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PubMed2005

Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells.

Like mesenchymal stem cells from bone marrow (BM-MSCs), adipose tissue-derived adult stem cells (ADAS cells) can differentiate into several lineages and present therapeutical potential for repairing damaged tissues. The use of allogenic stem cells can enlarge their therapeutical interest, provided that the grafted cells could be tolerated. We investigate here, for the first time, the immunosuppressive properties of ADAS cells compared with the well-characterized immunosuppressive properties of BM-MSCs. ADAS cells did not provoke in vitro alloreactivity of incompatible lymphocytes and, moreover, suppressed mixed lymphocyte reaction (MLR) and lymphocyte proliferative response to mitogens. The impairment of inhibition when ADAS cells and BM-MSCs were separated from lymphocytes by a permeable membrane suggests that cell contact is required for a full inhibitory effect. Hepatocyte growth factor is secreted by both stem cells but, similar to interleukin-10 and transforming growth factor-beta (TGF-beta), the levels of which were undetectable in supernatants of MLR inhibited by ADAS cells or BM-MSCs, it did not seem implicated in the stem cell suppressive effect. These findings support that ADAS cells share immunosuppressive properties with BM-MSCs. Therefore, ADAS cell-based reconstructive therapy could employ allogenic cells and because of their immunosuppressive properties, ADAS cells could be an alternative source to BM-MSCs to treat allogenic conflicts.

Adipose Tissue↗
PubMed1984

Expression of cell surface determinant(s) on murine myeloma stem cells and hematopoietic stem cells.

Murine B cell lymphomas and myelomas were examined for the expression of a determinant previously found exclusively on normal pluripotent stem cells colony-forming unit-spleen (CFU-s). This determinant(s), which is defined by a rabbit antimouse brain antiserum (R alpha MB), is present on the tumor stem cell population of some but not all B cell neoplasms examined. The determinant is not detected on tumor cells of the macrophage or T cell lineage. Absorption of the activity in R alpha MB with myeloma cells, concomitantly removed reactivity with the normal stem cell, CFU-s, and the myeloma stem cell, plasmacytoma CFU-s. Sorting analysis further showed that the antigen was diminished within a positive tumor population as cells acquired the capacity to secrete immunoglobulin. These studies suggest that this normal stem cell-associated antigen may also be an early differentiation antigen for the B cell lineage, and is expressed on some stem cells of B cell tumors.

Animals↗
PubMed2004

Genetic regulation of mouse stem cells: identification of two keratinocyte stem cell regulatory loci.

It is well documented that the bulge of hair follicle is a 'niche' for a significant population of mouse keratinocyte stem cells, and 95% of rodent clonogenic keratinocytes originate from the bulge region. The ability to form colonies in vitro is a well recognized test for keratinocyte stem cells. We analyzed the epidermis of seven mouse strains and their segregating crosses [(BALB/c x C57BL/6)F1; (BALB/c x CB6F1); (C57BL/ 6 x CB6F1); (CBF1 x CBF1)F2] for their clonogenic activity in vitro. We found that keratinocyte colony (KC) number is a new quantitative multigenic trait. The analysis of KC size in two parental strains (C57BL/6 and BALB/c), the F1 generation and the segregating crosses demonstrated that the size of KC is a quantitative complex trait also. We determined that mouse epidermis has at least two subpopulations of keratinocytes that gave small (< 2 mm2) and large (> 2 mm2) colonies. The differences in the number of small and large colonies between parental strains (C57BL/6, BALB/c) were significant (P < 0.01). A genome-wide scan of the intercross and the two backcrosses maps the number of small KC to the central region of mouse Chromosome 9 (genomewide P value = 0.01). We define this locus as Ksc1. The proximal region of chromosome 4 is associated with the high number of large KC. We defined this locus as Ksc2. We found that Ksc1 and minor loci on chromosomes 6 and 7 map close, if not equal to, loci associated with mouse skin carcinogenesis. We conclude that mouse epidermis has at least two subpopulations of clonogenic keratinocyte stem cells that are regulated by different genes. We suggest that keratinocyte stem cells responsible for small colonies may play a major role in the regulation of resistance or sensitivity to skin carcinogenesis. Investigation of the genes regulating the stem cell number should provide new insight into the mechanisms of skin carcinogenesis, and should help to develop new approaches for therapies not only against active proliferating tumor cells but also quiescent tumor stem cells.

