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• W2003281000 abstract "Induced pluripotent stem cell research has broadened possibilities for regenerative medicine and captured the world's attention in a way that science rarely does. However, clinical applications utilizing cultured stem cells have existed for >30 years and can assist benchers and bedsiders in identifying and expediting promising avenues for future therapies. Induced pluripotent stem cell research has broadened possibilities for regenerative medicine and captured the world's attention in a way that science rarely does. However, clinical applications utilizing cultured stem cells have existed for >30 years and can assist benchers and bedsiders in identifying and expediting promising avenues for future therapies. The stem cell community generally credits Till and McCulloch's transplantation experiments of the 1960s on the hematopoietic system for the demonstration that adult tissues contain stem cells (Till and McCulloch, 1961Till J.E. McCulloch E.A. Radiat. Res. 1961; 14: 213-222Crossref PubMed Scopus (3224) Google Scholar). In those experiments, so-called colony forming units (CFUs) were produced by short-term culture of isolated murine bone marrow cells and then individually transplanted into irradiated recipients to reconstitute the hematopoietic system. From these early in vivo experiments came the concept that stem cells are often rare cells that fuel homeostasis and wound repair through their ability to generate both the proliferating and the differentiating cells of our tissues. The notion that stem cells can do so long term also came from hematopoietic studies as researchers began to perform long-term experiments on hematopoietic stem cells that were isolated and purified directly from the bone marrow and serially transplanted through many generations. Although the hematopoietic system led the way in devising concepts for stem cell biology, the ability to passage stem cells long term in vitro began in the 1970s with the pioneering work of Howard Green on human epithelial stem cells. At the time, most researchers resorted to immortalized, transformed cell lines, which seemed to be the only cells that could proliferate and differentiate and yet easily be passaged long term. Cloned teratocarcinoma cells were particularly interesting to developmental biologists, who were examining the ability of these embryonic-like cells to differentiate along a variety of lineages in vitro. Green noticed that epithelial colonies were among the cell types present within teratocarcinoma cultures and discovered that he could clone and propagate them on a layer of lethally irradiated, diploid mouse 3T3 fibroblasts, a line that he had developed previously. When the strategy of using a fibroblast feeder layer was subsequently applied to human epidermal cells, large colonies of diploid epithelial keratinocytes grew that retained their ability to self renew and terminally differentiate long term (Rheinwald and Green, 1975Rheinwald J.G. Green H. Cell. 1975; 6: 331-343Abstract Full Text PDF PubMed Scopus (3900) Google Scholar). Green and his colleagues continued to improve upon the culture conditions (reviewed by Green, 1991Green H. Sci. Am. 1991; 265: 96-102Crossref PubMed Scopus (111) Google Scholar). They added epidermal growth factor purified from rat submaxillary glands to the culture conditions, as well as insulin and dexamethasone. They also spiked the media with cholera toxin, a constitutive activator of cyclic AMP, which also aided cell growth substantially. As the keratinocyte's enormous proliferative powers became increasingly exposed, so did the promise to generate sufficiently large sheets of cultured epidermal cells from a small piece of healthy skin to cover the damaged regions of a badly burned patient. These early studies represent the birth of what is now a 30 year successful application of purified human stem cells for regenerative medicine (reviewed by Green, 1991Green H. Sci. Am. 1991; 265: 96-102Crossref PubMed Scopus (111) Google Scholar). Therapeutic uses of cultured stem cells are often viewed by the public as futuristic, if not science fiction. We need to work harder to educate our society of the already fulfilled wonders of stem cells for medical applications. The clinical applications for epithelial cells have not ended at epidermal cells. Using very similar culture conditions, other stratified squamous epithelial stem cells, including corneal cells, can be cultured long term in vitro. This ability led to the subsequent application of cultured corneal progenitors to treat patients suffering from corneal blindness, and