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PubMed1990

[Clonality and stem cell defects in the molecular pathology of chronic myeloproliferative disorders].

The chronic myeloproliferative disorders (CMD) are characterized by sustained or progressive proliferations of bone marrow cells, affecting one or more lineages in varying combinations. They are classified in 4 subgroups but transitional forms and transformations among the different entities are common. Analysing RFLPs and methylation patterns of X-chromosomal genes we could show, that in each entity granulocytes as well as bone marrow cells are of monoclonal origin. These findings support the view that all forms of CMD have in common that they arise from a multipotent hematopoietic stem cell. CML can be differentiated from all other forms of CMD by the Philadelphia-chromosome which on the molecular level has been revealed as bcr-abl gene junction. We investigated 258 cases of CMD for rearrangement of the bcr gene and found that it selectively occurred in CML. The methods applied can be of diagnostic value in differentiating reactive from neoplastic proliferations by analysis of clonality, and in differentiation of CML from other types of CMD by detection of the bcr-rearrangement.

Bone Marrow↗
PubMed2004

Failure to express GAP-43 leads to disruption of a multipotent precursor and inhibits astrocyte differentiation.

The nervous system-specific protein GAP-43 is significantly upregulated in neurons and glia that are differentiating. In P19 EC cells that do not express GAP-43, neurogenesis is inhibited; many immature neurons apoptose and the survivors do not mature morphologically. Here we show that the initial defect is in an early precursor with characteristics of a neural stem cell, which failed to respond normally to retinoic acid (RA). As a consequence, its progeny had altered cell fates: In addition to the neuronal defects previously reported, RC1-labeled radial glia failed to exit the cell cycle, accumulated, and failed to acquire GFAP immunoreactivity. However, leukemia inhibitory factor (LIF) could stimulate GFAP expression suggesting that astrocytes not derived from radial glia are less affected by absence of GAP-43. Differentiation of radial glia-derived astrocytes was also inhibited in glial cultures from GAP-43 (-/-) cerebellum, and in GAP-43 (-/-) telencephalon in vivo, differentiation of astrocytes derived from both radial and nonradial glia lineages were both affected: In the glial wedge, GFAP-labeled radial glia-derived astrocytes were reduced consistent with the interpretation that they may be unable to deflect GAP-43 (-/-) commissural axons toward the midline. At the midline, both radial and nonradial glia-derived astrocytes were also decreased although it fused normally. The results demonstrate that GAP-43 expressed in multipotent precursors is required for appropriate cell fate commitment, and that its absence affects astrocyte as well as neuronal differentiation.

Animals↗
PubMed1991

Growth regulation of hematopoietic cells. An overview.

The production of mature blood cells is absolutely dependent on a small pool of pluripotent stem cells with high proliferative and self-renewal capacities. The hematopoietic stem cells develop gradually from pluripotent to unipotent, committed progenitor cells during which process they lose their self-renewal capacity. This development is dependent on interactions with specific hematopoietic growth factors, which by binding to surface receptors on the stem cells stimulate them to proceed to the next step of differentiation. During recent years several of the hematopoietic growth factors have been purified to homogeneity, their primary protein as well as genetic structures have been determined and today they are available for clinical trials as recombinant proteins produced in bacteria, yeast or mammalian cells. Our present knowledge sustains the notion that IL-3, and to a lesser extent GM-CSF, play a major role in multipotent hematopoietic stem cell survival, proliferation and differentiation into stem cells with restricted maturation programs. The programmed unipotent stem cells need stimulation by erythropoietin, G-CSF, M-CSF and IL-5 to proliferate and mature into their end stage products erythrocytes, neutrophils, monocytes and eosinophils respectively. Other cytokines such as IL-1, IL-4 and IL-6 fulfil important functions as cofactors in these processes and several others play the part of tentative physiological inhibitors. During the past decade major progress has been made in our understanding of the complex interplay between stem cells, accessory cells, growth factors, and their receptors, and the clinical trials now undertaken will certainly bring even more basic knowledge to the field of hematopoietic growth regulation.

Cell Division↗
PubMed1985

Origin and differentiation of natural killer cells. I. Characteristics of a transplantable NK cell precursor.