Animals↗
PubMed2005

The UK Stem Cell Bank: its role as a public research resource centre providing access to well-characterised seed stocks of human stem cell lines.

The rapidly expanding field of stem cell research offers the potential to develop therapeutic agents to treat diseases such as Parkinson's, diabetes and heart disease. It is important that stem cell lines derived from quality-controlled and well-characterised cell banks should be made available to both the scientific and clinical communities to promote high-quality research and development. The requirement in the United Kingdom (UK) for rigorous regulation of the procurement and use of embryonic stem (ES) cell lines led the UK government to fund the establishment of a national bank for stem cell lines. The UK Stem Cell Bank (UKSCB) hosted at the National Institute for Biological Standards and Control (NIBSC) is committed to working closely with the clinical and research communities to provide qualified stocks of human stem cell lines of adult, foetal and embryonic origin for both research use and for use in emerging human therapy.

Biological Specimen Banks↗
PubMed2005

The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals.

The stem cell niches at the apex of Drosophila ovaries and testes have been viewed as distinct in two major respects. While both contain germline stem cells, the testis niche also contains "cyst progenitor" stem cells, which divide to produce somatic cells that encase developing germ cells. Moreover, while both niches utilize BMP signaling, the testis niche requires a key JAK/STAT signal. We now show, by lineage marking, that the ovarian niche also contains a second type of stem cell. These "escort stem cells" morphologically resemble testis cyst progenitor cells and their daughters encase developing cysts before undergoing apoptosis at the time of follicle formation. In addition, we show that JAK/STAT signaling also plays a critical role in ovarian niche function, and acts within escort cells. These observations reveal striking similarities in the stem cell niches of male and female gonads, and suggest that they are largely governed by common mechanisms.

Animals↗
PubMed2005

Quiescence of hematopoietic stem cells and maintenance of the stem cell pool is not dependent on TGF-beta signaling in vivo.

OBJECTIVE: Maintained quiescence of hematopoietic stem cells (HSCs) is of critical importance to prevent premature exhaustion of the stem cell pool under conditions of hematopoietic stress. The growth inhibitory cytokine transforming growth factor beta (TGF-beta) has been shown to play a critical role in maintaining quiescence of HSCs in vitro. Here, we have used conditional knockout mice for the TGF-beta type I receptor (TbetaRI) to ask whether the naturally quiescent state of HSCs in vivo is dependent on TGF-beta signaling and thus whether TGF-beta serves as a protective factor for the stem cell pool during conditions of stress. METHODS: TbetaRI null and control bone marrow chimeras were subjected to repeated treatments with the cell cycle-specific cytotoxic drug 5-fluorouracil (5-FU) and surviving HSCs were assayed by competitive transplantation experiments. Exhaustion of stem cells was provoked by serially transplanting TGF-beta signaling-deficient as well as normal BM cells into lethally irradiated recipients, which were monitored for survival. RESULTS: Surprisingly, we found that TGF-beta receptor-deficient HSCs have similar susceptibility, compared to controls, to repeated 5-FU treatments, indicative of normally maintained quiescence in these cells. Likewise, hematopoietic failure occurred at similar stages in serially transplanted recipients of TbetaRI null and control BM, respectively, demonstrating normal consumption of the stem cell pool during hematopoietic stress. CONCLUSIONS: These findings clearly demonstrate that, despite a key role in vitro, TGF-beta does not provide the necessary signal that induces the quiescent state of HSCs and maintains the stem cell pool in vivo.

Animals↗
PubMed2003

Side population keratinocytes resembling bone marrow side population stem cells are distinct from label-retaining keratinocyte stem cells.

Very primitive hematopoietic stem cells have been identified as side population cells based on their ability to efflux a fluorescent vital dye, Hoechst 33342. In this study we show that keratinocytes with the same side population phenotype are also present in the human epidermis. Although side population keratinocytes have the same dye-effluxing phenotype as bone marrow side population cells and can be blocked by verapamil, they do not express increased levels of the ABCG2 transporter that is believed to be responsible for the bone marrow side population phenotype. Because bone marrow side population cells have stem cell characteristics, we sought to determine if side population keratinocytes represent a keratinocyte stem cell population by comparing side population keratinocytes with a traditional keratinocyte stem cell candidate, label-retaining keratinocytes. Flow cytometric analyses demonstrated that side population keratinocytes have a different cell surface phenotype (low beta1 integrin and low alpha6 integrin expression) than label-retaining keratinocytes and represent a unique population of keratinocytes distinctly different from the traditional keratinocyte stem cell candidate. Future in vivo studies will be required to analyze the function of side population keratinocytes in epidermal homeostasis and to determine if side population keratinocytes have characteristics of keratinocyte stem cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Maintenance of pluripotential embryonic stem cells by stem cell selection.

