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• W2034325891 abstract "Over the last several years much attention has focused on the differentiation abilities of stem cells. In particular, it has been suggested that traditional concepts and dogmas regarding the developmental potential of somatic tissue resident stem cells need to be revisited. A number of reports have suggested that stem cells obtained from, for instance, bone marrow or the nervous system may be able to “transdifferentiate” or “dedifferentiate” [1Blau H.M. Brazelton T.R. Weimann J.M. The evolving concept of a stem cell entity or function?.Cell. 2001; 105: 829Abstract Full Text Full Text PDF PubMed Scopus (934) Google Scholar, 2Fuchs E. Segre J.A. Stem cells a new lease on life.Cell. 2000; 100: 143Abstract Full Text Full Text PDF PubMed Scopus (648) Google Scholar, 3Graf T. Differentiation plasticity of hematopoietic cells.Blood. 2002; 99: 3089Crossref PubMed Scopus (290) Google Scholar, 4Weissman I.L. Anderson D.J. Gage F. Stem and progenitor cells origins, phenotypes, lineage commitments, and transdifferentiations.Annu Rev Cell Dev Biol. 2001; 17: 387Crossref PubMed Scopus (758) Google Scholar, 5Wulf G.G. Jackson K.A. Goodell M.A. Somatic stem cell plasticity current evidence and emerging concepts.Exp Hematol. 2001; 29: 1361Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. That is, bone marrow stem cells can be “induced” to make neural tissue [6Brazelton T.R. Rossi F.M. Keshet G.I. Blau H.M. From marrow to brain expression of neuronal phenotypes in adult mice.Science. 2000; 290: 1775Crossref PubMed Scopus (1585) Google Scholar, 7Mezey E. Chandross K.J. Harta G. Maki R.A. McKercher S.R. Turning blood into brain cells bearing neuronal antigens generated in vivo from bone marrow.Science. 2000; 290: 1779Crossref PubMed Scopus (1693) Google Scholar], and neural stem cells may be “induced” to produce blood and other tissues [8Bjornson C.R. Rietze R.L. Reynolds B.A. Magli M.C. Vescovi A.L. Turning brain into blood a hematopoietic fate adopted by adult neural stem cells in vivo.Science. 1999; 283: 534Crossref PubMed Scopus (1288) Google Scholar, 9Clarke D.L. Johansson C.B. Wilbertz J. et al.Generalized potential of adult neural stem cells.Science. 2000; 288: 1660Crossref PubMed Scopus (917) Google Scholar]. These are just two examples of numerous similar reports that include tissues such as muscle, liver, skin, gut, and lung [10Gussoni E. Soneoka Y. Strickland C.D. et al.Dystrophin expression in the mdx mouse restored by stem cell transplantation.Nature. 1999; 401: 390Crossref PubMed Scopus (1635) Google Scholar, 11Jackson K.A. Mi T. Goodell M.A. Hematopoietic potential of stem cells isolated from murine skeletal muscle.Proc Natl Acad Sci U S A. 1999; 96: 14482Crossref PubMed Scopus (874) Google Scholar, 12Jackson K.A. Majka S.M. Wang H. et al.Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells.J Clin Invest. 2001; 107: 1395Crossref PubMed Scopus (1766) Google Scholar, 13Krause D.S. Theise N.D. Collector M.I. et al.Multi-organ, multi-lineage engraftment by a single bone marrow–derived stem cell.Cell. 2001; 105: 369Abstract Full Text Full Text PDF PubMed Scopus (2464) Google Scholar, 14Lagasse E. Connors H. Al-Dhalimy M. et al.Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.Nat Med. 2000; 6: 1229Crossref PubMed Scopus (2130) Google Scholar, 15Orlic D. Kajstura J. Chimenti S. et al.Bone marrow cells regenerate infarcted myocardium.Nature. 2001; 410: 701Crossref PubMed Scopus (4679) Google Scholar, 16Orlic D. Kajstura J. Chimenti S. et al.Mobilized bone marrow cells repair the infarcted heart, improving function and survival.Proc Natl Acad Sci U S A. 2001; 98: 10344Crossref PubMed Scopus (1934) Google Scholar, 17Petersen B.E. Bowen W.C. Patrene K.D. et al.Bone marrow as a potential source of hepatic oval cells.Science. 1999; 284: 1168Crossref PubMed Scopus (2181) Google Scholar, 18Theise N.D. Nimmakayalu M. Gardner R. et al.Liver from bone marrow in humans.Hepatology. 2000; 32: 11Crossref PubMed Scopus (1153) Google Scholar]. The suggested “plasticity” of somatic tissue stem cells has a potential clinical impact and may revolutionize the way we think about tissue transplantation therapies and regenerative medicine [19Lagasse E. Shizuru J.A. Uchida N. Tsukamoto A. Weissman I.L. Toward regenerative medicine.Immunity. 