**3. Rationale for use of MSC and their cell-free derivatives in regenerative medicine**

MSCs are the most commonly used cells for cell-based therapy as they do not form teratomas, confer low immunogenicity, and are free of strict ethical concerns [12]. Despite these reasons, the difficulty to trace cell fate and survival in recipient has been a significant obstacle for understanding the mechanisms of the clinical efficacy that can be variable [13]. Furthermore, MSCs are highly heterogeneous and cannot be fully characterized in the context of identity and, finally, potency. At the same time, MSC CM was shown to mediate most of MSC beneficial effects. MSC CM includes various components such as cytokines, growth factors, ECM proteins and factors involved in ECM remodeling, different types of EV, and others. Using cell-free products based on biologically active factors secreted by stem and progenitor cells allows to significantly reduce the risks associated with a direct cell injection, while maintaining efficacy under wide manufacturing scalability and modification potential like fractionation, concentration, and combination with various carriers [14]. Therefore, the application of "cell-free therapeutics" based on the components secreted by MSC as a novel class of biopharmaceuticals represents a rapidly developing and promising approach in regenerative medicine.