As gastrulation proceeds, pluripotential stem cells with the capacity to contribute to all primary germ layers disappear from the mammalian embryo. The extinction of pluripotency also occurs during the formation of embryoid bodies from embryonic stem (ES) cells. In this report we show that if the initial differentiated progeny are removed from ES cell aggregates, further differentiation does not proceed and the stem cell population persists and expands. Significantly, the presence of even minor populations of differentiated cells lead to the complete loss of stem cells from the cultures. This finding implies that the normal elimination of pluripotent cells is dictated by inductive signals provided by differentiated progeny. We have exploited this observation to develop a strategy for the isolation of pluripotential cells. This approach, termed stem cell selection, may have widespread applicability to the derivation and propagation of stem cells.

Animals↗
PubMed2006

Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence.

Considerable progress has been made in characterizing epidermal stem cells by microarray analysis of FACS-selected populations. One limitation of this approach is that the gene expression profiles represent the average of the cell population, potentially masking cellular heterogeneity of functional significance. To overcome this problem, we have performed single-cell expression profiling. We have generated cDNA libraries from single human epidermal cells, designated as stem or transit-amplifying cells on the basis of Delta1 and melanoma-associated chondroitin sulfate proteoglycan expression. Of the 14 putative stem cell markers identified, we selected one, the EGF receptor antagonist leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1), for further study. Lrig1 was expressed in groups of basal cells in human interfollicular epidermis previously identified as enriched for stem cells. Overexpression of Lrig1 decreased keratinocyte proliferation but did not affect the proportion of stem and transit-amplifying cells, as judged by clonal growth characteristics. Down-regulation of Lrig1 using siRNA increased cell-surface EGF receptor levels, enhanced activation of downstream pathways, and stimulated proliferation. Lrig1 acted in part by negatively regulating the Myc promoter. We propose that Lrig1 maintains epidermal stem cells in a quiescent nondividing state, and that Lrig1 down-regulation triggers proliferation.

Biological Transport↗
PubMed2003

The effects of air flow and stem flexure on the mechanical and hydraulic properties of the stems of sunflowers Helianthus annuus L.

Many studies have shown that wind affects plant development, causing them to develop shorter and usually stronger stems. Many of these effects have been shown to be due to a response to mechanical flexing of the stem which is known as thigmomorphogenesis. However, it is not known how wind affects the hydraulic properties of stems, nor have the effects of air flow past leaves been examined in isolation from mechanical flexing. This study, therefore, used a factorial experiment to distinguish between the effects of stem flexing and air flow, and examined the morphology, hydraulics and mechanics of developing sunflowers Helianthus annuus. It was found that flexure and air flow had opposite effects on several aspects of development; air flow increased plant height and length-specific stem hydraulic conductivity, k(h), and reduced stem rigidity and strength, while flexing did the reverse. There was also a clear trade-off between hydraulic and mechanical capability: as one increased the other decreased. A plant's response to wind must, therefore, be a complex response to at least two different stimuli and this might help explain why it varies with species and environment.

Algorithms↗
PubMed2005

Highly efficient cellular labeling of mesoporous nanoparticles in human mesenchymal stem cells: implication for stem cell tracking.

Tracking the distribution of stem cells is crucial to their therapeutic use. However, the usage of current vectors in cellular labeling is restricted by their low internalizing efficiency. Here, we reported a cellular labeling approach with a novel vector composed of mesoporous silica nanoparticles (MSNs) conjugated with fluorescein isothiocyanate in human bone marrow mesenchymal stem cells and 3T3-L1 cells, and the mechanism about fluorescein isothiocyanate-conjugated MSNs (FITC-MSNs) internalization was studied. FITC-MSNs were efficiently internalized into mesenchymal stem cells and 3T3-L1 cells even in short-term incubation. The process displayed a time- and concentration-dependent manner and was dependent on clathrin-mediated endocytosis. In addition, clathrin-dependent endocytosis seemed to play a decisive role on more internalization and longer stay of FITC-MSNs in mesenchymal stem cells than in 3T3-L1 cells. The internalization of FITC-MSNs did not affect the cell viability, proliferation, immunophenotype, and differentiation potential of mesenchymal stem cells, and 3T3-L1 cells. Finally, FITC-MSNs could escape from endolysosomal vesicles and were retained the architectonic integrity after internalization. We conclude that the advantages of biocompatibility, durability, and higher efficiency in internalization suit MSNs to be a better vector for stem cell tracking than others currently used.

