Controversy on adult stem-cell plasticity and rules governing the use of fetal tissue in China.
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Distinct hematopoietic progenitor compartments are delineated by the expression of aldehyde dehydrogenase and CD34.
A broad range of hematopoietic stem cells and progenitors reside within a fraction of umbilical cord blood (UCB) that exhibits low light scatter properties (SSC(lo)) and high expression of aldehyde dehydrogenase (ALDH(br)). Many SSC(lo) ALDH(br) cells coexpress CD34; however, other cells express either ALDH or CD34. To investigate the developmental potential of these cell subsets, purified ALDH(br) CD34+, ALDH(neg) CD34+, and ALDH(br) CD34(neg) UCB cells were characterized within a variety of in vivo and in vitro assays. Primitive progenitors capable of multilineage development were monitored in long- and short-term repopulation assays performed on nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and in primary and secondary long-term culture assays. These progenitors were highly enriched within the ALDH(br) CD34+ fraction. This cell fraction also enriched short-term myeloid progenitors that were detected in vitro. By comparison, ALDH(neg) CD34+ cells contained few primitive progenitors and had diminished short-term myeloid potential but exhibited enhanced short-term natural killer (NK) cell development in vitro. The ALDH(br) CD34(neg) cells were not efficiently supported by any of the assays used. These studies suggested that in particular the expression of ALDH delineated distinct CD34+ stem cell and progenitor compartments. The differential expression of ALDH may provide a means to explore normal and malignant processes associated with myeloid and lymphoid development.
Aldehyde Dehydrogenase↗
Specification of neural crest cell formation and migration in mouse embryos.
Of all the model organisms used to study human development, rodents such as mice most accurately reflect human craniofacial development. Collective advances in mouse embryology and mouse genetics continue to shape our understanding of neural crest cell development and by extrapolation the etiology of human congenital head and facial birth defects. The aim of this review is to highlight the considerable progress being made in our understanding of cranial neural crest cell patterning in mouse embryos.
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Quantitative proteomic analysis using isobaric protein tags enables rapid comparison of changes in transcript and protein levels in transformed cells.
Isobaric tags for relative and absolute quantitation, an approach to concurrent, relative quantification of proteins present in four cell preparations, have recently been described. To validate this approach using complex mammalian cell samples that show subtle differences in protein levels, a model stem cell-like cell line (FDCP-mix) in the presence or absence of the leukemogenic oncogene TEL/PDGFRbeta has been studied. Cell lysates were proteolytically digested, and peptides within each sample were labeled with one of four isobaric, isotope-coded tags via their N-terminal and/or lysine side chains. The four labeled samples are mixed and peptides separated by two-dimensional liquid chromatography online to a mass spectrometer (LC-MS). Upon peptide fragmentation, each tag releases a distinct mass reporter ion; the ratio of the four reporters therefore gives relative abundances of the given peptide. Relative quantification of proteins is derived using summed data from a number of peptides. TEL/PDGFRbeta leukemic oncogene-mediated changes in protein levels were compared with those seen in microarray analysis of control and transfected FDCP-mix cells. Changes at the protein level in most cases reflected those seen at the transcriptome level. Nonetheless, novel differences in protein expression were found that indicate potential mechanisms for effects of this oncogene.
Amino Acid Sequence↗
Interleukin-7 is necessary to maintain the B cell potential in common lymphoid progenitors.
Interleukin-7 (IL-7) promotes survival and expansion of lymphoid precursors. We show here that, in addition, IL-7 has a fundamental role, as early as the stage of the multipotent (B/T/NK) common lymphoid progenitor (CLP), in maintaining the B cell differentiation program open. CLPs generated in the absence of IL-7 have normal T/NK differentiation potential, but severely impaired B potential. Accordingly, CLPs from IL-7-deficient mice express lower amounts of early B cell factor (EBF) and Pax5 than wild-type CLPs, but similar amounts of GATA-3. Importantly, induced overexpression of EBF is sufficient to restore the B potential in these cells. These results indicate that IL-7 directs commitment of CLPs by modulating EBF expression. This is the first example of a cytokine influencing lymphoid lineage commitment in multipotent progenitors and highlights the relevance of the expression of a functional IL-7 receptor at the CLP stage.
