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PubMed2005

Hematopoiesis from human embryonic stem cells: overcoming the immune barrier in stem cell therapies.

The multipotency and proliferative capacity of human embryonic stem cells (hESCs) make them a promising source of stem cells for transplant therapies and of vital importance given the shortage in organ donation. Recent studies suggest some immune privilege associated with hESC-derived tissues. However, the adaptability of the immune system makes it unlikely that fully differentiated tissues will permanently evade immune rejection. One promising solution is to induce a state of immune tolerance to a hESC line using tolerogenic hematopoietic cells derived from it. This could provide acceptance of other differentiated tissues from the same line. However, this approach will require efficient multilineage hematopoiesis from hESCs. This review proposes that more efficient differentiation of hESCs to the tolerogenic cell types required is most likely to occur through applying knowledge gained of the ontogeny of complex regulatory signals used by the embryo for definitive hematopoietic development in vivo. Stepwise formation of mesoderm, induction of definitive hematopoietic stem cells, and the application of factors key to their self-renewal may improve in vitro production both quantitatively and qualitatively.

Body Patterning↗
PubMed1991

[Morphological pursuit of blood stem cells emerging from aplastic bone marrow of mouse after a single high dose of 5-FU injection].

A single high dose of 5-fluorouracil (5-FU) was administered intravenously in mice to induce the aplastic bone marrow and to seize the morphological characteristics of blood stem cells. Time course observations of histological and cytological changes in bone marrow hematopoiesis and stem cell assay revealed that the day 2 bone marrow contained a number of quiescent blood stem cells. For advanced morphological studies of blood stem cells, the day 2 marrow cells were seeded in methylcellulose culture medium for stem cell assay. Blast cell colonies (BCC) which contained CFU-GEMM (colony-forming unit granulocyte, erythroid, monocyte/macrophage, megakaryocyte) were formed within 2 weeks. BCC-constituting cells (BCC-cell) were lifted and processed for morphological analyses. The BCC-cells were variable in size as well as morphology, and were divided into 3 sub-groups according to their size. Large-sized group (greater than 14 microns) consisted of large blastic cells with a tendency of differentiation into early granulocyte or monocyte/macrophage lineage. Medium-sized group (10-14 microns) consisted of more immature blastic cells which lacked a differentiation. Small-sized group (7-10 microns) consisted of two cell-types. One type (named 'transitional cell' or 'TC cell') had distinctive features as a dark nucleus and a narrow basophilic cytoplasm seemed to be the most immature cell type. The other (named 'lymphoid cell') was morphologically indistinguishable from the small lymphocyte. Blast cell colony-replating experiments disclosed that the proportion of small-sized cells in BCC-cells (about 4%) was equivalent to the incidence of GEMM colonies formed in replated culture (about 2-5%). Furthermore, immunohistochemical staining of wheat germ agglutinin (WGA), anti-Thy-1 antibody and anti-B cell antibody revealed that most of TC cells were positive for WGA suggesting of CFU-GEMM, and negative for anti-B cell antibody. Most of lymphoid cells were positive for anti-B cell antibody, and negative for WGA and anti-Thy-1 antibody, and were estimated to be true B-lymphocytes. Based on these results, it was reasonable to consider that a majority of TC cells were multipotent blood stem cells.

Animals↗
PubMed2006

Autocrine fibroblast growth factor 2 signaling is critical for self-renewal of human multipotent adipose-derived stem cells.

Adipose tissue-derived stem cells offer tremendous potential for regenerative medicine. However, characterization of their self-renewal ability has not been performed yet, although it is a crucial feature for in vitro expansion of undifferentiated cells and in vivo maintenance of stem cell pools. We have undertaken the identification of molecular events that are involved in in vitro self-renewal of human multipotent adipose-derived stem (hMADS) cells from young donors, by assessing their proliferation rate, their ability to grow at the single-cell level (clonogenicity), and their differentiation potential. As hMADS cells are propagated in culture, cell morphology changes dramatically, concomitantly to a progressive decrease in proliferation, clonogenicity, and differentiation potential. This decrease is associated with a decrease in fibroblast growth factor 2 (FGF2) expression and can be circumvented by chronic treatment with exogenous FGF2. Moreover, analysis of FGF2 secretion revealed that it is exported to hMADS cell surface without being released into the culture medium, suggesting a strictly autocrine loop. Indeed, treatment of FGF2-expressing hMADS cells with PD173074, a specific FGF receptor inhibitor, decreases dramatically their clonogenicity and differentiation potential. Thus, hMADS cells express a functional autocrine FGF loop that allows maintenance of their self-renewal ability in vitro. Finally, inhibition of mitogen-activated protein kinase kinase 1 reduces the clonogenic potential of hMADS cells but does not affect their differentiation potential, indicating that the extracellular signal-related kinases 1/2 signaling pathway is partly involved in FGF2-mediated self-renewal. Together, our data clearly identify the key function of FGF2 in the maintenance of self-renewal of adipose tissue-derived stem cells.

