[Surface antigens on multipotent hematopoietic stem cells].
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Results for “Multipotent Stem Cells”
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Comparison of different assays for multipotent hematopoietic stem cells.
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Animals↗
Hematopoietic stem cells and lymphoid progenitors express different Ikaros isoforms, and Ikaros is localized to heterochromatin in immature lymphocytes.
The generation of lymphoid cells in mice depends on the function of the Ikaros protein. Ikaros has been characterized as a lymphoid-restricted, zinc-finger transcription factor that is derived from an alternatively spliced message. Ikaros knockout mice have defects in multiple cell lineages, raising the question of whether the protein regulates multiple committed progenitors and/or multipotent stem cells. To address this issue, we examined Ikaros expression in purified populations of multipotent cells and more committed progenitors. We found that the DNA-binding isoforms of Ikaros were localized in the nucleus of the most primitive hematopoietic stem cell subset. Changes in the RNA splicing pattern of Ikaros occurred at two stages: (i) as long-term self-renewing stem cells differentiated into short-term self-renewing stem cells and (ii) as non-self-renewing multipotent progenitors differentiated into lymphoid-committed progenitors. Unexpectedly, we found Ikaros localized to heterochromatin in Abelson-transformed pre-B lymphocytes by using immunogold electron microscopy. These observations suggest a complex role for Ikaros in lymphoid development.
Animals↗
Restoration of the bone marrow pluripotent stem cells in AKR mice after arabinosylcytosine treatment.
The hypothesis of repression of multipotent stem cells (CFU) by leukemic cells to explain their depletion, previously demonstrated in AKR leukemic mice, was tested. Using arabinosylcytosine to destroy leukemic cells, it was shown that the bone marrow CFU pool was acutely depressed between 2 h and 12 h after treatment. However, 5 to 7 days later, this pool was restored, surpassing the value of the bone marrow pool in normal mice. This seems to indicate that the CFU pool in leukemic mice is potentially capable of proliferating but is repressed by leukemic cells.
Animals↗
Differentiation of dermis-derived multipotent cells into insulin-producing pancreatic cells in vitro.
AIM: To observe the plasticity of whether dermis-derived multipotent cells to differentiate into insulin-producing pancreatic cells in vitro. METHODS: A clonal population of dermis-derived multipotent stem cells (DMCs) from newborn rat with the capacity to produce osteocytes, chondrocytes, adipocytes and neurons was used. The gene expression of cultured DMCs was assessed by DNA microarray using rat RGU34A gene expression probe arrays. DMCs were further cultured in the presence of insulin complex components (Insulin-transferrin-selenium, ITS) to observe whether DMCs could be induced into insulin-producing pancreatic cells in vitro. RESULTS: DNA microarray analysis showed that cultured DMCs simultaneously expressed several genes associated with pancreatic cell, neural cell, epithelial cell and hepatocyte, widening its transcriptomic repertoire. When cultured in the specific induction medium containing ITS for pancreatic cells, DMCs differentiated into epithelioid cells that were positive for insulin detected by immunohistochemistry. CONCLUSION: Our data indicate that dermal multipotent cells may serve as a source of stem/progenitor cells for insulin-producing pancreatic cells.
Animals↗
A side order of stem cells: the SP phenotype.
A defining property of murine hematopoietic stem cells (HSCs) is low fluorescence after staining with Hoechst 33342 and Rhodamine 123. These dyes have proven to be remarkably powerful tools in the purification and characterization of HSCs when used alone or in combination with antibodies directed against stem cell epitopes. Hoechst low cells are described as side population (SP) cells by virtue of their typical profiles in Hoechst red versus Hoechst blue bivariate fluorescent-activated cell sorting dot plots. Recently, excitement has been generated by the findings that putative stem cells from solid tissues may also possess this SP phenotype. SP cells have now been isolated from a wide variety of mammalian tissues based on this same dye efflux phenomenon, and in many cases this cell population has been shown to contain apparently multipotent stem cells. What is yet to be clearly addressed is whether cell fusion accounts for this perceived SP multipotency. Indeed, if low fluorescence after Hoechst staining is a phenotype shared by hematopoietic and organ-specific stem cells, do all resident tissue SP cells have bone marrow origins or might the SP phenotype be a property common to all stem cells? Subject to further analysis, the SP phenotype may prove invaluable for the initial isolation of resident tissue stem cells in the absence of definitive cell-surface markers and may have broad-ranging applications in stem cell biology, from the purification of novel stem cell populations to the development of autologous stem cell therapies.