Animals↗
In vitro identification of human pro-B cells that give rise to macrophages, natural killer cells, and T cells.
In this study we report the molecular and functional characterization of very early interleukin 7 receptor alpha (IL-7Ralpha)+-CD79a+CD19- B-cell progenitors, produced by human CD34+CD19-CD10- cord blood cells grown in the presence of stromal cells and cytokines. Purified IL-7Ralpha+CD79a+CD19- cells transcribed the B-lymphoid specific genes E2A, EBF, TdT, Rag-1, had initiated DJH rearrangements, but almost lacked Pax-5 mRNA. When exposed to appropriate environmental conditions, these cells repressed B-cell genes and completely differentiated into CD14+ macrophages, CD56+ natural killer cells, and CD4high T cells. Retention of the DJH rearranged genes in both CD14+ and CD56+ cells unambiguously demonstrates that early B-cell genes, expressed prior to Pax-5, can be activated in a multipotent human progenitor cell whose final fate, including in non-B lineages, is determined by external signals.
Antigens, CD↗
Prolonged cell cycle transit is a defining and developmentally conserved hemopoietic stem cell property.
Adult mouse hemopoietic stem cells (HSCs) are typically quiescent and enter and progress through the cell cycle rarely in steady-state bone marrow, but their rate of proliferation can be dramatically enhanced on demand. We have studied the cell cycle kinetics of HSCs in the developing fetal liver at a stage when they expand extensively. Despite that 100% of fetal liver HSCs divide within a 48-h period, their average cell cycle transit time (10.6 h) is twice that of their downstream progenitors, translating into a prolonged G(1) transit and a period of relative quiescence (G(0)). In agreement with their prolonged G(1) transit when compared with hemopoietic progenitors, competitive transplantation experiments demonstrate that fetal HSCs are highly enriched in G(1) but also functional in S-G(2)-M. This observation combined with experimental data demonstrating that adult HSCs forced to expand ex vivo also sustain a uniquely prolonged cell cycle and G(1) transit, demonstrate at least in part why purified HSCs at any state of development or condition are highly enriched in the G(0)-G(1) phases of the cell cycle. We propose that a uniquely prolonged cell cycle transit is a defining stem cell property, likely to be critical for their maintenance and self-renewal throughout development.
Animals↗
[Articular cartilage repair with cell transplantation].
Articular cartilage has a limited capacity for repair. Repair of articular cartilage has been an important theme for orthopaedic surgeons. With the progress of tissue engineering in the treatment of articular cartilage injury, we can obtain good results, to some extent, by cell transplantations. This review summarized the present status of the treatment of articular cartilage injuries by cell transplantations.
Animals↗
[Cell transplantation for therapy of rheumatoid arthritis].
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Animals↗
[Characteristics of human embryonic neuronal cells procured by non-enzyme method].
Isolation and culturing of human neuronal progenitor cells is of significant value for both fundamental research and therapeutic purposes. In this work, human embryonic neuronal cells were characterized as a heterogeneous population of progenitor cells with various differentiation potentials. During in vitro culturing the cells are capable of re-inoculating, proliferating, differentiating and migrating. While differentiating, these cells form neurons and glial cells. The present research demonstrates that depending upon the culturing conditions the embryonic neuronal cells may either form floating aggregates (incubation with embryonic serum), attach (incubation without serum), proliferate, or form neurospheres. Besides, peculiarities of aggregate differentiation during their incubation under various media are described.
Cell Culture Techniques↗
Cerebellum- and forebrain-derived stem cells possess intrinsic regional character.
