The Stem State: Plasticity Is Essential, Whereas Self-Renewal and Hierarchy Are Optional
http://www.100md.com
《干细胞学杂志》
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
Key Words. Stem state ? Stem cells ? Plasticity ? Hierarchy ? Self-renewal
Correspondence: Dov Zipori, Ph.D., Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel. Telephone: 972-8-9342484; Fax: 972-8-9344125; e-mail: dov.zipori@weizmann.ac.il
ABSTRACT
While observing the whereabouts and changes that cell populations undergo in vivo and in vitro, investigators arrived at the "stem cell" notion that basically explains a major puzzle: cells in the embryo and in the adult organism reach a state of full functional differentiation that is viewed as "terminal" in that it is irreversible. The cells may further die through apoptosis or other death mechanisms. How is this cell loss compensated? The prevailing explanation is that tissues contain a small fraction of stem cells that are endowed with unique properties inherently different from those of the mature ones. These rare cells can divide by producing more of themselves; thus, they are capable of self-renewal and also possess the potential to differentiate into many different mature cell types and therefore are multipotential. This theory was dramatically successful upon the isolation of rare cells within the bone marrow, hemopoietic stem cells (HSCs), which are multipotent in that they give rise to all types of cells in the blood and are capable of long-term repopulation of irradiated recipients. Isolated HSCs have been shown to give rise to committed progenitors that are restricted to a single lineage within the hemopoietic system (myeloid, erythroid, megakaryocytic, or lymphocytic series). However, intermediate stages wherein the cells are still multipotent but are already biased to a particular pathway have been described. The committed progenitors are followed by yet further differentiated progeny that are gradually losing their proliferation potential while maturing and acquiring differentiated functions (Fig. 1A) (reviewed by ). This succession of steps from the early stem cell to differentiated products is referred to as the stem cell tree. Thus, the hemopoietic system is viewed as a hierarchical organization wherein the stem cell is positioned at the origin, while branching leads to the differentiation into mature cells that are the end products (Fig. 1A). The direction of flow in this system is from the stem cell down to the mature cell, a flow that is irreversible. The identification of HSCs and the hemopoietic tree is commonly regarded as the ultimate proof of the stem cell concept, pointing to the possible presence of such cells in different organs and tissue. Indeed, evidence to this effect exists for the embryo , adult skin , nervous system , pancreas , heart , liver , and others. The depth of the available information about these other stem cell–based systems is not as detailed as that relating to HSCs. Nevertheless, while examining the different kinds of stem cells, the general impression that emerges is that indeed the stem cell theory has a sound basis.
Figure 1. The established hierarchy of increasing specification in the hemopoietic system is not matched by a similar organization of cells derived from the mesenchymal stem cell (MSC). Question mark denotes the lack of information regarding uncommitted and lineage-restricted steps of mesenchymal differentiation. Dotted line marks putative differentiation steps. Abbreviations: B, B lymphocyte; CL, common lymphoid; CM, common myeloid; DGM, dendritic/granulocyte/macrophage; E, erythroid; LTRSC, long-term repopulating stem cell; MAPC, multipotential adult progenitor cell; MK, megakaryoid; NK, natural killer cell; OB, osteoblast; OP, osteogenic progenitor; P, progenitor; STRSC, short-term repopulating stem cell; T, T lymphocyte; USSC, unrestricted somatic stem cells; VSMC, vascular smooth muscle cell.