3T3-L1 Cells↗
PubMed2004

Efficient production of neural stem cells and neurons from embryonic stem cells.

We have developed a simple method to efficiently produce a large number of neural stem cells and neurons from mouse embryonic stem (ES) cells. When cultured in astrocyte-conditioned medium (ACM) with mitogens (FGF-2 and EGF) under free-floating conditions, colonies of undifferentiated ES cells give rise to neural stem spheres (NSSs), composed of plentiful neural stem cells. Subsequent culture of the NSSs on an adhesive substrate with mitogens results in the migration of neural stem cells onto the substrate. These cells can be expanded, preserved by freezing, and differentiated into functional neurons. Neural stem cells and neurons provided by this NSS method may be valuable as potential donor cells for neuronal transplantation and also as convenient alternatives to tissue-derived neural cells.

Animals↗
PubMed1998

Epidermal stem cells: markers, patterning and the control of stem cell fate.

Within the epidermis, proliferation takes place in the basal layer of keratinocytes that are attached to an underlying basement membrane. Cells that leave the basal layer undergo terminal differentiation as they move towards the tissue surface. The basal layer contains two types of proliferative keratinocyte: stem cells, which have unlimited self-renewal capacity, and transit amplifying cells, those daughters of stem cells that are destined to withdraw from the cell cycle and terminally differentiate after a few rounds of division. Stem cells express higher levels of the beta 1-integrin family of extracellular matrix receptors than transit amplifying cells and this can be used to isolate each subpopulation of keratinocyte and to determine its location within the epidermis. Variation in the levels of E-cadherin, beta-catenin and plakoglobin within the basal layer suggests that stem cells may also differ from transit amplifying cells in intercellular adhesiveness. Stem cells have a patterned distribution within the epidermal basal layer and patterning is subject to autoregulation. Constitutive expression of the transcription factor c-Myc promotes terminal differentiation by driving keratinocytes from the stem cell compartment into the transit amplifying compartment.

Animals↗
PubMed2005

A RING domain gene is expressed in different cell types of leaf trace, stem, and juvenile bundles in the stem vascular system of zinnia.

The in vitro zinnia (Zinnia elegans) mesophyll cell system, in which leaf mesophyll cells are induced to transdifferentiate into tracheary elements with high synchrony, has become an established model for studying xylogenesis. The architecture of the stem vascular system of zinnia cv Envy contains three anatomically distinct vascular bundles at different stages of development. Juvenile vascular strands of the subapical region develop into mature vascular strands with leaf trace segments and stem segments. Characteristic patterns of gene expression in juvenile, leaf trace, and stem bundles are revealed by a molecular marker, a RING domain-encoding gene, ZeRH2.1, originally isolated from a zinnia cDNA library derived from differentiating in vitro cultures. Using RNA in situ hybridization, we show that ZeRH2.1 is expressed preferentially in two specific cell types in mature zinnia stems. In leaf trace bundles, ZeRH2.1 transcript is abundant in xylem parenchyma cells, while in stem bundles it is abundant in phloem companion cells. Both of these cell types show wall ingrowths characteristic of transfer cells. In addition, ZeRH2.1 transcript is abundant in some phloem cells of juvenile bundles and in leaf palisade parenchyma. The complex and developmentally regulated expression pattern of ZeRH2.1 reveals heterogeneity in the vascular anatomy of the zinnia stem. We discuss a potential function for this gene in intercellular transport processes.

Amino Acid Sequence↗
PubMed2006

Are stem cells drugs? The regulation of stem cell research and development.

Stem cell research and its clinical application have become political, social, and medical lightning rods, polarizing opinion among members of the lay community and among medical/scientific professionals. A potpourri of opinion, near-anecdotal observation, and scientifically sound data has sown confusion in ways rarely seen in the medical arts and sciences. A major issue is regulation, with different aspects of stem cell research falling within the purview of different government agencies and local offices. An overarching clearinghouse to review the field and recommend policy is lacking. In the following pages, I touch on the societal framework for regulation, the known and potential risks and benefits of cardiovascular stem cell therapies, whether stem cells should be regulated as drugs or in analogy to drugs, and if there is to be regulation, then by whom. In so doing, I refer to the stem cell literature only as it relates to the discussion of regulation because this is not a review of stem cell research; it is an opinion regarding regulation.

