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At least 19 recordsLinked to original sources
PubMed2001

The skeletal muscle satellite cell: stem cell or son of stem cell?

The concept of the adult tissue stem cell is fundamental to models of persistent renewal in functionally post-mitotic tissues. Although relatively ignored by stem cell biology, skeletal muscle is a prime example of an adult tissue that can generate terminally differentiated cells uniquely specialized to carry out tissue-specific functions. This capacity is attributed to satellite cells, a population of undifferentiated, quiescent precursors that become activated to divide and differentiate in response to the demands of growth or damage. The aim of this review is to discuss the role of the satellite cell as an adult tissue-specific stem cell. We examine evidence for the presence of behaviourally and phenotypically distinct subpopulations of precursor within the satellite cell pool. Further, we speculate on the possible identity, origins and relevance of multipotent muscle stem cells, a population with both myogenic and hematopoietic potentials that has been isolated from whole muscle. Taken together, current evidence suggests the possibility that the regenerative compartment of adult skeletal muscle may conform to an archetypal stem cell-based hierarchy, maintained within a stem cell niche. It therefore remains to be seen whether all satellite cells are skeletal muscle-specific stem cells, or whether some or all are the progeny of an as yet unidentified muscle stem cell.

Animals↗
PubMed2003

Embryonic stem cells. Stem cell programs.

The availability of human embryonic stem cell lines provides an important tool for scientists to explore the fundamental mechanisms that regulate differentiation into specific cell types. When more is known about the mechanisms that govern these processes, human embryonic stem cells may be clinically useful in generating cell types that have been damaged or depleted by a variety of human diseases. The NIH is actively pursuing a variety of initiatives to promote this developing research field, while continuing and expanding its long-standing investment in adult stem cells and research.

Advisory Committees↗
PubMed2005

Changes in circulating mesenchymal stem cells, stem cell homing factor, and vascular growth factors in patients with acute ST elevation myocardial infarction treated with primary percutaneous coronary intervention.

OBJECTIVE: To investigate the spontaneous occurrence of circulating mesenchymal stem cells (MSC) and angiogenic factors in patients with ST elevation acute myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). DESIGN: In 20 patients with STEMI, blood samples were obtained on days 1, 3, 7, 14, 21, and 28 after the acute PCI. Fifteen patients with a normal coronary angiography formed a control group. MSC (CD45-/CD34-), plasma stromal derived factor 1 (SDF-1), vascular endothelial growth factor A (VEGF-A), and fibroblast growth factor 2 (FGF-2) were measured by multiparametric flow cytometry and enzyme linked immunosorbent assay (ELISA). RESULTS: Circulating CD45-/CD34- cells were significantly decreased on day 7 compared with day 3. Cell counts normalised one month after the acute onset of STEMI. The changes were mainly seen in patients with a large infarction. Plasma SDF-1 increased significantly from day 3 to day 28, and VEGF-A and FGF-2 increased significantly from day 7 to day 28. CONCLUSIONS: Spontaneous sequential fluctuations in MSC and the increase in vascular growth factor concentrations after STEMI suggest that the optimal time for additional stem cell therapy is three weeks after a myocardial infarction to obtain the maximum effects by stimulating endogenous growth factors on the delivered stem cells.

Angioplasty, Balloon, Coronary↗
PubMed2004

Routes to regenerating islet cells: stem cells and other biological therapies for type 1 diabetes.

New biological therapies for type 1 diabetes are emerging from the forefront of stem cell and islet cell biology. Basic research in animal models has uncovered a variety of mechanisms by which natural regeneration of pancreatic islet cells occurs, despite the underlying autoimmune defect. Two mechanisms - in particular, beta-islet cell proliferation and stem cell differentiation - can be harnessed in innovative ways in order to regenerate islets lost to disease. This review provides a background on stem cells and describes a range of potential biological therapies for type 1 diabetes, including the use of adult stem cells from the spleen, an organ not previously considered a source of pancreatic stem cells. Stem cells of the spleen have been demonstrated to home to the pancreas, where they mature into fully functional islet cells responsible for restoring normoglycemia. If the underlying autoimmune defect can be eradicated, stem cells of the spleen, as well as related strategies, can be used in order to regrow islets destroyed by type 1 diabetes.