The early mouse or human embryo at the blastocyst stage is a source of cells designated embryonic stem (ES) cells. The mode of derivation of these, which are in fact cell lines capable of continuously growing in culture, is isolation of the inner cell mass (ICM) from the blastocyst and propagation of this tissue fragment in tissue culture. At a later stage it is possible to clone single cells and further propagate them while maintaining their growth potential. ES cell lines are pluripotential, as judged by their capacity to differentiate in vitro into a variety of mature progeny according to the stimulus provided to them. More importantly, upon introduction into an early embryo, cultured mouse ES cells integrate into the developing animal and give rise to cells of most tissues and organs, including the germ line. This pluripotentiality is suggested to be a distinct property of embryo-derived stem cells, a notion that seems reasonable and logical in view of the fact that the cells within the embryo are indeed capable of differentiating into all eventual cellular constituents of the organism. By contrast, HSCs are multipotent in that they give rise to all the constituents of the blood system; however, they are viewed as being tissue-specific and capable of giving rise to cells of their tissue of origin only. Accordingly, stem cells derived from other tissues, such as the heart, liver, and brain, are supposed to be restricted to their respective organ of origin. Figures 2A–2C show schematically how a totipotent zygote is supposed to give rise to pluripotent ES cells that characterize the early embryo, whereas these will eventually produce tissue-specific stem cells that are first multipotent and eventually oligopotent or monopotent. At this stage they are ready to terminally differentiate. Once again, this is logical in view of our knowledge of development and differentiation. However, data accumulated in recent years seem to shatter the current model of stemness. Alternative models have been proposed , and I have recently suggested the concept of the "stem state"; cells may enter a stem state reversibly, and thus stemness is a state rather than a cellular entity . The present review is aimed at further re-evaluating the stem cell notion and suggests that plasticity is the major trait of the stem state. On the other hand, properties such as ability to self-renew or give rise to a hierarchy of branching specificities are dispensable options.
Figure 2. (A, B): Appearance and persistence of stem cells with varying potencies as a function of development. (C): Several key steps in development aligned with the prevailing notion of decreasing stem cell potentials associated with the progression of development and maturation. (D): This view is contrasted to the new findings indicating that highly pluripotent stem cells prevail and persist until old age.
INCONSISTENCIES IN THE PREVAILING STEM CELL THEORY
Thanks are due to the Charles and David Wolfson Charitable Trust for the support of Stem Cell Research at the Weizmann Institute of Science. The study was supported by grants from the Gabrielle Rich Center for Transplantation Biology, the Minerva Foundation, Germany, Michael Krasny, Daniel and Rhonda Shapiro, Jerrald and Helene Wulff, Dr. and Mrs. Murray Goldberg, and the Isabelle and Leonard Goldenson Association. The author is an incumbent of the Joe and Celia Weinstein Professorial Chair at the Weizmann Institute of Science.
REFERENCES
Weissman IL. Stem cells: units of development, units of regeneration, and units in evolution. Cell 2000;100:157–168.
Thomson JA, Itskovitz-Eldor J, Shapiro SS et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145–1147.
Blanpain C, Lowry WE, Geoghegan A et al. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 2004;118:635–648.
Stemple DL, Anderson DJ. Isolation of a stem cell for neurons and glia from the mammalian neural crest. Cell 1992;71:973–985.
Rietze RL, Valcanis H, Brooker GF et al. Purification of a pluripotent neural stem cell from the adult mouse brain. Nature 2001;412:736–739.
Seaberg RM, Smukler SR, Kieffer TJ et al. Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat Biotechnol 2004;22:1115–1124.
Beltrami AP, Barlucchi L, Torella D et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114:763–776.
Yang L, Li S, Hatch H et al. In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci U S A 2002;99:8078–8083.
Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function? Cell 2001;105:829–841.
Cerny J, Quesenberry PJ. Chromatin remodeling and stem cell theory of relativity. J Cell Physiol 2004;201:1–16.
Kirkland MA. A phase space model of hemopoiesis and the concept of stem cell renewal. Exp Hematol 2004;32:511–519.
Zipori D. The nature of stem cells: state rather than entity. Nat Rev Genet 2004;5:873–878.
Zwaka TP, Thomson JA. A germ cell origin of embryonic stem cells? Development 2005;132:227–233.
Kues WA, Petersen B, Mysegades W et al. Isolation of murine and porcine fetal stem cells from somatic tissue. Biol Reprod 2005;72:1020–1028.
Kogler G, Sensken S, Airey JA et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 2004;200:123–135.
Lee OK, Kuo TK, Chen WM et al. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 2004;103:1669–1675.
Kanatsu-Shinohara M, Inoue K, Lee J et al. Generation of pluripotent stem cells from neonatal mouse testis. Cell 2004;119:1001–1012.
Jiang Y, Vaessen B, Lenvik T et al. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp Hematol 2002;30:896–904.
Jiang Y, Jahagirdar BN, Reinhardt RL et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41–49.
Owen M, Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp 1988;136:42–60.
Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–147.
Toma JG, Akhavan M, Fernandes KJ et al. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol 2001;3:778–784.
Fernandes KJ, McKenzie IA, Mill P et al. A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol 2004;6:1082–1093.