2001; 14: 425Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar]. Unlike most advances in the life sciences, the possibility of stem cell plasticity has been immediately put to use by various political and citizen's group forces. In particular, if somatic stem cells can be shown to have developmental potentials resembling those of embryonic stem cells, then, some would argue, it is not necessary to pursue research using the latter. The somatic vs embryonic stem cell debate is a classic example of seizing on extremely incomplete scientific data to promote political interests. In view of the above scientific, clinical, and political considerations, this special issue of Experimental Hematology comes at a very appropriate time. The “richness” of stem cell plasticity as an area that is ripe for investigation is illustrated by the broad range of articles presented here. The individual articles offer a glimpse of the intellectual, methodological, and conceptual challenges that stem cell plasticity offers. It is not my purpose in this overview to provide a comprehensive review and assessment of the various studies that have shaped the nascent field of stem cell plasticity. A thoughtful and comprehensive critique has recently appeared in this publication [5Wulf G.G. Jackson K.A. Goodell M.A. Somatic stem cell plasticity current evidence and emerging concepts.Exp Hematol. 2001; 29: 1361Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar]. Rather, I would like to slightly “wind back the clock” and take the opportunity to highlight some of the basic concepts of stem cell biology in general and how these might apply to the plasticity issue in particular. It is useful to begin by attempting to define the concept of stem cell as it has evolved over the last few decades. I will confine the following discussion to stem cells as homeostatic biological activities or entities; that is, stem cells that reside in somatic tissues. The physiological roles of these stem cell populations are to replenish mature cell populations of the given tissue or organ, and to respond to situations of organismal stress. The rationale for not including embryonic stem cells is that these cells, by definition, can produce all tissue types of the organism and therefore confuse the concept of plasticity as it applies to stem cell populations destined for steady-state, lifelong function in adult individuals. Perhaps to the surprise and amusement of some colleagues, I will state, “Of course, somatic stem cells are plastic.” In fact, plasticity is a necessary overall component of a definition of stem cells. Confusion has resulted from the exact meaning of the word “plasticity” as it is used in different contexts. Consider hematopoietic stem cells as an example; these cells are plastic in at least three ways, each of which has been defined and demonstrated by numerous studies dating back to the mid-sixties [20Lemischka IR (2001) In: Zon LI (ed.) Hematopoiesis: A Developmental Approach. New York: Oxford University PressGoogle Scholar]. First, hematopoietic stem cells are plastic in their ability to balance the cell fate decisions to either self-renew or embark on pathways of differentiation. Thus, a single stem cell must be plastic in its ability to make one of these choices. Second, hematopoietic stem cells are plastic in their decisions to produce at least 10 very different lineages of mature blood cells in their sufficient quantities throughout the organism's life. This is not a fixed developmental program, but is sensitive to specific demands that are a function of the overall physiological state of the organism. Third, a hematopoietic stem cell is plastic in the regulation of its proliferative activity. This proliferative ability is vast, given that in the murine transplantation system, for example, a single stem cell is both necessary and sufficient for the restoration of lifelong hematopoietic function [21Jordan C.T. Lemischka I.R. Clonal and systemic analysis of long-term hematopoiesis in the mouse.Genes Dev. 1990; 4: 220Crossref PubMed Scopus (448) Google Scholar, 22Lemischka I.R. What we have learned from retroviral marking of hematopoietic stem cells.Curr Top Microbiol Immunol. 1992; 177: 59PubMed Google Scholar, 23Osawa M. Hanada K. Hamada H. Nakauchi H. Long-term lymphohematopoietic reconstitution by a single CD34low/negative hematopoietic stem cell.Science. 1996; 273: 242Crossref PubMed Scopus (1717) Google Scholar]. In fact, it has been strongly suggested that the proliferative dysregulation of the most primitive hematopoietic stem cell underlies at least some leukemic disorders [24Reya T. Morrison S.J. Clarke M.F. Weissman I.L. Stem cells, cancer, and cancer stem cells.Nature. 