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W2023096476 abstract "Developmental studies over the last few decades have provided us with an understanding of cell ancestries, i.e. how the major classes of cells in the body are generated. Until recently, the dogma has been that adult mammalian stem cells progress in one direction only along differentiation pathways, from totipotent, pluripotent or multipotent stem cells to more differentiated cells and, once committed to a somatic cell lineage, do not differentiate across different embryonic-derived somatic lineages. Even though most cells in adulthood are differentiated cells, ‘self-renewing’ stem cells are also maintained in many, if not all, tissues. Such adult stem cells serve multiple functions. Where there is a need to replenish mature cells constantly (e.g. blood and skin) or to replace the differentiated cells in the case of injury or stress to the tissue, stem cells will have an active role. Stem cells may also persist in tissues as the residue of embryonic development and may rarely contribute to tissue renewal in the adult. While embryonic stem (ES) cells are thought to have an unlimited life span, and to generate most cell lineages, adult stem cells generally appear to have a limited life span and, until recently, were thought to have a restricted potential to generate primarily the cell types present in the specific tissue in which they reside. The concept of tissue- and organ-specific stem cells has been addressed in a number of studies published in recent years. Scientists have postulated that adult stem cells may be either more ‘plastic’ than previously thought or have extraordinary potentials that are regulated by the microenvironment they occupy. In a new or different environment, the adult stem cell would be able to respond to new cues and therefore reprogramme itself to generate unrelated lineages or cells that are appropriate components of the new environment. This plasticity or potentiality has been proposed to be a reflection of cellular differences in organisms, the ontogenic stage of the stem cell (i.e. embryonic, fetal, adult) or the environmental conditions to which the stem cell is exposed (Wells, 2002). Although many experimental situations, in which adult stem cell plasticity or potentiality has been reported, were carried out in mice (Ferrari et al, 1998; Bjornson et al, 1999; Brazelton et al, 2000; Clarke et al, 2000; Lagasse et al, 2000; Mezey et al, 2000; Krause et al, 2001), there are several examples in humans (Table I). Transplants have been carried out in patients who have received tissue from a donor of the opposite sex, therefore making it possible to trace the progeny of the engrafted cells. Liver cells, for example, that stain positive for the Y-chromosome, have been found in women who have received bone marrow or haematopoietic stem cells (HSC) from male donors (Alison et al, 2000). Likewise, XY cells were detected in female livers engrafted in male patients (Theise et al, 2000a,b). The results of these studies suggest that, in humans, both blood- and bone marrow-derived stem cells can generate hepatocytes and vice versa. Similar results have been found in the brain following human bone marrow transplants (Mezey et al, 2003). Is it plasticity, cell fusion or potentiality that makes a progenitor/stem cell or more mature cell change its fate? There is evidence that stem cells can be influenced by external cues to generate unrelated cell lineages (Kondo et al, 2000). Equally, several reports demonstrate that stem cells from haematopoietic tissues have the potential to generate multiple lineages (Krause et al, 2001). Both plasticity and potentiality are characteristics that may co-exist in a stem cell and represent its hallmark. More recently, evidence that cells may fuse to take on the characteristics of their partners has also been reported (Terada et al, 2002; Ying et al, 2002; Vassilopoulos et al, 2003; Wang et al, 2003a). This review will focus on the concept of plasticity in murine and human adult haematopoietic stem cells, discussing some of the most recent examples reported to date. The rationale for not including embryonic stem cells is that, by definition, these cells are able to generate most tissue types of an organism. The review will also focus on the