Animals↗
In search of adult renal stem cells.
The therapeutic potential of adult stem cells in the treatment of chronic degenerative diseases has becoming increasingly evident over the last few years. Significant attention is currently being paid to the development of novel treatments for acute and chronic kidney diseases too. To date, promising sources of stem cells for renal therapies include adult bone marrow stem cells and the kidney precursors present in the early embryo. Both cells have clearly demonstrated their ability to differentiate into the kidney's specialized structures. Adult renal stem cells have yet to be identified, but the papilla is where the stem cell niche is probably located. Now we need to isolate and characterize the fraction of papillary cells that constitute the putative renal stem cells. Our growing understanding of the cellular and molecular mechanisms behind kidney regeneration and repair processes - together with a knowledge of the embryonic origin of renal cells - should induce us, however, to bear in mind that in the kidney, as in other mesenchymal tissues, the need for a real stem cell compartment might be less important than the phenotypic flexibility of tubular cells. Thus, by displaying their plasticity during kidney maintenance and repair, terminally differentiated cells may well function as multipotent stem cells despite being at a later stage of maturation than adult stem cells. One of the major tasks of Regenerative Medicine will be to disclose the molecular mechanisms underlying renal tubular plasticity and to exploit its biological and therapeutic potential.
Animals↗
Skin: a promising reservoir for adult stem cell populations.
Plasticity of adult cells has been identified in several post-natal tissues in the past few years and has attracted special attention in regenerative medicine. Skin is the biggest organ in the body. Adult skin consists of epidermis, dermis and appendages such as hairs and glands which are linked to the epidermis but project deep into the dermal layer. Skin stem cell biology has been a focus of increasing interest in current life science. Committed stem cells with limited differentiation potential for regeneration and repair of epidermis have been known for decades. Recent studies further report that adult skin tissues contain cell populations with pluripotent characteristics. Multipotent stem cells from hair follicle and non-follicular skin, both in epidermal and dermal tissues, are found to have the differentiation capacity to generate multiple cell lineages. Basing on the present data, our hypothesis is that skin may serve as a local reservoir of various adult stem cell populations, including committed stem cell populations and pluripotent stem cell populations both in epidermal and dermal tissues. Given its easy accessibility, stem cells in skin will not only provide an experimental model for skin biology, but also may provide an experimental model for studying the epithelial-mesenchymal interactions of several other organs outside of skin. The stem cell populations in skin tissues may also have extensive therapeutic implications in the replacement of skin and may serve as an alternative source of stem cells for several other organs outside of skin. The in situ activation and mobilization of stem cell populations in the skin is an ideal way to renew and repair epidermis and dermis, even appendages.
Adult↗
Macrophage inflammatory protein-1 alpha mediated growth inhibition in a haemopoietic stem cell line is associated with inositol 1,4,5 triphosphate generation.
Macrophage Inflammatory Protein-1 alpha (MIP-1 alpha) can inhibit the proliferation of multipotent haemopoietic cells. Using the FDCP-Mix A4 multipotent stem cell line, MIP-1 alpha was shown to inhibit 1L-3 stimulated cell cycling (assessed using the [3H]-thymidine "suicide" assay). Furthermore, MIP-1 alpha can inhibit 1L-3-stimulated [3H]-thymidine incorporation in FDCP-Mix cells, with half maximal inhibition observed at 3 ng/ml MIP-1 alpha. Prostaglandin E2, but not MIP-1 alpha was able to elevate cyclic AMP levels in FDCP-Mix A4 cells although both agents can cause growth inhibition. However, MIP-1 alpha addition resulted in a pertussis-toxin-insensitive increase in the level of the second messenger inositol 1,4,5 triphosphate (Ins 1,4,5P3). This response was both rapid (maximal at 5 seconds) and transient. A half maximal effect was observed at 5 ng/ml MIP-1 alpha and the dose dependency correlated with that for MIP-1 alpha mediated growth inhibition. A rapid increase in cytosolic Ca2+ levels was also observed in response to MIP-1 alpha. Inositol lipid hydrolysis and an increase in cytosolic Ca2+ (signals normally associated with proliferation) may therefore be implicated in growth inhibitory mechanisms in multipotent cells.
