Review Article

Medical Progress

Prometheus's Vulture and the Stem-Cell Promise

Nadia Rosenthal, Ph.D.

N Engl J Med 2003; 349:267-274July 17, 2003

Article

When Prometheus transgressed the law of the ancient gods and stole fire for humankind, to teach them civilization and the arts, his punishment was typically brutal. Jupiter had the great Titan chained to the side of Mount Caucasus, where a vulture preyed daily on his liver, which was renewed as quickly as it was devoured.

We mere mortals do not possess livers with quite so vigorous a regenerative capacity, but the legend captures well the remarkable potential of the body to rebuild itself. Throughout our lives we sustain less gruesome injuries from which we recover spontaneously, often without realizing we were hurt. Wound healing involves the recruitment and proliferation of cells capable of restoring tissues and even organs to their original form and function. These cells must retain a collective memory of the complex developmental process by which the tissue was first constructed. Fortunately for Prometheus, whose name means forethought, his liver was well prepared for its daily renewal, since it is one of the most highly regenerative organs of the human body.

What determines the healing potential of an injured tissue? If Prometheus's vulture had chosen a different organ on which to dine — the heart, for instance — the hero might not have survived his ordeal. Until recently, it was presumed that aboriginal populations of undifferentiated, self-renewing progenitor cells contributed exclusively to the regeneration of the organ in which they resided. This restriction of progenitor-cell activity neatly explained why some organs could not regenerate as well as others: they simply did not maintain a sufficiently robust population of progenitor cells.

This concept of organ-specific regeneration has been challenged by discoveries that multipotent cells can be isolated from many tissues of the body, even from some, such as the nervous system, that have historically been considered incapable of regeneration. Loosely referred to as stem cells, these cells in the adult body resemble pluripotent cell populations derived from the early embryo, which can contribute to virtually any type of tissue under appropriate experimental conditions. In the past two decades, embryonic stem cells have been the focus of intense study. It is important to note that embryonic stem cells originate from undetermined early embryos, with no possible history of differentiation, whereas the provenance of adult stem cells found in mature tissues is far less well understood. Nevertheless, our imaginations have been captivated by the possibility that our bodies have retained a population of reserve stem cells, perhaps set aside during gestation, that might be coerced into renewed regenerative service later in life. And if we cannot become Titans using our own stem-cell resources, perhaps we can resist the onslaught of time's vulture by transplanting pluripotent cells derived from early embryos to supplement our own waning supplies of stem cells.

Embryonic Stem Cells Explained

The flurry of recent studies touting the near-miraculous properties of stem cells underscores the need for more rigorous definitions. A true stem cell must satisfy several operational criteria. First, it must be clonogenic, capable of unlimited self-renewal by symmetric division. Second, it must be able to divide asymmetrically, one daughter resembling its mother, the other daughter giving rise to multiple types of differentiated cells representing all three primitive embryonic germ layers (the ectoderm, mesoderm, and endoderm). Third, it must originate from an embryonic or adult stem-cell source. Thus, stem-cell reservoirs in the hematopoietic compartment can contribute to other tissue lineages, such as the pancreas or liver.1,2

A culture of embryonic stem cells derived from the inner cell mass, or embryoblast, of an embryonic blastocyst satisfies all three criteria (Figure 1Figure 1The Origin and Pluripotency of Embryonic Stem Cells.). These differentiated derivatives of embryonic stem cells must retain a normal chromosomal complement and must maintain their functional properties when placed in vivo. Candidate embryonic stem cells can be tested in mice by using markers on embryonic stem cells used to form chimeric embryos and determining the contribution of these identifiable cells to the different types of tissue in the resulting mouse pups.3,4 In another test, embryonic stem cells are injected into immunodeficient mice to produce teratomas, which are themselves pluripotent in cell culture and which contain differentiated derivatives of all three germ layers if left in the host.5 A third approach, only successfully achieved with mouse, primate, and human embryonic stem cells, involves inducing the cells to differentiate in culture to form embryoid bodies containing multiple types of cells.6-8

One of the complex technical issues surrounding the isolation and propagation of embryonic stem cells in vitro is the identification of the proper culture conditions, which can keep the cells in an undifferentiated state or induce their differentiation into a particular type of cell. In addition to soluble factors, plastic surfaces can affect cell morphology, cell density can influence interactions between cells, and the transfection of differentiation-inducing genes can help guide the pluripotent embryonic stem cell to a specific cell fate. This process is more an art than a science, and current studies rarely satisfy both of the operational criteria for embryonic stem cells. Yet with the use of these techniques, single mouse precursor cells cultured from the inner cell mass have been induced to generate multiple types of cells, including vascular,9 neuronal,10 and pancreatic11 precursors and even haploid oocytes.12

A parallel set of studies has focused on human embryonic germ cells, isolated from the fetal gonadal ridge of 8-to-10-week-old embryos.13 Like embryonic stem cells, embryonic germ cells are highly proliferative, and when differentiated in culture, they express multiple differentiation-specific markers. Although to date embryonic germ cells have been shown to be viable for only 70 to 80 passages in culture, a potential advantage is that they do not form teratomas when injected into mice, and they may therefore represent a safer source of transplantable tissue.

Although similar studies involving human cells date only from 1998, when human embryonic stem cells were first successfully propagated,8,13 this milestone relied heavily on the gradual progress made in the previous 20 years,14,15 when mouse and primate embryonic stem cells were also being extensively characterized.16 Generating cultures of embryonic stem cells from early human embryos that were not used for in vitro fertilization procedures required certain adjustments, such as delaying the dissociation of the embryo until five days after conception, a time when normal human implantation would occur. The requirement for mouse feeder-cell layers in cultures of human embryonic stem cells was only recently overcome.17 Nevertheless, the past five years have witnessed an exponential increase in experiments aimed at generating human tissues for transplantation, such as pancreatic endocrine cells, skeletal myocytes, and neurons. In a recent test of the therapeutic potential of embryonic stem cells,18 dopamine-producing neurons were derived from embryonic stem cells expressing a transgenic neuronal determinant, and they established appropriate electrophysiologic connections when they were injected into the brains of rats with symptoms of Parkinson's disease. Remarkably, motor function was improved, with no associated tumor formation, removing yet another stumbling block to therapies based on embryonic stem cells.