a 10 year study of successfully treating 100 such patients was recently published by Michele De Luca, Grazia Pellegrini, and colleagues (reviewed by Rama et al., 2010Rama P. Matuska S. Paganoni G. Spinelli A. De Luca M. Pellegrini G. N. Engl. J. Med. 2010; 363: 147-155Crossref PubMed Scopus (816) Google Scholar). These early culture methods did much more than ever imagined at the time. Moreover, they not only paved the way for these impressive clinical applications, but in addition they opened the door for embryonic stem cell (ESC) research as we know it today. The concept of coculturing epithelial cells with a fibroblast feeder layer was quickly adapted to mouse ESCs and worked particularly well when used in conjunction with conditioned medium from teratocarcinoma cells (Evans and Kaufman, 1981Evans M.J. Kaufman M.H. Nature. 1981; 292: 154-156Crossref PubMed Scopus (6427) Google Scholar, Martin, 1981Martin G.R. Proc. Natl. Acad. Sci. USA. 1981; 78: 7634-7638Crossref PubMed Scopus (4291) Google Scholar). Once the hurdle of culturing primary ESCs was overcome, germline transmission was soon achieved, providing graphic illustration that ESCs are truly pluripotent, able to generate the ∼210 cell types of the mouse (Robertson et al., 1986Robertson E. Bradley A. Kuehn M. Evans M. Nature. 1986; 323: 445-448Crossref PubMed Scopus (559) Google Scholar). Although the early mammalian cell culture studies were instrumental in bringing stem cells to a clinical setting, a two decade gap separated those advances from the ones of Yamanaka and colleagues that have captivated the interests of scientists and public alike (Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (18842) Google Scholar). What accounted for this gap and how can we expedite progress in regenerative medicine in the years to come? Below are a few ideas based upon the history of the field and my own experiences as a stem cell biologist. As a postdoctoral fellow and biochemist in Green's laboratory in the late 1970s, I was far more fascinated by studying how epidermal stem cells balance growth and differentiation at a molecular level than I was in the scientifically more mundane, albeit more immediately relevant, task of optimizing culture conditions for burn therapy. Although placing stem cells into a molecular framework has taken three additional decades to evolve, there are several recent indications that continuing to build upon this foundation will be the engine that drives regenerative medicine in the future. In this regard, it is intriguing that cyclic AMP, one of the culture additives that advanced epithelial regenerative medicine in the 1970s, was recently found to act downstream in the Wnt signaling pathway (Goessling et al., 2011Goessling W. Allen R.S. Guan X. Jin P. Uchida N. Dovey M. Harris J.M. Metzger M.E. Bonifacino A.C. Stroncek D. et al.Cell Stem Cell. 2011; 8: 445-458Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar), known to have a powerful impact on stem cells and tissue regeneration. This new knowledge has now been translated into an FDA-approved phase 1 clinical trial that could significantly improve human cord blood transplantations (Goessling et al., 2011Goessling W. Allen R.S. Guan X. Jin P. Uchida N. Dovey M. Harris J.M. Metzger M.E. Bonifacino A.C. Stroncek D. et al.Cell Stem Cell. 2011; 8: 445-458Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar). On a similar note, in converting skin fibroblasts to iPSCs, Yamanaka and coworkers achieved their success by exploiting not only mammalian cell culture technology but also knowledge of the molecular differences between human ESCs and fibroblasts. By employing an amazingly simple screen to weed out nonessential genes in these differential patterns of gene expression, the researchers honed in on the key transcription factors that promote an embryonic-like fate (Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (18842) Google Scholar). This knowledge, based squarely upon the molecular foundations of ESC biology, is now fueling efforts to identify small molecules that will optimize iPSC derivation and culture. In other words, while the field began with cell culture to fuel molecular insights into stem cell biology (as discussed in, for example, Blanpain and Fuchs, 2009Blanpain C. Fuchs E. Nat. Rev. Mol. Cell Biol. 2009; 10: 207-217Crossref PubMed Scopus (857) Google Scholar), the molecular insights are now fueling approaches to expand the repertoire and populations of cultured stem cells that can be applied in the clinics. Another relevant lesson stemming from the dawn of epidermal stem cell biology is that keratinocytes alter their program of gene