Cell Differentiation↗
PubMed2003

Studies on BrdU labeling of hematopoietic cells: stem cells and cell lines.

Studies using chronic in vivo BrdU exposure, isolating primitive stem cells, and determining BrdU labeling, indicate that stem cells cycle. BrdU is also incorporated into DNA during damage/repair. DNA, which has incorporated BrdU due to cycle transit is heavier than normal, while the density of DNA with damage/repair incorporation is intermediate. DNA density of purified lineage-rhodamine low (rho(low)) Hoechst low (Ho(low)) stem cells or FDC-P1 cell line cells-was assessed in vitro, after exposure to cytokines and BrdU (cycling model) or cytokines and BrdU with bleomycin to induce strand breaks and hydroxyurea to halt cycle progression (damage/repair model). We determined DNA density using cesium chloride (CsCl) gradients and either fluorometry or dot blot chemiluminesence. DNA from BrdU labeled cycling Lin-rho(lo)Ho(lo) or FDC-P1 cells was heavier than normal DNA, while damage repair DNA had an intermediate density. We then assessed BrdU labeling of Lin-rho(lo)Ho(lo) cells in vivo. We found that 70.9% of lin-rho(lo)Ho(lo) cells labeled at 5 weeks. DNA density of these cells was low, in the damage/repair range, but similar results were obtained with stem cells, which had proliferated in vivo. Dilution of BrdU in in vitro culture of proliferating FDC-P1 cells also resulted in damage/repair density. We conclude that in vitro BrdU labeling models can distinguish between proliferation and damage/repair, but that we cannot obtain high enough in vivo levels to address this issue. All together, while we cannot absolutely exclude damage/repair as contributing to stem cell BrdU labeling, the data indicate that primitive bone marrow stem cells are probably a cycling population.

Animals↗
PubMed2001

Pluripotent cells (stem cells) and their determination and differentiation in early vertebrate embryogenesis.

Mammalian embryonic stem cells can be obtained from the inner cell mass of blastocysts or from primordial germ cells. These stem cells are pluripotent and can develop into all three germ cell layers of the embryo. Somatic mammalian stem cells, derived from adult or fetal tissues, are more restricted in their developmental potency. Amphibian ectodermal and endodermal cells lose their pluripotency at the early gastrula stage. The dorsal mesoderm of the marginal zone is determined before the mid-blastula transition by factors located after cortical rotation in the marginal zone, without induction by the endoderm. Secreted maternal factors (BMP, FGF and activins), maternal receptors and maternal nuclear factors (beta-catenin, Smad and Fast proteins), which form multiprotein transcriptional complexes, act together to initiate pattern formation. Following mid-blastula transition in Xenopus laevis (Daudin) embryos, secreted nodal-related (Xnr) factors become important for endoderm and mesoderm differentiation to maintain and enhance mesoderm induction. Endoderm can be induced by high concentrations of activin (vegetalizing factor) or nodal-related factors, especially Xnr5 and Xnr6, which depend on Wnt/beta-catenin signaling and on VegT, a vegetal maternal transcription factor. Together, these and other factors regulate the equilibrium between endoderm and mesoderm development. Many genes are activated and/or repressed by more than one signaling pathway and by regulatory loops to refine the tuning of gene expression. The nodal related factors, BMP, activins and Vg1 belong to the TGF-beta superfamily. The homeogenetic neural induction by the neural plate probably reinforces neural induction and differentiation. Medical and ethical problems of future stem cell therapy are briefly discussed.

Animals↗
PubMed2003

A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference.

RNA interference (RNAi) has recently emerged as a specific and efficient method to silence gene expression in mammalian cells either by transfection of short interfering RNAs (siRNAs; ref. 1) or, more recently, by transcription of short hairpin RNAs (shRNAs) from expression vectors and retroviruses. But the resistance of important cell types to transduction by these approaches, both in vitro and in vivo, has limited the use of RNAi. Here we describe a lentiviral system for delivery of shRNAs into cycling and non-cycling mammalian cells, stem cells, zygotes and their differentiated progeny. We show that lentivirus-delivered shRNAs are capable of specific, highly stable and functional silencing of gene expression in a variety of cell types and also in transgenic mice. Our lentiviral vectors should permit rapid and efficient analysis of gene function in primary human and animal cells and tissues and generation of animals that show reduced expression of specific genes. They may also provide new approaches for gene therapy.