Adipocytes↗
PubMed1990

The role of hemopoietic growth factors in self-renewal and differentiation of IL-3-dependent multipotential stem cells.

A multipotent hemopoietic cell line has been employed to assess the influence of the hemopoietic growth factors, IL-3, GM-CSF, G-CSF, and CSF-1 on the processes of self-renewal, the generation of lineage restricted progenitor cells and the production of mature neutrophils and macrophages. At a high concentration of IL-3, the cells undergo self-renewal and demonstrate little or no ability to undergo differentiation in the presence of the other growth factors. In the absence of IL-3, the cells show minimal (GM-CSF) or no (G-CSF or CSF-1) ability to respond to these other growth factors. When combined with a low concentration of IL-3, the ability of the cells to respond to GM-CSF, G-CSF, and CSF-1 is enhanced and a selective preference for the neutrophil or macrophage lineage is seen depending on the combination used, i.e., the presence of CSF-1 preferentially promotes macrophage development and G-CSF preferentially promotes neutrophil development. Conditions optimal for neutrophil development were seen using a combination of low IL-3 concentrations plus GM-CSF plus G-CSF. In such conditions, the cells undergo extensive proliferation and progressively lose their clonogenic potential (i.e., differentiation much greater than self-renewal) and acquire the biochemical markers characteristic of fully mature phagocytes.

Animals↗
PubMed2003

Expression of cytokines by multipotent neural progenitor cells.

Recent work with mammalian neural stem cells has highlighted the role of cytokine signaling in the proliferation and differentiation of these multipotent cells. While the responsiveness of neural progenitors to exogenously applied growth factors has been demonstrated in vivo as well as in vitro, little attention has been given to the production of cytokines by these cells. Here we use immunocytochemistry, RT-PCR, and ELISA to show that under standard growth conditions multipotent neural progenitor cells from humans express multiple cytokines including IL-1alpha, IL-1beta, IL-6, TGF-beta1, TGF-beta2, TNF-alpha, but not IL-2, IL-4, or IFN-gamma. Neural progenitor cells from rat and mouse express some, but not all, of these cytokines under similar conditions. While the function of cytokine expression by neural progenitor cells remains to be elucidated, these signaling molecules are known to be involved in neural development and may play a role in the activation of quiescent stem cells by a variety of pathological processes.

Animals↗
PubMed2003

Neurons and astrocytes secrete factors that cause stem cells to differentiate into neurons and astrocytes, respectively.

We examined the role of soluble factors secreted by neurons and astrocytes in the differentiation of CNS stem cells. We showed that the soluble factors from neurons strongly induced multipotent cortical stem cells to acquire neuronal identity, while the factors from astrocytes promoted astrocytic differentiation. Neurons secreted the brain-derived neurotrophic factor and neurotrophin-3 to induce neuron differentiation, while astrocytes secreted ciliary neurotrophic factor for astrocyte differentiation. Both neurons and astrocytes secrete bone morphogenetic proteins (BMPs). Using BMP antagonists it was shown that BMPs were responsible for the neuron-induced neuronal differentiation, as well as the astrocyte-induced astrocytic differentiation. These findings demonstrate the importance of soluble signals in lineage-specific differentiation and provide evidence for the roles of neurons and astrocytes in stem cell differentiation.

Animals↗
PubMed2004

Modification of the brain-derived neurotrophic factor gene: a portal to transform mesenchymal stem cells into advantageous engineering cells for neuroregeneration and neuroprotection.

