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PubMed2006

Mechanisms of cell death of neural progenitor cells caused by trophic support deprivation.

Cell death of neural progenitor cells is the primary problem limiting the value of neural progenitor cell-based therapy for central nervous system disorders. However, little is known about the mechanism of cell death of neural progenitor cells. In this study, we investigated the mechanisms of cell death of a multipotent cell line, MEB5, caused by deprivation of epidermal growth factor (EGF). When EGF was removed from the culture medium, the total number of viable MEB5 cells reduced, and nuclear condensation and elevation of caspase-3-like enzyme activity were observed in MEB5 cells. Treatment with a broad-range caspase inhibitor reduced cell death in a concentration-dependent manner, indicating that MEB5 cells undergo caspase-mediated apoptotic cell death caused by EGF deprivation. We also investigated the effects of glutamate receptor antagonists, antioxidants and nitric oxide synthase inhibitor on EGF deprivation-induced cell death. N-methyl-D-aspartate (NMDA) glutamate receptor antagonists, alpha-amino-3-hydrozy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor antagonist and nitric oxide synthase inhibitor failed to reduce cell death. In contrast, two antioxidants with different chemical structures reduced cell death in a concentration-dependent manner. The production of reactive oxygen species was detected in MEB5 cells after EGF deprivation by monitoring dichlorodihydrofluorescein fluorescence as a marker of reactive oxygen species-related radicals. Our results suggest that oxidative stress triggers caspase-mediated apoptosis of neural progenitor cells by trophic support deprivation.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2005

FGF-2 promotes neurogenesis and neuroprotection and prolongs survival in a transgenic mouse model of Huntington's disease.

There is no satisfactory treatment for Huntington's disease (HD), a hereditary neurodegenerative disorder that produces chorea, dementia, and death. One potential treatment strategy involves the replacement of dead neurons by stimulating the proliferation of endogenous neuronal precursors (neurogenesis) and their migration into damaged regions of the brain. Because growth factors are neuroprotective in some settings and can also stimulate neurogenesis, we treated HD transgenic R6/2 mice from 8 weeks of age until death by s.c. administration of FGF-2. FGF-2 increased the number of proliferating cells in the subventricular zone by approximately 30% in wild-type mice, and by approximately 150% in HD transgenic R6/2 mice. FGF-2 also induced the recruitment of new neurons from the subventricular zone into the neostriatum and cerebral cortex of HD transgenic R6/2 mice. In the striatum, these neurons were DARPP-32-expressing medium spiny neurons, consistent with the phenotype of neurons lost in HD. FGF-2 was neuroprotective as well, because it blocked cell death induced by mutant expanded Htt in primary striatal cultures. FGF-2 also reduced polyglutamine aggregates, improved motor performance, and extended lifespan by approximately 20%. We conclude that FGF-2 improves neurological deficits and longevity in a transgenic mouse model of HD, and that its neuroprotective and neuroproliferative effects may contribute to this improvement.

Analysis of Variance↗
PubMed2004

Microarray analysis of in vitro pericyte differentiation reveals an angiogenic program of gene expression.

The vasculature consists of endothelial cells (ECs) lined by pericyte/vascular smooth muscle cells (vSMCs). Pericyte/vSMCs provide support to the mature vasculature but are also essential for normal blood vessel development. To determine how pericyte-EC communication influences vascular development, we used the well-established in vitro model of TGFbeta-stimulated differentiation of 10T1/2 cells into pericyte/vSMCs. Microarray analysis was performed to identify genes that were differentially expressed by induced vs. uninduced 10T1/2 cells. We discovered that these cells show an angiogenic program of gene expression, with up-regulation of several genes previously implicated in angiogenesis, including VEGF, IL-6, VEGF-C, HB-EGF, CTGF, tenascin C, integrin alpha5, and Eph receptor A2. Up-regulation of some genes was validated by Western blots and immunocytochemistry. We also examined the functional significance of these gene expression changes. VEGF and IL-6 alone and in combination were important in 10T1/2 cell differentiation. Furthermore, we used a coculture system of 10T1/2 and human umbilical vein ECs (HUVECs), resulting in the formation of cordlike structures by the HUVECs. This cordlike structure formation was disrupted when neutralizing antibodies to VEGF or IL-6 were added to the coculture system. The results of these studies show that factors produced by pericytes may be responsible for recruiting ECs and promoting angiogenesis. Therefore, a further understanding of the genes involved in pericyte differentiation could provide a novel approach for developing anti-angiogenic therapies.