Animals↗
PubMed1998

Evaluation of the gemini infusion pump for the safe delivery of peripheral blood progenitor cells (stem cells).

The purpose of this in vitro study was to determine whether the Gemini PC-2TX infusion pump could safely deliver peripheral stem cells (PSC) for an autologous PSC transplant. For purposes of hypothesis testing, it was assumed that there would be no significant difference in CD34+ cell counts and colony-forming units-granulocyte, macrophage (CFU-GM) when the PSCs were administered by an IMED PC-2TX infusion pump as opposed to an intravenous push method. The American Red Cross collected 50-ml samples of PSCs from four donors by apheresis. These cells were tested for CD34+ using flow cytometry and for functional progenitor cells using a CFU-GM assay. The cells were cryopreserved after testing. For our study, samples were tested simultaneously at a single facility. Each sample was individually thawed and a baseline thaw sample collected; 10 ml of the donor specimen was pushed through a syringe into a specimen container (intravenous push sample). The remainder of the specimen was infused through the IMED Gemini PC-2TX pump into a specimen container (intravenous pump sample). All samples were assayed for CD34+ cell counts and CFU-GM. Data analyses were conducted using the t-test for paired samples, with values of P < 0.05 considered significant. Results failed to demonstrate a statistically significant difference between the CD34+ or CFU-GM results of the intravenous push and intravenous pump specimens. Additionally, we failed to find a statistically significant difference when we compared the intravenous push and the intravenous pump specimens with the baseline thaw sample. The results of this study support the hypothesis that the Gemini PC-2TX infusion pump can safely deliver PSCs for the purposes of stem cell transplantation.

Antigens, CD34↗
PubMed1999

In vitro growth and quantification of early (CD33-/CD38-) myeloid progenitor cells: stem cell factor requirement and effects of previous chemotherapy.

BACKGROUND AND OBJECTIVE: All culture systems exploring the early (pre-CFU) hematopoietic compartment are generally complex, time-consuming and unsuitable for routine application. The aim of our study was to develop a stroma-free culture system to quantify early bone marrow (BM) myeloid progenitor cells. DESIGN AND METHODS: Low density, progenitor cell enriched BM cells underwent a double cytotoxic treatment with CD38 and CD33 monoclonal antibodies + rabbit complement, which depleted 99% of CFU-GM and BFU-E. Then they were cultured, both in agar and in limiting-dilution liquid culture, in the presence of 5637 cell line supernatant (containing GM-CSF, G-CSF and interleukin 1 ), stem cell factor (SCF) and interleukin 3 (IL3). RESULTS: The largest number (median 14.9 on 1x10(5) cells) and size (>50,000 cells) of myelomonocytic cell clones from CD33Eth /CD38Eth progenitors was reached after 3-4 weeks of liquid culture. SCF, but not IL3, was essential for that growth. The frequency of CD33-/ CD38- progenitors grown in liquid culture was approximately three times greater than the LTC-IC frequency in the same cell suspension. An average 93% of CD33-/CD38- progenitors displayed HLA-DR antigens and 43% generated secondary CFU-GM. In the BM of 9/10 patients, previously exposed to chemotherapy, CD33-/CD38- progenitor frequency was quite low (median 0.9 on 1x10(5) cells), in spite of normal cellularity and morphology and sustained disease remission. INTERPRETATION AND CONCLUSIONS: CD33-/CD38- progenitors can be grown and quantified in a stroma-free culture system in a relatively short time. The test can reveal long-lasting, subclinical BM damage induced by chemotherapy and could also be valuable for estimating the amount of early myeloid progenitors for transplantation purposes.

ADP-ribosyl Cyclase↗
PubMed2006

Epigenetics of germ cells, stem cells, and early embryos.

The International Symposium entitled "Germ Cells, Epigenetics, Reprogramming, and Embryonic Stem Cells" was organized by Norio Nakatsuji (Kyoto University) and Hiromitsu Nakauchi (University of Tokyo) in Kyoto, Japan (November 15-18, 2005). The meeting provided an overview of this important research area and highlighted recent advances.

