**Acknowledgements**

*Innovations in Cell Research and Therapy*

with age. It was also reported that BMMNCs isolated from patients with chronic ischemic heart disease have a significantly reduced migratory and colonyforming activity in vitro and a reduced neovascularization capacity in vivo, as compared to healthy controls [145]. Therefore, for the patients that are elderly and suffer from pathological insults, they may not benefit from treatment using their own cells. For allogeneic cells, the cell dose is less of an issue than autologous cells. As off-the-shelf products, they are presumably validated for safety and efficacy before being applied to patients. However, generation of cell lots with consistent potency and comparability has been recognized as a significant issue for clinical translation. Recently, two independent investigations reported that clinical-grade human neural stem cell product (HuCNS-SC; proprietary of StemCells, Inc.), in contrast to the research-grade NSCs provided by the same company, failed to demonstrate the efficacy in animal models of spinal cord injury and Alzheimer's disease, respectively [144, 146]. However, despite being informed of the negative impact of stem cell engraftment on functional outcome in the animal model, the company initiated a clinical trial testing this product in patients with cervical spinal cord injury (NCT02163876) in December 2014 and subsequently reported a small improvement in motor strength in 4/5 subjects in the 6-month interim report. However, the clinical trial was terminated in May 2016, due to a lack of significant improvements and the lack of a trend for improvements over time [146]. In this study, there were no details on how the clinical- and research-grade products were made differently that might contribute to the disparity on the efficacy of animal studies. HuCNS-SC was derived from donated fetal brain tissue based on fluorescence-activated cell sorting of

 cells and expanded as neurospheres. It is possible that the clinical- and research-grade products were from different donors with varying genetic background and/or developmental stage. It is also possible that the scale-up production of the cell products under good manufacturing practice (GMP) unfavorably changed the therapeutic function of the cells. Nevertheless, the lack of efficacy of the cell product in the animal model was consistent with the failure of the clinical trial. It has to be noted that in vivo preclinical testing of the final clinical product is not required by the FDA, because "human-derived cellular therapy products intended for clinical administration in animals may not be informative" [147]. As a result, stem cell products are increasingly entering clinical studies for various disease conditions without prior efficacy studies in animal models, outpacing our understanding on their potential mechanisms of action. Although it is true that not all the animal models recapitulate spectrum of human diseases and it is difficult to extrapolate the results from the animal study to human, the lesson learned from the failures of clinical studies including HuCNS-SC is the importance of robust and reliable potency assays to characterize the cells and to ensure the consistency between different manufacturing lots before applying to patients. Recently, the International Society of Stem Cell Research (ISSCR) released updated guidelines on stem cell research and clinical translation, recommending that the cells entering clinical trials are based on sound scientific rationales with robust manufacturing and animal efficacy data, in addition to a safety package to

We are at the end of the beginning in the field of stem cell research and stem

cell regenerative medicine. Particularly, the development of iPSCs and gene editing techniques have opened a new era of disease modeling and personalized

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support clinical trials [148].

**4. Conclusion**

CD133<sup>+</sup>

The authors would like to thank Erin Morris, RN, for assistance in the preparation of this chapter. This work was supported by grants from the Pediatric Cancer Research Foundation to MSC, DEBRA International funding to MSC, and National Natural Science Foundation of China (81472141) to HZ.
