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The human adipose tissue is a source of multipotent stem cells.

Multipotent stem cells constitute an unlimited source of differentiated cells that could be used in pharmacological studies and in medicine. Recently, several publications have reported that adipose tissue contains a population of cells able to differentiate into different cell types including adipocytes, osteoblasts, myoblasts, and chondroblasts. More recently, stem cells with a multi-lineage potential at the single cell level have been isolated from human adipose tissue. These cells, called human Multipotent Adipose-Derived Stem (hMADS) cells, have been established in culture and interestingly, maintain their characteristics with long-term passaging. The adipocyte differentiation of hMADS cells has been thoroughly studied and differentiated cells exhibit the unique feature of human adipocytes. Finally, potential applications of stem cells isolated from adipose tissue in medicine will be discussed.

Adipocytes↗

Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells.

Multipotent stem cells that generate both neurons and glia are widespread components of the early neuroepithelium. During CNS development, neurogenesis largely precedes gliogenesis: how is this timing achieved? Using clonal cell culture combined with long-term time-lapse video microscopy, we show that isolated stem cells from the embryonic mouse cerebral cortex exhibit a distinct order of cell-type production: neuroblasts first and glioblasts later. This is accompanied by changes in their capacity to make neurons versus glia and in their response to the mitogen EGF. Hence, multipotent stem cells alter their properties over time and undergo distinct phases of development that play a key role in scheduling production of diverse CNS cells.

Animals↗

Quiescent neural cells regain multipotent stem cell characteristics influenced by adult neural stem cells in co-culture.

The source of cells participating in central nervous system (CNS) tissue repair and regeneration is poorly defined. One possible source is quiescent neural cells that can persist in CNS in the form of dormant progenitors or highly specialized cell types. Under appropriate conditions, these quiescent cells may be capable of re-entering the mitotic cell cycle and contributing to the stem cell pool. The aim of this study was to determine whether in vitro differentiated neural stem cells (NSC) can regain their multipotent-like stem cell characteristics in co-culture with NSC. To this end, we induced neural differentiation by plating NSC, derived from the periventricular subependymal zone (SEZ) of ROSA26 transgenic mice in Neurobasal A/B27 medium in the absence of bFGF. Under these conditions, NSC differentiated into neurons, glia, and oligodendrocytes. While the level of Nestin expression was downregulated, persistence of dormant progenitors could not be ruled out. However, further addition of bFGF or bFGF/EGF with conditioned medium derived from adult NSC did not induce any noticeable cell proliferation. In another experiment, differentiated neural cells were cultured with adult NSC, isolated from the hippocampus of Balb/c mice, in the presence bFGF. This resulted in proliferating colonies of ROSA26 derived cells that mimicked NSC in their morphology, growth kinetics, and expressed NSC marker proteins. The average nuclear area and DAPI fluorescence intensity of these cells were similar to that of NSC grown alone. We conclude that reactivation of quiescent neural cells can be initiated by NSC-associated short-range cues but not by cell fusion.

Animals↗

The origin of human B and T cells from multipotent stem cells: a study of the Tn syndrome.

The Tn (or polyagglutinability) syndrome corresponds to a human nonmalignant acquired condition which results from a somatic mutation occurring at the level of bone marrow stem cells. This model offers therefore a unique opportunity to study the contribution of multipotential stem cells to the maintenance of cells from the lymphoid lineage. We found that the Tn mutation is expressed by both myeloid and lymphoid mature blood cells. Whereas a large proportion of surface IgM-bearing B cells carry the Tn mutation, only a small percentage of T cells and IgA- or IgG-bearing B cells are defective, showing that under physiological conditions the penetration of stem cells into the various myeloid and lymphoid compartments is variable.

ABO Blood-Group System↗

Tcf3 and Lef1 regulate lineage differentiation of multipotent stem cells in skin.