To study the origin and differentiation of natural killer (NK) cells, we developed an assay for the transplantable precursor of NK(YAC-1) cells present in the bone marrow. Mice were depleted of endogenous NK(YAC-1) cells by injection of anti-asialo GM1 antibody, followed by lethal whole body irradiation. Normal syngeneic bone marrow cells were transplanted into such pretreated mice. Regeneration of NK(YAC-1) activity in the recipient mice was monitored by two different assays: the ability of spleen cells to lyse YAC-1 cells in vitro and the ability to clear i.v. injected, 125IUdR-labeled YAC-1 cells from the lungs. With both assays, a dose-response relationship between the number of bone marrow cells injected and the degree of NK(YAC-1) activity generated could be demonstrated. However, the lung clearance assay appeared superior because the NK regeneration could be detected earlier and with lower numbers of injected marrow cells. With this assay, several characteristics of the NK precursors and their differentiation could be defined. 1) The generation of mature, lytic NK cells from their transplantable precursor requires an intact "marrow microenvironment" in the recipient mice, because differentiation failed to occur in mice rendered osteopetrotic by estradiol treatment. 2) The NK(YAC-1) precursors lack the surface antigens (NK-2.1, asialo GM1, Qa-5, Thy-1) that are characteristically seen on mature NK cells. 3) The NK-precursors could be eliminated from the bone marrow with anti-Qa-2 or anti-H-2 antisera + complement, indicating that these two antigens are expressed on the precursors. The relationship between NK(YAC-1) precursors and multipotent myeloid stem cells (CFU-S) was investigated by utilizing W/Wv and Sl/Sld mutant mice. Bone marrow cells of W/Wv anemic mice, although markedly deficient in CFU-S, have a normal frequency of NK(YAC-1) precursors. Sl/Sld mice that lack a suitable microenvironment for the development of CFU-S allowed normal differentiation of NK(YAC-1) precursors when transplanted with normal bone marrow cells. Together, these data suggest that multipotent myeloid progenitor cells, as defined by the CFU-S assay, and the NK(YAC-1) precursors are not closely related.

Animals↗
PubMed2004

G-CSF treatment increases side population cell infiltration after myocardial infarction in mice.

Granulocyte-colony stimulating factor (G-CSF) has been reported to mobilize bone marrow multi-potent stem cells, which differentiate into cardiac myocytes after myocardial infarction (MI). However, there have not been any reports regarding the effect of G-CSF on stem cell infiltration in the MI site. Hearts of mice that had undergone coronary occlusion were isolated and digested with collagenase. Infiltrating cells in the heart were collected using Percoll density gradients. The infiltrating cells were sorted for side population (SP) cells using Hoechst 33342 dye. Hundreds of infiltrating SP cells were found in the heart from 1 to 14 d after MI. There were only a few SP cells in hearts without infarction. Infiltrating SP cells were increased in the 4-d G-CSF treated group compared with the vehicle group (1106 +/- 106 vs. 323 +/- 26/heart, P < 0.05). The infiltration of inflammatory cells was not influenced by the G-CSF treatment. In a separate series of experiments, we confirmed that the infiltrating SP cells were derived from bone marrow. That is, SP cells in the infarcted hearts of mice, which had been transplanted with bone marrow from ROSA 26 (beta-galactosidase transgenic) mice, were positive for beta-galactosidase. In the immunohistochemical examination, Sca-1(+)/CD45(-) cells were existed in the infarcted site after MI. Therefore, SP cells may infiltrate into infarcted heart. G-CSF augmented this kind of stem cell infiltration without increasing inflammatory cells. These results suggest that G-CSF may enhance myocardial regeneration without aggravated inflammation in the infarcted heart.

Animals↗
PubMed2003

[The generation of neural stem cells: induction of neural stem cells from embryonic stem (ES) cells].

Neural stem cells are considered the ultimate lineage precursors to all neurons and glia. Despite the significance of neural stem cells in the mammalian brain development, their ontogenesis remains unclear. We have established a colony-forming embryonic stem (ES) sphere assay, where ES cells were cultured in serum-free media in the presence of leukemia inhibitory factor (LIF) to form floating spheres. LIF-dependent ES cell-derived sphere cells showed self-renewal and neural multipotentiality, cardinal features of the neural stem cell, but retained some non-neural properties and broader potential. We dabbed the cells in the ES cell-derived sphere of primitive neural stem cells. LIF-dependent sphere-forming cells were also present in the epiblast of embryonic day 5.5-7.5 mouse embryos. The generation of the in vivo primitive neural stem cell was independent of Notch signaling but the activation of Notch pathway was necessary for the transition from the primitive neural stem cell to the neural stem cell. We propose that the neural stem cell originates from the pluripotent inner cell mass/epiblast cell via the primitive neural stem cell stage under the control of Notch signaling.

Animals↗
PubMed2005

Caveolin-1 is expressed on multipotent cells of hair follicles and might be involved in their resistance to chemotherapy.