Animals↗
Genes involved in stem cell fate decisions and commitment to differentiation play a role in skin disease.
Multipotent stem cells residing in the bulge region of the hair follicle give rise to cells of different fates including those forming hair follicles, interfollicular epidermis, and associated glands. Stem cell fate determination is regulated by genes involved in both proliferation and differentiation, which are tightly regulated processes. Understanding the molecular mechanisms by which proliferation and differentiation are regulated will provide useful insight into treating human diseases caused by the deregulation of these processes. Two genes involved in regulating proliferation and differentiation are c-Myc and p63, both of which have been found to be deregulated/mutated in several human diseases. Accelerating proliferation leads to neoplastic human diseases and deregulated c-Myc has been implicated in a variety of cancers. Evidence indicates that c-Myc also diverts stem cells to an epidermal and sebaceous gland fate at the expense of the hair follicle fate. Therefore, deregulation of c-Myc has the potential to not only accelerate tumorigenesis, but also influence skin tumor phenotype. In addition, the inhibition of differentiation may also predispose to the development of skin cancer. Recent evidence suggests that the transcription factor p63, is not only responsible for the initiation of an epithelial stratification program during development, but also the maintenance of the proliferative potential of basal keratinocytes in mature epidermis. Mutations in the p63 gene have been shown to cause ectodermal dysplasias and deregulated expression of p63 has been observed in squamous cell carcinomas. In this review, we will discuss recent data implicating a role for both c-Myc and p63 in human skin diseases.
Animals↗
[The replicative potential of hepatocytes and liver stem cells].
The cellular basis of liver growth is reviewed from overall recent and previous data. According to the present-day ideas, the adult mammalian liver contains at least two cellular populations with many properties similar to the stem cells of renewing tissues that provide for the liver postnatal growth and parenchyma regeneration under various conditions. According to the present nomenclature, the differentiated parenchyma cells--hepatocytes--are a unipotent committed population of stem cells. In addition, there is a system of nonparenchymal multipotent stem cells or oval cells in the liver. Certain key models of liver growth, regeneration, and repopulation that contributed to development of these notions are considered. The recent data are discussed in the context of yet unclear cellular mechanisms providing for the tremendous replicative potential of hepatocytes, the role of polyploidy in the growth effects, and the sources of malignant transformation in the liver.
Animals↗
Clonality in the myelodysplastic syndromes.
The myelodysplastic syndromes (MDSs) comprise a heterogeneous group of stem cell disorders involving cytopenia and dysplastic changes in 3 hematopoietic lineages. Although it is accepted that MDS is a clonal disorder, the exact nature of the involvement of multipotent stem cells and progenitor cells has not been resolved. Most clonality studies of MDS support the proposal that the primary neoplastic event occurs, in most patients, at the level of a committed myeloid progenitor cell, capable of differentiation into multiple myeloid lineages. The extent of the involvement of T and B lymphocytes in MDS remains controversial. Much of the variation reported may result from disease heterogeneity and technical issues such as skewed methylation patterns occurring in studies analyzing X-chromosome inactivation patterns (XCIP) and possible impurities in lymphocyte preparation. A great deal of the evidence in support of T-lymphocyte involvement in MDS has been generated by XCIP studies, and some of these data need to be treated with caution, especially data from studies in which appropriate controls were omitted. In contrast, B-lymphocyte involvement in some patients with MDS is based on studies using more robust technology including combined immunophenotyping and fluorescence in situ hybridization. Clonality studies involving myeloid and lymphoid cells in MDS have yielded discrepant results with regard to the potential involvement of multipotent (lympho-myeloid) hematopoietic stem cells (HSCs). However, failure to detect a clonal marker in all cells of all lineages does not preclude multipotent-HSC involvement. Some recent studies have produced compelling evidence to show that, in some patients with MDS, the multipotent HSC is the target of the primary neoplastic event. It now seems probable that MDS arises in multipotent HSCs more commonly than previously recognized. Such data not only provide important new insights into the biology of MDS but also may have therapeutic implications. The determination of whether multipotent HSCs are involved in the MDS clone may be important for the use of autologous stem cell transplantation in these patients.
Cell Lineage↗
Matrix cells from Wharton's jelly form neurons and glia.