Young HE, Steele TA, Bray RA et al. Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors. Anat Rec 2001;264:51–62.
D’Ippolito G, Diabira S, Howard GA et al. Marrow-isolated adult multi-lineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J Cell Sci 2004;117:2971–2981.
Blattman JN, Antia R, Sourdive DJ et al. Estimating the precursor frequency of naive antigen-specific CD8 T cells. J Exp Med 2002;195:657–664.
Ben-Nun A, Wekerle H, Cohen IR. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol 1981;11:195–199.
MacMillan JR, Wolf NS. Depletion of reserve in the hemopoietic system, II: decline in CFU-S self-renewal capacity following prolonged cell cycling. STEM CELLS 1982;2:45–58.
Kamminga LM, van Os R, Ausema A et al. Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging. STEM CELLS 2005;23:82–92.
Odelberg SJ. Inducing cellular dedifferentiation: a potential method for enhancing endogenous regeneration in mammals. Semin Cell Dev Biol 2002;13:335–343.
Zipori D. The renewal and differentiation of hemopoietic stem cells. FASEB J 1992;6:2691–2697.
Zipori D. Cell interactions in the bone marrow microenvironment: role of endogenous colony-stimulating activity. J Supramol Struct Cell Biochem 1981;17:347–357.
Zipori D. Regulation of hemopoiesis by cytokines that restrict options for growth and differentiation. Cancer Cells 1990;2:205–211.
Trentin A, Glavieux-Pardanaud C, Le Douarin NM et al. Self-renewal capacity is a widespread property of various types of neural crest precursor cells. Proc Natl Acad Sci U S A 2004;101:4495–4500.
Potten CS, Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties: lessons for and from the crypt. Development 1990;110:1001–1020.
Charbord P, Oostendorp R, Pang W et al. Comparative study of stromal cell lines derived from embryonic, fetal, and postnatal mouse blood-forming tissues. Exp Hematol 2002;30:1202–1210.
Muraglia A, Cancedda R, Quarto R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. J Cell Sci 2000;113:1161–1166.
Zipori D, Friedman A, Tamir M et al. Cultured mouse marrow cell lines: interactions between fibroblastoid cells and monocytes. J Cell Physiol 1984;118:143–152.
Zipori D, Duksin D, Tamir M et al. Cultured mouse marrow stromal cell lines, II: distinct subtypes differing in morphology, collagen types, myelopoietic factors, and leukemic cell growth modulating activities. J Cell Physiol 1985;122:81–90.
Zipori D, Lee F. Introduction of interleukin-3 gene into stromal cells from the bone marrow alters hemopoietic differentiation but does not modify stem cell renewal. Blood 1988;71:586–596.
Benayahu D, Fried A, Zipori D et al. Subpopulations of marrow stromal cells share a variety of osteoblastic markers. Calcif Tissue Int 1991;49:202–207.
Prindull G, Zipori D. Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood 2004;8:2892–2899.
Houghton J, Stoicov C, Nomura S et al. Gastric cancer originating from bone marrow-derived cells. Science 2004;306:1568–1571.
O’Donoghue K, Chan J, de la Fuente J et al. Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet 2004;364:179–182.
Kaufman DS, Hanson ET, Lewis RL et al. Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 2001;98:10716–10721.
Vodyanik MA, Bork JA, Thomson JA et al. Human embryonic stem cell-derived CD34+ cells: efficient production in the coculture with OP9 stromal cells and analysis of lymphohematopoietic potential. Blood 2005;105:617–626.
Carotta S, Pilat S, Mairhofer A et al. Directed differentiation and mass cultivation of pure erythroid progenitors from mouse embryonic stem cells. Blood 2004;104:1873–1880.
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.
Sata M, Saiura A, Kunisato A et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002;8:403–409.
Camargo FD, Green R, Capetanaki Y et al. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med 2003;9:1520–1527.
Bailey AS, Jiang S, Afentoulis M et al. Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells. Blood 2004;103:13–19.
Wagers AJ, Sherwood RI, Christensen JL et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002;297:2256–2259.
Kanazawa Y, Verma IM. Little evidence of bone marrow-derived hepatocytes in the replacement of injured liver. Proc Natl Acad Sci U S A 2003;100(suppl 1):11850–11853.
