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PubMed2004

Adipocyte differentiation of multipotent cells established from human adipose tissue.

In this study multipotent adipose-derived stem cells isolated from human adipose tissue (hMADS cells) were shown to differentiate into adipose cells in serum-free, chemically defined medium. During the differentiation process, hMADS cells exhibited a gene expression pattern similar to that described for rodent clonal preadipocytes and human primary preadipocytes. Differentiated cells displayed the key features of human adipocytes, i.e., expression of specific molecular markers, lipolytic response to agonists of beta-adrenoreceptors (beta2-AR agonist > beta1-AR agonist >> beta3-AR agonist) and to the atrial natriuretic peptide, insulin-stimulated glucose transport, and secretion of leptin and adiponectin. hMADS cells were able to respond to drugs as inhibition of adipocyte differentiation was observed in the presence of prostaglandin F2alpha, tumour necrosis factor-alpha, and nordihydroguaiaretic acid, a natural polyhydroxyphenolic antioxidant. Thus, for the first time, human adipose cells with normal karyotype and indefinite life span have been established. They represent a novel and valuable tool for studies of fat tissue development and metabolism.

Adipocytes↗
PubMed1994

Intravascular leiomyomatosis with uterine lipoleiomyoma.

A very rare case of uterine lipoleiomyomata with intravascular leiomyoma in a 48-year-old woman is described. Located in the corpus of the uterus, the lipoleiomyomata showed proliferation of leiomyocytes intermingling with mature adipocytes. Intravascular leiomyoma was present in the broad ligament. It exhibited only spindle cells, and was reactive for HHF35 actin, without adipocytes. No continuity was detected between these tumors. Immunohistochemical studies revealed that the same portion of the intravascular leiomyoma was positive for S-100 alpha protein, NSE, factor VIII-related antigen, and HHF35 actin. These findings suggest that the leiomyomatous tumor components arise from multipotent undifferentiated mesenchymal stem cells.

Adipose Tissue↗
PubMed2005

Stem cells are units of natural selection in a colonial ascidian.

Stem cells are highly conserved biological units of development and regeneration. Here we formally demonstrate that stem cell lineages are also legitimate units of natural selection. In a colonial ascidian, Botryllus schlosseri, vascular fusion between genetically distinct individuals results in cellular parasitism of somatic tissues, gametes, or both. We show that genetic hierarchies of somatic and gametic parasitism following fusion can be replicated by transplanting cells between colonies. We prospectively isolate a population of multipotent, self-renewing stem cells that retain their competitive phenotype upon transplantation. Their single-cell contribution to either somatic or germline fates, but not to both, is consistent with separate lineages of somatic and germline stem cells or pluripotent stem cells that differentiate according to the niche in which they land. Since fusion is restricted to individuals that share a fusion/histocompatibility allele, these data suggest that histocompatibility genes in Botryllus evolved to protect the body from parasitic stem cells usurping asexual or sexual inheritance.

Animals↗
PubMed2006

Mesenchymal stem cells reside in virtually all post-natal organs and tissues.

Mesenchymal stem cells (MSCs) are multipotent cells which can give rise to mesenchymal and non-mesenchymal tissues in vitro and in vivo. Whereas in vitro properties such as (trans)differentiation capabilities are well known, there is little information regarding natural distribution and biology in the living organism. To investigate the subject further, we generated long-term cultures of cells with mesenchymal stem cell characteristics from different organs and tissues from adult mice. These populations have morphology, immunophenotype and growth properties similar to bone marrow-derived MSCs. The differentiation potential was related to the tissue of origin. The results indicate that (1) cells with mesenchymal stem characteristics can be derived and propagated in vitro from different organs and tissues (brain, spleen, liver, kidney, lung, bone marrow, muscle, thymus, pancreas); (2) MSC long-term cultures can be generated from large blood vessels such as the aorta artery and the vena cava, as well as from small vessels such as those from kidney glomeruli; (3) MSCs are not detected in peripheral blood. Taken together, these results suggest that the distribution of MSCs throughout the post-natal organism is related to their existence in a perivascular niche. These findings have implications for understanding MSC biology, and for clinical and pharmacological purposes.