Animals↗
PubMed2002

Functional recovery of cholinergic basal forebrain neurons under disease conditions: old problems, new solutions?

Recognition of the involvement of cholinergic neurons in the modulation of cognitive functions and their severe dysfunction in neurodegenerative disorders, such as Alzheimer's disease, initiated immense research efforts aimed at unveiling the anatomical organization and cellular characteristics of the basal forebrain (BFB) cholinergic system. Concomitant with our unfolding knowledge about the structural and functional complexity of the BFB cholinergic projection system, multiple pharmacological strategies were introduced to rescue cholinergic nerve cells from noxious attacks; however, a therapeutic breakthrough is still awaited. In this review, we collected recent findings that significantly contributed to our better understanding of cholinergic functions under disease conditions, and to the design of effective means to restore lost or damaged cholinergic functions. To this end, we first provide a brief survey of the neuroanatomical organization of BFB nuclei with emphasis on major evolutionary differences among mammalian species, in particular rodents and primates, and discuss limitations of the translation of experimental data to human therapeutic applications. Subsequently, we summarize the involvement of cholinergic dysfunction in the pathogenesis of severe neurological conditions, including stroke, traumatic brain injury, virus encephalitis and Alzheimer's disease, and emphasize the critical role of pro-inflammatory cytokines as common mediators of cholinergic neuronal damage. Moreover, we review leading functional concepts on the limited recovery of cholinergic neurons and their impaired plastic re-modeling, as well as on the hampered interplay of the ascending cholinergic and monoaminergic projection systems under neurodegenerative conditions. In addition, recent advances in the dynamic labeling of living cholinergic neurons by fluorochromated antibodies, referred to as in vivo labeling, and novel neuroimaging approaches as potential diagnostic tools of progressive cholinergic decline are surveyed. Finally, the potential of cell replacement strategies using embryonic and adult stem cells, and multipotent neural progenitors, as a means to recover damaged cholinergic functions, is discussed.

Acetylcholine↗
PubMed1986

Establishment of eosinophilic sublines from human promyelocytic leukemia (HL-60) cells: demonstration of multipotentiality and single-lineage commitment of HL-60 stem cells.

Recent observations indicating that the HL-60 human acute promyelocytic leukemia cell line contains a minor eosinophil population in addition to neutrophil and mononuclear phagocyte progenitors suggest the multipotentiality of HL-60 stem cells. In order to clarify multilineage differentiation and commitment to single-lineage progenitors we analyzed HL-60 colonies formed in methylcellulose. In an HL-60 parent line with a relatively high eosinophil content (5.5%), 36% of the spontaneous colonies consisted partly or wholly of eosinophilic cells. After two rounds of subcloning in methylcellulose, two eosinophilic sublines and two neutrophilic sublines were established. These lines have been in continuous liquid culture for more than four months, and they show stable single-lineage differentiation. Purified biosynthetic GM-CSF, which stimulates normal CFU-GM and CFU-EO, induced monocytic differentiation but no eosinophilic differentiation in the neutrophilic sublines and no neutrophilic or monocytic differentiation in the eosinophilic sublines. These observations indicate that HL-60 stem cells are multipotent and capable of spontaneous commitment to single-lineage progenitors. The eosinophilic HL-60 sublines should facilitate studies on the production and function of human eosinophils and the single-lineage sublines will allow further analysis of leukemic cell differentiation and stem cell commitment.