expression in culture. Based upon what we currently understand about the extraordinary complexities of skin stem cell niches (reviewed in Blanpain and Fuchs, 2009Blanpain C. Fuchs E. Nat. Rev. Mol. Cell Biol. 2009; 10: 207-217Crossref PubMed Scopus (857) Google Scholar), it seems unlikely that this will be fully rectified no matter what we may do to optimize culture conditions. That said, the long-standing success of cultured human keratinocytes for burn therapy and the absence of skin cancers in patients engrafted decades ago suggests that epidermal progenitors do not lose their stemness when passaged in vitro, nor do they become transformed. Analogously, when engrafted onto the backs of hairless mice, murine hair follicle stem cells passaged in vitro can generate epidermis, sebaceous glands, and hair follicles, and they even seem to be able to collaborate with dermal cells in recreating a new stem cell niche (reviewed in Blanpain and Fuchs, 2009Blanpain C. Fuchs E. Nat. Rev. Mol. Cell Biol. 2009; 10: 207-217Crossref PubMed Scopus (857) Google Scholar). These findings suggest that as long as their capacity for long-term self-renewal and differentiation can be faithfully maintained in vitro, cultured stem cells should continue to hold promise for regenerative medicine even if they transiently adopt a new molecular program when propagated outside their normal microenvironment. As exciting as this concept is, with few exceptions, stem cell populations are in limited supply, posing significant hurdles even for stem cells such as corneal or hematopoietic stem cells where clinical applications are well established. Taking a page from developmental biology, it would seem that one good way to overcome these barriers would be to funnel our collective research energies into enhancing our knowledge of stem cell activation and self-renewal. Such strategies are ones that are already being actively pursued by a number of stem cell researchers. Indeed, the aim to enhance hematopoietic stem cell self-renewal in vitro was behind the Zon group's efforts to conduct their cleverly devised zebrafish screen for FDA-approved small molecules that could enhance the process in vivo. This in turn resulted in the identification of dimethyl-prostaglandin E2 (dmPGE2), which has not only provided a possible link between cAMP and Wnt stem cell signaling pathways but has also led to the phase 1 clinical trials described above (Goessling et al., 2011Goessling W. Allen R.S. Guan X. Jin P. Uchida N. Dovey M. Harris J.M. Metzger M.E. Bonifacino A.C. Stroncek D. et al.Cell Stem Cell. 2011; 8: 445-458Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar). And in a recent RNAi screen for self-renewing hair follicle stem cell genes, clues have surfaced that might be exploited to improve epithelial stem cell expansion in vitro (Chen et al., 2012Chen T. Heller E. Beronja S. Oshimori N. Stokes N. Fuchs E. Nature. 2012; (in press)Google Scholar). If so, this could aid current treatments for corneal blindness, where stem cell numbers are often the rate-limiting step to success (reviewed by Rama et al., 2010Rama P. Matuska S. Paganoni G. Spinelli A. De Luca M. Pellegrini G. N. Engl. J. Med. 2010; 363: 147-155Crossref PubMed Scopus (816) Google Scholar). An alternative route to overcoming the limited supplies of cultured stem cells is to transdifferentiate closely related cells that are either in greater supply or which can be propagated more easily in vitro than the desired stem cell. For instance, if we can gain an understanding of the transcriptional differences between corneal and skin stem cells, can we exploit this information to transdifferentiate skin stem cells into corneal stem cells? Given the close relation between these two types of stratified squamous epithelial progenitors, such an approach seems like a baby step relative to Yamanaka's giant step that launched the game of transdifferentiation hopscotch. Although the borders between dreaming and thinking beyond the box can sometimes be quite blurred, the recent successes of Wernig and others (reviewed by Chambers and Studer, 2011Chambers S.M. Studer L. Cell. 2011; 145: 827-830Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar) suggest that this may be the most accessible route to future clinical applications. E.F. is an Investigator of the Howard Hughes Medical Institute and receives grant support from the National Institutes of Health and the New York State Stem Cell Initiative." @default.
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• W2003281000 title "The Impact of Cell Culture on Stem Cell Research" @default.
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