Although human embryonic stem cells are as pluripotent in vitro as those isolated directly from embryos19-22 it is obviously not possible to test them as rigorously as animal models, since reimplantation into a human embryo is not ethical. In addition, cultures of embryonic stem cells may include rare “cancer” stem cells, which may then proliferate.23 Many other uncertainties remain. First, mammalian embryonic stem cells derive from the inner cell mass of the preimplantation embryo, yet it is not known whether these cells, if left in place, would go on to exhibit the features they display in culture. Second, since most of our knowledge comes from experiments in mice, we cannot be sure that human stem cells possess the same potential. Third, human embryonic stem cells, like mouse embryonic stem cells, appear capable of unlimited proliferation in vitro, but it is still a matter of debate whether prolonged culturing affects their pluripotency.

Adult Stem Cells Unbound

The astonishing capacity of embryonic stem cells to give rise to virtually any type of tissue has intensified the search for similar cell lineages in the adult that may contribute to self-renewal. Rigorous criteria are required to distinguish a stem cell in the adult milieu from partially committed precursor cells that have more limited potential. Like embryonic stem cells, adult stem cells must be clonogenic and self-renewing during the lifetime of an organism through asymmetric division, with one daughter cell remaining multipotent to maintain a stem-cell lineage and the other daughter cell free to mature into a specialized type of cell with typical morphology and function. The task facing the committed daughter cell is daunting: it must take up residence in the right place, attain the necessary shape, set up the correct contacts, and perform the necessary functions for multiple adult tissues, behaving appropriately in a variety of different cellular environments. The criteria for defining stem cells in the adult are still difficult to satisfy experimentally. There is no predictable location for stem cells in most adult tissues, and we still possess only limited tools for identifying them.

Searches for adult stem cells have relied on information derived primarily from studies of stem cells in the bone marrow, which must renew themselves daily to maintain the body's blood supply. In mouse bone marrow, stem cells are as rare as 1 in 10,000 cells, and they may be even less common in humans, yet they proliferate constantly to replace circulating blood cells that die.24 They give rise to intermediate precursor- or progenitor-cell populations that partially differentiate and commit to various blood-cell lineages. Stem-cell–containing populations can be highly purified as a side population by means of fluorometric cytometry.25 Hematopoietic stem cells have additional characteristic morphologic appearances and cell-surface markers26-28 that allow them to be labeled and tracked in the bloodstream and target tissues or to be isolated and cultured in vitro.

An understanding of the plasticity of adult stem cells initially grew from observations that donor cells were found in nonhematopoietic tissues in the recipients of bone marrow transplants. Accounts of the repopulation of adult organs by stem cells derived from bone marrow have since flooded the literature, suggesting that under the right conditions, these rare cells can contribute to virtually any type of tissue. As proof of principle, a lone hematopoietic stem cell, genetically marked and mixed with unmarked bone marrow, was injected into a mouse that had received a lethal dose of radiation. Several weeks later, the marked descendants of that stem cell were found in multiple tissues, attesting to the plasticity of bone marrow precursors.29

These dramatic reports of the versatility of stem cells must be tempered with a note of caution. A separate analysis involving the use of a single marked cell to reconstitute lethally irradiated mouse bone marrow failed to detect appreciable numbers of descendants of the stem cell in non-hematopoietic tissues.30 Two other studies31,32 challenged the intrinsic plasticity of tissue stem cells on the basis of the observation that the spontaneous fusion of embryonic stem cells with cocultured brain cells resulted in tetraploid hybrids that retained full pluripotency, including their multilineage contribution to chimeras when they were injected into mouse blastocysts. More recently, two reports have verified that cell fusion is the most prevalent source of bone marrow–derived hepatocytes.33,34 These findings offer an alternative explanation for the presumed transdifferentiation of hematopoietic stem cells in new environments, but they also carry the broader, more interesting implication that fusion may be just another facet of stem-cell biology.

Stromal cells from adult bone marrow are a richer, if less well characterized, source of stem cells that can be induced to undergo differentiation in a variety of adult tissues.35 These cells may be identical to mesenchymal stem cells.36 The ready proliferation of cultured mesenchymal stem cells makes them attractive candidates for therapy.37 In one instance, purified mesenchymal stem cells from adult human bone marrow engrafted into the heart of an immunodeficient mouse persisted in the myocardium, taking on the characteristics of cardiomyocytes.38 Mesenchymal stem cells are likely to be a heterogeneous population, in which only a percentage of cells maintain true pluripotency. With the use of appropriate conditions, it may be possible to culture this subpopulation. This point was recently evidenced by the isolation of unusually versatile multipotent adult progenitor cells derived from culturing rat, mouse, and human bone marrow, which readily differentiated into multiple types of cell in culture.39 When reintroduced into mouse blastocysts, multipotent adult progenitor cells could contribute all three embryonic germ layers and appeared as blood and epithelia when they were injected intravenously into adult mice, providing new promise for the therapeutic use of adult stem cells.

One uncontested concept emerging from the flurry of recent articles is that injury is a prerequisite for circulating-cell participation in differentiated tissue structure and function. Although the reported low frequencies at which adult stem cells repopulate injured tissues preclude their use in the regeneration of whole organs, small numbers of stem cells may be all that is necessary to induce endogenous regenerative programs. Mice or rats with experimentally induced myocardial infarcts had surprising recoveries after bone-marrow–derived stem cells were administered either directly into the heart40 or through the circulation.41 Although in both studies the number of foreign stem cells lodged in the injured myocardium was far too low to replace necrotic tissues, the cells were more concentrated in the infarcted area than elsewhere in the heart, suggesting that stem-cell repopulation of certain tissues may actually be triggered by injury. Increasing evidence suggests that stem cells, like metastatic tumor cells, use common chemoattractive mechanisms to home to damaged tissues (Figure 2Figure 2The Chemoattractive Hypothesis of Stem-Cell Homing.).42 Furthermore, one of the studies reported the induction of neovascularization of surrounding host tissues in the border zone,41 which presumably contributed to the improvement in recovery. If stem cells can home to sites of injury and promote healing in damaged tissues, we may not need as many of them as we think.