haematopoietic system as a model, as a large number of the experiments have been described in this system, and haematopoietic tissues, together with neuronal stem cells, seem to be particularly promiscuous in their lineage commitment. We will also discuss some of the questions that arise when testing plasticity in adult stem cells, and will examine the robustness of these experimental results. Finally, a brief overview of experimental outcomes required to test stem cell plasticity or potentiality will be presented. The term, stem cell plasticity, has been interpreted differently by different researchers. As highlighted recently (reviewed by Lemischka, 1999, 2002; Metcalf, 1999), haematopoietic stem cells may be regarded as plastic in their ability to balance proliferation or self-renewal with differentiation into multiple blood cell lineages. However, controversy has arisen from more recent concepts of stem cell plasticity. In very broad terms, these newer concepts of stem cell plasticity refer to the ability of a given stem cell from a specific tissue or organ to acquire the phenotype of another cell from a different tissue or organ and, in some cases, to switch between somatic mesodermal, ectodermal, neural crest and endodermal lineages. These newer concepts will be described in this review. There are at least four alternative pathways for a stem cell or more committed cell to switch lineages (Fig 1). The first is transdetermination. This is the situation in which a stem cell that is programmed to generate certain lineages switches to another stem cell and gives rise to cell types of that precursor, i.e. its potential is redirected. An example of this occurs when cells are transplanted between imaginal discs in the Drosophila larvae. The imaginal discs give rise to specialized organs, such as wings and legs. Cells transplanted between these discs generally maintain their identity, but some of them gain the identity of the new location (Maves & Schubiger, 1999). Such studies could also suggest that the precursor or stem cell is multipotent and has not undergone irreversible commitment to a defined lineage. The second pathway is transdifferentiation. In this process, a differentiated cell can gain the phenotype of another differentiated cell. There are indications for transdifferentiation occurring during normal mammalian development when smooth muscle cells give rise to skeletal myocytes in the oesophagus (Patapoutian et al, 1995). The third pathway to a new identity is the dedifferentiation of a progenitor or precursor cell, followed by differentiation to another lineage. An illustration of this is seen after limb amputation in newts, where myocytes dedifferentiate to generate cells of different lineages (Casimir et al, 1988). The fourth occurs via cell fusion. An experimental example has been demonstrated with therapeutic cloning. Here, a mature lineage-restricted cell nucleus can be reprogrammed by its insertion into an enucleated ovum, with the altered environment reprogramming the potential of the mature nucleus to form tissues of many or all types (Campbell et al, 1996; Smith, 2001). Fusion of male myocytes with embryonal carcinoma cells activates the inactive X-chromosome (Takagi et al, 1983). Furthermore, fusion between bone marrow and liver cells can generate hepatocytes in mice (Vassilopoulos et al, 2003; Wang et al, 2003a). Despite the numerous reports describing adult stem cell plasticity in mammals, none of them provides conclusive evidence for or against one common pathway for a lineage switch for all cell types in which plasticity is identified. Similarly, some of the examples of dedifferentiation and transdifferentiation might not seem very clear or convincing (Casimir et al, 1988; Patapoutian et al, 1995). An alternative explanation is that very primitive stem cells or heterogeneous populations of stem cells reside in many, if not all, organs, and that these will exhibit their appropriate potential when placed in defined environments. Pathways to cell differentiation. Traditionally, a hierarchical model of cell differentiation has been accepted. Pluripotent or multipotent stem cells give rise to progenitor cells that gradually differentiate into committed cell lineages. Newer models of stem cell plasticity propose that the pathways to new