Animals↗
PubMed2003

The effect of brain-derived neurotrophic factor on neuritogenesis and synaptic plasticity in Aplysia neurons and the hippocampal cell line HiB5.

Brain-derived neurotrophic factor (BDNF) plays a key role in the differentiation and neuritogenesis of developing neurons, and in the synaptic plasticity of mature neurons, in the mammalian nervous system. BDNF binds to the receptor tyrosine kinase TrkB and transmits neurotrophic signals by activating neuron-specific tyrosine phosphorylation pathways. However, the neurotrophic function of BDNF in Aplysia neurons is poorly understood. We examined the specific effect of BDNF on neurite outgrowth and synaptic plasticity in cultured Aplysia neurons and a multipotent rat hippocampal stem cell line (HiB5). Our study indicates that mammalian BDNF has no significant effect on the neuritogenesis, neurotransmitter release, excitability, and synaptic plasticity of cultured Aplysia neurons in our experimental conditions. In contrast, BDNF in combination with platelet-derived growth factor (PDGF) increases the length of the neurites and the number of spine-like structures in cells of HiB5.

Animals↗
PubMed2005

Patterning definitive hematopoietic stem cells from embryonic stem cells.

Derived from the inner cell mass of blastocysts, embryonic stem cells (ESCs) retain the pluripotent features of early embryonic epiblast cells. In vitro, ESCs undergo spontaneous differentiation into a multitude of tissues, and thus are a powerful tool for the study of early developmental processes and a promising resource for cell-based therapies. We have pursued the derivation of functional, multipotent and engraftable hematopoietic stem cells (HSCs) from ESCs in order to investigate the genetic pathways specifying blood formation, as well as to lay the foundation for hematopoietic cell replacement therapies based on engineered ESCs. Theoretically, the generation of HSCs from patient-specific ESCs derived by nuclear transfer could provide for autologous hematopoietic therapies for the treatment of malignant and genetic bone marrow disorders. Although significant progress has been made in achieving hematopoietic differentiation from both murine and human ESCs, we have only a primitive understanding of the underlying mechanisms that specify hematopoietic cell fate, and a very limited capacity to direct the differentiation of the definitive HSC that would be suitable for clinical engraftment studies. Here we will review the progress to date and the significant problems that remain, and outline a strategy to achieve the directed differentiation of HSCs under conditions that might be appropriate for clinical scale-up and disease applications.

Animals↗
PubMed1994

[An improved colorimetric assay for chicken M-CSF like activity using chicken bone marrow cells cultured on micro-culture plates].

The role of M-CSF in the process of mammalian development has been drawing attention. Unlike mammalian embryonic development, in which M-CSF is supplied by the maternal body, avian embryonic development begins and proceeds under the influence of a certain amount of M-CSF present in each fertilized egg, and its concentration can be experimentally controlled while observing the embryo's developmental state. Apart from this fact, aves provide us with many other advantages in the study of embryonic development. It is, however, not easy to separate multipotent hematopoietic stem-cell fractions from avian bone marrow. In addition, because a macrophage colony forming assay in soft agar, though it has been widely used, requires a large number of cells and a long culture period, the method of assay is not adequate for the sensitive detection of M-CSF activity in small scale samples. We have established a method for the depletion of nucleated erythrocytes from chicken bone marrow cell suspensions using percoll density gradient centrifugation, and have also developed a new method for determining chicken M-CSF-like activity employing a liquid culture. In this method, a 100 microliters aliquot of fractionated hematopoietic stem cells, 1 x 10(5), was placed in a well of 96-well flat-bottom culture plate, 100 microliters of sample was then added to each well, and the uptake of neutral red was measured after 4 days of culture. These procedures represent a simple and sensitive means of detecting M-CSF-like activity in chicken serum of x60 to x32 dilutions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Asymmetrical lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors.