Balsam LB, Wagers AJ, Christensen JL et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004;428:668–673.
Wang X, Willenbring H, Akkari Y et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003;422:897–901.
Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422:901–904.
Jang YY, Collector MI, Baylin SB et al. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol 2004;6:532–539.
Cao B, Zheng B, Jankowski RJ et al. Muscle stem cells differentiate into haematopoietic lineages but retain myogenic potential. Nat Cell Biol 2003;5:640–646.
Hermann A, Gastl R, Liebau S et al. Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. J Cell Sci 2004;117:4411–4422.
Pochampally RR, Neville BT, Schwarz EJ et al. Rat adult stem cells (marrow stromal cells) engraft and differentiate in chick embryos without evidence of cell fusion. Proc Natl Acad Sci U S A 2004;101:9282–9285.
Condorelli G, Borello U, De Angelis L et al. Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: implications for myocardium regeneration. Proc Natl Acad Sci U S A 2001;98:10733–10738.
Brawley C, Matunis E. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 2004;304:1331–1334.
Tanaka EM. Cell differentiation and cell fate during urodele tail and limb regeneration. Curr Opin Genet Dev 2003;13:497–501.
Grafi G. How cells dedifferentiate: a lesson from plants. Dev Biol 2004;268:1–6.
Barda-Saad M, Shav-Tal Y, Rozenszajn AL et al. The mesenchyme expresses T cell receptor mRNAs: relevance to cell growth control. Oncogene 2002;21:2029–2036.
Goolsby J, Marty MC, Heletz D et al. Hematopoietic progenitors express neural genes. Proc Natl Acad Sci U S A 2003;100:14926–14931.
Golan-Mashiach M, Dazard JE, Gerecht-Nir S et al. Design principle of gene expression used by human stem cells: implication for pluripotency. FASEB J 2005;19:147–149.(Dov Zipori)
Key Words. Stem state ? Stem cells ? Plasticity ? Hierarchy ? Self-renewal
Correspondence: Dov Zipori, Ph.D., Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel. Telephone: 972-8-9342484; Fax: 972-8-9344125; e-mail: dov.zipori@weizmann.ac.il
ABSTRACT
While observing the whereabouts and changes that cell populations undergo in vivo and in vitro, investigators arrived at the "stem cell" notion that basically explains a major puzzle: cells in the embryo and in the adult organism reach a state of full functional differentiation that is viewed as "terminal" in that it is irreversible. The cells may further die through apoptosis or other death mechanisms. How is this cell loss compensated? The prevailing explanation is that tissues contain a small fraction of stem cells that are endowed with unique properties inherently different from those of the mature ones. These rare cells can divide by producing more of themselves; thus, they are capable of self-renewal and also possess the potential to differentiate into many different mature cell types and therefore are multipotential. This theory was dramatically successful upon the isolation of rare cells within the bone marrow, hemopoietic stem cells (HSCs), which are multipotent in that they give rise to all types of cells in the blood and are capable of long-term repopulation of irradiated recipients. Isolated HSCs have been shown to give rise to committed progenitors that are restricted to a single lineage within the hemopoietic system (myeloid, erythroid, megakaryocytic, or lymphocytic series). However, intermediate stages wherein the cells are still multipotent but are already biased to a particular pathway have been described. The committed progenitors are followed by yet further differentiated progeny that are gradually losing their proliferation potential while maturing and acquiring differentiated functions (Fig. 1A) (reviewed by ). This succession of steps from the early stem cell to differentiated products is referred to as the stem cell tree. Thus, the hemopoietic system is viewed as a hierarchical organization wherein the stem cell is positioned at the origin, while branching leads to the differentiation into mature cells that are the end products (Fig. 1A). The direction of flow in this system is from the stem cell down to the mature cell, a flow that is irreversible. The identification of HSCs and the hemopoietic tree is commonly regarded as the ultimate proof of the stem cell concept, pointing to the possible presence of such cells in different organs and tissue. Indeed, evidence to this effect exists for the embryo , adult skin , nervous system , pancreas , heart , liver , and others. The depth of the available information about these other stem cell–based systems is not as detailed as that relating to HSCs. Nevertheless, while examining the different kinds of stem cells, the general impression that emerges is that indeed the stem cell theory has a sound basis.
