Abstract
Mesenchymal stromal/stem cells (MSCs) have been applied in clinical trials with an increasing number in recent years. MSCs showed their great potentials in regenerative medicine for their extensive sources, multilineage differentiation potential, low immunogenicity and self-renewal ability. However, the clinical application of MSCs still confronts many challenges including the requirement of large quantity of cells, low survival ability in vivo and the loss of main original characteristics due to two-dimensional (2D) culture although it is beneficial to cells fast expansion. Three-dimensional (3D) culture artificially creates an environment that permits cells to grow or interact with their surroundings in all three dimensions. Therefore, 3D culture was widely regarded as a more preferable and closer physiological microenvironment for cells growth. Recently, many different 3D spheroid culture methods have been developed to optimize MSCs biological characteristics to meet the demand of regenerative medicine. In this review, we comprehensively discussed the merits and demerits of different spheroid formation methods, expounded the mechanisms of spheroid formation and its microenvironment, and illustrated their optimized biological functions and the pre-clinical applications in various tissue injury and regeneration. In the end, we prospected the trends of this research field and proposed the key problems needed to be solved in the future.
Highlights
Mesenchymal stromal/stem cells (MSCs) are nonhematopoietic multipotent stem cells originated from the mesoderm
Caspase 3/7 activity was increased with spheroid size especially over 500 μm in diameter, but Annexin V was not detected in these spheroids [66]. These results indicated that the enhanced function of MSC spheroids is not oxygen mediated, which contradicts many hypotheses that spheroid formation potentiates cell function by generating a hypoxic core within spheroids with large diameters
Spheroid cultured MSCs have shown the abilities of anti-apoptosis, enhanced stemness, increased sections, anti-inflammatory and immunomodulatory properties as well as induced angiogenesis in vitro and in vivo
Summary
Mesenchymal stromal/stem cells (MSCs) are nonhematopoietic multipotent stem cells originated from the mesoderm. Optimization of cell-based therapy by spheroid culture of MSCs has been widely recognized because it can maintain stemness, improve the ability of anti-apoptosis and homing post-transplantation, enhance anti-inflammatory and immunomodulatory effects, and increase paracrine capacity compared to traditional 2D-cultured MSCs [13, 32, 33].
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