We have identified an easily attainable source of primitive, potentially multipotent stem cells from Wharton's jelly, the matrix of umbilical cord. Wharton's jelly cells have been propagated in culture for more than 80 population doublings. Several markers for stem cells, including c-kit (CD117), and telomerase activity are expressed in these cells. Treatment with basic fibroblast growth factor overnight and low-serum media plus butylated hydroxyanisole and dimethylsulfoxide induced Wharton's jelly cells to express a neural phenotype. Within several hours of this treatment, Wharton's jelly cells developed rounded cell bodies with multiple neurite-like extensions, similar to the morphology of neural stem cells. Neuron-specific enolase (NSE), a neural stem cell marker, was expressed in these cells, as shown by immunocytochemistry. Immunoblot analysis showed similar levels of NSE expression in both untreated and induced Wharton's jelly cells. After 3 days, the induced Wharton's jelly cells resembled bipolar or multipolar neurons, with processes that formed networks reminiscent of primary cultures of neurons. The neuron-like cells in these cultures stained positively for several neuronal proteins, including neuron-specific class III beta-tubulin, neurofilament M, an axonal growth-cone-associated protein, and tyrosine hydroxylase. Immunoblot analysis showed increasing levels of protein markers for mature neurons over time post induction. Markers for oligodendrocytes and astrocytes were also detected in Wharton's jelly cells. These exciting findings show that cells from the matrix of umbilical cord have properties of stem cells and may, thus, be a rich source of primitive cells. This study shows their capacity to differentiate into a neural phenotype in vitro.
2',3'-Cyclic-Nucleotide Phosphodiesterases↗
Studies of intestinal stem cells using normal, chimeric, and transgenic mice.
The mouse intestinal epithelium represents a continuous developmental system. Its four principal differentiated cell types--enterocytes, goblet, enteroendocrine, and Paneth cells--are derived from a common multipotent stem cell located near the base of monoclonal crypts. Members of these four lineages undergo rapid and perpetual renewal along an anatomically well-defined pathway. The gut epithelium provides a unique mammalian model for studying the biological features of stem cells (e.g., their ability to undergo asymmetric division, their enormous proliferative potential, their capacity for functional anchorage in a niche), examining how stem cell hierarchies are established and maintained in renewing cell populations, analyzing the relationships between passage through the cell cycle and lineage allocation (commitment), and defining the mechanisms that give stem cells a "positional address" along the cephalocaudal axis, allowing them to generate regional differences in the differentiation programs of their derived lineages (axial pattern formation).
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Use of transgenic mice to infer the biological properties of small intestinal stem cells and to examine the lineage relationships of their descendants.
Transgenes, composed of elements of the 5' nontranscribed region of the liver fatty acid-binding protein (L-FABP) gene linked to various reporters, have previously been used to explore the cellular, regional, and temporal differentiation of the mouse intestinal epithelium. In this report, we have analyzed a pedigree of L-FABP/human growth hormone (hGH) transgenic mice that display a stable, heritable, mosaic pattern of reporter expression: wholly hGH-positive or hGH-negative populations of differentiating enterocytes arise from hGH-positive or hGH-negative crypts, respectively, and migrate as vertical coherent bands up the villus producing striped (polyclonal) villi. The ability of enteroendocrine cells within a given villus stripe to support hGH expression coincides with the enterocytic reporter phenotype, suggesting that these two terminally differentiated cells arise from a common multipotent stem cell. hGH-negative crypts are nonrandomly distributed around each villus and their frequency increases along the duodenal-to-ileal axis. Statistical analysis of the observed villus striping pattern suggests that transgene expression is not independently determined in individual crypts but rather in multicrypt "patches." The intact endogenous mouse L-FABP gene (Fabpl) exhibits a similar striped villus pattern of expression in a portion of the distal small intestine. These studies indicate that Fabpl and L-FABP/hGH transgenes represent sensitive markers for exploring the biological properties of gut stem cells and how positional information is encoded in this rapidly and continuously renewing epithelium.
Animals↗
Stable expression of the alkaline phosphatase marker gene by neural cells in culture and after transplantation into the CNS using cells derived from a transgenic rat.