cell identities take place by transdetermination (1), transdifferentiation (2), dedifferentiation, followed by differentiation into a new lineage (3) or cell fusion (4). Interestingly, five recent publications raise the possibility that some of the results that support the first three mechanisms of stem cell plasticity described above may be misinterpreted. The first four reports relate these results to cell fusion (Terada et al, 2002; Ying et al, 2002; Vassilopoulos et al, 2003; Wang et al, 2003a). In one of these studies, murine bone marrow or purified HSCs were mixed with murine embryonic stem (ES) cells. In both cases, a very small proportion of the bone marrow cells (1:105−106) fused with the ES cells, subsequently adopting the phenotypes of the ES cells as they differentiated (Terada et al, 2002). In the second study, co-culture of unfractionated mouse brain cells or cultured neural stem cells with murine ES cells led to the spontaneous appearance of hybrid cells (1:104−105) that showed multipotency and developed into different lineages when injected into blastocysts (Ying et al, 2002). These two studies confirm that adult cells can gain plasticity by fusion with less differentiated embryonic/progenitor cells. However, these experimental situations, in which stem cell plasticity has been suggested, are far from being conceptually similar to the studies discussed above. The frequency with which cell fusion occurs in these studies seems to be extremely low to justify it being the explanation for many of the results credited to stem cell plasticity. However, very recent studies by Wang et al (2003b) and Vassilopoulos et al (2003) demonstrate fusion between bone marrow-derived cells (BMDC) and liver cells to produce functional hepatocytes in mice. In other studies on pancreatic endocrine and glomerular mesangial cells, cell fusion has not been shown to be of significance (Ianus et al, 2003; Masuya et al, 2003). A further consideration is that cells cultured in vitro may undergo transforming events, genetic or epigenetic alterations, that result in the inappropriate expression of markers considered to be specific for a given lineage or in the development of another lineage (Morshead et al, 2002). These alternatives point out important caveats that should be considered in future experimental designs and in the interpretation of existing and new results. The haematopoietic stem cell (HSC) (Till & McCulloch, 1961) is the best characterized of all adult tissue stem cells. All the experimental strategies and paradigms applicable to adult stem cells in general were first defined in this system (reviewed by Dexter et al, 1988; Watt & Visser, 1992; Morrison et al, 1997; Metcalf, 1999, 2001; Zandstra et al, 2000; McCulloch, 2003 and references therein). HSCs have the ability to balance self-renewal, or at least extensive proliferative potential, with differentiation into all functional committed blood cell lineages over an individual lifespan (Fig 2). This is the hallmark of the HSC and the basis for defining somatic stem cell characteristics in other tissues. HSCs are rare, occurring with a frequency of 1 in 104−105 total blood cells, and are slowly cycling. Although they can be purified by identification of surface markers, practically they are considered a heterogeneous population. Post-natally, HSCs can be isolated from haematopoietic tissues such as bone marrow, umbilical cord blood and mobilized peripheral blood. Their capacity to repopulate the whole haematopoietic system has been proven in vivo in mice by transplantation of single stem cells into syngeneic animals (Osawa et al, 1996; Krause et al, 2001), in non-human primate studies (Heim & Dunbar, 2000) and after transplantation for haemotological diseases in humans (reviewed by Gratwohl et al, 2002 and references therein). Surrogate in vivo animal models of human haematopoiesis also exist. These include the use of severe combined immunodeficient (SCID), non-obese diabetic (NOD)/SCID, beige-nude-SCID (bnx), Rag-1-deficient/NOD, nude/NOD/SCID and β2-microglobulin-deficient NOD/SCID mice to measure human scid-repopulating cells (SCR) from haematopoietic tissues (Lapidot et al, 1992; Pflumio et al, 1996; Christianson et al, 1997; Arevalo et al, 1999; Kollet et al, 2000; Shultz et al, 2000; Glimm et al, 2001; Uchida