Figure 1. The established hierarchy of increasing specification in the hemopoietic system is not matched by a similar organization of cells derived from the mesenchymal stem cell (MSC). Question mark denotes the lack of information regarding uncommitted and lineage-restricted steps of mesenchymal differentiation. Dotted line marks putative differentiation steps. Abbreviations: B, B lymphocyte; CL, common lymphoid; CM, common myeloid; DGM, dendritic/granulocyte/macrophage; E, erythroid; LTRSC, long-term repopulating stem cell; MAPC, multipotential adult progenitor cell; MK, megakaryoid; NK, natural killer cell; OB, osteoblast; OP, osteogenic progenitor; P, progenitor; STRSC, short-term repopulating stem cell; T, T lymphocyte; USSC, unrestricted somatic stem cells; VSMC, vascular smooth muscle cell.
The early mouse or human embryo at the blastocyst stage is a source of cells designated embryonic stem (ES) cells. The mode of derivation of these, which are in fact cell lines capable of continuously growing in culture, is isolation of the inner cell mass (ICM) from the blastocyst and propagation of this tissue fragment in tissue culture. At a later stage it is possible to clone single cells and further propagate them while maintaining their growth potential. ES cell lines are pluripotential, as judged by their capacity to differentiate in vitro into a variety of mature progeny according to the stimulus provided to them. More importantly, upon introduction into an early embryo, cultured mouse ES cells integrate into the developing animal and give rise to cells of most tissues and organs, including the germ line. This pluripotentiality is suggested to be a distinct property of embryo-derived stem cells, a notion that seems reasonable and logical in view of the fact that the cells within the embryo are indeed capable of differentiating into all eventual cellular constituents of the organism. By contrast, HSCs are multipotent in that they give rise to all the constituents of the blood system; however, they are viewed as being tissue-specific and capable of giving rise to cells of their tissue of origin only. Accordingly, stem cells derived from other tissues, such as the heart, liver, and brain, are supposed to be restricted to their respective organ of origin. Figures 2A–2C show schematically how a totipotent zygote is supposed to give rise to pluripotent ES cells that characterize the early embryo, whereas these will eventually produce tissue-specific stem cells that are first multipotent and eventually oligopotent or monopotent. At this stage they are ready to terminally differentiate. Once again, this is logical in view of our knowledge of development and differentiation. However, data accumulated in recent years seem to shatter the current model of stemness. Alternative models have been proposed , and I have recently suggested the concept of the "stem state"; cells may enter a stem state reversibly, and thus stemness is a state rather than a cellular entity . The present review is aimed at further re-evaluating the stem cell notion and suggests that plasticity is the major trait of the stem state. On the other hand, properties such as ability to self-renew or give rise to a hierarchy of branching specificities are dispensable options.
Figure 2. (A, B): Appearance and persistence of stem cells with varying potencies as a function of development. (C): Several key steps in development aligned with the prevailing notion of decreasing stem cell potentials associated with the progression of development and maturation. (D): This view is contrasted to the new findings indicating that highly pluripotent stem cells prevail and persist until old age.
INCONSISTENCIES IN THE PREVAILING STEM CELL THEORY
Thanks are due to the Charles and David Wolfson Charitable Trust for the support of Stem Cell Research at the Weizmann Institute of Science. The study was supported by grants from the Gabrielle Rich Center for Transplantation Biology, the Minerva Foundation, Germany, Michael Krasny, Daniel and Rhonda Shapiro, Jerrald and Helene Wulff, Dr. and Mrs. Murray Goldberg, and the Isabelle and Leonard Goldenson Association. The author is an incumbent of the Joe and Celia Weinstein Professorial Chair at the Weizmann Institute of Science.
REFERENCES
Weissman IL. Stem cells: units of development, units of regeneration, and units in evolution. Cell 2000;100:157–168.
Thomson JA, Itskovitz-Eldor J, Shapiro SS et al. Embryonic stem cell lines derived from human blastocysts. Science 1998;282:1145–1147.
Blanpain C, Lowry WE, Geoghegan A et al. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 2004;118:635–648.
Stemple DL, Anderson DJ. Isolation of a stem cell for neurons and glia from the mammalian neural crest. Cell 1992;71:973–985.
Rietze RL, Valcanis H, Brooker GF et al. Purification of a pluripotent neural stem cell from the adult mouse brain. Nature 2001;412:736–739.