Multipotent stem cells and more developmentally restricted precursors have previously been isolated from the developing nervous system and their properties analyzed by culture assays in vitro and by transplantation in vivo. However, the variety of labeling techniques that have been used to identify grafted cells in vivo have been unsatisfactory. In this article we describe the characteristics of cells isolated from a transgenic rat in which the marker gene human placental alkaline phosphatase (hPAP) is linked to the ubiquitously active R26 gene promoter. We show that hPAP is readily detected in embryonic neuroepithelial stem cells, neuronal-restricted precursor cells, and glial-restricted precursor cells. Transgene expression is robust and can be detected by both immunocytochemistry and histochemistry. Furthermore, the levels of hPAP on the cell surface are sufficient for live cell labeling and fluorescence-activated cell sorting. Expression of hPAP is stable in isolated cells in culture and in cells transplanted into the spinal cord for at least 1 month. We submit that cells isolated from this transgenic rat will be valuable for studies of neural development and regeneration.
Alkaline Phosphatase↗
Subsets of CD34+ cells and rapid hematopoietic recovery after peripheral-blood stem-cell transplantation.
PURPOSE: To study whether there is a relationship between transplanted cell dose and rate of hematopoietic recovery after peripheral-blood stem-cell (PBSC) transplantation, and to obtain an indication whether specific subsets of CD34+ cell populations contribute to rapid recovery of neutrophils or platelets. PATIENTS AND METHODS: Based on data from 59 patients, we calculated for each day after PBSC transplantation the dose of CD34+ cells that resulted in rapid recovery of either neutrophils or platelets in the majority (> 70%) of patients. Using dual-color flow cytometry, subsets of peripheral-blood CD34+ cells were quantified and the numbers of CD34+ cells belonging to each of the reinfused subsets correlated with hematopoietic recovery following high-dose chemotherapy. RESULTS: The calculated threshold values with a high probability of engraftment showed a steep dose-effect relationship between CD34+ cell dose and time to recovery of both neutrophils or platelets. Predominantly CD34+ cells with the phenotype of myeloid precursors were mobilized. A minority of CD34+ cells expressed the erythroid and megakaryocytic lineage-associated antigens and a low but distinct population of CD34+ cells expressed antigens associated with multipotent stem cells. Analysis showed that the number of CD34+CD33- cells (r = -.74, P < .05), as well as the number of CD34+CD41+ cells (r = -.81, P < .005), correlated significantly better with time to neutrophil and platelet recovery, respectively, than with the total number of CD34+ cells (r = -.55 and r = -.56, respectively). CONCLUSION: The numbers of CD34+CD33- cells and CD34+CD41+ cells may help to predict short-term repopulation capacity of PBSCs, especially when relatively low numbers of CD34+ cells per kilogram are reinfused.
Adolescent↗
Growth and differentiation of progenitor/stem cells derived from the human mammary gland.
Estrogen is necessary for the full development of the mammary gland and it is also involved in breast cancer development. We set out to identify and characterise progenitor/stem cells in the human mammary gland and to explore the role of estrogen in their proliferation and differentiation. Three candidate stem cell populations were isolated: double positive (DP) cells co-expressed the luminal and myoepithelial markers, EMA and CALLA, respectively, whereas double negative (DN) cells did not express these cell surface markers; side population (SP) cells were characterised by their differential ability to efflux the dye Hoechst 33342. The ABC transporter, breast cancer resistance protein (BCRP) was more highly expressed in SP cells than in non-SP cells and a specific BCRP inhibitor, Ko143, reduced SP formation, suggesting that BCRP confers the SP phenotype in mammary epithelial cells, as has been demonstrated in other tissues. Interestingly, SP cells were double negative for the EMA and CALLA antigens and therefore represent a separate and distinct population to DP cells. Single cell multiplex RT-PCR indicated that the SP and DN cells do not express detectable levels of ERalpha or ERbeta, suggesting that estrogen is not involved in their proliferation. DP cells expressed ERalpha but at a lower level than differentiated luminal cells. These findings invoke a potential strategy for the breast stem/progenitor cells to ignore the mitogenic effects of estrogen. All three cell populations generated mixed colonies containing both luminal and myoepithelial cells from a single cell and therefore represent candidate multipotent stem cells. However, DN cells predominately generated luminal colonies and exhibited a much higher cloning efficiency than differentiated luminal cells. Further characterisation of these candidate progenitor/stem cells should contribute to a better understanding of normal mammary gland development and breast tumorigenesis.
ATP Binding Cassette Transporter, Subfamily G, Mem↗