br Experimental Procedures br Author Contributions br Acknow

Experimental Procedures
Author Contributions
Acknowledgments The authors gratefully acknowledge Dr. H. Kimura for his critical comments and useful suggestions. The authors also thank S. Iwasaki and C. Huang for their technical assistance. The authors are deeply grateful to Prof. Naoto Ishii, who kindly supplied the OT-I transgenic mice. We would like to thank Dr. Julian Tang of the Department of Education for Clinical Research, National Center for Child Health and Development, for proofreading and editing this article. This study was supported by research grants from the National Center for Child Health and Development (26-6, 26-27 and 27-21), Ministry of Education, Culture, Sports, Science and Technology of Japan (Grants-in-Aid 15F15756 and 15K10043), Kawano Masanori Memorial Public Interest Incorporated Foundation for Promotion of Pediatrics, National Natural Science Foundation of China (grant nos. 81202302, 81370230, 81570279, and 81671550), Natural Science Foundation of Guangdong Province, China (grant no. 2014A030311041), and Science and Technology Program of Guangzhou, China (grant no. 201508020107).
Introduction The therapeutic promise of stem cell interventions has led to substantial international investment in research and clinical translation (Aging Analytics Agency, 2014; Caulfield et al., 2010). While most clinical trials of stem cell interventions remain focused on malignant and benign hematopoietic disorders, for which stem cell transplantation has been the standard of care for decades (Rettig et al., 2007), innovative but as yet unproven therapies are in clinical development (Heathman et al., 2015; Li et al., 2014; Trounson and McDonald, 2015), and a small number have received regulatory approval. Advances in stem cell research have raised the expectations of policy makers, funders, patients, and the public, but there is a large gap between expectations and clinical realities (Bubela et al., 2012). The public expects regenerative and possibly curative therapies for neurological conditions and injuries, Phenyl sulfate disease, and autoimmune disorders (Bubela et al., 2012). High expectations combined with a lengthy trajectory of clinical development have created the environment for an expanding industry of clinics that provide unproven and questionable stem cell therapies (Charo, 2016; Master et al., 2014; Master and Resnik, 2011; Levine, 2010; Lau et al., 2008). Regulators and the research community are concerned about the rise in stem cell tourism, driven in part by patient anecdotes and high-profile/celebrity treatment profiles. Clinics exist in countries with lower regulatory standards and, in the United States, exploit regulatory loopholes to treat a wide range of conditions via the autologous administration of cell-based products (e.g., adipose-derived stem cells) (Turner and Knoepfler, 2016). Evidence suggests these clinics may harm patients; the New England Journal of Medicine reported on a case of glioproliferative lesion of the spinal cord that originated from infusions of “mesenchymal, embryonic, and fetal neural cells” at clinics in China, Argentina, and Mexico (Berkowitz, et al., 2016) and on three patients with age-related macular degeneration (AMD) who experienced severe bilateral vision loss after receiving autologous adipose-derived stem cell intravitreal injections at a clinic in Florida, an activity that does not require an investigational new drug application to the US Food and Drug Administration (Kuriyan et al., 2017). While the toxicity profile is well understood for many hematopoietic stem cell interventions, long-term safety concerns persist for other cell types (Goldring et al., 2011; von Tigerstrom, 2008). The same properties that potentially make stem cells therapeutically valuable, such as proliferation, differentiation, migration/homing, and paracrine activity, make them potentially harmful (Sipp and Turner, 2012). Some cells, unlike a biologic or a small-molecule drug, are not metabolized and excreted from the body but are integrated into host tissue; it is conceivable, therefore, that safety issues may not become apparent for decades (Chapman and Scala, 2012; Dlouhy et al., 2014). Elevated risks give rise to expectations for precautionary measures that should be exercised in the design of early-stage clinical trials (Committee for Medicinal Products for Human Use, 2007), but trends in some countries are moving in the reverse direction. Researchers around the world are watching legislative reforms in Japan where regenerative medicine is a national priority. Japan has lowered the regulatory bar for regenerative medicine products by enabling up to 7 years of market approval, with concomitant reimbursement by the Japanese health system, based on data from early-stage trials that demonstrate safety and are “likely to predict efficacy” (Sipp, 2015).