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    • To date safety studies in humans do not have

    2018-11-08

    To date, safety studies in humans do not have extended follow-up in particular with respect to the evaluation of MSC tumorigenic potential. Investigations described in this review were certainly validated by institutional ethics committees; however, not only registered- and university affiliated-investigators use MSCs in humans for clinical applications (Anon., 2012), therefore it remains important to obtain national regulatory agency approval to warrant maximal safety in the clinical environment (Prockop and Olson, 2007). Questions regarding efficacy, safety and mechanisms of action may be answered by a highly regulated large-scale multicenter study. In conclusion, the prospect of using MSCs as cell therapy for treating liver diseases is encouraging but will require an improved understanding of the mechanism behind their therapeutic effects and a stronger validation in preclinical and clinical settings.
    Authorship
    Introduction Avian embryos are a powerful model to study developmental and stem cell biology (Stern, 1996, 2004a, 2005). They offer several advantages as a model for studying stem cell biology including their convenient size and ease of obtaining eggs (Berg et al., 1999), their year-round availability and ease of access to the embryo for manipulations, which among other applications led it to be used as a favourite model for toxicity testing since very early days (Halldin, 2005; Halldin et al., 2005). To date, avians are the only non-mammalian group from which stable embryonic stem cell and germ cell lines have been established. Both cES and chick embryonic germ (cEG) SB269652 are considered to be pluripotent (Petitte et al., 2004), but cES cells have been shown to be able to contribute only to somatic tissues and not to the germ line (Pain et al., 1996), while chick embryonic germ cells can contribute to the germ line (van de Lavoir et al., 2006a). However, surprisingly little attention has been given to the biology of avian stem cells, especially regarding similarities and differences between chick embryonic stem (cES) cells, germ cells, and stem cells obtained from other embryonic and adult tissues. Here we provide information on avian stem cells, emphasizing sources, methods for derivation and culture of pluripotent cells from chick embryos. The avian embryo spends its first 20h or so in utero; the shell is deposited as the egg descends down the maternal oviduct (for review see Stern, 2004b). During this time, cell division occurs in a meroblastic pattern (open cleavage planes, from the centre out to the yolk) to generate a disc. By the time the egg is laid, the blastodisc comprises 20,000–50,000 cells arranged mainly as a single-cell-thick layer (epiblast) underlain by islands of more yolky cells (hypoblast — extraembryonic endoderm of the future yolk sac stalk) (Stern, 2004b). The entire embryo will arise from the centre of the epiblast, but it retains a remarkable ability to regenerate. Fragments of blastodisc can regenerate the entire embryo and re-establish polarity (Bertocchini et al., 2004; Bertocchini and Stern, 2012; Spratt and Haas, 1960), suggesting plasticity of the embryo and perhaps pluripotency of the component cells. It is from these early (pre-primitive streak) stages of development that cell lines analogous to mammalian embryonic stem cells (ESCs) can be established from cells dissociated from the central epiblast; these cells can be perpetuated in culture, perhaps indefinitely (Etches et al., 1996, 1997; Pain et al., 1996). The biology of germ cells in bird embryos is particularly interesting and unique. Primordial germ cells (PGCs) appear to arise at pre-primitive streak stages (see above) by ingression from the epiblast, joining the hypoblast cells below (Ginsburg, 1997; Ginsburg and Eyal-Giladi, 1986, 1987; Karagenc et al., 1996; Petitte et al., 1997). The hypoblast forms a continuous layer of cells that then moves to the most anterior part of the embryo, under the pre-amnion, carrying the PGCs to this region, known as the Germinal Crescent. One remarkable feature is that primordial germ cells use the embryonic blood vasculature as a vehicle to migrate out of the germinal crescent, until they eventually settle in the embryonic gonads (Fujimoto et al., 1976; Kuwana and Rogulska, 1999; Nakamura et al., 2007; Nieuwkoop and Sutasurya, 1979). Another unique characteristic of the gonads in female birds is that the right ovary regresses, and only the left ovary remains functional in the adult (Romanoff, 1960; Smith and Sinclair, 2001, 2004). However even male embryos have a greater number of PGCs in the left gonad (Intarapat and Stern, 2013).