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    • Although the FDA considers analogous cell product data an

    2018-10-24

    Although the FDA considers analogous cell product data an acceptable option for preclinical studies, it requires substantial similarity between analogous animal and human products (FDA, 2013). Due to the significant differences in the innate and adaptive immune system (Mestas and Hughes, 2004), hematopoietic system homeostasis, cell surface markers, and the requirements for hematopoietic cell engraftment (Harding et al., 2013; Trobridge and Kiem, 2010), rodent models are unlikely to fulfill this FDA requirement. The NHP model will be able to overcome these inherent limitations of rodent models, especially limitations related to completely different structure and MHC binding specificity between mouse and human KIRs (Natarajan et al., 2002; Parham et al., 2010). Because tumorigenicity associated with cell therapies may manifest several years after stem cell injection (Amariglio et al., 2009), NHP models would be critical in evaluating the long-term safety of stem cell therapies. The utility of an NHP model for safety evaluation can be appreciated from the lessons learned from AMG 925 studies. The assumption about the safety of replication-incompetent retroviral vectors for gene therapy made in small animal studies was proved wrong in gene therapy trials targeting HSCs in children with X-linked severe combined immunodeficiency, who later developed vector-related leukemia several years after treatment with retrovirally modified stem cells (Hacein-Bey-Abina et al., 2003a, 2003b). Evidence that such retroviral-mediated gene therapy targeting HSCs can cause potential leukemia or malignant transformation has subsequently emerged from studies using NHPs (Seggewiss et al., 2006; Zhang et al., 2008).
    Experimental Procedures
    Acknowledgments This work was supported by funds from the National Institute of Health (P51 OD011106, U01HL099773, UL1TR000427) and The Charlotte Geyer Foundation. We thank Toru Nakano at Osaka University Japan for providing the OP9 bone marrow stromal cell line, and Mathew Raymond for editorial assistance.
    Introduction One of the key early events in the establishment of pregnancy is the development of trophoblast subpopulations from the trophectoderm (TE) of the implanting blastocyst (Rossant, 2001). Ethical and logistical difficulties limit our knowledge of these earliest stages of placentation in humans. In the mouse, trophoblast stem cells (TSC) have been isolated, but there is still no reliable source of such cells for humans. While it is possible to isolate primary trophoblast from human first-trimester placentas, they rapidly differentiate and do not proliferate in vitro. Attempts have been made to overcome this problem by obtaining trophoblast cell lines from early placentas by transformation, or by driving human embryonic stem cells (hESC) along the trophoblast differentiation pathway (Xu et al., 2002; Nagamatsu et al., 2004; Harun et al., 2006; James et al., 2007; Genbacev et al., 2011; Marchand et al., 2011; Takao et al., 2011; Udayashankar et al., 2011; Amita et al., 2013). However, all these strategies have been plagued with difficulties in identifying the cells as “trophoblast” in culture (Roberts et al., 2014). In vivo, trophoblast cells can be identified by their anatomical location and the expression of particular markers. In vitro, there is a lack of consensus about the best criteria to use to define trophoblast. A distinctive feature of trophoblast is its profile of human leukocyte antigen (HLA) class I expression. There are two main differentiation pathways in human placentas, villous (VCT) and extravillous (EVT) cytotrophoblast. VCTs fuse to form an overlying syncytiotrophoblast (ST), and EVTs form multinucleated placental bed giant cells deep in the decidua and myometrium. ST and VCT are HLA class I null, whereas EVT express HLA-C and -E molecules, and HLA-G, which is uniquely expressed by trophoblast (Apps et al., 2009). In contrast, most normal somatic cells are HLA class I positive and express HLA-A, -B, -C, and -E (Wei and Orr, 1990). Only neurons, glial cells, germ cells, hepatocytes, and exocrine pancreas are negative (Fleming et al., 1981; Anderson et al., 1984; Lampson and Hickey, 1986; Jalleh et al., 1993). Thus, human first-trimester trophoblast cells never express HLA-A and -B, and are the only cells that normally express HLA-G.