One Stem Cell Fixes All?

The remarkable plasticity and pluripotency of bone marrow cells raise the exciting possibility of a universal stem cell that can roam throughout the body, taking up residence wherever it is needed to promote regeneration. Recent evidence suggests that the plasticity of stem cells residing locally in adult tissues may be similar to that of bone marrow cells.43,44 The option of using a nonhematopoietic stem cell for clinical applications would be particularly relevant in the treatment of circulating tumors, since such cells could provide a source of healthy autologous cells to repopulate irradiated bone marrow (Table 1Table 1Potential Plasticity of Stem Cells.).

The pluripotency of adult stem cells from nonhematopoietic sources has been demonstrated most convincingly by studies in which cells extracted from various adult tissues were transplanted into irradiated animals and took up residence in the bone marrow, reconstituting the entire hematopoietic system. Even tissues that have historically been considered terminally differentiated, with low potential for regeneration, contain enough stem cells to qualify. Stem cells harvested from the central nervous system have now been coaxed to reconstitute bone marrow46 or skeletal muscle47 in adult animals. These results lend further support to the concept of the plasticity of neural cells, which was previously suggested by studies demonstrating increased neurogenesis in the adult brain after injury. Although contradictory reports question how frequent a phenomenon neural stem-cell repopulation might be,48 differing protocols may be responsible for the variable rates of success in demonstrating engraftment and differentiation of these progenitors.49

Stem cells isolated from skeletal muscle were also capable of repopulating the bone marrow after transplantation into hosts that had received lethal doses of irradiation.26,50 It is not yet known whether these cells are the progenitors of muscle satellite cells, a population of precursor cells capable of regenerating muscle and demonstrating self-renewal but presumably committed to the myogenic lineage. It is equally probable that the regenerative potential of the tissues in these studies derived from circulating hematopoietic stem cells, as suggested by a recent report documenting the hematopoietic origin of muscle-derived stem cells.28 Further studies are needed to determine whether heterogeneous populations of stem cells emanating from the bone marrow and lodging in peripheral postmitotic tissues may constitute the true developmental origin of most peripheral stem cells.51

Ultimately, a naturally rejuvenating tissue such as the skin would be a more likely source of stem cells. In an initial test of this possibility, genetically marked skin-derived stem cells were obtained from neonatal mice and introduced into early mouse embryos, where their descendants integrated into multiple cell lineages and could later be found in various tissues of the adult progeny.52 It remains to be seen whether the demonstrated plasticity of epidermal stem cells would be maintained beyond the permissive environment of the early embryo, but if they are truly pluripotent, the skin could provide a readily accessible source of stem cells for use in the clinic.

These examples highlight the necessity for a more extensive battery of markers for stem cells of different origins to confirm their provenance. In general, the process of documenting that a stem cell from one tissue generates differentiated types of cells in another must be particularly rigorous, in order to rule out the possible contribution of cell fusion or of circulating hematopoietic stem cells. However, research to date suggests that stem-cell populations in adult mammals are not fixed entities and that after exposure to a new cellular environment, they may be able to contribute to the regeneration of multiple types of tissue.

Although the accumulating experimental evidence of the plasticity of adult stem cells is ever more convincing, there are several hurdles to overcome. The origin of stem cells in the bone marrow is well established, but the location of stem cells in other tissues remains elusive. What are the sources of these cells? Has the body had enough forethought to set aside pluripotent stem cells from its early moments as an embryo? If not, how do adult stem cells arise in nonhematopoietic tissues, and how do they remain in suspended animation until repair is necessary? Do they need a stimulus, such as traumatic injury, to expand the population for repair of the injured tissue? If adult stem cells are truly pluripotent, why is the response to injury to tissues such as the heart or spinal cord so inefficient under normal circumstances? Do adult stem cells carry surface markers that would make them immunogenic in a foreign host, making embryonic stem cells better tolerated in the recipient? These questions may seem academic, but the future of adult stem-cell–mediated therapies depends on their resolution.

The Promethean Promise Pending

The prospect of improved regeneration is not the only promise held out by stem-cell research. Critical studies of the unique aspects of early human development are now within reach with the use of embryonic stem cells (Figure 3Figure 3The Use of Human Embryonic Stem-Cell Cultures for Basic Research.). The origin and mechanistic basis of chromosomal abnormalities underlying many congenital defects can be elucidated, and the early childhood tumors resulting from these mutations could be analyzed in the culture dish. Embryonic stem cells also provide a potential source of material for the preclinical testing of candidate therapeutic drugs in multiple types of human tissue. And given the promising preclinical evidence,17 therapeutic trials of embryonic stem cells in neurodegenerative disease are probably imminent. The specter of human genetic engineering should not preclude the exploration of therapeutic applications once our understanding of these extraordinary cells is broadened.

Even if results in animals are cleared by ethical committees for study in humans, formidable obstacles need to be overcome before the therapeutic utility of embryonic stem cells is tested in the clinic. To demonstrate the safety of embryonic stem cells, researchers need to rule out any chance that the administration of embryonic stem cells could cause tumor formation or the transmission of infectious agents. This may require screening cells for neoplastic potential or for signs of viral infection or delivering cells that have already been differentiated into the desired type of tissue. To be effective, cells derived from embryonic stem cells must integrate into host tissue in sufficient numbers and, once engrafted, take over or at least induce appropriate physiological functions. In a dramatic proof of principle, a genetic defect in the mouse hematopoietic system was successfully treated through the engraftment of genetically corrected autologous embryonic stem cells.53 Preventing immunorejection under these circumstances in humans may require the use of immunosuppression unless the cultured cells are placed in an immunoprivileged tissue such as the brain or are genetically engineered to be tolerated by the host tissues.