et al, 2001). An alternative is the in utero transplantation of human cells into sheep (Zanjani et al, 1996). None of these surrogate models shows full human donor-derived haematopoiesis in vivo but, depending on the system used, they contribute to most haematopoietic lineages. Thus, successful long-term transplantation of human stem cells into patients with haematological malignancies or genetic diseases, which was introduced in 1968, remains the gold standard for transplantation for other diseases. More than 50 000 transplants per annum are now carried out worldwide, with more than 20 000 in Europe (reviewed by Gratwohl et al, 2002 and references therein). In this setting, both autologous and allogeneic [identical twin, human leucocyte antigen (HLA)-matched sibling, other family members, HLA-matched unrelated donors] transplants are performed. Procedures have been fine-tuned in order to improve the outcome of the therapy, with engraftment and chimaerism depending on careful donor and patient selection, HLA typing and matching, intensity of conditioning, disease status, quality of the stem cell product, graft-versus-host disease, the introduction of standard operating procedures for manipulating recipients and grafts, identification of donor cell origins using tandem repeat polymorphism analyses, and supportive care (including T-cell depletion and antiviral T-cell therapies) (Chakrabarti et al, 2001; Gratwohl et al, 2002; Moosmann et al, 2002; Peggs et al, 2002). Schematic representation of blood development. HS, haemopoietic stem cell; CM, common myeloid progenitor; CL, common lymphoid progenitor; Pla, platelets; RBC, red blood cells; Eosi, eosinophils; Bas, basophils; Neut, neutrophils; Mono, monocytes; Myeloid DC, myeloid dendritic cell, B cells, B lymphocytes; T cells, T lymphocytes, NK cells, natural killer cells and Lymphoid DC, lymphoid dendritic cells. Stem cells from haematopoietic organs also have the potential to generate cell types other than haematopoietic cells (reviewed by Moore, 2002; Orkin & Zon, 2002 and references therein), such as bone, cartilage, neural cells, pneumocytes, muscle, skin, blood vessel endothelia, epithelial cells, hepatocytes, etc. It has been proposed that these cells can therefore give rise to cells of all somatic lineages, the ectodermal, mesodermal, neural crest and endodermal cell lineages (Friedenstein et al, 1966; Friedenstein, 1989; Jiang et al, 2002a). Thus, patterns of long-term engraftment observed after stem cell transplantation of patients with haematological disorders will be relevant to other areas of regenerative medicine. As well as HSC, at least three more primitive progenitor/stem cell subsets have been defined to varying extents in tissues that generate haematopoietic cells (reviewed by Moore 2002; see Fig 3). These are (i) the haemangioblast (HB), a precursor for haematopoietic and blood vessel endothelial cells (Dieterlen-Lievre et al, 2002); (ii) mesenchymal stem cells (MSC) (Friedenstein et al, 1966; Friedenstein, 1989; Prockop, 1997; Pittenger et al, 1999) that give rise to cartilage, bone, adipocytes, neural cells, supporting haematopoietic stroma, muscle, etc.; and (iii) multipotent adult progenitor cells (MAPC) that generate all or most cell lineages of ectodermal, endodermal and mesodermal origin (Jiang et al, 2002a; Reyes et al, 2002). These primitive cells can be enriched using a variety of procedures that are often dependent, although not exclusively, on cell surface markers. For many years, CD34 was cited as the marker for enriching both HSC and a proportion of their more mature offspring in humans (Civin et al, 1984; Katz et al, 1985; Cardoso et al, 1995). More recently, in both mice and man, repopulating haematopoietic stem cells have been located within both the CD34+ and CD34– subsets. These cells also lack lineage markers (Lin–) and, in the human, are generally CD38–. It has been proposed that CD34 is an activation marker of stem cells and that CD34+ HSC can revert to CD34– cells and vice versa (Osawa et al, 1996; Goodell et al, 1997; Bhatia et al, 1998; Zanjani et al, 1998; Chan & Watt, 2001, Krause et al, 2001; Uchida et al, 2001). There are also indications that CD34– cells may be more primitive than CD34+ cells. CD133 is also found on human HSCs and marks both the CD34– subset