Mesenchymal stem cells as promoters, enhancers, and playmakers of the translational regenerative medicine

Since their first isolation and characterization by Friedenstein et al. in 1974 [1], mesenchymal stem cells (MSCs) were proven essential for tissue regeneration and homeostasis. Over the years, thanks to a better understanding of the molecular mechanisms underlying the therapeutic effects of MSCs, several approaches with MSC-based therapies have been proposed, in order to treat different human diseases [2]. In this light, MSCs are currently being tested in preclinical in vivo settings as well as in early-stage clinical trials for their ability to modulate immune responses, fostering wound healing and tissue regeneration of various tissue types and organs, including the skin, bone, cartilage, brain, muscle, and tendons [3]. As defined by the International Society for Cellular Therapy (ISCT) in 2006, culture-expanded MSCs [4], harvested from bone marrow, adipose tissue, umbilical cord, dental tissues, and other sources, are being studied in clinical trials across evidence-based practice and numerous regulatory jurisdictions worldwide [5–9]. Recent reports have demonstrated therapeutic effects by MSCs on animal models, explained by the ability of MSCs to be activated by signals from injured tissues: in these damaged areas, MSCs showed regenerative behaviour, with the promotion of the tissue healing, and paracrine activities, with the secretion of anti-inflammatory factors [10]. Experimental in vivo models showed that the direct administration of the same factors secreted by MSCs replicated the local anti-inflammatory effects, highlighting the double role of MSCs as players of tissue regeneration and as regulators of the local environment in many pathological conditions [10–12].