2001; 414: 105Crossref PubMed Scopus (7810) Google Scholar]. Other aspects of hematopoietic plasticity need to be highlighted. For example, a number of studies have challenged our view that differentiation along a given hematopoietic lineage is unidirectional and irreversible [3Graf T. Differentiation plasticity of hematopoietic cells.Blood. 2002; 99: 3089Crossref PubMed Scopus (290) Google Scholar]. Rather, it seems that even cells considered to be close to terminally mature can be reprogrammed to unexpected hematopoietic fates [3Graf T. Differentiation plasticity of hematopoietic cells.Blood. 2002; 99: 3089Crossref PubMed Scopus (290) Google Scholar]. It also has been shown that the apparent biological abilities of a stem cell can vary dramatically as a function of exact cell-cycle status [25Berrios V.M. Dooner G.J. Nowakowski G. et al.The molecular basis for the cytokine-induced defect in homing and engraftment of hematopoietic stem cells.Exp Hematol. 2001; 29: 1326Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Few, if any, of these manifestations of hematopoietic stem cell plasticity raise eyebrows or engender controversy. These features of hematopoietic stem cells have been widely accepted due to many years of precise clonal studies that accurately measured the potentials of individual cells. From all of these elegant studies one can distill the basic hallmark properties of hematopoietic and, by extrapolation, other somatic stem cell populations. These properties are: 1) the ability to balance self-renewal and differentiation; 2) the ability to produce robust populations of mature cells in a tightly, though flexibly regulated, manner; and in the case of hematopoietic and some other somatic stem cells, 3) an ability to produce numerous distinct cell lineages. I suggest that these features, and only these, can currently be considered as known and necessary properties of somatic stem cells. Given these arguments, why is the broader issue of somatic stem cell plasticity controversial? In my opinion, there are several clear reasons. One is the “surprise factor”; specifically, it never occurred to most investigators that, for example, blood-forming stem cells give rise to anything other than blood cells. The reasons for this are numerous: 1) hematologists primarily look at blood cells in hematopoietic transplant recipients; 2) The assay systems (such as bone marrow ablation followed by reconstitution) may only reveal a select subset of differentiation abilities; even in the well-studied hematopoietic system, different assays can yield a variety of answers for such fundamental questions as the number of stem cells in an individual mouse or human; 3) the embryological dogma of the three germ layers states that these are irreversibly specified to be discrete at gastrulation, and a broad range of other issues exist ranging from the experimental to the conceptual. Surprises in science are a way of life. In particular, the life sciences have seen their share of surprises, even on a yearly basis. The surprise factor should not be a reason for controversy simply because it is a necessary consequence of keeping an open mind. Particularly, in this post-Dolly era, the ability of somatic stem cells to assume unexpected fates must be considered a real possibility. Keeping an open mind does not mean relaxing scientific standards, however, which brings me to another reason for the plasticity controversy: Researchers want to believe plasticity exists. It is this mentality that has unfortunately led to a less than satisfactory degree of scientific rigor in a number of reports that claim to demonstrate somatic stem cell plasticity, particularly across germ layer “boundaries.” Sadly, the culture of scientific publication, and a desire for recognition, has sometimes resulted in a rush to report findings that can at best be described as preliminary and incomplete. This has been exacerbated by the interest of the popular media, often resulting in initial publication of potentially important results in non-peer-reviewed venues. Peer review is the guardian of scientific endeavor; one cannot abandon or circumvent it in the scientific profession. A necessary feature of correct scientific method is that novel results must be independently confirmed before transitioning from the “preliminary” category, but the present culture of science does not look favorably on the publication of negative findings. The significance of this is that once an extraordinary report has been published, the failure to reproduce it independently is not generally greeted as a priority for publication. Therefore, often the irreproducibility of a given result is known only anecdotally to a small group of specialists. Fortunately, in the field of stem cell plasticity, this situation is being remedied as illustrated by a number of recent publications [26Kawada H. Ogawa M. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle.Blood. 2001; 98: 2008Crossref PubMed Scopus (174) Google Scholar, 27McKinney-Freeman S.L. Jackson K.A. Camargo F.D. Ferrari G. Mavilio F. Goodell M.A. Muscle-derived hematopoietic stem cells are hematopoietic in origin.Proc Natl Acad Sci U S A. 2002; 99: 1341Crossref PubMed Scopus (424) Google Scholar, 28Morshead C.M. Benveniste P. Iscove N.N. van der Kooy D. Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations.Nat Med. 2002; 8: 268Crossref PubMed Scopus (336) Google Scholar, 29Terada N. Hamazaki T. Oka M. et al.Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion.Nature. 2002; 416: 542Crossref PubMed Scopus (1765) Google Scholar]. Interestingly, in the case of animals cloned from somatic cell nuclei, numerous recent publications have highlighted the fact that most, possibly all, cloned mammals suffer from a variety of defects [30Rideout 3rd, W.M. Eggan K. Jaenisch R. Nuclear cloning and epigenetic reprogramming of the genome.Science. 2001; 293: 1093Crossref PubMed Scopus (626) Google Scholar]. These have served as a welcome reality check. So what is to be done in order to elucidate the various possibilities of somatic stem cell plasticity? It is valuable in this regard to consider the experimental criteria employed in the original establishment of the stem cell concept. Once again, the hematopoietic system serves as an appropriate model. The foundation of our understanding of the hematopoietic system resides in the extensive use of clonal analysis. Simply stated, clonal analysis permits the functional evaluation of individual stem cells. In regard to the plastic behavior of hematopoietic stem cells, clonal analysis is responsible for defining all of the specific examples listed above. Indeed, it is difficult to imagine the knowledge of any of the hallmark properties of the hematopoietic stem cell without clonal analysis. This type of functional analysis defined the basic properties of hematopoietic stem cells long before these could be prospectively identified by cell purification techniques, thus indicating its experimental power. Clonal analysis has been generally utilized in studies of stem cells from other tissues, although, for the most part, it is lacking in studies reporting unexpected plasticity behaviors. Two studies have shown that highly purified bone marrow hematopoietic stem cells can contribute to liver and to heart tissue [14Lagasse E. Connors H. Al-Dhalimy M. et al.Purified hematopoietic stem cells can differentiate into hepatocytes in vivo.Nat Med. 2000; 6: 1229Crossref PubMed Scopus (2130) Google Scholar, 15Orlic D. Kajstura J. Chimenti S. et al.Bone marrow cells regenerate infarcted myocardium.Nature. 2001; 410: 701Crossref PubMed Scopus (4679) Google Scholar]. In both studies, it may be that the canonical blood-forming stem cell contributed to nonhematopoietic tissues, but this remains speculative. The most that can be said is that the physical phenotypes of the blood-forming and non–blood-forming stem cell activities are largely overlapping. It should be pointed out that it may be enough for certain applications to show that bone marrow has cells that are capable of differentiating to liver, muscle, and other tissues. In particular, just this fact alone would be of relevance to potential clinical applications. From a biological perspective, a direct demonstration of somatic stem cell plasticity at the clonal level must precede any efforts to reinterpret and revise traditionally established paradigms. One study employed such a degree of precision [13Krause D.S. Theise N.D. Collector M.I. et al.Multi-organ, multi-lineage engraftment by a single bone marrow–derived stem cell.Cell. 2001; 105: 369Abstract Full Text Full Text PDF PubMed Scopus (2464) Google Scholar]. While intriguing, this observation has yet to be independently verified and therefore may not reflect the general degree of somatic stem cell plasticity. A direct demonstration of somatic stem cell plasticity would have significant clinical impact. Specifically, it would