**Acknowledgements**

Regarding human *in vivo* research, Sekiya et al. reported a promising study involving 10 individuals with articular defects. SM-MSCs were successfully applied locally and rested for 10 min for adherence, as the same investigators reported before in pigs and rabbits. The therapy efficacy *in vivo* was evaluated, according to MRI, histological, and clinical scores. Only one patient presented fibrous cartilage in the deep-zone, although, in general, the results were

De Bari and his group investigated the potential use of SM-MSCs for muscle repair in mdx mouse model for DMD. They demonstrated that human SM-MSCs had the capacity to contribute for the formation of myofibers and long-term persisting SC. The cells were injected into the blood stream, engrafting in several tissues. However, they only acquired muscle phenotype within the skeletal muscle tissue, verifying their sensitiveness to environmental cues. They observed that the administration of SM-MSCs restored the sacrolemmal expression of dystrophin and rescued the expression of mouse mechano-growth factor (MGF). MGF is involved in muscle repair and maintenance but is undetectable in dystrophic mdx mouse, even after mechanical stimulation. They also reported that a subpopulation of the injected cell remained for several months as SC. These findings suggest the significant role of SM-MSCs in restoring pathophysiologic features of the dystrophic muscle in the animal model [22].

In summary, MSCs play an important role in embryonic development, postnatal growth, repair, and regeneration mechanisms, as well as in maintaining tissue homeostasis, and synovial membrane mesenchymal stem cells are a promising, easily available source. Despite relevant recent advances, challenges still remain on the use of MSCs as standard therapeutic

Although BM-MSCs remain the most studied source of MSCs, as they were the first to be characterized, SM-MSCs are an easily available source with proven enhanced chondrogenic, osteogenic, and myogenic differentiation ability. Nonetheless, their characterization, as established by the expression of specific cell surface markers, may be affected by interindividual heterogeneity and major differences in cellular marker expression profiles may be found in

The most effective administration route for SM-MSC application *in vivo* remains to be defined and the genetic stability of the cells must be assured both *in vitro* and *in vivo*. Also, the biomechanics and secretory profile of these cells must be further studied, in order to comprehend the mechanism of regenerative capacity of these cells and secretion profile in signaling factors, growth factors, cytokines, and other bioactive molecules, and their role on chondrogenic as

SM-MSCs present themselves as a promising source of MSCs that are becoming the targets of several research groups worldwide. Their application *in vivo* in preclinical and clinical trials

satisfactory and promising [60].

88 Tissue Regeneration

**4. Conclusion**

nonhuman species.

options for clinical applications.

well as osteogenic and myogenic differentiation.

is envisioned for the therapeutics of musculoskeletal disorders.

This work was supported by Programa Operacional Regional do Norte (ON.2-O Novo Norte), QREN, FEDER with the project "iBone Therapies: Terapias inovadoras para a regeneração óssea," ref. NORTE-01-0247-FEDER-003262, and by the program COMPETE-Programa Operacional Factores de Competitividade, Projects PEst-OE/AGR/UI0211/2011 funding from FCT. This work was also supported by Programa Operacional Competitividade e Internacionalização (P2020), Fundos Europeus Estruturais e de Investimento (FEEI), and FCT with the project "BioMate-A novel bio-manufacturing system to produce bioactive scaffolds for tissue engineering" with reference PTDC/EMS-SIS/7032/2014 and by COMPETE 2020, from ANI-Projectos ID&T Empresas em Copromoção, Programas Operacionais POCI, by the project "insitu. Biomas-Reinvent biomanufacturing systems by using an usability approach for in situ clinic temporary implants fabrication" with the reference POCI-01-0247-FEDER-017771. This work also received financial support from the framework of QREN through Project NORTE-07-0124-FEDER-000066. Ana Rita Caseiro (SFRH/BD/101174/2014) and Rui Damásio Alvites (SFRH/BD/116118/2016) acknowledge FCT for financial support.