Despite these caveats, the prospect of harnessing the prodigious powers of embryonic stem cells for clinical applications has impelled scientists to pursue the isolation of specific lineages derived from embryonic stem cells. Experimental schemes are being developed that will select for a particular characteristic in a culture of embryonic stem cells by exposure to specific mixtures of growth factors, by screening homogeneous populations of embryonic stem cells for certain surface markers, or by genetically engineering embryonic stem cells to generate differentiated phenotypes. We still do not have sufficient information to identify the stages of differentiation of embryonic stem cells that are optimal for transplantation or to ensure the survival and function of transplanted human embryonic stem cells as an integral part of the host tissue. Sorting through all these variables will require further research, and such research can only be carried out if the basic material is available for study. Once we gain a more complete understanding of the prodigious capacity of embryonic stem cells for self-renewal, we may then be able to apply this information to the manipulation of adult stem cells.

Perhaps the biggest hurdle to the clinical application of research on adult stem cells is the small number of cells that can be isolated from any adult tissue. The recent successful propagation of a multipotent adult stem cell39 and the development of cytokine “cocktails” for optimizing the proliferation of adult stem cells54 suggest that expansion in culture may be the answer. Yet it is still possible that extensive culture of human adult stem cells ex vivo may subtly change their intrinsic properties, rendering them unfit for restoring injured or diseased tissues in patients.

The Promethean promise notwithstanding, the low level of repopulation of exogenous stem cells in injured tissues argues against the possibility that this approach can be used to rebuild entire organs. Other mechanisms at work in the natural process of regeneration may be more successfully harnessed to increase the efficiency of stem-cell–mediated regeneration. A lesson might be learned from the behavior of metastatic tumor cells, which, once dissociated from the primary neoplasm, roam the body much like a stem cell, drawn to their selective target organs through specific chemoattractive mechanisms. Remarkably, many of the surface chemoreceptors expressed by tumor cells are also found on stem cells,55,56 and it is tempting to speculate that metastasis is the dark side of regeneration, with tumor cells coopting similar guidance pathways for more nefarious purposes. If this is the case, specific chemoattractants might be identified and protocols might be developed to enhance the migration of healing stem cells into the lesions of specific types of tissue. Another avenue to be explored is the potential paracrine action in stem-cell–mediated regeneration. If this proves to be a general principle, stem cells might be engineered to express increased levels of these paracrine factors, acting as a targeted, readily administered system of delivery for therapeutic molecules.

In the process of pursuing the elusive stem cell and its promise of universal healing, we stand to gain important insight into the nature of human life itself. Along with our obvious advances, we have evolved into a species with remarkably restricted regenerative capacity. Our bodies have long lost the forethought of indefinite growth possessed by the sequoia or the carp. Unlike starfish or newts, we can no longer replace lost limbs. And as we grow older, our own aging populations of stem cells cannot keep up with our failing bodies. We have paid a heavy price for our high vantage point on the evolutionary tree. It remains to be seen whether a growing understanding of our own phylogenetic limitations will be sufficiently profound to overcome them. The Promethean prospect of eternal regeneration awaits us, while time's vulture looks on.

Source Information

From the European Molecular Biology Laboratory Mouse Biology Programme, Rome.

Address reprint requests to Dr. Rosenthal at Mouse Biology Programme, the European Molecular Biology Laboratory, Via Ramarini 32, 00016 Monterotondo, (Rome), Italy, or at rosenthal@embl-monterotondo.it.

References

References

1. 1

   Grompe M. Pancreatic-hepatic switches in vivo. Mech Dev 2003;120:99-106
   CrossRef | Web of Science | Medline

2. 2

   Austin TW, Lagasse E. Hepatic regeneration from hematopoietic stem cells. Mech Dev 2003;120:131-135
   CrossRef | Web of Science | Medline

3. 3

   Nagy A, Gocza E, Diaz EM, et al. Embryonic stem cells alone are able to support fetal development in the mouse. Development 1990;110:815-821
   Web of Science | Medline

4. 4

   Nagy A, Rossant J, Nagy R, Abramow-Newerly W, Roder JC. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A 1993;90:8424-8428
   CrossRef | Web of Science | Medline

5. 5

   Smith AG. Embryo-derived stem cells: of mice and men. Annu Rev Cell Dev Biol 2001;17:435-462
   CrossRef | Web of Science | Medline

6. 6

   Thomson JA, Kalishman J, Golos TG, et al. Isolation of a primate embryonic stem cell line. Proc Natl Acad Sci U S A 1995;92:7844-7848
   CrossRef | Web of Science | Medline

7. 7

   Nishikawa SI, Nishikawa S, Hirashima M, Matsuyoshi N, Kodama H. Progressive lineage analysis by cell sorting and culture identifies FLK1+VE-cadherin+ cells at a diverging point of endothelial and hemopoietic lineages. Development 1998;125:1747-1757
   Web of Science | Medline

8. 8

   Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145-1147[Erratum, Science 1998;282:1827.]
   CrossRef | Web of Science | Medline

9. 9

   Yamashita J, Itoh H, Hirashima M, et al. Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors. Nature 2000;408:92-96
   CrossRef | Web of Science | Medline

10. 10

    Lee SH, Lumelsky N, Studer L, Auerbach JM, McKay RD. Efficient generation of midbrain and hindbrain neurons from mouse embryonic stem cells. Nat Biotechnol 2000;18:675-679
    CrossRef | Web of Science | Medline

11. 11

    Lumelsky N, Blondel O, Laeng P, Velasco I, Ravin R, McKay R. Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets. Science 2001;292:1389-1394[Erratum, Science 2001;293:428.]
    CrossRef | Web of Science | Medline

12. 12

    Hubner K, Fuhrmann G, Christenson LK, et al. Derivation of oocytes from mouse embryonic stem cells. Science 2003;300:1251-1256
    CrossRef | Web of Science | Medline

13. 13

    Shamblott MJ, Axelman J, Littlefield JW, et al. Human embryonic germ cell derivatives express a broad range of developmentally distinct markers and proliferate extensively in vitro. Proc Natl Acad Sci U S A 2001;98:113-118
    CrossRef | Web of Science | Medline

14. 14

    Thompson S, Stem PL, Webb M, et al. Cloned human teratoma cells differentiate into neuron-like cells and other cell types in retinoic acid. J Cell Sci 1984;72:37-64
    Web of Science | Medline