open up the possibilities that well-characterized stem cell populations could be reprogrammed to assume alternate fates. Thus, if the mechanisms for such reprogramming could be unraveled, it may become feasible to mediate this phenomenon in noninvasive contexts. For example, if hematopoietic stem cells truly can contribute to the regeneration of heart tissue, it should be possible to devise ways by which these endogenous cells would be recruited to repair cardiac damage in the actual patient [16Orlic D. Kajstura J. Chimenti S. et al.Mobilized bone marrow cells repair the infarcted heart, improving function and survival.Proc Natl Acad Sci U S A. 2001; 98: 10344Crossref PubMed Scopus (1934) Google Scholar]. It would seem that a second relevant point to establishing somatic stem cell plasticity should be a demonstration of robust contribution to an unexpected tissue. Many reports of plasticity describe, at best, infrequent contributions, or possible “transdifferentiation” events. The apparently rare nature of these observations has several important consequences. The identification of rare cells makes it difficult to rigorously prove membership in any type of defined cell population. Commonly, histochemical or other visible markers are employed to demonstrate origin and establish the ultimate phenotype of a given cell. These types of analyses can be fraught with artifactual complications and in general, the less detectable a cell is, the more difficult it becomes to employ multiple markers or functional criteria. Very few things are necessarily absolute in biology. For example, although primary cells generally undergo senescence, rare genetic or epigenetic events often result in “immortalized,” permanently growing cells that have survived the classical crisis period. It may be that a very rare contribution by a hematopoietic stem cell to an unexpected tissue reflects a similar aberrant and low-probability event. Importantly, just as it is very difficult to precisely identify the exact alteration(s) that permits “immortalized” growth of rare cells that have escaped crisis, it may prove difficult to pin down the exact mechanism(s) of suggested “transdifferentiation” phenomena. Indeed, two recent publications have shown that rare cell fusion events may be responsible for somatic cell plasticity phenomena [29Terada N. Hamazaki T. Oka M. et al.Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion.Nature. 2002; 416: 542Crossref PubMed Scopus (1765) Google Scholar, 31Ying Q.L. Nichols J. Evans E.P. Smith A.G. Changing potency by spontaneous fusion.Nature. 2002; 416: 545Crossref PubMed Scopus (1356) Google Scholar]. The lesson here is that the greater the selection pressure, or the harder one tries to identify alleged plasticity phenomena, the greater the probability that aberrant events will rise to the fore. It would seem that the possibility of cell fusion should complicate any interpretation of contribution to muscle fibers by nonmyogenic cells [32Galli R. Borello U. Gritti A. et al.Skeletal myogenic potential of human and mouse neural stem cells.Nat Neurosci. 2000; 3: 986Crossref PubMed Scopus (421) Google Scholar]. It is, after all, the business of myoblasts to fuse, and it is possible that nonmyoblastic cells could get caught up in the fusion process. It is also important to demonstrate that the cellular products of plasticity events are functionally integrated into their respective tissues. The functional reconstitution of a blood system is the endpoint readout for hematopoietic stem cells. Similarly, it is up to investigators who claim to show stem cell plasticity to demonstrate cell function. Merely demonstrating single or infrequent bone marrow (or other) cell–derived cells in a traditionally “inappropriate” tissue such as muscle or brain is not sufficient. One possible source of confusion is that most tissues contain resident macrophages, clearly derived from hematopoietic sources. One role of these cells is to ingest and eliminate debris from dying cells in various organs. It is certainly conceivable that a macrophage caught in the process of phagocytosis would contain histochemically detectable protein products derived from the ingested cell. The detection of such proteins in rare cells that also contain a donor marker must be viewed with extreme caution. Somatic stem cell systems such as those in the hair follicle, skin, and the gut epithelium have been fairly well characterized with respect to their geography [33Booth C. Potten C.S. Gut instincts thoughts on intestinal epithelial stem cells.J Clin Invest. 