Seaberg RM, Smukler SR, Kieffer TJ et al. Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat Biotechnol 2004;22:1115–1124.
Beltrami AP, Barlucchi L, Torella D et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114:763–776.
Yang L, Li S, Hatch H et al. In vitro trans-differentiation of adult hepatic stem cells into pancreatic endocrine hormone-producing cells. Proc Natl Acad Sci U S A 2002;99:8078–8083.
Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function? Cell 2001;105:829–841.
Cerny J, Quesenberry PJ. Chromatin remodeling and stem cell theory of relativity. J Cell Physiol 2004;201:1–16.
Kirkland MA. A phase space model of hemopoiesis and the concept of stem cell renewal. Exp Hematol 2004;32:511–519.
Zipori D. The nature of stem cells: state rather than entity. Nat Rev Genet 2004;5:873–878.
Zwaka TP, Thomson JA. A germ cell origin of embryonic stem cells? Development 2005;132:227–233.
Kues WA, Petersen B, Mysegades W et al. Isolation of murine and porcine fetal stem cells from somatic tissue. Biol Reprod 2005;72:1020–1028.
Kogler G, Sensken S, Airey JA et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 2004;200:123–135.
Lee OK, Kuo TK, Chen WM et al. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 2004;103:1669–1675.
Kanatsu-Shinohara M, Inoue K, Lee J et al. Generation of pluripotent stem cells from neonatal mouse testis. Cell 2004;119:1001–1012.
Jiang Y, Vaessen B, Lenvik T et al. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp Hematol 2002;30:896–904.
Jiang Y, Jahagirdar BN, Reinhardt RL et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41–49.
Owen M, Friedenstein AJ. Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp 1988;136:42–60.
Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–147.
Toma JG, Akhavan M, Fernandes KJ et al. Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol 2001;3:778–784.
Fernandes KJ, McKenzie IA, Mill P et al. A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol 2004;6:1082–1093.
Young HE, Steele TA, Bray RA et al. Human reserve pluripotent mesenchymal stem cells are present in the connective tissues of skeletal muscle and dermis derived from fetal, adult, and geriatric donors. Anat Rec 2001;264:51–62.
D’Ippolito G, Diabira S, Howard GA et al. Marrow-isolated adult multi-lineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J Cell Sci 2004;117:2971–2981.
Blattman JN, Antia R, Sourdive DJ et al. Estimating the precursor frequency of naive antigen-specific CD8 T cells. J Exp Med 2002;195:657–664.
Ben-Nun A, Wekerle H, Cohen IR. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol 1981;11:195–199.
MacMillan JR, Wolf NS. Depletion of reserve in the hemopoietic system, II: decline in CFU-S self-renewal capacity following prolonged cell cycling. STEM CELLS 1982;2:45–58.
Kamminga LM, van Os R, Ausema A et al. Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging. STEM CELLS 2005;23:82–92.
Odelberg SJ. Inducing cellular dedifferentiation: a potential method for enhancing endogenous regeneration in mammals. Semin Cell Dev Biol 2002;13:335–343.
Zipori D. The renewal and differentiation of hemopoietic stem cells. FASEB J 1992;6:2691–2697.
Zipori D. Cell interactions in the bone marrow microenvironment: role of endogenous colony-stimulating activity. J Supramol Struct Cell Biochem 1981;17:347–357.
Zipori D. Regulation of hemopoiesis by cytokines that restrict options for growth and differentiation. Cancer Cells 1990;2:205–211.
Trentin A, Glavieux-Pardanaud C, Le Douarin NM et al. Self-renewal capacity is a widespread property of various types of neural crest precursor cells. Proc Natl Acad Sci U S A 2004;101:4495–4500.
Potten CS, Loeffler M. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties: lessons for and from the crypt. Development 1990;110:1001–1020.
Charbord P, Oostendorp R, Pang W et al. Comparative study of stromal cell lines derived from embryonic, fetal, and postnatal mouse blood-forming tissues. Exp Hematol 2002;30:1202–1210.
Muraglia A, Cancedda R, Quarto R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. J Cell Sci 2000;113:1161–1166.
Zipori D, Friedman A, Tamir M et al. Cultured mouse marrow cell lines: interactions between fibroblastoid cells and monocytes. J Cell Physiol 1984;118:143–152.