Multipotential mesenchymal stem cells (MSCs) are ideal seed cells for recruiting the loss of neural cells due to their strong proliferative capacity, easy acquisition, and considerable tolerance of genetic modifications. After transduction of brain-derived neurotrophic factor (BDNF) gene via recombinant retroviral vectors into the human MSCs, nearly 100% of cells expressed BDNF (which were therefore transformed into BNDF-MSCs) as detected by immunocytochemistry, and the quantity of BDNF in the culture medium was increased by approximately 20,000-fold. In spite of the genomic integration of an exogenous gene, BDNF-MSCs did not present any structural aberration in the chromosomes. All-trans-retinoic acid (RA) induction caused the BDNF-MSCs to differentiate into neural cells with significantly increased expressions of such neural-specific proteins as nestin, NeuN, O4, and glial fibrillary acidic protein (GFAP). The voltage-dependent K+/Ca2+ currents were recorded from the induced BDNF-MSCs using patch-clamp technique. Compared with the MSCs induced by both RA and BDNF, BDNF-MSCs survived in significantly greater number in the induction medium, and also more cells were induced into neuron-like cells (NeuN, P < 0.01) and oligodendrocyte-like cells (O4, P < 0.05). We suppose that, once engrafted into human central nervous system, the BDNF-MSCs would not only recruit the neuronal losses, but also provide, by way of paracrine, large quantities of BDNF that effectively perform the functions of neuroprotection and neuroregeneration, promoting the activation of endogenous neural stem/progenitor cells and their chemotactic migration. On the other hand, the BDNF-MSCs that can survive in the host environment and differentiate subsequently into functional mature cells may also serve as specifically targeting vectors for ex vivo gene therapy.

Adult↗
PubMed2005

Stem cells and their applications in skin-cell therapy.

Skin stem cell biology is a rapidly advancing field in the life sciences. There is increasing evidence that skin represents a larger reservoir for adult stem cells (including mesenchymal, hematopoietic and neural stem cells) than the epidermis. Given that skin is easily accessible and immune privileged, skin stem cells will not only provide hope for the functional repair of the skin itself but will also offer a potential source of adult stem cells for the cell-based therapy of injuries and diseases throughout the body. This article reviews the current status of research in this area and discusses the occurrence, plasticity and potential uses of skin stem cells.

Animals↗
PubMed2000

Lymphoid precursors.

Lymphopoiesis of mature and diverse populations of T, B and NK (natural killer) cells from multipotent hematopoietic stem cells is an ideal model of tissue generation and regeneration. Identification and isolation of hematolymphoid stem and progenitor cells in several laboratories over the past several years have provided populations that can be studied biologically for lineage commitment and biochemically for receptor function, signal transduction and selective gene expression. These studies may ultimately provide candidate genes involved in lineage commitment, cell death or survival, self-renewal and migratory capacities of progenitors.

Animals↗
PubMed2006

Stem cells from umbilical cord blood.

The study of hematopoiesis, the generation of blood cell lines throughout life, has provided conceptual, experimental, and therapeutic approaches useful to all stem cell biologists. From a clinical perspective, no other area of stem cell biology has been applied as successfully as has transplantation of bone marrow and cord blood for the treatment of blood diseases. In the last few years, research in stem cell biology has expanded rapidly to include the study of stem cells from embryonic, fetal, and various adult tissues, engendering novel perspectives regarding the identity, origin, and full therapeutic potential of tissue-specific stem cells. Rather than focusing on the use of cord blood stem cells for reconstitution of bone marrow, this article reviews the biology of stem cells found in the cord blood in the context of cell plasticity and their therapeutic potential for repair of the nervous system.

Animals↗
PubMed2003

The ultimate source of human hematopoietic stem cells: thinking outside the marrow.

The ability to reconstitute cellular components of the hematopoietic system has immense utility in several areas of clinical medicine. These include replacement of cells responsible for innate and acquired immunity, providing red cells for oxygen transport, and ultimately the ability to recover hematopoietic function by repopulating all lineages comprising the entire blood system. This latter property functionally defines the mammalian hematopoietic stem cell (HSC). Recently, human embryonic stem cells (ESCs) have been suggested to be a viable source of transplantable hematopoietic cells. Although the number of human ESCs is virtually unlimited, the ability to efficiently differentiate adequate numbers of cells that possess hematopoietic repopulating ability remains to be determined. Achieving this goal is confounded by the difficulty of experimentally generating murine hematopoietic cell types capable of in vivo reconstitution from mouse ESC, suggesting that similar limitations may arise using human counterparts. Although the use of human ESCs and adult somatic HSCs have their independent merits, a direct comparison between HSCs derived from each source using similar assays will ultimately be required to determine the best source for clinical use. Here we will summarize the results from efforts to differentiate and assay primitive hematopoietic cells derived from ESCs, and compare these findings to similar parameters using putative mammalian HSCs harvested from the adult.

Animals↗
PubMed2004

Environmental guidance of normal and tumor cell plasticity: epithelial mesenchymal transitions as a paradigm.