15. 15

    Bongso A, Fong CY, Ng SC, Ratnam S. Isolation and culture of inner cell mass cells from human blastocysts. Hum Reprod 1994;9:2110-2117
    Web of Science | Medline

16. 16

    Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature 1981;292:154-156
    CrossRef | Web of Science | Medline

17. 17

    Xu C, Inokuma MS, Denham J, et al. Feeder-free growth of undifferentiated human embryonic stem cells. Nat Biotechnol 2001;19:971-974
    CrossRef | Web of Science | Medline

18. 18

    Kim JH, Auerbach JM, Rodriguez-Gomez JA, et al. Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 2002;418:50-56
    CrossRef | Web of Science | Medline

19. 19

    Amit M, Carpenter MK, Inokuma MS, et al. Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol 2000;227:271-278
    CrossRef | Web of Science | Medline

20. 20

    Itskovitz-Eldor J, Schuldiner M, Karsenti D, et al. Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers. Mol Med 2000;6:88-95
    Web of Science | Medline

21. 21

    Schuldiner M, Yanuka O, Itskovitz-Eldor J, Melton DA, Benvenisty N. Effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 2000;97:11307-11312
    CrossRef | Web of Science | Medline

22. 22

    Reubinoff BE, Itsykson P, Turetsky T, et al. Neural progenitors from human embryonic stem cells. Nat Biotechnol 2001;19:1134-1140
    CrossRef | Web of Science | Medline

23. 23

    Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001;414:105-111
    CrossRef | Web of Science | Medline

24. 24

    Weissman IL. Stem cells: units of development, units of regeneration, and units in evolution. Cell 2000;100:157-168
    CrossRef | Web of Science | Medline

25. 25

    Goodell MA, Rosenzweig M, Kim H, et al. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med 1997;3:1337-1345
    CrossRef | Web of Science | Medline

26. 26

    Jackson KA, Mi T, Goodell MA. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci U S A 1999;96:14482-14486
    CrossRef | Web of Science | Medline

27. 27

    Lagasse E, Connors H, Al-Dhalimy M, et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000;6:1229-1234
    CrossRef | Web of Science | Medline

28. 28

    McKinney-Freeman SL, Jackson KA, Camargo FD, Ferrari G, Mavilio F, Goodell MA. Muscle-derived hematopoietic stem cells are hematopoietic in origin. Proc Natl Acad Sci U S A 2002;99:1341-1346
    CrossRef | Web of Science | Medline

29. 29

    Krause DS, Theise ND, Collector MI, et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001;105:369-377
    CrossRef | Web of Science | Medline

30. 30

    Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002;297:2256-2259
    CrossRef | Web of Science | Medline

31. 31

    Ying QL, Nichols J, Evans EP, Smith AG. Changing potency by spontaneous fusion. Nature 2002;416:545-548
    CrossRef | Web of Science | Medline

32. 32

    Wang X, Willenbring H, Akkari Y, et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003;422:897-901
    CrossRef | Web of Science | Medline

33. 33

    Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422:901-904
    CrossRef | Web of Science | Medline

34. 34

    Terada N, Hamazaki T, Oka M, et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002;416:542-545
    CrossRef | Web of Science | Medline

35. 35

    Bianco P, Riminucci M, Gronthos S, Robey PG. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 2001;19:180-192
    CrossRef | Web of Science | Medline

36. 36

    Pittenger MF, Mosca JD, McIntosh KR. Human mesenchymal stem cells: progenitor cells for cartilage, bone, fat and stroma. Curr Top Microbiol Immunol 2000;251:3-11
    CrossRef | Web of Science | Medline

37. 37

    Caplan AI, Bruder SP. Mesenchymal stem cells: building blocks for molecular medicine in the 21st century. Trends Mol Med 2001;7:259-264
    CrossRef | Web of Science | Medline

38. 38

    Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 2002;105:93-98
    CrossRef | Web of Science | Medline

39. 39

    Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41-49
    CrossRef | Web of Science | Medline

40. 40

    Orlic D, Kajstura J, Chimenti S, et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001;410:701-705
    CrossRef | Web of Science | Medline

41. 41

    Kocher AA, Schuster MD, Szabolcs MJ, et al. Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001;7:430-436
    CrossRef | Web of Science | Medline

42. 42

    Orlic 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;98:10344-10349
    CrossRef | Web of Science | Medline

43. 43

    Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function? Cell 2001;105:829-841
    CrossRef | Web of Science | Medline

44. 44

    Kuehnle I, Goodell MA. The therapeutic potential of stem cells from adults. BMJ 2002;325:372-376
    CrossRef | Web of Science | Medline

45. 45

    Tsonis PA. Regenerative biology: the emerging field of tissue repair and restoration. Differentiation 2002;70:397-409
    CrossRef | Web of Science | Medline

46. 46

    Bjornson CR, Rietze RL, Reynolds BA, Magli MC, Vescovi AL. Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science 1999;283:534-537
    CrossRef | Web of Science | Medline

47. 47

    Galli R, Borello U, Gritti A, et al. Skeletal myogenic potential of human and mouse neural stem cells. Nat Neurosci 2000;3:986-991
    CrossRef | Web of Science | Medline

48. 48

    Morshead CM, Benveniste P, Iscove NN, 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;8:268-273
    CrossRef | Web of Science | Medline

49. 49

    Theise ND, Krause DS, Sharkis S. Comment on “Little Evidence for Developmental Plasticity of Adult Hematopoietic Stem Cells.“ Science 2003;299:1317-1317
    CrossRef | Web of Science | Medline

50. 50

    Gussoni E, Soneoka Y, Strickland CD, et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 1999;401:390-394
    Web of Science | Medline

51. 51

    Orkin SH, Zon LI. Hematopoiesis and stem cells: plasticity versus developmental heterogeneity. Nat Immunol 2002;3:323-328
    CrossRef | Web of Science | Medline

52. 52

    Liang L, Bickenbach JR. Somatic epidermal stem cells can produce multiple cell lineages during development. Stem Cells 2002;20:21-31
    CrossRef | Web of Science | Medline