Zipori D, Duksin D, Tamir M et al. Cultured mouse marrow stromal cell lines, II: distinct subtypes differing in morphology, collagen types, myelopoietic factors, and leukemic cell growth modulating activities. J Cell Physiol 1985;122:81–90.
Zipori D, Lee F. Introduction of interleukin-3 gene into stromal cells from the bone marrow alters hemopoietic differentiation but does not modify stem cell renewal. Blood 1988;71:586–596.
Benayahu D, Fried A, Zipori D et al. Subpopulations of marrow stromal cells share a variety of osteoblastic markers. Calcif Tissue Int 1991;49:202–207.
Prindull G, Zipori D. Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm. Blood 2004;8:2892–2899.
Houghton J, Stoicov C, Nomura S et al. Gastric cancer originating from bone marrow-derived cells. Science 2004;306:1568–1571.
O’Donoghue K, Chan J, de la Fuente J et al. Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet 2004;364:179–182.
Kaufman DS, Hanson ET, Lewis RL et al. Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc Natl Acad Sci U S A 2001;98:10716–10721.
Vodyanik MA, Bork JA, Thomson JA et al. Human embryonic stem cell-derived CD34+ cells: efficient production in the coculture with OP9 stromal cells and analysis of lymphohematopoietic potential. Blood 2005;105:617–626.
Carotta S, Pilat S, Mairhofer A et al. Directed differentiation and mass cultivation of pure erythroid progenitors from mouse embryonic stem cells. Blood 2004;104:1873–1880.
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.
Sata M, Saiura A, Kunisato A et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002;8:403–409.
Camargo FD, Green R, Capetanaki Y et al. Single hematopoietic stem cells generate skeletal muscle through myeloid intermediates. Nat Med 2003;9:1520–1527.
Bailey AS, Jiang S, Afentoulis M et al. Transplanted adult hematopoietic stems cells differentiate into functional endothelial cells. Blood 2004;103:13–19.
Wagers AJ, Sherwood RI, Christensen JL et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002;297:2256–2259.
Kanazawa Y, Verma IM. Little evidence of bone marrow-derived hepatocytes in the replacement of injured liver. Proc Natl Acad Sci U S A 2003;100(suppl 1):11850–11853.
Balsam LB, Wagers AJ, Christensen JL et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004;428:668–673.
Wang X, Willenbring H, Akkari Y et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003;422:897–901.
Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422:901–904.
Jang YY, Collector MI, Baylin SB et al. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol 2004;6:532–539.
Cao B, Zheng B, Jankowski RJ et al. Muscle stem cells differentiate into haematopoietic lineages but retain myogenic potential. Nat Cell Biol 2003;5:640–646.
Hermann A, Gastl R, Liebau S et al. Efficient generation of neural stem cell-like cells from adult human bone marrow stromal cells. J Cell Sci 2004;117:4411–4422.
Pochampally RR, Neville BT, Schwarz EJ et al. Rat adult stem cells (marrow stromal cells) engraft and differentiate in chick embryos without evidence of cell fusion. Proc Natl Acad Sci U S A 2004;101:9282–9285.
Condorelli G, Borello U, De Angelis L et al. Cardiomyocytes induce endothelial cells to trans-differentiate into cardiac muscle: implications for myocardium regeneration. Proc Natl Acad Sci U S A 2001;98:10733–10738.
Brawley C, Matunis E. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 2004;304:1331–1334.
Tanaka EM. Cell differentiation and cell fate during urodele tail and limb regeneration. Curr Opin Genet Dev 2003;13:497–501.
Grafi G. How cells dedifferentiate: a lesson from plants. Dev Biol 2004;268:1–6.
Barda-Saad M, Shav-Tal Y, Rozenszajn AL et al. The mesenchyme expresses T cell receptor mRNAs: relevance to cell growth control. Oncogene 2002;21:2029–2036.
Goolsby J, Marty MC, Heletz D et al. Hematopoietic progenitors express neural genes. Proc Natl Acad Sci U S A 2003;100:14926–14931.
Golan-Mashiach M, Dazard JE, Gerecht-Nir S et al. Design principle of gene expression used by human stem cells: implication for pluripotency. FASEB J 2005;19:147–149.(Dov Zipori)