and variable proportions of CD34+ cells depending on their source (Miraglia et al, 1997; Yin et al, 1997; Corbeil et al, 1998, 2000; Watt et al, 2000). Other important markers that have been used in the purification of stem cells with haematopoietic potential include vascular endothelial growth factor receptor 2 (VEGFR-2) or kinase insert domain receptor (KDR), CD90 (Thy-1), CD117 (c-kit), CD164, CXC-chemokine receptor 4 (CXCR-4), P-glycoprotein [multidrug resistance (MDR), rhodamine 123, Hoechst 33342], Sca-1, AA4, CD45, Bcrp1/ATP binding cassette (ABC) G2, etc. (Craig et al, 1993; Goodell et al, 1996, 1997; Watt et al, 1998, 2000; Zanjani et al, 1998; Zannettino et al, 1998; Buhring et al, 1999; Peled et al, 1999; Petrenko et al, 1999; Ziegler et al, 1999; Doyonnas et al, 2000; Rosu-Myles et al, 2000; Watt & Chan, 2000; Bhatia, 2001; Chan et al, 2001; Uchida et al, 2001; Zhou et al, 2001; de Bruijn et al, 2002; Howell et al, 2002; Jiang et al, 2002b; Mahmud et al, 2002; Tamura et al, 2002). The importance of these markers varies with both species and ontogenic stage of development (reviewed by Chan et al, 2001 and references therein). Stem cell potential in haematopoietic tissues. (A) The development of blood vessel endothelial cells and haematopoietic stem cells (HSCs) during normal embryonic development. The haemangioblast (HB) represents a precursor for HSCs and angioblasts that give rise to blood and endothelial cells respectively. (B) A sequence of the proposed lineage development from multipotent adult stem cell (MAPC) and mesenchymal stem cells (MSCs) in the bone marrow (after Moore, 2002). HSC, MAPC and MSC have been found in haematopoietic tissues, suggesting that stem cells from these tissues have a wide developmental or differentiation potential. In the human, the CD34+ subset contains cells capable of generating not only HSC but also blood vessel endothelial cells, while CD45+ C1qRp+ CD34+/– cells produce both HSC and oval stem cells of the liver (Danet et al, 2002). MSC and MAPC are found in the CD45– fraction of haematopoietic tissues, and may be enriched before their selection in culture (Prockop, 1997; Phinney et al, 1999; Pittenger et al, 1999; Jiang et al, 2002a). MSC are generated rapidly in culture, but the cultures are described as heterogeneous, containing self-renewing, spindle and cuboidal cell types (Prockop, 1997; Pittenger et al, 1999). MAPC are generated more slowly in sufficient numbers for analyses after long-term cultures (e.g. 100 d after isolation). MSC, HSC, MAPC, endothelial, neural and muscle precursors are enriched in the CD133+ subsets from either haematopoietic or other tissues (Uchida et al, 2000; Reyes et al, 2002). A variety of progenitors is also found in the side population (SP cells) after Hoechst 33342 separation by flow cytometry (Goodell et al, 1997). These SP cells contain both HSC and other progenitors (e.g. muscle progenitors). They occur in bone marrow, cord blood and fetal liver, as well as in other tissues (e.g. muscle), with Bcrp1/ABC G2 expression being a molecular determinant of the SP cell phenotype (Zhou et al, 2001). Single-cell, genotypic or gene tracking studies, together with functional in vitro and in vivo analyses of purified stem cells, represent the only conclusive way to demonstrate the potentiality or plasticity of stem cells. However, very few studies have achieved these aims. Thus, it is unclear if we are seeing examples of plasticity, a reflection of stem cell potentials, cell fusion or genetic or epigenetic alterations induced by ex vivo culture. Nevertheless, these studies provide us with the opportunity to extend our expertise in haematopoietic stem cell manipulation and transplantation and to use cells from haematopoietic organs in other areas of regenerative medicine (for recent examples, see Table I). Although the plasticity or potentiality of non-HSCs, such as neural cells (Bjornson et al, 1999) or skeletal muscle cells (Jackson et al, 1999), has been reported by several other groups, in this review, we will limit the discussion to the examples where stem cells from haematopoietic tissues have been studied. In order to simplify the issue of stem cell plasticity, we will describe examples of the differentiation of stem cells derived from haematopoietic tissues into non-HSC lineages (see also recent review by Moore, 2002; Fig 3). Studies in animals have shown that BMDC can migrate in the brain and differentiate into neural cells after transplantation into the brain of neonatal and adult mice and rats. These cells were found in several regions of the brain, such as the cortex, hippocampus, thalamus, brain stem and cerebellum, and were positive for neuronal-, microglial- or astroglial-specific markers (Eglitis & Mezey, 1997; Kopen et al, 1999; Brazelton et al, 2000; Mezey et al, 2000, 2003; Nakano et al, 2001; Priller et al, 2001; Sanchez-Ramos et al, 2001; Zhao et al, 2002). It has also been demonstrated that human, rat and mouse MSC and MAPC, obtained from the bone marrow mononuclear cell subset, can generate neurones, oligodendrocytes and astrocytes in vitro (Jiang et al, 2002a). The majority, if not all, of these studies assessed the end-point cell population or lineages by expression of specific tissue markers and not necessarily by cell function. Recently, Mezey et al (2003) have reported the occurrence of donor Y-chromosome-containing cells in the brains of human female recipients who had received bone marrow transplants for lymphoid leukaemias or immune deficiencies using immunohistochemistry and fluorescence in situ hybridization (FISH) analyses. Cells were mostly non-neuronal (e.g. endothelial and circulating haematopoietic cells), but a smaller proportion of donor-derived cells appeared to include oligodendrocytes, astrocytes, microglia, meningeal and ependymal cells. In contrast to most studies, the donor cell distribution did not appear to be random. These researchers have proposed that stem cells are called into areas of the brain, where they expand clonally to repair the tissue. In order to consider the exploitation of BMDC as therapeutics for neurological diseases, functional in vivo assays of the neural cells derived from haematopoietic tissues should be addressed. Animal models for multiple sclerosis, Parkinson's disease (rodent and non-human primate models) and for spinal cord injuries exist and have been or are being used to assess improvement in neurodegenerative diseases after treatment with neuronal stem/progenitor cells (Studer et al, 1998; Uchida et al, 1999, 2000; Martin-Rendon et al, 2001; Sorman et al, 2001; Azzouz et al, 2002; Kim et al, 2002; Pluchino et al, 2003). Similarly, there are reports to suggest that the brain contains neural precursors that can differentiate into haematopoietic cells (Rietze et al, 2001), although recent studies could not demonstrate this as a normal mechanism of differentiation after in vitro manipulation (Morshead et al, 2002). The satellite cells that surround the muscle fibres have been considered to be responsible for the growth and repair of skeletal muscle under normal conditions in post-natal life (reviewed by Goldring et al, 2002). They are regarded as myogenic progenitors, making up to 5% of cell nuclei in muscle fibres, dividing extensively and fusing to form myocytes during the repair of damaged muscle. In vitro, human MAPC generate skeletal muscle cells when treated with 5-azacytidine (Jiang et al, 2002a; Reyes et al, 2002), and MAPC have been isolated from murine skeletal muscle (Jiang et al, 2002b). Adult human MSCs have also been shown to generate human myocytes after in utero injection into sheep (Liechty et al, 2000). The regeneration of damaged muscle fibres by migrating BMDCs has been demonstrated in mice (Ferrari et al, 1998). Thus, marrow-derived progenitors could potentially provide an alternative therapeutic strategy for the treatment of muscular dystrophies. Highly purified ‘HSCs’, or SP cells derived from muscle, from male donors injected intravenously into female recipients have integrated into myotubes in the mdx mouse model of Duchenne muscular dystrophy (Gussoni et al, 1999; Cossu & Mavilio, 2000), with 1% of muscle fibres expressing dystrophin. However, these results may require further consideration as the formation of myotubes from ‘HSCs’ seems to be very infrequent in the mdx mouse model, and it has been suggested recently that mdx mice have the potential to produce revertant dystrophin expressing fibres (Ferrari et al, 2001). When Sca-1+ CD45+ muscle-derived cells were transplanted into lethally irradiated mice, they could generate haematopoietic