BACKGROUND: Caveolin-1 is the principal protein that composes caveolae, which are vesicular invaginations present on the plasma membrane of different cell types. Caveolae are involved in a variety of cellular functions including regulation of proliferation rate and resistance to chemotherapeutic drugs. Chemotherapy frequently induces alopecia which is reversible most probably due to the low proliferative rate of hair follicle stem cells and due to the expression of proteins which confer resistance. OBJECTIVES: Using a specific animal model and immunohistochemistry, we analysed the expression of both caveolin-1 and the cell proliferation marker beta-catenin, at different stages of the hair follicle cycle, both before and after doxorubicin (DXR) -induced alopecia. METHODS: Seven-week-old C57BL/6 mice were depilated in order to synchronize hair follicle cycle in the anagen phase. Chemotherapy with DXR 15 mg kg(-1) was used to induce alopecia. Control and treated mice were then sacrificed at precise time points and caveolin-1 expression in hairs at different stages of the cycle were analysed by immunohistochemistry. By double immunofluorescence, colocalization of caveolin-1 and cytokeratin-15 was confirmed in the bulge region. The state of proliferation of cells composing hair follicle was assessed by beta-catenin immunohistochemistry. RESULTS: Caveolin-1 was expressed by the cells of the bulge area, the multipotent compartment of the hair follicle, during all phases of growth (anagen), regression (catagen) and resting (telogen). During the anagen phases, nuclear beta-catenin labelling was not observed in bulge cells, but rather in the deeper portion of the follicle. Damaged hair follicles from DXR-treated mice presented bulge cells which still expressed caveolin-1, suggesting that this protein might play a role in their drug resistance. As expected, no beta-catenin nuclear staining was detectable in DXR-treated hair follicles, indicating the complete lack of proliferative processes. The differential localization of caveolin-1 and beta-catenin suggests that the mutually exclusive expression of these proteins is useful for correct hair regrowth, whether during the physiological cycle or after chemotherapy-induced alopecia. CONCLUSIONS: Expression of caveolin-1 within the multipotent cell compartment of the hair follicle can explain the resistance of bulge cells to many chemotherapeutics, suggested by the reversibility of chemotherapy-induced alopecia.

Alopecia↗
PubMed2003

Neuronal stem cells.

Stem cells are self regenerating multipotential cells, found in the human brain which have the potential to differentiate into neurons, astrocytes and oligodendrocytes, and to self renew sufficiently to provide adequate number of cells in the brain. Neural stem cell grafts have been studied in a variety of animal models for various diseases like metabolic disorders, muscular dystrophies, neurodegenerative disorders, spinal cord repair, brain tumors and demyelinating disease. Stem cells may be derived from autologus, allogeneic or xenogenic sources. Histocompatibility is prerequisite for transplantation of allogeneic stem cells. Fetal tissue is the best current tissue source for human neural stem cells, however ethical issues are a major concern. Thus the prospect that stem cells could potentially be used to promote neurogenesis following injury and disease may seem attractive, yet the inherent problems associated with isolation and rejection in case of stem cells from another source, the potential to form tumors and ethical issues are the major challenges.

Central Nervous System Diseases↗
PubMed2002

Significant improvement of heart function by cotransplantation of human mesenchymal stem cells and fetal cardiomyocytes in postinfarcted pigs.

BACKGROUND: Viable cardiomyocytes after myocardial infarction (MI) are unable to repair the necrotic myocardium due to their limited capability of regeneration. The present study investigated whether intramyocardial transplantation of human mesenchymal stem cells (hMSCs) or cotransplantation of hMSCs plus human fetal cardiomyocytes (hFCs; 1:1) reconstituted impaired myocardium and improved cardiac function in MI pigs. METHODS AND RESULTS: Cultured hMSCs were transfected with green fluorescent protein (GFP). Six weeks after MI induction and cell transplantation, cardiac function was significantly improved in MI pigs transplanted with hMSCs alone. However, the improvement was even markedly greater in MI pigs cotransplanted with hMSCs plus hFCs. Histological examination demonstrated that transplantation of hMSCs alone or hMSCs plus hFCs formed GFP-positive engrafts in infarcted myocardium. In addition, immunostaining for cardiac alpha-myosin heavy chain and troponin I showed positive stains in infarcted regions transplanted with hMSCs alone or hMSCs plus hFCs. CONCLUSIONS: Our data demonstrate that transplantation of hMSCs alone improved cardiac function in MI pigs with a markedly greater improvement from cotransplantation of hMSCs plus hFCs. This improvement might result from myocardial regeneration and angiogenesis in injured hearts by engrafted cells.