In skin, multipotent stem cells generate the keratinocytes of the epidermis, sebaceous gland, and hair follicles. In this paper, we show that Tcf3 and Lef1 control these differentiation lineages. In contrast to Lef1, which requires Wnt signaling and stabilized beta-catenin to express the hair-specific keratin genes and control hair differentiation, Tcf3 can act independently of its beta-catenin interacting domain to suppress features of epidermal terminal differentiation, in which Tcf3 is normally shut off, and promote features of the follicle outer root sheath (ORS) and multipotent stem cells (bulge), the compartments which naturally express Tcf3. These aspects of Tcf3's action are dependent on its DNA binding and Groucho repressor-binding domains. In the absence of its beta-catenin interacting domain, Lef1's behavior (Delta NLef1) seems to be markedly distinct from that of Delta NTcf3. Delta NLef1 does not suppress epidermal differentiation and promote ORS/bulge differentiation, but rather suppresses hair differentiation and gives rise to sebocyte differentiation. Taken together, these findings provide powerful evidence that the status of Tcf3/Lef complexes has a key role in controlling cell fate lineages in multipotent skin stem cells.

Animals↗

Multipotent stem cells from adult olfactory mucosa.

Multipotent stem cells are thought to be responsible for the generation of new neurons in the adult brain. Neurogenesis also occurs in an accessible part of the nervous system, the olfactory mucosa. We show here that cells from human olfactory mucosa generate neurospheres that are multipotent in vitro and when transplanted into the chicken embryo. Cloned neurosphere cells show this multipotency. Multipotency was evident without prior culture in vitro: cells dissociated from adult rat olfactory mucosa generate leukocytes when transplanted into bone marrow-irradiated hosts, and cells dissociated from adult mouse olfactory epithelium generated numerous cell types when transplanted into the chicken embryo. It is unlikely that these results can be attributed to hematopoietic precursor contamination or cell fusion. These results demonstrate the existence of a multipotent stem-like cell in the olfactory mucosa useful for autologous transplantation therapies and for cellular studies of disease.

Adult↗

Stem cells in the treatment of Parkinson's disease.

Stem cells have been suggested as candidate therapeutic tools for neurodegenerative disorders, given their ability to give rise to the appropriate cell types after grafting in vivo. In this review I summarize some of the evidence currently available concerning two approaches for the treatment of Parkinson's disease: (1) The generation of dopaminergic neurons from embryonic stem cells, multipotent stem cells, and neuronal progenitor cells for cell replacement therapy. (2) The engineering of multipotent stem cells to release glial cell-line derived neurotrophic factor, a potent neurotrophic factor for dopaminergic neurons, in a neuroprotective and neuroregenerative approach to the treatment of Parkinson's disease.

Animals↗

[Long-term culture of dermis-derived multipotent stem cells and the effects of collagen sponge on their growth in vitro].

Autologous multipotent stem cells are most relevant cells for regenerative medicine and show prosperous future in the treatment of human diseases. Previous reports have indicated that multipotent stem cells (MSCs) can be obtained from bone marrow and adipose tissues. In this study, we proved that dermis may be another source of these cells. MSCs were isolated from the dermis of newborn rats one day old by adhesion competition and successive culture. These cells conserved the ability to differentiate to osteoblasts, chondrocytes and adipocytes by induction media containing dexamethasone. After long term of more than 6 months, till 25th generation, the cells still maintained the characteristics of stem cells: high activity of self-renewal and multipotency. Mixed collagen matrix from dermis could promote the growth of dermis-derived multipotent stem cells and collagen sponge stent could promote their three-dimensional growth in vitro.

Animals↗

Control of nerve cell formation from multipotent stem cells in Hydra.

Feeding of starved animals provides a very short signal which determines stem cells to differentiate into nerve cells after the next mitosis. Only those stem cells become determined which are just in the middle of their S-phase at the time of feeding. Stem cells of any other stage of the cycle do not become determined. Nerve cell determination is suppressed by very low concentrations of an endogenous inhibitor. The inhibitor exerts its effect only during the first half of the S-phase, not before and not after this period. Based on these finding it is proposed that stem cells are susceptible to 2 different signals during the first half of their S-phase; one signal allows the development into nerve cells, the other prevents this development. Within this period the decision whether to become a nerve cell or not is reversible. It becomes fixed at the end of this period.

Animals↗

Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart.