2000; 105: 1493Crossref PubMed Scopus (294) Google Scholar, 34Oshima H. Rochat A. Kedzia C. Kobayashi K. Barrandon Y. Morphogenesis and renewal of hair follicles from adult multipotent stem cells.Cell. 2001; 104: 233Abstract Full Text Full Text PDF PubMed Scopus (866) Google Scholar, 35Watt F.M. Stem cell fate and patterning in mammalian epidermis.Curr Opin Genet Dev. 2001; 11: 410Crossref PubMed Scopus (210) Google Scholar]. That is, the exact location of the stem cells and the geographical elaboration of their maturing progeny have been defined. From this point of view, it is difficult to assign biological significance to individual bone marrow–derived cells that are located at some position along the axis of an intestinal crypt. In a more general sense, often a conceptual gulf exists between the demonstration of individual cell products of suggested plasticity events and what is known about the clonogenic properties of stem and progenitor cell systems. Why do these cells not occur in groups or in clusters that would indicate progenitor cell–derived clones? Where exactly are the precursors of these mature cells? Are we to assume that plasticity phenomena can occur at the level of individual mature cells? The latter is not out of the question given the documented ability to reprogram relatively mature hematopoietic cell types [3Graf T. Differentiation plasticity of hematopoietic cells.Blood. 2002; 99: 3089Crossref PubMed Scopus (290) Google Scholar]. However, if this type of plasticity is the reason for the surprising observations, then it is certainly inaccurate to call it stem cell plasticity. This possibility has more than pedantic implications because in order to be clinically useful, plasticity phenomena must be documented at the level of highly clonogenic cells. Several studies have shown that somatic stem cells injected into early embryos can contribute to a variety of unexpected cell populations [9Clarke D.L. Johansson C.B. Wilbertz J. et al.Generalized potential of adult neural stem cells.Science. 2000; 288: 1660Crossref PubMed Scopus (917) Google Scholar, 36Clarke D. Frisen J. Differentiation potential of adult stem cells.Curr Opin Genet Dev. 2001; 11: 575Crossref PubMed Scopus (83) Google Scholar]. In principle, these results clearly show plasticity, especially when performed with cloned stem cell populations. In the interpretation of these studies the possibility of cell fusion (with cells from the inner cell mass, for example) must be kept in mind. In addition, one must recall that experiments from many years ago documented the ability of transformed teratocarcinoma cell lines to contribute to normal tissues of mice [37Mintz B. Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells.Proc Natl Acad Sci U S A. 1975; 72: 3585Crossref PubMed Scopus (901) Google Scholar]. These cells are tumorigenic and certainly abnormal. Therefore, the ability of somatic stem cells to contribute to embryos demonstrated in the recent studies cannot be taken as proof of normal differentiation potential. This must be kept in mind when considering possible clinical applications. So far, a convincing demonstration of somatic stem cell plasticity must meet at least two criteria. First, single stem cells must be shown to be capable of both the expected and unexpected differentiation. As stated above, this will require precise experiments with single prospectively isolated stem cells, or alternatively, the use of clonal marker techniques. Second, a robust ability to contribute to the expected and unexpected tissues must be demonstrated. This does not rule out the ability of single, more mature cells to transdifferentiate; however, it is difficult to ascribe this ability to actual somatic stem cells. The ultimate criteria to rigorously prove plasticity behavior of somatic stem cells should involve a direct demonstration of nuclear reprogramming from one stem cell fate to another. Intriguing studies have suggested that undifferentiated hematopoietic stem cells express a low level of gene products typically associated with their mature blood cell progeny [38Enver T. Greaves M. Loops, lineage, and leukemia.Cell. 1998; 94: 9Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 39Hu M. Krause D. Greaves M. et al.Multilineage gene expression precedes commitment in the hemopoietic system.Genes Dev. 1997; 11: 774Crossref PubMed Scopus (613) Google Scholar]. This has been described as the “ground state” of