Animals↗
PubMed2004

Identification of pleiotrophin in conditioned medium secreted from neural stem cells by SELDI-TOF and SELDI-tandem mass spectrometry.

Neural stem cells (NSCs) are multipotential progenitor cells that have self-renewal activity. Since the fates of the NSCs in situ depend on their niche containing growth factors and cytokines, we performed surface enhanced laser desorption/ionization time-of flight mass spectrometry (SELDI-TOF-MS) to screen for differentially secreted proteins in conditioned medium of neural stem cells and compared with that of NIH3T3 cells. A 15.3-kDa protein detected only in the conditioned medium of neural stem cells was determined as pleiotrophin (PTN) by SELDI-TOF-MS and ProteinChip-tandem MS systems. Identification of pleiotrophin was further confirmed by one-dimensional SDS gel electrophoresis and Edman degradation analysis. The mRNA transcripts of PTN and its receptors [receptor protein tyrosine phosphatase (RPTP) beta/zeta, N-syndecan and anaplastic lymphoma kinase (ALK)] were detected in neurosphere, suggesting that pleiotrophin signaling systems are present in the neural stem cells and are involved in the modulation of fate of neural stem cells.

Anaplastic Lymphoma Kinase↗
PubMed1990

Therapeutic administration of recombinant human granulocyte colony-stimulating factor accelerates hemopoietic regeneration and enhances survival in a murine model of radiation-induced myelosuppression.

The primary cause of death after radiation exposure is infection resulting from myelosuppression. Because granulocytes play a critical role in host defense against infection and because granulocyte proliferation and differentiation are enhanced by granulocyte colony-stimulating factor (G-CSF), this agent was evaluated for the ability to accelerate hemopoietic regeneration and to enhance survival in irradiated mice. C3H/HeN mice were irradiated and G-CSF (2.5 micrograms/day, s.c.) or saline was administered on days 3-12, 1-12 or 0-12 post-irradiation. Bone marrow, splenic and peripheral blood cellularity, and bone marrow and splenic granulocyte-macrophage progenitor cell recoveries were evaluated in mice exposed to 6.5 Gy. Mice exposed to 8 Gy were evaluated for multipotent hemopoietic stem cell recovery (using endogenous spleen colony-forming units) and enhanced survival. Results demonstrated that therapeutic G-CSF 1) accelerates hemopoietic regeneration after radiation-induced myelosuppression, 2) enhances survival after potentially lethal irradiation and 3) is most effective when initiated 1 h following exposure.

Agranulocytosis↗
PubMed1999

Cell differentiation in the embryonic mammalian spinal cord.

The acquisition of cell type specific properties in the spinal cord is a process of a sequential restriction in developmental potential. Multipotent neuroepithelial stem cells (NEP cells) can give rise to all the major cell types in the central nervous system. The generation of these multiple cell types occurs via the generation of intermediate precursor cells, which are restricted in their differentiation potential, but are still able to give rise to more than one cell type. These intermediate precursor cells are different from NEP cells and are different from each other. We have identified neuronal restricted precursor cells (NRP's) which can only generate neurons but no longer glial cells and glial restricted precursor cells (GRP's), which give rise to glial cells but not to neurons. These intermediate precursor cells can be purified and expanded in vitro and might offer a new tool for gene discovery, drug screening and transplantation approaches.

Animals↗
PubMed2003

Neural stem cells and the regulation of adult neurogenesis.

Presumably, the 'hard-wired' neuronal circuitry of the adult brain dissuades addition of new neurons, which could potentially disrupt existing circuits. This is borne out by the fact that, in general, new neurons are not produced in the mature brain. However, recent studies have established that the adult brain does maintain discrete regions of neurogenesis from which new neurons migrate and become incorporated into the functional circuitry of the brain. These neurogenic zones appear to be vestiges of the original developmental program that initiates brain formation. The largest of these germinal regions in the adult brain is the subventricular zone (SVZ), which lines the lateral walls of the lateral ventricles. Neural stem cells produce neuroblasts that migrate from the SVZ along a discrete pathway, the rostral migratory stream, into the olfactory bulb where they form mature neurons involved in the sense of smell. The subgranular layer (SGL) of the hippocampal dentate gyrus is another neurogenic region; new SGL neurons migrate only a short distance and differentiate into hippocampal granule cells. Here, we discuss the surprising finding of neural stem cells in the adult brain and the molecular mechanisms that regulate adult neurogenesis.

Adrenal Cortex Hormones↗
PubMed2003

Multilineage potential of cells from the artery wall.