Arodent cardiac side population cell fraction formed clonal spheroids in serum-free medium, which expressed nestin, Musashi-1, and multi-drug resistance transporter gene 1, markers of undifferentiated neural precursor cells. These markers were lost following differentiation, and were replaced by the expression of neuron-, glial-, smooth muscle cell-, or cardiomyocyte-specific proteins. Cardiosphere-derived cells transplanted into chick embryos migrated to the truncus arteriosus and cardiac outflow tract and contributed to dorsal root ganglia, spinal nerves, and aortic smooth muscle cells. Lineage studies using double transgenic mice encoding protein 0-Cre/Floxed-EGFP revealed undifferentiated and differentiated neural crest-derived cells in the fetal myocardium. Undifferentiated cells expressed GATA-binding protein 4 and nestin, but not actinin, whereas the differentiated cells were identified as cardiomyocytes. These results suggest that cardiac neural crest-derived cells migrate into the heart, remain there as dormant multipotent stem cells-and under the right conditions-differentiate into cardiomyocytes and typical neural crest-derived cells, including neurons, glia, and smooth muscle.

Animals↗

Successful stem cell therapy using umbilical cord blood-derived multipotent stem cells for Buerger's disease and ischemic limb disease animal model.

Buerger's disease, also known as thromboangiitis obliterans, is a nonatherosclerotic, inflammatory, vasoocclusive disease. It is characterized pathologically as a panangiitis of medium and small blood vessels, including both arteries and adjacent veins, especially the distal extremities (the feet and the hands). There is no curative medication or surgery for this disease. In the present study, we transplanted human leukocyte antigen-matched human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) into four men with Buerger's disease who had already received medical treatment and surgical therapies. After the stem cell transplantation, ischemic rest pain suddenly disappeared from their affected extremities. The necrotic skin lesions were healed within 4 weeks. In the follow-up angiography, digital capillaries were increased in number and size. In addition, vascular resistance in the affected extremities, compared with the preoperative examination, was markedly decreased due to improvement of the peripheral circulation. Because an animal model of Buerger's disease is absent and also to understand human results, we transplanted human UCB-derived MSCs to athymic nude mice with hind limb ischemia by femoral artery ligation. Up to 60% of the hind limbs were salvaged in the femoral artery-ligated animals. By in situ hybridization, the human UCB-derived MSCs were detected in the arterial walls of the ischemic hind limb in the treated group. Therefore, it is suggested that human UCB-derived MSC transplantation may be a new and useful therapeutic armament for Buerger's disease and similar ischemic diseases.

Adult↗

Metanephric mesenchyme contains multipotent stem cells whose fate is restricted after induction.

At least fourteen epithelial cell types of the mammalian nephron develop from the metanephric mesenchyme. To distinguish whether this single embryological primordium contains a heterogenous population of committed renal cell lines or a multipotent stem cell, the lac-Z gene was introduced into individual renal progenitors by retroviral mediated gene transfer. The differentiated fate of lac-Z-tagged daughters derived from single metanephric mesenchymal cells was characterized after cytodifferentiation. We found that the metanephric mesenchyme contains multipotent stem cells that can generate at least three distinct cell types; glomerular, proximal and distal epithelia. After induction the fate of this multipotent cell becomes restricted to populate a single nephron segment.

Animals↗

[Humoral factors in the regulation of cell proliferation in haematopoiesis. II. Erythropoiesis, megakaryopoiesis, multipotent stem cell (author's transl)].

Diffusible factors probably play an important role in the control of cell proliferation during haematopoiesis. Several stimulators of erythropoiesis including erythropoietin are to be found in sera. Inhibitors are found in erythrocyte supernatants, in the urin of newborn children, and in plasma of patients with renal insufficiency. Stimulators of megakaryopoiesis have been shown to be present in conditioned media of lymphoid cells and bone marrow cells. Inhibitors have been detected in various sera. Proliferation of multipotent stem cells is probably also regulated by a humoral mechanism. Stimulators and inhibitors are present in bone marrow extracts. Clinical relevance of these factors is discussed.

Cell Division↗

Chronic myelomonocytic leukemia with a chromosome abnormality (46,XY,20q-) in all dividing myeloid cells: evidence for clonal origin in a multipotent stem cell common to granulocyte, monocyte, erythrocyte, and thrombocyte.

In a typical case of chronic myelomonocytic leukemia (CMML), a chromosome abnormality, 46,XY,20q-, was observed in all the dividing cells including up to 16-ploid cells in the bone marrow and the blood. As the mitotic figures could be easily seen not only in myelomonocytoid cells but also in erythroblasts in the bone marrow smear, it was concluded that all the cell lineages except lymphocytes had the abnormality. The present case will support the view that the leukemic process in CMML affects a multipotent stem cell rather than a granulocyte-monocyte committed stem cell.