this type of stem cell. It would seem that the plastic interconversion of somatic stem cells to other stem cell fates should first involve a resetting of the appropriate “ground state.” The variety of technologies, reagents, and tools available in the postgenome era should certainly allow one to address this possibility. In short, the more remarkable the claim, the greater the need for extraordinary care in assembling and interpreting experimental data. An instructive example for an appropriate degree of such care is a recent publication that revisits the issue of whether terminally differentiated somatic cell nuclei can be reprogrammed to produce cloned mice [40Hochedlinger K. Jaenisch R. Monoclonal mice generated by nuclear transfer from mature B and T donor cells.Nature. 2002; 415: 1035Crossref PubMed Scopus (446) Google Scholar]. Although it had been tacitly assumed that this is the case, the low frequency of successful cloning attempts suggested that the actual nucleus leading to a cloned animal may, in fact, be derived from a less than fully differentiated somatic cell. In order to prove the point it was necessary to use nuclei with heritable markers of terminal differentiation, specifically nuclei obtained from B and T lymphocytes that contain signature DNA rearrangements in their antigen receptor loci. Assuming that all of the above criteria are met and somatic stem cells turn out to be remarkably plastic, this will only represent one half of the puzzle. As in all developmental systems, there are cell-autonomous and microenvironmental components in cell fate regulatory mechanisms [41Nishimura E.K. Jordan S.A. Oshima H. et al.Dominant role of the niche in melanocyte stem-cell fate determination.Nature. 2002; 416: 854Crossref PubMed Scopus (698) Google Scholar, 42Spradling A. Drummond-Barbosa D. Kai T. Stem cells find their niche.Nature. 2001; 414: 98Crossref PubMed Scopus (1212) Google Scholar, 43Watt F.M. Hogan B.L. Out of Eden stem cells and their niches.Science. 2000; 287: 1427Crossref PubMed Scopus (1470) Google Scholar]. As such, the most relevant way to view a stem cell is as a biological activity, rather than a discrete, independently existing cellular entity. Therefore, it will not only be necessary to measure molecular, plasticity-associated changes in the stem cells, but also to define the instructive, microenvironmental mechanisms that signal or facilitate their plastic behavior. In fact, all reports of stem cell plasticity at least implicitly require that a given stem cell assume a fate consistent with its tissue location. Unfortunately, the cellular and molecular definition of stem cell microenvironments has lagged behind similar analyses in the actual stem cells. Clearly, more effort in defining stem cell microenvironments or niches is called for. To conclude, I do not wish to leave the reader with a negative impression of my views on the possibility of somatic stem cell plasticity. Taken together, all studies that suggest such plastic behavior persuasively argue that there is something to this phenomenon. I am not a betting individual; however, if pressed, I would predict that at least some degree of unexpected plasticity will be rigorously established in the near future. I question, however, whether such plasticity should warrant alterations to traditional paradigms and dogmas in any fundamentally biological manner. For example, if the differentiation of hematopoietic stem cells to endothelial tissue had been documented years ago, then such differentiation would now be considered part of that stem cell's developmental repertoire. On the other hand, a rigorous demonstration of inter–germ layer plasticity would call for possible revisions to our typically unidirectional views of ontogenic specification. The first step that is necessary, before anything of fundamental importance can be derived from speculation, is a return to the rigorous experimental criteria set forth in the early experiments that first defined the concept of the stem cell. These and many subsequent studies have provided paradigms that are sufficient for our current explorations of stem cell biology. Interpreting and understanding many of the recent exciting observations within such a well-established contextual framework will surely lead to valuable insights." @default.
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• W2034325891 title "A few thoughts about the plasticity of stem cells" @default.
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