cells. The results of these experiments indicate that muscle-derived stem cells are of haematopoietic origin (Kawada & Ogawa, 2001; McKinney-Freeman et al, 2002). These studies contradict earlier experiments (Gussoni et al, 1999; Jackson et al, 1999), although CD45– muscle cells with in vivo haematopoietic potential and CD45– MAPC have been isolated from skeletal muscle (Howell et al, 2002; Jiang et al, 2002b; Mahmud et al, 2002). Whether HSC, their offspring or their precursors fuse with myoblasts or myocytes to generate muscle cells has not been addressed sufficiently to date. Cardiomyocytes possess a modest capacity to regenerate after injury (Beltrami et al, 2001). They have been derived in vitro from MSC and MAPC in haematopoietic organs (Wakitani et al, 1995; Prockop, 1997; Makino et al, 1999; Pittenger et al, 1999; Hakumo et al, 2002). The potential of HSCs to transdifferentiate into cardiomyocytes, as well as endothelial and smooth muscle cells, has been examined in a mouse model of myocardial infarction (Orlic et al, 2001a). BMDC from male green fluorescent protein (GFP) transgenic donors were injected directly into the infarcted myocardium of female mice. The results of this experiment showed that the male GFP Lin– c-kit+-expressing bone marrow cells had proliferated, colonizing the infarcted area. These cells expressed markers that were characteristic of cardiac muscle, endothelial and smooth muscle cells (Orlic et al, 2001a). SP cells isolated from murine bone marrow also contribute to cardiomyocyte and blood vessel formation, although their engraftment capacity is low (0·02% for donor cardiomyocytes and 3·3% for donor endothelial cells), and their functional effects were not demonstrated (Jackson et al, 2001). Rat BMDC can also generate both cardiac muscle and endothelial cells when transplanted into the heart after injury. Tomita et al (1999) found that the injection of rat bone marrow cells into cryoscarred hearts promoted angiogenesis. When treated with 5-azacytidine (to induce cardiac-like muscle cell differentiation), rat bone marrow-derived MSC integrated within the scar tissue and restored myocardial function (Tomita et al, 1999). This is the first animal study in which improved cardiac function was reported after transplantation of donor cells into the injured tissue, suggesting that stem cells from haematopoietic tissues may have a great impact in treating cardiovascular diseases. Isogenic bone marrow MSC (not treated with 5-azacytidine) can also generate cardiomyocytes in rats (Wang et al, 2001). When human bone marrow-derived mononuclear cells were injected into the left ventricle of immunodeficient mice, donor cells differentiated into cardiomyocytes (Toma et al, 2002). In this study, however, the function of the injected cells was not assessed. Further studies have revealed that both granulocyte colony-stimulating factor (G-CSF)-mobilized and purified CD34+ human bone marrow precursors injected into rats with acute myocardial infarction can contribute to the revascularization of the damaged heart (Kocher et al, 2001). In vivo mobilization (with stem cell factor, G-CSF or VEGF) of murine HSCs is also associated with an improvement in cardiac function through cardiomyocyte and blood vessel repair (Orlic et al, 2001b) and revascularization of ischaemic retina (Grant et al, 2002). However, these studies have not as yet been efficiently reproduced in non-human primates or for human treatments for cardiovascular disease (Orlic et al, 2002;Norol et al, 2002). Lately, three groups have reported the use of BMDC as stimulators of angiogenesis in ischaemic heart disease in humans (Assmus et al, 2002; Masuya et al, 2003; Stamm et al, 2003; Tse et al, 2003). The first group carried out percutaneous delivery of autologous unfractionated BMDC as a sole therapy (Tse et al, 2003). The second group injected purified bone marrow-derived haematopoietic precursor cells (CD133+ cells) along the infarct zone at the time of coronary artery bypass (Stamm et al, 2003" @default.
W2023096476 created "2016-06-24" @default.
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W2023096476 date "2003-09-01" @default.
W2023096476 modified "2023-10-10" @default.
W2023096476 title "Stem cell plasticity" @default.
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