53. 53

    Rideout WM III, Hochedlinger K, Kyba M, Daley GQ, Jaenisch R. Correction of a genetic defect by nuclear transplantation and combined cell and gene therapy. Cell 2002;109:17-27
    CrossRef | Web of Science | Medline

54. 54

    Deasy BM, Qu-Peterson Z, Greenberger JS, Huard J. Mechanisms of muscle stem cell expansion with cytokines. Stem Cells 2002;20:50-60
    CrossRef | Web of Science | Medline

55. 55

    Kollet O, Spiegel A, Peled A, et al. Rapid and efficient homing of human CD34(+) CD38(-/low)CXCR4(+) stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2m(null) mice. Blood 2001;97:3283-3291
    CrossRef | Web of Science | Medline

56. 56

    Shen H, Cheng T, Olszak I, et al. CXCR-4 desensitization is associated with tissue localization of hemopoietic progenitor cells. J Immunol 2001;166:5027-5033
    Web of Science | Medline

Citing Articles (62)

Citing Articles

1. 1

   Yoichi Yamada, Sayaka Nakamura, Minoru Ueda, Kenji Ito. (2011) Osteotome technique with injectable tissue-engineered bone and simultaneous implant placement by cell therapy. Clinical Oral Implants Researchn/a-n/a
   CrossRef

2. 2

   Esmat Elhami, Andrew L. Goertzen, Bo Xiang, Jixian Deng, Chris Stillwell, Shadreck Mzengeza, Rakesh C. Arora, Darren Freed, Ganghong Tian. (2011) Viability and proliferation potential of adipose-derived stem cells following labeling with a positron-emitting radiotracer. European Journal of Nuclear Medicine and Molecular Imaging 38:7, 1323-1334
   CrossRef

3. 3

   Gaetano Romano. 2011. Recent Advances in the Field of Stem Cell Research: Toward the Definition of the Epigenetic and Genetic Codes of Pluripotency. , 299-313.
   CrossRef

4. 4

   Sun-Ouck Kim, Hee Sam Na, Dongdeuk Kwon, Soo Yeon Joo, Hyung Suck Kim, Youngkeun Ahn. (2011) Bone-Marrow-Derived Mesenchymal Stem Cell Transplantation Enhances Closing Pressure and Leak Point Pressure in a Female Urinary Incontinence Rat Model. Urologia Internationalis 86:1, 110-116
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5. 5

   Lucia Formigli, Susanna Benvenuti, Raffaella Mercatelli, Franco Quercioli, Alessia Tani, Carlo Mirabella, Aida Dama, Riccardo Saccardi, Benedetta Mazzanti, Ilaria Cellai, Sandra Zecchi-Orlandini. (2011) Dermal matrix scaffold engineered with adult mesenchymal stem cells and platelet-rich plasma as a potential tool for tissue repair and regeneration. Journal of Tissue Engineering and Regenerative Medicinen/a-n/a
   CrossRef

6. 6

   Anca Chiriac, Andre Terzic, Sungjo Park, Yasuhiro Ikeda, Randolph Faustino, Timothy J. Nelson. (2010) SDF-1-Enhanced Cardiogenesis Requires CXCR4 Induction in Pluripotent Stem Cells. Journal of Cardiovascular Translational Research 3:6, 674-682
   CrossRef

7. 7

   Elizabeth N. Kuhn, Sean M. Wu. (2010) Origin of cardiac progenitor cells in the developing and postnatal heart. Journal of Cellular Physiology 225:2, 321-325
   CrossRef

8. 8

   E. Polykandriotis, L. M. Popescu, R. E. Horch. (2010) Regenerative medicine: then and now - an update of recent history into future possibilities. Journal of Cellular and Molecular Medicine 14:10, 2350-2358
   CrossRef

9. 9

   Christopher J. Pino, H. David Humes. (2010) Stem cell technology for the treatment of acute and chronic renal failure. Translational Research 156:3, 161-168
   CrossRef

10. 10

    Dina G. Tiniakos, Apostolos Kandilis, Stephen A. Geller. (2010) Tityus: A forgotten myth of liver regeneration. Journal of Hepatology 53:2, 357-361
    CrossRef

11. 11

    K. D. DEB. 2010. Stem cells for organ regeneration. , 147-176.
    CrossRef

12. 12

    Nicol Siegel, Alessandro Valli, Christiane Fuchs, Margit Rosner, Markus Hengstschläger. (2009) Induction of mesenchymal/epithelial marker expression in human amniotic fluid stem cells. Reproductive BioMedicine Online 19:6, 838-846
    CrossRef

13. 13

    Zhaohua Qiu, Shannon W. Longshore, Brad W. Warner, David A. Rudnick. (2009) Murine Functional Liver Mass is Reduced Following Partial Small Bowel Resection. Journal of Gastrointestinal Surgery 13:12, 2176-2182
    CrossRef

14. 14

    Massimo F Piepoli. (2009) Transplantation of progenitor cells and regeneration of damaged myocardium: more facts or doubts? Insights from experimental and clinical studies. Journal of Cardiovascular Medicine 10:8, 624-634
    CrossRef

15. 15

    Timothy J. Nelson, Atta Behfar, Satsuki Yamada, Almudena Martinez-Fernandez, Andre Terzic. (2009) Stem Cell Platforms for Regenerative Medicine. Clinical and Translational Science 2:3, 222-227
    CrossRef

16. 16

    Cristianne Silva Alexandre, Rildo Aparecido Volpini, Maria Heloísa Shimizu, Talita Rojas Sanches, Patricia Semedo, Vera Lúcia di Jura, Niels Olsen Câmara, Antonio Carlos Seguro, Lúcia Andrade. (2009) Lineage-Negative Bone Marrow Cells Protect Against Chronic Renal Failure. Stem Cells 27:3, 682-692
    CrossRef

17. 17

    Lei Wang, Jixian Deng, Jian Wang, Bo Xiang, Tonghua Yang, Marco Gruwel, Tarek Kashour, Boguslaw Tomanek, Randy Summer, Darren Freed, Davinder S. Jassal, Guangping Dai, Miriam Glogowski, Roxanne Deslauriers, Rakesh C. Arora, Ganghong Tian. (2009) Superparamagnetic iron oxide does not affect the viability and function of adipose-derived stem cells, and superparamagnetic iron oxide–enhanced magnetic resonance imaging identifies viable cells. Magnetic Resonance Imaging 27:1, 108-119
    CrossRef

