Mesenchymal stem cell spheroids: potential cell resource for cell therapy

Mesenchymal stromal/stem cells (MSCs) have been applied in an increasing number of clinical trials in recent years. MSCs have many advantages in cell therapy for regenerative medicine for their extensive sources, low immunogenicity, self-renewal ability and multilineage differentiation potential. However, the clinical application of MSCs is still confronted by many challenges including low survival ability in vivo, the loss of main original characteristics due to two-dimensional (2D) culture for fast expansion, and the lack of technologies for mass production of high-quality MSCs. Three-dimensional (3D) culture has been widely regarded as a more preferable and closer physiological microenvironment for cell survival, growth and behavior, because 3D culture can artificially create an environment allowing cells to interact with their surroundings in complete three dimensions. Recently, many different 3D spheroid culture methods have been developed to optimize the biological characteristics of MSCs to meet the demand of regenerative medicine. In this review, we comprehensively discuss the merits and demerits of different spheroid formation methods, expound the mechanisms of spheroid formation and its microenvironment, and illustrate their optimized biological functions and the pre-clinical applications in tissue injury and regeneration. In the end, we prospect the trends of this research field and propose the key problems needed to be solved in the future.