## 6 Perspectives of MSCs Spheroids in Healthcare  
Because of their unique functions and applications, MSCs have been recently named by Professor [PERSON] as medicinal signaling cells [74]. MSCs are not only capable of differentiating into osteocytes, chondrocytes, as well as adipocytes, they secrete several trophic proteins to modulate immune response and to promote tissue regeneration, indicating the versatile roles of MSCs in regenerative medicine [75]. Based on the accumulating experimental evidence, the approaches to induce the specific differentiation of MSCs might be gradually established in the near future. For clinical applications, the origins and amplification protocols have to be concerned in MSC therapies. The heterogeneity of MSCs from different individuals and tissues has been demonstrated [76]. Therefore, for treating the specific disorders, the most suitable origin of MSCs has to be determined. Continuous improvement of biotechnology in the study of secretome, epigenetics, genomics, and proteomics is helpful for clarifying the differentiation and therapeutic capacities for MSCs derived from different origins [77]. To obtain a sufficient number of MSCs for medical applications, an appropriate expansion procedure is required. During the MSC amplification, the maintenance of stemness and differentiation capacities is a critical issue. As mentioned in the previous sections, the differentiation capacities of spheroid-forming MSCs are enhanced, and their differentiation tendencies are further controllable by the planar culture substratum combined with specific induction. Furthermore, MSC spheroids generated by scaffold-free culture platforms are more convenient than those grown within the 3D scaffolds for actual applications, such as intravenous injection. Therefore, the 3D MSC spheroids assembled on a planar scaffold-free culture substrate are promising therapeutic tools or agents to restore the functions of damaged organs in the era of regenerative medicine.  
Recently, the relatively common and reliable origins of MSCs are bone marrow and adipose tissues. However, surgical requirement remains for isolating MSCs from these tissues. Circulating MSCs may be a great another resource. The similar properties of circulating MSCs have been identified as compared to the bone marrow-derived MSCs. The expression levels of surface markers such as CD44, CD90, and CD73 were almost identical in the circulating MSCs and bone marrow-derived MSCs [78]. The critical drawback of circulating MSCs is low quantity. Therefore, a reliable protocol or strategy used for isolating MSCs from blood and further amplifying in vitro is essential for in vivo applications of circulating MSCs. According to the current evidence, CS-based substrates may be a potential platform to isolate and expand the MSCs from blood circulation.  
In addition to regenerative medicine, MSCs also display potential in acting as diagnostic tools. For example, the patients with hypertrophic cardiomyopathy had increased circulating MSCs in the blood stream, comparing to the normal individuals [79]. As mentioned above, the cellular properties of MSCs derived from the respective individuals are different. After the development of a reliable protocol used for MSC isolation and amplification, circulating MSCs and other MSCs would be characterized from the individuals with different healthy status, age, nationality, or lifestyle, and this database of MSCs may be further organized into a smart healthcare platform in the future (Figure 2).