Aged↗

Morphogenesis and renewal of hair follicles from adult multipotent stem cells.

The upper region of the outer root sheath of vibrissal follicles of adult mice contains multipotent stem cells that respond to morphogenetic signals to generate multiple hair follicles, sebaceous glands, and epidermis, i.e., all the lineages of the hairy skin. At the time when hair production ceases and when the lower region of the follicle undergoes major structural changes, the lower region contains a significant number of clonogenic keratinocytes, and can then respond to morphogenetic signals. This demonstrates that multipotent stem cells migrate to the root of the follicle to produce whisker growth. Moreover, our results indicate that the clonogenic keratinocytes are closely related, if not identical, to the multipotent stem cells, and that the regulation of whisker growth necessitates a precise control of stem cell trafficking.

Animals↗

A 37-year-old spinal cord-injured female patient, transplanted of multipotent stem cells from human UC blood, with improved sensory perception and mobility, both functionally and morphologically: a case study.

HLA-matched UC blood-derived multipotent stem cells were directly transplanted into the injured spinal cord site of a 37-year-old female patient suffering from spinal cord injury (SPI). In this case, human cord blood (UCB)-derived multipotent stem cells improved sensory perception and movement in the SPI patient's hips and thighs within 41 days of cell transplantation. CT and MRI results also showed regeneration of the spinal cord at the injured site and some of the cauda equina below it. Therefore, it is suggested that UCB multipotent stem cell transplantation could be a good treatment method for SPI patients.

Adult↗

Multipotent stem cells from the mouse basal forebrain contribute GABAergic neurons and oligodendrocytes to the cerebral cortex during embryogenesis.

During CNS development, cell migrations play an important role, adding to the cellular complexity of different regions. Earlier studies have shown a robust migration of cells from basal forebrain into the overlying dorsal forebrain during the embryonic period. These immigrant cells include GABAergic neurons that populate the cerebral cortex and hippocampus. In this study we have examined the fate of other basal forebrain cells that migrate into the dorsal forebrain, identifying basal cells using an antibody that recognizes both early (dlx1/2) and late (dlx 5/6) members of the dlx homeobox gene family. We found that a subpopulation of cortical and hippocampal oligodendrocytes are also ventral-derived. We traced the origin of these cells to basal multipotent stem cells capable of generating both GABAergic neurons and oligodendrocytes. A clonal analysis showed that basal forebrain stem cells produce significantly more GABAergic neurons than dorsal forebrain stem cells from the same embryonic age. Moreover, stem cell clones from basal forebrain are significantly more likely to contain both GABAergic neurons and oligodendrocytes than those from dorsal. This indicates that forebrain stem cells are regionally specified. Whereas dlx expression was not detected within basal stem cells growing in culture, these cells produced dlx-positive products that are capable of migration. These data indicate that the developing cerebral cortex incorporates both neuronal and glial products of basal forebrain and suggest that these immigrant cells arise from a common progenitor, a dlx-negative basal forebrain stem cell.

Animals↗

Homeobox gene expression profile in human hematopoietic multipotent stem cells and T-cell progenitors: implications for human T-cell development.

Class I homeobox (HOX) genes comprise a large family of transcription factors that have been implicated in normal and malignant hematopoiesis. However, data on their expression or function during T-cell development is limited. Using degenerated RT-PCR and Affymetrix microarray analysis, we analyzed the expression pattern of this gene family in human multipotent stem cells from fetal liver (FL) and adult bone marrow (ABM), and in T-cell progenitors from child thymus. We show that FL and ABM stem cells are similar in terms of HOX gene expression, but significant differences were observed between these two cell types and child thymocytes. As the most immature thymocytes are derived from immigrated FL and ABM stem cells, this indicates a drastic change in HOX gene expression upon entry into the thymus. Further analysis of HOX-A7, HOX-A9, HOX-A10, and HOX-A11 expression with specific RT-PCR in all thymocyte differentiation stages showed a sequential loss of 3' region HOX-A cluster genes during intrathymic T-cell development and an unexpected expression of HOX-A11, previously not recognized to play a role in hematopoiesis. Also HOX-B3 and HOX-C4 were expressed throughout thymocyte development. Overall, these data provide novel evidence for an important role of certain HOX genes in human T-cell development.

Adult↗