Animals↗
PubMed2026

AML1-ETO hijacks a distal enhancer of NAT10 to reprogram glutathione metabolism and sustain leukemia stem cell stemness.

Chromosomal translocations produce oncogenic fusion proteins such as AML1-ETO, which predominantly occupy gene promoters to induce transcriptional reprogramming in leukemia stem cells (LSCs), consequently driving the pathogenesis of t(8;21) acute myeloid leukemia (AML). However, whether AML1-ETO is recruited to additional regulatory DNA elements to orchestrate oncogenic gene expression programs has not been fully addressed. Here, we define AML1-ETO and H3K27ac CUT&Tag landscapes in primary t(8;21) AML CD34+ cells and t(8;21) AML cell lines, revealing AML1-ETO binding at a distal enhancer of the RNA N4-acetylcytidine (ac4C) writer N-acetyltransferase 10 (NAT10), thereby driving its transcriptional activation. Genetic ablation or pharmacological inhibition of NAT10 restricted the survival and self-renewal of LSCs in primary t(8;21) AML CD34+ cells, as well as in a retroviral AML1-ETO9a-driven t(8;21) AML mouse model, establishing NAT10 as a potential therapeutic vulnerability. Mechanistically, NAT10 is recruited to glutathione S-transferase omega 2 (GSTO2) mRNA to catalyze ac4C modification, thereby enhancing transcript stability and reprogramming glutathione metabolism, as demonstrated by ac4C profiling, RNA immunoprecipitation (RIP), and dCas13b-NAT10-based analyses. Silencing of GSTO2 in primary t(8;21) AML CD34+ cells decreased intracellular reduced glutathione (GSH) levels and compromised LSC survival and self-renewal, whereas GSTO2 overexpression or GSH supplementation largely rescued LSC maintenance following NAT10 loss. Collectively, these findings enrich and extend the understanding of AML1-ETO regulatory programs by linking distal enhancer activity to a NAT10-GSTO2 ac4C-GSH axis that integrates epigenomic, posttranscriptional, and metabolic reprogramming to sustain LSC stemness, highlighting this circuit as a potential therapeutic vulnerability in t(8;21) AML.

Humans↗
PubMed2006

Hepatic progenitor cells, stem cells, and AFP expression in models of liver injury.

Adult hepatocytes and liver-cell progenitors play a role in restoring liver tissue after injury. For the study of progenitor cells in liver repair, experimental models included (a) surgical removal of liver tissue by partial hepatectomy; (b) acute injury by carbontetrachloride; (c) acute injury by d-galactosamine (GalN) and N-nitrosomorpholine (NNM); and (d) chemical hepatocarcinogenesis by feeding NNM in low and high doses. Serological and immunohistological detection of alpha-fetoprotein gene expression served to follow pathways of cellular differentiation. Stem cells were not required in models of surgical removal of parenchyma and in carbon tetrachloride intoxication of adult hepatocytes. In contrast, regeneration of liver occurred through biliary epithelial cells in injuries induced by GalN and NNM. These biliary epithelial cells, collectively called oval cells, are most probably derived from the canals of Hering. Proliferating bile duct cells reached a level of differentiation with reactivation of foetal genes and significant alpha-1-fetoprotein (AFP) synthesis signalling a certain degree of retrodifferentiation with potential stemness. Due to the same embryonic origin of bile ducts and hepatocytes, biliary epithelium and its proliferating progeny (oval cells) have a defined role in liver regeneration as a transit and amplification compartment. In their early proliferation stage, oval cells were heavily engaged in DNA synthesis ([3H]thymidine labelling). Pulse-chase experiments during experimental hepatocarcinogenesis exhibited their development into hepatocytes with high risk for transformation and leading to foci of altered hepatocytes. Hepatocellular carcinomas may arise either from proliferating/differentiating oval cells or from adult hepatocytes; both cell types have stem-like properties. AFP-positive and AFP-negative carcinomas occurred in the same liver. They may represent random clonal origin. The heterogeneity of phenotypic marker (AFP) correlated with a process of retrodifferentiation.

Animals↗
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↗