Biomedical Research↗
PubMed2005

CD133-positive hematopoietic stem cell "stemness" genes contain many genes mutated or abnormally expressed in leukemia.

Affymetrix human Hu133A oligonucleotide arrays were used to study the expression profile of CD133+ cord blood (CB) and peripheral blood (PB) using CD133 cell-surface marker. An unsupervised hierarchical clustering of 14,025 valid probe sets showed a clear distinction between the CD133+ cells representing the hematopoietic stem cell (HSC) population and CD133-differentiated cells. Two hundred forty-four genes were found to be upregulated by at least twofold in the CD133-positive cells of both CB and PB compared with the CD133-negative cells. These genes represent the hematopoietic "stemness," whereas the 218 and 304 upregulated genes exclusively in PB and CB, respectively, represent tissue specificity. Some of the stemness genes were also common to HSC genes found to be upregulated in several recently published studies. Among these common stemness genes, we identified several groups of genes that have an important role in hematopoiesis: growth factor receptors, transcription factors, genes that have an important role in development, and genes involved in cell growth. Sixteen selected stemness genes are known to be mutated or abnormally regulated in acute leukemias. It can be suggested that key hematopoietic stemness machinery genes may lead to abnormal proliferation and leukemia upon mutation or change of their expression.

AC133 Antigen↗
PubMed2003

Designing, testing, and validating a focused stem cell microarray for characterization of neural stem cells and progenitor cells.

Fetal neural stem cells (NSCs) have received great attention not only for their roles in normal development but also for their potential use in the treatment of neurodegenerative disorders. To develop a robust method of assessing the state of stem cells, we have designed, tested, and validated a rodent NSC array. This array consists of 260 genes that include cell type-specific markers for embryonic stem (ES) cells and neural progenitor cells as well as growth factors, cell cycle-related genes, and extracellular matrix molecules known to regulate NSC biology. The 500-bp polymerase chain reaction products amplified and validated by using gene-specific primers were arrayed along with positive controls. Blanks were included for quality control, and some genes were arrayed in duplicate. No cross-hybridization was detected. The quality of the arrays and their sensitivity were also examined by using probes prepared by conventional reverse transcriptase or by using amplified probes prepared by linear polymerase replication (LPR). Both methods showed good reproducibility, and probes prepared by LPR labeling appeared to detect expression of a larger proportion of expressed genes. Expression detected by either method could be verified by RT-PCR with high reproducibility. Using these stem cell chips, we have profiled liver, ES, and neural cells. The cell types could be readily distinguished from each other. Nine markers specific to mouse ES cells and 17 markers found in neural cells were verified as robust markers of the stem cell state. Thus, this focused neural stem array provides a convenient and useful tool for detection and assessment of NSCs and progenitor cells and can reliably distinguish them from other cell populations.

Animals↗
PubMed2005

Stem cell therapy for neurologic disorders: therapeutic potential of adipose-derived stem cells.

There is growing evidence to suggest that reservoirs of stem cells may reside in several types of adult tissue. These cells may retain the potential to transdifferentiate from one phenotype to another, presenting exciting possibilities for cellular therapies. Recent discoveries in the area of neural differentiation are particularly exciting given the limited capacity of neural tissue for intrinsic repair and regeneration. Adult adipose tissue is a rich source of mesenchymal stem cells, providing an abundant and accessible source of adult stem cells. These cells have been termed adipose derived stem cells (ASC). The characterization of these ASCs has defined a population similar to marrow-derived and skeletal muscle-derived stem cells. The success seen in differentiating ASC into various mesenchymal lineages has generated interest in using ASC for neuronal differentiation. Initial in vitro studies characterized the morphology and protein expression of ASC after exposure to neural induction agents. Additional in vitro data suggests the possibility that ASCs are capable of neuronal activity. Progress in the in vitro characterization of ASCs has led to in vivo modeling to determine the survival, migration, and engraftment of transplanted ASCs. While work to define the mechanisms behind the transdifferentiation of ASCs continues, their application to neurological diseases and injuries should also progress. The subject of this review is the capacity of adipose derived stem cells (ASC) for neural transdifferentiation and their application to the treatment of various neurologic disorders.

Adipocytes↗