18. 18

    Brent R. DeGeorge, Jr., Marc Rosenberg, Volker Eckstein, Erhe Gao, Nicole Herzog, Hugo A. Katus, Walter J. Koch, Norbert Frey, Patrick Most. (2008) BMP-2 and FGF-2 Synergistically Facilitate Adoption of a Cardiac Phenotype in Somatic Bone Marrow c-kit+/Sca-1+ Stem Cells. Clinical and Translational Science 1:2, 116-125
    CrossRef

19. 19

    Timothy J. Nelson, Atta Behfar, Andre Terzic. (2008) Strategies for Therapeutic Repair: The “R ³ ” Regenerative Medicine Paradigm. Clinical and Translational Science 1:2, 168-171
    CrossRef

20. 20

    Donatella Piro, Joanna Rejman, Massimo Conese. (2008) Stem cell therapy for cystic fibrosis: current status and future prospects. Expert Review of Respiratory Medicine 2:3, 365-380
    CrossRef

21. 21

    Bruno Lorenzi, Federica Pessina, Paola Lorenzoni, Serena Urbani, Remo Vernillo, Giampietro Sgaragli, Renato Gerli, Benedetta Mazzanti, Alberto Bosi, Riccardo Saccardi, Marco Lorenzi. (2008) Treatment of Experimental Injury of Anal Sphincters with Primary Surgical Repair and Injection of Bone Marrow-Derived Mesenchymal Stem Cells. Diseases of the Colon & Rectum 51:4, 411-420
    CrossRef

22. 22

    Dennis Smiler, Muna Soltan, Maher Albitar. (2008) Toward the Identification of Mesenchymal Stem Cells in Bone Marrow and Peripheral Blood for Bone Regeneration. Implant Dentistry 17:3, 236-247
    CrossRef

23. 23

    Nicol Siegel, Margit Rosner, Michaela Hanneder, Alessandro Valli, Markus Hengstschläger. (2007) Stem Cells in Amniotic Fluid as New Tools to Study Human Genetic Diseases. Stem Cell Reviews 3:4, 256-264
    CrossRef

24. 24

    Fabrício Carvalho Torres, Consuelo Junqueira Rodrigues, Ithamar Nogueira Stocchero, Marcus Castro Ferreira. (2007) Stem Cells from the Fat Tissue of Rabbits: An Easy-To-Find Experimental Source. Aesthetic Plastic Surgery 31:5, 574-578
    CrossRef

25. 25

    Alfred A. Kocher, Bernhard Schlechta, Aneta Gasparovicova, Ernst Wolner, Nikolaos Bonaros, Günther Laufer. (2007) Stem cells and cardiac regeneration. Transplant International 20:9, 731-746
    CrossRef

26. 26

    Sarah Snykers, Mathieu Vinken, Vera Rogiers, Tamara Vanhaecke. (2007) Differential role of epigenetic modulators in malignant and normal stem cells: a novel tool in preclinical in vitro toxicology and clinical therapy. Archives of Toxicology 81:8, 533-544
    CrossRef

27. 27

    A. Burd, K. Ahmed, S. Lam, T. Ayyappan, L. Huang. (2007) Stem cell strategies in burns care. Burns 33:3, 282-291
    CrossRef

28. 28

    Rebecca Allan, Malek Kass, Christopher Glover, Haissam Haddad. (2007) Cellular transplantation: future therapeutic options. Current Opinion in Cardiology 22:2, 104-110
    CrossRef

29. 29

    Rumi SAWADA, Tomomi ITO, Toshie TSUCHIYA. (2007) Safety Evaluation of Tissue Engineered Medical Devices Using Normal Human Mesenchymal Stem Cells. YAKUGAKU ZASSHI 127:5, 851-856
    CrossRef

30. 30

    Jisun Cha, Vincent Falanga. (2007) Stem cells in cutaneous wound healing. Clinics in Dermatology 25:1, 73-78
    CrossRef

31. 31

    Conrad C. Daly. (2006) The Sound of Science: The Power to Bless or to Burn. Southern Medical Journal 99:12, 1416-1418
    CrossRef

32. 32

    Daniel P. Sulmasy. (2006) Promethean Medicine: Spirituality, Stem Cells, and Cloning. Southern Medical Journal 99:12, 1419-1423
    CrossRef

33. 33

    Agneta M. Sutton. (2006) “Yes” to Adult Stem Cells. Southern Medical Journal 99:12, 1444-1445
    CrossRef

34. 34

    M Miura, Y Miura, W Sonoyama, T Yamaza, S Gronthos, S Shi. (2006) Bone marrow-derived mesenchymal stem cells for regenerative medicine in craniofacial region. Oral Diseases 12:6, 514-522
    CrossRef

35. 35

    Rumi Sawada, Tomomi Ito, Toshie Tsuchiya. (2006) Changes in expression of genes related to cell proliferation in human mesenchymal stem cells during in vitro culture in comparison with cancer cells. Journal of Artificial Organs 9:3, 179-184
    CrossRef

36. 36

    Jackie R Bickenbach, Matthew M Stern, Katie L Grinnell, Antonio Manuel, Sathivel Chinnathambi. (2006) Epidermal Stem Cells Have the Potential to Assist in Healing Damaged Tissues. Journal of Investigative Dermatology Symposium Proceedings 11:1, 118-123
    CrossRef

37. 37

    Kai C Wollert, Helmut Drexler. (2006) Cell-based therapy for heart failure. Current Opinion in Cardiology 21:3, 234-239
    CrossRef

38. 38

    Xavier Stéphenne, Mustapha Najimi, Catherine Sibille, Marie–Cécile Nassogne, Françoise Smets, Etienne M. Sokal. (2006) Sustained Engraftment and Tissue Enzyme Activity After Liver Cell Transplantation for Argininosuccinate Lyase Deficiency. Gastroenterology 130:4, 1317-1323
    CrossRef

