cells, thereby providing new insights for the therapeutic use of MSCs-derived products.

Keywords: Mesenchymal stromal/stem cells; cell-free therapies; paracrine mechanism; priming; regenerative medicine.

Figure 1

Role of mesenchymal stromal/stem cells (MSCs) in tissue injury and repair. After injury, the damaged tissue activates MSCs through different inflammatory signals (IL-1β, IFN-γ, TNF-α, LPS; hypoxia). MSC activation leads to coordination of the microenvironment by both the production of immunomodulatory factors (to modulate the progression of inflammation) and the production of growth factors which subsequently stimulate endothelial cells, fibroblasts cells and tissue progenitor cells. The physiological and orderly action of these factors allows tissue repair through angiogenesis, remodeling of the extracellular matrix (ECM) and functional tissue restoration through tissue progenitor cells differentiation.

Figure 2

Schematic representation of the molecular effects after priming of MSCs. MSCs can be primed through different stimuli, including hypoxia, three-dimensional cultures, growth factors and cytokines, to enhance their therapeutic potential. In these cases, MSCs produce inducible regulatory factors such as growth factors, cytokines, chemokines and exosomes (which contain both proteins and microRNAs). Primed MSCs promote tissue regeneration/repair regulating different processes including inflammation and angiogenesis, the production of the extracellular matrix (ECM) and the regeneration of functional cells by differentiation of their progenitor cells.