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  • Importantly STS and STS have been shown to have overlapping

    2018-10-24

    Importantly, STS1 and STS2 have been shown to have overlapping functions (Carpino et al., 2002; Carpino et al., 2004). However, although expansion of LSK, increased serial colony growth, and hyperphosphorylation of FLT3 were largely attributable to the loss of STS1, further loss of STS2 strengthened the phenotype, and depletion of STS2 showed in vivo phosphatase activity as well. Because STS1 and STS2 differ in their substrate specificity (Chen et al., 2009a, 2009b) and their expression pattern differs in hematopoiesis, we suspect that subtle functional difference exist between STS1 and STS2. Studies on several other phosphatases, such as SHP2, PRL2, PTPσ, and PTPζ, indicate a frequent involvement of phosphatases in HSC regulation. Among these, PTPσ and PTPζ are transmembrane receptor tyrosine phosphatases. Knockout of these proteins augments HSC function. However, their effects are non-autonomous and are rather due to their interaction with the bone marrow microenvironment (Himburg et al., 2012; Quarmyne et al., 2015). SHP2 and PRL2 are both intra-cytoplasmic phosphatases and have been shown to increase HSC self-renewal as opposed to STS1/STS2 (Chan et al., 2011; Kobayashi et al., 2014; Zhu et al., 2011). None of the phosphatases (SHP2, PRL2, PTPσ, and PTPζ) have been reported to directly dephosphorylate RTKs.
    Experimental Procedures
    Author Contributions
    Acknowledgments
    Introduction Induced pluripotent stem cell (iPSC)-based therapy is a newly developing field and builds on several key technical advances that have enabled the widespread use of embryonic stem cell (ESC)-based technology (Ellerström et al., 2006; Rao 2008; Rao and Condic 2008; Chen et al., 2012) for drug discovery and basic biology. Companies such as Geron, Asteris, Ocata (formerly known as Advanced Cell Technology), Biotime, Viacyte, and J&J have developed products from ESCs, several have initiated early-stage clinical trials (Carpenter and Rao, 2015), and several patients have been treated with no deleterious side effects (Schwartz et al., 2012). These results have led companies such as Healios and Megakaryon to initiate plans to generate products using iPSCs. Recently, a study involving one patient treated with retinal pigment epithelium (RPE) Erismodegib derived from iPSCs was carried out using cells manufactured in a current good laboratory practice (cGLP) environment using autologous cells (http://www.dddmag.com/articles/2014/10/japan-starts-world-first-stem-cell-trial-plans-more). These groups have demonstrated to the Food and Drug Administration (FDA) that products derived from pluripotent stem cells (PSCs) can be manufactured without a demonstrable risk of contaminating undifferentiated cells. Although current good manufacturing practice (cGMP) compliant cells have been generated from ESCs (Crook et al., 2007; Tannenbaum et al., 2012), most of the cells were derived under non-cGMP conditions and then qualified for cGMP by additional testing. The cells were exposed to xenogeneic agents and feeder cells, and/or, in some cases, donor consent would not permit their use as a commercial product. To our knowledge, no fully cGMP-compliant cell line has been generated where the entire manufacturing process, from tissue sourcing to cell expansion and banking processes as well as documentation, raw materials, staff training, cell therapy facility, and quality control (QC) testing, was validated. Developing a cGMP-compliant manufacturing protocol or using integration-free methods and xenogeneic-free material in a cGMP-compliant facility will not be sufficient to ensure clinically relevant products, nor will adding certification or training complete the process. Conformation to regulations governing the acquisition of human donor tissue will need to be ensured (in the United States according to FDA 21 CFR 1271 Human Cells, Tissues, and Cellular and Tissue-based Products). Reference or control material will need to be developed to generate convincing data on in-process testing, lot-to-lot variability, and release assays. The assays themselves will need to be developed and qualified or validated (depending on the clinical trial phase of application). Moreover, cGMP manufacturing requirements that are incompatible with cell manufacture need to be modified, including developing specific guidance for sterility/aseptic processes for patient-specific cells. Attention will need to be paid to the different interpretations of ethical issues, patent law, and the special property rights issues that arise for cells that may make gametes (Andrews et al., 2014). In addition to being in compliance with FDA regulations, one will need to comply with requirements that are imposed by institutional review boards (IRBs), the Health Insurance Portability and Privacy Act (HIPPA), and the Office for Human Research Protection (OHRP). Furthermore, given that iPSC-derived cells may be distributed internationally, the cell manufacturing process will need to adhere to additional country-specific guidelines as well. Developers will also have to devise a strategy for international distribution in countries where regulations are still being formulated (http://c.ymcdn.com/sites/www.celltherapysociety.org/resource/resmgr/2014AnnualMeeting/ISCT2014-AcademicProgram_Web.pdf).