The mechanism of lineage commitment from hematopoietic stem cells (HSCs) is not well understood. Although commitment to either the lymphoid or the myeloid lineage is popularly viewed as the first step of lineage restriction from HSCs, this model of hematopoietic differentiation has recently been challenged. The previous identification of multipotent progenitors (MPPs) that can produce lymphocytes and granulocyte/macrophages (GMs) but lacks erythroid differentiation ability suggests the existence of an alternative HSC differentiation program. Contribution to different hematopoietic lineages by these MPPs under physiological conditions, however, has not been carefully examined. In this study, we performed a refined characterization of MPPs by subfractionating three distinct subsets based on Flt3 and vascular cell adhesion molecule 1 expression. These MPP subsets differ in their ability to give rise to erythroid and GM lineage cells but are equally potent in lymphoid lineage differentiation in vivo. The developmental hierarchy of these MPP subsets demonstrates the sequential loss of erythroid and then GM differentiation potential during early hematopoiesis. Our results suggest that the first step of lineage commitment from HSCs is not simply a selection between the lymphoid and the myeloid lineage.

Animals↗
PubMed2004

Circulating hematopoietic progenitors with T lineage potential.

The thymus is seeded via the blood, but the identity of hematopoietic progenitors with access to the circulation in adult mice is unknown. We report here that the only progenitors in blood with efficient T lineage potential were lineage negative with high expression of stem cell antigen 1 and c-Kit (LSK cells). The blood LSK population, like its counterpart in the bone marrow, contained hematopoietic stem cells and nonrenewing, multipotent progenitors, including early lymphoid progenitors and CD62L(+) cells previously described as efficient T lineage progenitors. Common lymphoid progenitors could not be identified in the circulation, suggesting they are not physiological T lineage precursors. We conclude that blood LSK cells are the principal circulating progenitors with T lineage potential.

Animals↗
PubMed2006

Stem cells and cystic fibrosis.

Although cystic fibrosis at first sight appears to be one of the most obvious human diseases to treat with gene therapy, since it is caused by a single-gene defect and the main affected organ is the lung which is relatively easily accessible, clinical results have thus far been disappointingly limited. At least one cause for this lack of success is the failure to permanently correct the gene defect in addition to the rapid turnover of lung epithelial cells. Alternative approaches therefore involve the search for and use of stem cell populations. This review presents an overview of recent attempts to identify lung- or bone marrow-derived populations of stem cells or progenitor cells and to apply such cells, heterologous or gene-corrected autologous, to colonize the airways while differentiating into functional respiratory columnar epithelial cells. The most successful approaches thus far appear to be obtained with bone marrow-derived cells such as mesenchymal stem cells, although the transdifferentiation rate thus far has been limited to below the 1% level. As an alternative the proven multipotent nature of bronchioalveolar stem cells isolated from lung tissue may provide another promising approach for successful stem cell therapy.

Animals↗
PubMed1999

Epithelial stem cells in the mammary gland: casting light into dark corners.

The epithelial structures of the human breast or the mouse mammary gland are derived from a relatively small number of multipotent, tissue-specific stem cells, of which we are surprisingly ignorant. We do not know how many are required to produce a complete mammary gland, how many times they divide during the process, where they are situated in the gland, or even what they look like. We want to know the answers to these questions, not just to satisfy intellectual curiosity, but also because the answers may shed light on the evolution of breast cancer. Now, studies carried out by Kordon and Smith at the National Cancer Institute have pointed the way toward a new understanding of mammary stem cells and their progeny.

Animals↗
PubMedDate not supplied

Stem cell generation and choice of fate: role of cytokines and cellular microenvironment.