The existence of stem cells in the adult nervous system is well recognized; however, the potential of these cells is still widely debated. We demonstrate that neural stem cells exist within the embryonic and adult cerebellum. Comparing the potential of neural stem cells derived from the forebrain and cerebellum, we find that progeny derived from each of these brain regions retain regional character in vitro as well as after homotopic transplantation. However, when ectopically transplanted, neurosphere-derived cells from either region are largely unable to generate neurons. With regard specifically to embryonic and adult cerebellar stem cells, we observe that they are able to give rise to neurons that resemble different select classes of cerebellar subclasses when grafted into the perinatal host cerebellum. Most notably, upon transplantation to the perinatal cerebellum, cerebellar stem cells from all ages are able to acquire the position and mature electrophysiological properties of cerebellar granule cells.
Aging↗
Foxd3 is required in the trophoblast progenitor cell lineage of the mouse embryo.
The murine blastocyst contains two nonoverlapping pools of progenitor cells: the embryonic component contributes to the fetus and generates embryonic stem cells in vitro, whereas the extraembryonic pool contributes to the placenta and generates trophoblast stem cells in vitro. The transcriptional repressor Foxd3 is required for maintenance of the epiblast and the in vitro establishment of embryonic stem cell lines. Here, we demonstrate that Foxd3 is also required in the trophoblast lineage. Trophoblast progenitors in Foxd3-/- embryos do not self-renew and are not multipotent, but instead give rise to an excess of trophoblast giant cells. Injection of Foxd3-/- blastocysts with wild type ES cells fails to rescue Foxd3-/- placentas and such chimeras die around 10 days of embryogenesis. These results indicate an essential role for Foxd3 in two nonoverlapping progenitor cell populations that require different secreted factors to maintain their multipotent properties in vitro and give rise to divergent tissues in vivo. Moreover, this provides support for the hypothesis that there are conserved molecular mechanisms for maintaining the self-renewing properties of diverse progenitor cell types.
Amino Acid Sequence↗
Early T lymphocyte progenitors.
The earliest steps along the pathway leading to T cells in mice and humans are reviewed. These are the steps between the multipotent hemopoietic stem cell (HSC) and the fully committed precursors undergoing T cell receptor (TCR) gene rearrangement. At this level significant differences between adult and fetal lymphopoiesis have been demonstrated. The extent of lymphoid commitment of precursors within bone marrow is still unresolved, although HSCs clearly undergo developmental changes before migration to the thymus. Both multipotent and T-restricted precursors have now been isolated from fetal blood, suggesting both may seed the thymus. Within the thymus, several minute but discrete populations of T precursors precede the stage of TCR gene rearrangement. They include precursors that are not exclusively T-lineage committed, although they are distinct from HSCs. These precursors have a potential to form NK cells, B cells, dendritic cells, and sometimes other myeloid cells. Some factors that control early lymphoid development are discussed, including IL-7 and the Ikaros transcription factors. These will eventually help to clarify the process of T-lineage commitment.
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The chronic myeloproliferative disorders: clonality and clinical heterogeneity.
The chronic myeloproliferative disorders (MPD), polycythemia vera (PV), chronic idiopathic myelofibrosis (IMF), essential thrombocytosis (ET), and chronic myelogenous leukemia (CML), are thought to be clonal disorders arising in a multipotent hematopoietic progenitor cell. However, establishing the diagnosis of an MPD other than CML is problematic due to a lack of clinically applicable clonal markers. Furthermore, in some patients, in whom a classical MPD phenotype is present, the hematopoietic stem cells appear to be polyclonal, suggesting that the chronic MPD other than CML may actually be a genetically heterogeneous group of disorders. Furthermore, since the aberrant clone is believed to arise from a multipotent hematopoietic stem cell, the non-CML chronic MPD-ET, PV, and IMF-could be related. Additional unresolved issues regarding the MPD include: identification of the multipotent hematopoietic progenitor cell involved, the molecular basis for the clinical heterogeneity amongst the individual MPD, the clinical significance of clonality in non-CML MPD, and reconciliation of therapy with the clonal and clinical heterogeneity of these disorders. Determination of clonality has largely been carried out using X chromosome-linked polymorphisms, but such studies are limited to women and with increasing patient age are compromised by skewing of allelic expression in both neutrophils and T lymphocytes, making the results difficult to interpret. X chromosome-linked polymorphism studies have indicated that in PV the target stem cell is one that gives rise to both lymphoid and myeloid progenitors. Recently, two epigenetic markers have been identified in the MPD: impaired expression of the thrombopoietin receptor, Mpl, in platelets and megakaryocytes, and overexpression in neutrophils of the mRNA of a gene designated polycythemia rubra vera-1 (PRV-1). The role of these epigenetic abnormalities in the diagnosis of the MPD remains to be established. Currently, given the unresolved issues with respect to the clinical and clonal heterogeneity of the MPD, treatment needs to be tailored individually in patients with an MPD.