BACKGROUND: In diabetes or atherosclerosis, ectopic bone, fat, cartilage, and marrow often develop in arteries. However the mechanism is unknown. We have previously identified a subpopulation of vascular cells (calcifying vascular cells, CVC), derived by dilutional cloning of bovine aortic medial cells, and showed that they undergo osteoblastic differentiation and mineralization. We now show that CVC have the potential to differentiate along other mesenchymal lineages. METHODS AND RESULTS: To determine the multilineage potential of CVC, molecular and functional markers of multiple mesenchymal lineages were assessed. Chondrogenic potential of CVC was evidenced by expression of types II and IX collagen and cytochemical staining for Alcian blue. Leiomyogenic potential of CVC was evidenced by the expression of smooth muscle-alpha actin, calponin, caldesmon, and myosin heavy chain. Stromogenic potential of CVC was evidenced by the ability to support growth of colony-forming units of hematopoietic progenitor cells from human CD34+ umbilical cord blood cells for a period of 5 weeks. Adipogenic potential was not observed. CVC were immunopositive to antigens to CD29 and CD44 but not to CD14 or CD45, consistent with other mesenchymal stem cells. CVC retained multipotentiality despite passaging and expansion through more than 20 to 25 population triplings, indicating a capacity for self-renewal. CONCLUSIONS: These results suggest that the artery wall contains cells that have the potential for multiple lineages similar to mesenchymal stem cells but with a unique differentiation repertoire.

Animals↗
PubMed2004

Persistent and injury-induced neurogenesis in the vertebrate retina.

The brains of all vertebrates are persistently neurogenic. However, this is not true for the neural retinas. Only three extant classes of vertebrates show significant posthatch/postnatal retinal neurogenesis: amphibians, birds and fish. The retinas of these animals contain an annulus of progenitors at the margin, from which differentiated neurons emerge. In posthatch amphibians and fish the vast majority of the adult retina is added from the margin and neurogenesis is lifelong, whereas in posthatch birds neurogenesis is limited. Unique to fish, rod photoreceptors are added in situ from stem cells within the mature retina. Strikingly, for each class of animal retinal lesions stimulate neuronal regeneration, however the cellular source differs for each: the retinal pigmented epithelium in amphibians and embryonic birds, Müller glia in posthatch birds and intrinsic stem cells in fish. The molecular events surrounding injury-induced neuronal regeneration are beginning to be identified.

Animals↗
PubMed2006

A review of insect stem cell types.

Insect stem cells have been described from both embryonic and adult tissues from a diversity of insect species, although much of the focus in insect stem cell research has been on Drosophila. Insects are a vast and diverse group and it is surprising that a critical aspect of their development like stem cells has not received more attention. In this review we discuss the current state of knowledge of insect stem cell types. We examine what stem cell types have been identified from insects, and briefly discuss what is known about their regulation.

Animals↗
PubMed2005

Multipotential differentiation of adipose tissue-derived stem cells.

Tissue engineering offers considerable promise in the repair or replacement of diseased and/or damaged tissues. The cellular component of this regenerative approach will play a key role in bringing these tissue engineered constructs from the laboratory bench to the clinical bedside. However, the ideal source of cells still remains unclear and may differ depending upon the application. Current research for many applications is focused on the use of adult stem cells. The properties of adult stem cells that make them well-suited for regenerative medicine are (1) ease of harvest for autologous transplantation, (2) high proliferation rates for ex vivo expansion and (3) multilineage differentiation capacity. This review will highlight the use of adipose tissue as a reservoir of adult stem cells and draw conclusions based upon comparisons with bone marrow stromal cells.

Adipose Tissue↗
PubMed2005

Jagged1 signals in the postnatal subventricular zone are required for neural stem cell self-renewal.

Neural stem cells (NSCs) in the postnatal mammalian brain self-renew and are a source of neurons and glia. To date, little is known about the molecular and cellular mechanisms regulating the maintenance and differentiation of these multipotent progenitors. We show that Jagged1 is required by mitotic cells in the subventricular zone (SVZ) and stimulates self-renewal of multipotent epidermal growth factor-dependent NSCs. Jagged1-expressing cells line the adult SVZ and are juxtaposed to Notch1-expressing cells, some of which are putative NSCs. In vitro, endogenous Jagged1 acts through Notch1 to promote NSC maintenance and multipotency. In vivo, reducing Jagged1/Notch1 signaling decreases the number of proliferating cells in the SVZ. In addition, soluble Jagged1 promotes self-renewal and neurogenic potential of multipotent neural progenitors in vitro. Our findings suggest a central role for Jagged1 in the NSC niche in the SVZ for maintaining a population of NSCs in the postnatal brain.

Animals↗