Epithelial mesenchymal transitions are a remarkable example of cellular plasticity. These transitions are the hallmark of embryo development, are pivotal in cancer progression, and seem to occur infrequently in adult organisms. The reduced incidence of transitions in the adult could result from restrictive functions of the microenvironment that stabilizes adult cell phenotypes and prevents plastic behavior. Multipotential progenitor cells exhibiting a mesenchymal phenotype have been derived from various adult tissues. The ability of these cells to differentiate into all germ layer cell types, raises the question as to whether mesenchymal epithelial transitions occur in the adult organism more frequently than presently appreciated. A series of cytokines are known to promote the transitions between epithelium and mesenchyme. Moreover, several transcription factors and other intracellular regulator molecules have been conclusively shown to mediate these transitions. However, the exact molecular basis of these transitions is yet to be resolved. The identification of the restrictive mechanisms that prevent cellular transitions in adult organisms, which seem to be unleashed in cancerous tissues, may lead to the development of tools for therapeutic tissue repair and effective tumor suppression.

Animals↗
PubMed2002

Expansion of human adult stem cells from bone marrow stroma: conditions that maximize the yields of early progenitors and evaluate their quality.

There is considerable interest in the biology and therapeutic potential of adult stem cells from bone marrow stroma, variously referred to as mesenchymal stem cells or marrow stromal cells (MSCs). Human MSCs can expand rapidly in culture, but the rate of expansion and the yields of multipotential progenitors are inversely related to the plating density and incubation time of each passage. We have defined conditions for optimizing the yields of cultures enriched for early progenitors. Also, we developed a simple method for assessing the quality of the cultures by phase-contrast microscopy and image analysis or by forward light scatter in a flow cytometer. The cells expanded most rapidly on day 4 after plating, with a minimum average doubling time of about 10 hours for cells initially plated at 10 or 50 cells/cm(2). After plating the cells at 1 to 1000 cells/cm(2), the cultures underwent a time-dependent transition from early progenitors, defined as thin, spindle-shaped cells (RS-1A), to wider, spindle-shaped cells (RS-1B), and to still wider, spindle-shaped cells (RS-1C). Assays for adipogenesis demonstrated that the adipogenic potential of cultures was directly related to their ability to generate single-cell-derived colonies and their enrichment for RS-1A cells. In contrast, cultures enriched for RS-1B cells showed the greatest potential to differentiate into cartilage in a serum-free system. The results indicate that, when preparing cultures of human MSCs, it is necessary to compromise between conditions that provide the highest overall yields and those that provide the highest content of early progenitor cells.

Adipocytes↗
PubMed2003

Identification, rare-event detection and analysis of dendritic cell subsets in broncho-alveolar lavage fluid and peripheral blood by flow cytometry.

Dendritic cells (DCs) and their precursors play important roles, not only as antigen presenting cells, but components of the immunoregulatory network. Depending on their lineage, activation and differentiation state, DCs can promote a strong T-cell response or a state of anergy, and can polarize the T helper response in the direction of TH1 or TH2. The lung comprises one of the major interfaces between the host and the environment and regularly comes into contact with antigens, allergens and pathogens. Inflammation in response to these stimuli must be very carefully regulated in the lung since perturbations, especially of a chronic nature, can result in immunopathology that interferes with the lungs' critical function of gas exchange. Especially in disease states such as chronic obstructive pulmonary disease, which has been associated with a chronic TH1 response, and asthma, which is TH2-driven, the ability to access and characterize DCs and their precursors is critical to the understanding of immune modulation in these processes. In this report we will demonstrate that mature DCs and their monocytoid and plasmacytoid precursors can be sampled in the lung by the minimal invasive procedure of broncho-alveolar lavage (BAL) despite their relative scarcity and can be detected by rare event multiparameter flow cytometry.

Antigens, CD↗
PubMed2003

[Adult neural stem cells: therapeutic potential in neurology].

The existence of continuously dividing neural stem cells in the adult mammalian central nervous system including humans contradicts a long-standing neuroscientific dogma of the last century. Multipotential neural stem cells have been identified in neurogenic regions such as the hippocampus and the subventricular zone. Global stimuli, but also defined molecular signals modulate the proliferation, migration, differentiation, and survival of theses cells both in vivo and in vitro. The development of neural stem cell-based therapies for the regeneration of the injured or diseased brain includes 1. the activation of the endogenous pool of neural stem cells for "self repair" and/or 2. the autologous transplantation of adult neural stem cells into sites of damaged or missing cells. The aim of these strategies is to promote structural and functional recovery of the brain for numerous neurologic diseases.

Adult↗