Hematopoietic stem cells (HSC) have provided a model for the isolation, enrichment and transplantation of stem cells. Gene targeting studies in mice have shown that expression of the thrombopoietin receptor (TpoR) is linked to the accumulation of HSCs capable to generate long-term blood repopulation when injected into irradiated mice. The powerful increase in vivo in HSC numbers by retrovirally transduced HOX4B, a homeotic gene, along with the role of the TpoR, suggested that stem cell fate, renewal, differentiation and number can be controlled. The discovery of the precise region of the mouse embryo where HSCs originate and the isolation of supporting stromal cell lines open the possibility of identifying the precise signals required for HSC choice of fate. The completion of human genome sequencing coupled with advances in gene expression profiling using DNA microarrays will enable the identification of key genes deciding the fate of stem cells. Downstream from HSCs, multipotent hematopoietic progenitor cells appear to co-express a multiplicity of genes characteristic of different blood lineages. Genomic approaches will permit the identification of the select group of genes consolidated by the commitment of these multipotent progenitors towards one or the other of the blood lineages. Studies with neural stem cells pointed to the unexpected plastic nature of these cells. Isolation of stem cells from multiple tissues may suggest that, providing the appropriate environment/ signal, tissues could be regenerated in the laboratory and used for transplantation. A spectacular example of influence of the environment on cell fate was revealed decades ago by using mouse embryonic stem cells (ES). Injected into blastocysts, ES cells contribute to the formation of all adult tissues. Injected into adult mice, ES cells become cancer cells. After multiple passages as ascites, when injected back into the blastocyst environment, ES- derived cancer cells behaved again as ES cells. More recently, the successful cloning of mammals and reprogramming of transferred nuclei by factors in the cytoplasm of oocytes turned back the clock by showing that differentiated nuclei can be "re-booted" to generate again the stem cells for different tissues.

Journal Article↗
PubMed2005

Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function.

The purpose of this study was to determine whether the heart in large mammals contains cardiac progenitor cells that regulate organ homeostasis and regenerate dead myocardium after infarction. We report that the dog heart possesses a cardiac stem cell pool characterized by undifferentiated cells that are self-renewing, clonogenic, and multipotent. These clonogenic cells and early committed progeny possess a hepatocyte growth factor (HGF)-c-Met and an insulin-like growth factor 1 (IGF-1)-IGF-1 receptor system that can be activated to induce their migration, proliferation, and survival. Therefore, myocardial infarction was induced in chronically instrumented dogs implanted with sonomicrometric crystals in the region of the left ventricular wall supplied by the occluded left anterior descending coronary artery. After infarction, HGF and IGF-1 were injected intramyocardially to stimulate resident cardiac progenitor cells. This intervention led to the formation of myocytes and coronary vessels within the infarct. Newly generated myocytes expressed nuclear and cytoplasmic proteins specific of cardiomyocytes: MEF2C was detected in the nucleus, whereas alpha-sarcomeric actin, cardiac myosin heavy chain, troponin I, and alpha-actinin were identified in the cytoplasm. Connexin 43 and N-cadherin were also present. Myocardial reconstitution resulted in a marked recovery of contractile performance of the infarcted heart. In conclusion, the activation of resident primitive cells in the damaged dog heart can promote a significant restoration of dead tissue, which is paralleled by a progressive improvement in cardiac function. These results suggest that strategies capable of activating the growth reserve of the myocardium may be important in cardiac repair after ischemic injury.

Animals↗
PubMed1987

Characterization of a human multilineage-colony-stimulating factor cDNA clone identified by a conserved noncoding sequence in mouse interleukin-3.

Blood-cell production is regulated by hemopoietic growth factors, which act at specific stages of hemopoietic cell differentiation. Murine interleukin-3 (mIL-3)/multilineage colony-stimulating factor (multi-CSF) has been shown to stimulate colony formation in vitro by multipotent hemopoietic cells and production of spleen colony-forming units (CFU-S) in suspension cultures. The molecular cloning of the human counterpart of mIL-3 is described here. Hybridization of radiolabeled mIL-3 cDNA with a cDNA library obtained from mRNA of stimulated human lymphocytes resulted in the identification of a human (h)multi-CSF cDNA clone. Sequence homology (73%) in the 3'-noncoding region of mIL-3 enabled the detection of the hmulti-CSF cDNA clone. Whereas only 45% sequence homology was found in the coding region, specific A + T-rich domains in the 3'-noncoding region were highly conserved (93%). As far as we know, this is the first example of gene identification by sequence homology occurring only within the 3'-noncoding region. The protein encoded by this hmulti-CSF cDNA stimulates in vitro colony formation by multipotent human hemopoietic stem cells. In addition, the growth factor strongly stimulates the in vitro proliferation of human leukemic blast cells.

Animals↗
PubMed2005

Increased survival and migration of engrafted mesenchymal bone marrow stem cells in 6-hydroxydopamine-lesioned rodents.

Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra. Attempted replacement of these neurons by stem cells has proved inconclusive. Bone marrow mesenchymal stem cells (MSC) are multipotent, differentiating into a variety of cells, including neuron-like cells. We used the 6-hydroxydopamine (6-OHDA) animal model of Parkinson's disease to assess migration and differentiation of transplanted MSC. We found in rodents that transplanted MSC survive better in the 6-OHDA-induced damaged hemisphere compared to the unlesioned side. Moreover, contralaterally engrafted MSC migrated through the corpus callosum to populate the striatum, thalamic nuclei and substantia nigra of the 6-OHDA-lesioned hemisphere. In conclusion, we demonstrate that 6-OHDA-induced damage increases the viability of transplanted MSC and attracts these cells from the opposite hemisphere.

Animals↗
PubMed2003

The profile of gene expression of human marrow mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are multipotent precursors present in adult bone marrow, that differentiate into osteoblasts, adipocytes and myoblasts, and play important roles in hematopoiesis. We examined gene expression of these cells by serial analysis of gene expression, and found that collagen I, secreted protein acidic and rich in cysteine (osteonectin), transforming growth factor beta- (TGF-beta) induced, cofilin, galectin-1, laminin-receptor 1, cyclophilin A, and matrix metalloproteinase-2 are among the most abundantly expressed genes. Comparison with a library of CD34(+) cells revealed that MSCs had a larger number of expressed genes in the categories of cell adhesion molecule, extracellular and development. The two types of cells share abundant transcripts of many genes, some of which are highly expressed in myeloid progenitors (thymosin-beta 4 and beta 10, fos and jun). Interleukin-11 (IL-11), IL-15, IL-27 and IL-10R, IL-13R and IL-17R were the most expressed genes among the cytokines and their receptors in MSCs, and various interactions can be predicted with the CD34(+) cells. MSCs express several transcripts for various growth factors and genes suggested to be enriched in stem cells. This study reports the profile of gene expression in MSCs and identifies the important contribution of extracellular protein products, adhesion molecules, cell motility, TGF-beta signaling, growth factor receptors, DNA repair, protein folding, and ubiquination as part of their transcriptome.

Adult↗
PubMed2004

Cultured autologous human cells for hard tissue regeneration: preparation and characterization of mesenchymal stem cells from bone marrow.

Mesenchymal stem cells (MSCs) are multipotent cells and can be induced in vitro and in vivo to differentiate not only into the variety of mesodermal cells, but into either ectodermal or endodermal cells. This capability indicates the usefulness of MSCs for tissue engineering. Cell surface antigen analyses using various types of CD antibodies demonstrated that adherent fibroblastic cells derived from fresh human bone marrow are mesenchymal types and the cells showed extensive capability for proliferation and/or differentiation. We labeled the adherent cultured marrow cells as MSCs and, significantly, found the MSCs could even proliferate from aged marrow cells. After about sixteen days of culturing, we were able to harvest 100 million MSCs from only 3 ml of fresh human marrow. Moreover, the MSCs could be cryopreserved at -80 degrees C without noticeable loss of viability and capability of osteoblastic differentiation. These results indicate that MSCs hold promise for utilization in hard tissue regeneration.

Bone Marrow Cells↗
PubMed2003

[Study on rabbit mesenchymal stem cells differentiation to the adipogenic or osteogenic lineage in vitro].

Rabbit bone marrow-derived mesenchymal stem cells(MSCs) are multipotent. We studied the adipogenic and osteogenic differentiation potent using adipogenic supplement (AS) or osteogenic supplement (OS) in vitro. Specific markers of this induced adipogenic and osteogenic lineage were identified. The findings showed that the rabbit MSCs are capable of differentiating into adipogenic and osteogenic lineages spontaneously. On the 21st day, approximately 75% rabbit MSCs were induced to adipogenic or osteogenic cells in medium containing AS or OS, respectively. These results demonstrated that the differentiation of MSCs could be regulated in vitro. The underlying molecular mechanisms of adipogenic or osteogenic differentiation await elucidation.

Adipose Tissue↗