Age Factors↗
Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium.
Endocrine cells of the pancreas and the gastrointestinal tract derive from multipotent endodermal stem cells. We have shown previously that the basic helix- loop-helix (bHLH) transcription factor neurogenin3 (ngn3) is required for the specification of the endocrine lineage in uncommitted progenitors in the developing pancreas. We investigate herein the expression and the function of ngn3 in the control of endocrine cell development in the intestinal and gastric epithelium. Our results indicate that as in the pancreas, gastrointestinal endocrine cells derive from ngn3-expressing progenitors. Mice homozygous for a null mutation in ngn3 fail to generate any intestinal endocrine cells, and endocrine progenitor cells are lacking. The other main intestinal epithelial cell types differentiate properly. In contrast, in the glandular stomach, the differentiation of the gastrin- (G cells) and somatostatin (D cells)-secreting cells is impaired whereas serotonin- (enterochromaffin EC cells), histamine- (enterochromaffin-like ECL cells) and ghrelin (X/A cells)-expressing cells are still present. Thus, ngn3 is strictly required for endocrine cell fate specification in multipotent intestinal progenitor cells, whereas gastric endocrine development is both ngn3 dependent and independent.
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Neural stem cells: plasticity and their transdifferentiation potential.
The presence of resident stem cells in adult tissues is of fundamental importance for the maintenance of their structural and functional integrity. In fact, throughout life, somatic stem cells attend to the critical function of substituting terminally differentiated cells lost to physiological turnover, injury or disease. Thence, one of the basic dogmata in tissue biology holds that the differentiation potential of an adult stem cell is restricted to the generation of the mature cell lineages found in the tissue to which the stem cell belongs. A plethora of recent evidences from many groups, including ours, is now providing evidence that adult stem cells may possess a broader differentiation repertoire than expected and that their fate potential may not be as tissue specific as once thought. The initial example of an unforeseen, trans-germ layer plasticity - that seems now to emerge as a prototypic functional trait of various somatic stem cells of different origin - has come from the reported awakening of a latent hemopoietic developmental capacity in stem cells isolated from the adult mammalian brain following their transplantation into sub-lethally irradiated mice. More recently, it has been shown that adult neural stem cells can differentiate into a wide array of bodily cells of different origin when injected into the blastocyst and into myogenic cells when transplanted into the adult regenerating skeletal muscle. Moreover, bone marrow stem cells can now give rise to skeletal muscle, hepatic and brain cells, whereas muscle precursors can generate blood cells. In this article, we review some of the basic notions regarding the functional properties of the adult neural stem cells and discuss findings in the expanding area of trans-germ layer conversion, with emphasis on the neural stem cell.
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Defining a developmental path to neural fate by global expression profiling of mouse embryonic stem cells and adult neural stem/progenitor cells.
To understand global features of gene expression changes during in vitro neural differentiation, we carried out the microarray analysis of embryonic stem cells (ESCs), embryonal carcinoma cells, and adult neural stem/progenitor (NS) cells. Expression profiling of ESCs during differentiation in monolayer culture revealed three distinct phases: undifferentiated ESCs, primitive ectoderm-like cells, and neural progenitor cells. Principal component (PC) analysis revealed that these cells were aligned on PC1 over the course of 6 days. This PC1 represents approximately 4,000 genes, the expression of which increased with neural commitment/differentiation. Furthermore, NS cells derived from adult brain and their differentiated cells were positioned along this PC axis further away from undifferentiated ESCs than embryonic stem-derived neural progenitors. We suggest that this PC1 defines a path to neural fate, providing a scale for the degree of commitment/differentiation.
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