39. 39

    Antonio Uccelli, Emanuela Zappia, Federica Benvenuto, Francesco Frassoni, Gianluigi Mancardi. (2006) Stem cells in inflammatory demyelinating disorders: a dual role for immunosuppression and neuroprotection. Expert Opinion on Biological Therapy 6:1, 17-22
    CrossRef

40. 40

    W FRISHMAN. (2006) Stem Cells in the Dog Heart Are Self-Renewing, Clonogenic, and Multipotent and Regenerate Infarcted Myocardium, Improving Cardiac FunctionLinke A, Müller P, Nurzynska D, et al (New York Med College, Valhalla; Univ of Saarland, Homburg, Germany) Proc Natl Acad Sci U S A 102:8966–8971, 2005§. Yearbook of Medicine 2006, 323-324
    CrossRef

41. 41

    J. M. Zimmet, J. M. Hare. (2005) Emerging role for bone marrow derived mesenchymal stem cells in myocardial regenerative therapy. Basic Research in Cardiology 100:6, 471-481
    CrossRef

42. 42

    Raymund E. Horch, Jürgen Kopp, Ulrich Kneser, Justus Beier, Alexander D. Bach. (2005) Tissue engineering of cultured skin substitutes. Journal of Cellular and Molecular Medicine 9:3, 592-608
    CrossRef

43. 43

    Martin Lauss, Martina Stary, Julia Tischler, Gerda Egger, Sonja Puz, Alice Bader-Allmer, Christian Seiser, Georg Weitzer. (2005) Single inner cell masses yield embryonic stem cell lines differing in lifr expression and their developmental potential. Biochemical and Biophysical Research Communications 331:4, 1577-1586
    CrossRef

44. 44

    Stefano Pluchino, Lucia Zanotti, Michela Deleidi, Gianvito Martino. (2005) Neural stem cells and their use as therapeutic tool in neurological disorders. Brain Research Reviews 48:2, 211-219
    CrossRef

45. 45

    Daniel J. Garry, Amanda M. Masino, R Haris Naseem, Cindy M. Martin, Norman M. Kaplan, Biff F. Palmer. (2005) Ponce de Leon???s Fountain: Stem Cells and the Regenerating Heart. The American Journal of the Medical Sciences 329:4, 190-201
    CrossRef

46. 46

    Stefanie Dimmeler, Andreas M. Zeiher, Michael D. Schneider. (2005) Unchain my heart: the scientific foundations of cardiac repair. Journal of Clinical Investigation 115:3, 572-583
    CrossRef

47. 47

    Karl-Ludwig Laugwitz, Alessandra Moretti, Jason Lam, Peter Gruber, Yinhong Chen, Sarah Woodard, Li-Zhu Lin, Chen-Leng Cai, Min Min Lu, Michael Reth, Oleksandr Platoshyn, Jason X.-J. Yuan, Sylvia Evans, Kenneth R. Chien. (2005) Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 433:7026, 647-653
    CrossRef

48. 48

    Roberta Fiaccavento, Felicia Carotenuto, Marilena Minieri, Cristina Fantini, Giancarlo Forte, Arnaldo Carbone, Luciana Carosella, Roberto Bei, Laura Masuelli, Camilla Palumbo, Andrea Modesti, Maria Prat, Paolo Di Nardo. (2005) Stem cell activation sustains hereditary hypertrophy in hamster cardiomyopathy. The Journal of Pathology 205:3, 397-407
    CrossRef

49. 49

    Suzanne V. Mcdiarmid. 2005. Liver Transplantation for Metabolic Disease. , 337-366.
    CrossRef

50. 50

    Masathoshi Haruta, Masayo Takahashi. (2005) Embryonic Stem Cells: Potential Source for Ocular Repair. Seminars in Ophthalmology 20:1, 17-23
    CrossRef

51. 51

    Michael D. Schneider. (2004) Regenerative medicine: Prometheus unbound. Nature 432:7016, 451-453
    CrossRef

52. 52

    Donald W. Landry, Howard A. Zucker. (2004) Embryonic death and the creation of human embryonic stem cells. Journal of Clinical Investigation 114:9, 1184-1186
    CrossRef

53. 53

    Jackie R. Bickenbach, Katie L. Grinnell. (2004) Epidermal stem cells: interactions in developmental environments. Differentiation 72:8, 371-380
    CrossRef

54. 54

    Frank P Luyten. (2004) Mesenchymal stem cells in osteoarthritis. Current Opinion in Rheumatology 16:5, 599-603
    CrossRef

55. 55

    Ali Salim, Amato J. Giaccia, Michael T. Longaker. (2004) Stem cell differentiation. Nature Biotechnology 22:7, 804-805
    CrossRef

56. 56

    Gianvito Martino. (2004) How the brain repairs itself: new therapeutic strategies in inflammatory and degenerative CNS disorders. The Lancet Neurology 3:6, 372-378
    CrossRef

57. 57

    Adrian Reuben. (2004) Prometheus and Pandora?together again. Hepatology 39:5, 1460-1463
    CrossRef

58. 58

    (2003) The Vulture and Stem Cells. New England Journal of Medicine 349:15, 1480-1481
    Full Text

59. 59

    Antonio P. Beltrami, Laura Barlucchi, Daniele Torella, Mathue Baker, Federica Limana, Stefano Chimenti, Hideko Kasahara, Marcello Rota, Ezio Musso, Konrad Urbanek, Annarosa Leri, Jan Kajstura, Bernardo Nadal-Ginard, Piero Anversa. (2003) Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration. Cell 114:6, 763-776
    CrossRef

60. 60

    Drazen, Jeffrey M., . (2003) Legislative Myopia on Stem Cells. New England Journal of Medicine 349:3, 300-300
    Full Text

61. 61

    Daley, George Q., . (2003) Cloning and Stem Cells — Handicapping the Political and Scientific Debates. New England Journal of Medicine 349:3, 211-212
    Full Text

62. 62

    &NA;. (2003) Therapeutic potential of stem cells. Inpharma Weekly &NA;:1397, 4
    CrossRef

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