Cell Differentiation↗
PubMed2005

Intracellular Helicobacter pylori in gastric epithelial progenitors.

Helicobacter pylori is generally viewed as an extracellular pathogen. We have analyzed the tropism of H. pylori clinical isolates in a gnotobiotic transgenic mouse model of human chronic atrophic gastritis, a preneoplastic condition. These mice lack acid-producing parietal cells and have an amplified population of dividing gastric epithelial progenitors (GEPs) that express NeuAc alpha 2,3Gal beta 1,4-glycans recognized by H. pylori adhesins. Scanning confocal and transmission electron microscopic studies of stomachs that had been colonized for 1 month or 1 year revealed intracellular bacterial collections (IBCs) in a small subset of multi- and oligopotential epithelial progenitors. Transmission electron microscopic and multilabel immunohistochemical analyses disclosed bacteria with several morphotypes, including spiral-shaped, in the cytoplasm and endosomes. Several stages in IBC evolution were documented, from a few solitary bacteria to consolidated populations in dividing and nondividing GEPs, to microorganisms traversing breaches in the GEP plasma cell membrane. IBC formation was not a unique feature of H. pylori strains isolated from patients with chronic atrophic gastritis. The notion that adult mammalian epithelial progenitors can function as a repository for H. pylori broadens the view of host habitats available to this and perhaps other pathogens.

Animals↗
PubMed2006

Loss of p53 induces changes in the behavior of subventricular zone cells: implication for the genesis of glial tumors.

The role of multipotential progenitors and neural stem cells in the adult subventricular zone (SVZ) as cell-of-origin of glioblastoma has been suggested by studies on human tumors and transgenic mice. However, it is still unknown whether glial tumors are generated by all of the heterogeneous SVZ cell types or only by specific subpopulations of cells. It has been proposed that transformation could result from lack of apoptosis and increased self-renewal, but the definition of the properties leading to neoplastic transformation of SVZ cells are still elusive. This study addresses these questions in mice carrying the deletion of p53, a tumor-suppressor gene expressed in the SVZ. We show here that, although loss of p53 by itself is not sufficient for tumor formation, it provides a proliferative advantage to the slow- and fast-proliferating subventricular zone (SVZ) populations associated with their rapid differentiation. This results in areas of increased cell density that are distributed along the walls of the lateral ventricles and often associated with increased p53-independent apoptosis. Transformation occurs when loss of p53 is associated with a mutagenic stimulus and is characterized by dramatic changes in the properties of the quiescent adult SVZ cells, including enhanced self-renewal, recruitment to the fast-proliferating compartment, and impaired differentiation. Together, these findings provide a cellular mechanism for how the slow-proliferating SVZ cells can give rise to glial tumors in the adult brain.

Animals↗
PubMed2006

Neural precursors derived from embryonic stem cells, but not those from fetal ventral mesencephalon, maintain the potential to differentiate into dopaminergic neurons after expansion in vitro.

Neural precursors (NPs) derived from ventral mesencephalon (VM) normally generate dopaminergic (DA) neurons in vivo but lose their potential to differentiate into DA neurons during mitogenic expansion in vitro, hampering their efficient use as a transplantable and experimental cell source. Because embryonic stem (ES) cell-derived NPs (ES NP) do not go through the same maturation process during in vitro expansion, we hypothesized that expanded ES NPs may maintain their potential to differentiate into DA neurons. To address this, we expanded NPs derived from mouse embryonic day-12.5 (E12.5) VM or ES cells and compared their developmental properties. Interestingly, expanded ES NPs fully sustain their ability to differentiate to the neuronal as well as to the DA fate. In sharp contrast, VM NPs almost completely lost their ability to become neurons and tyrosine hydroxylase-positive (TH(+)) neurons after expansion. Expanded ES NP-derived TH(+) neurons coexpressed additional DA markers such as dopa decarboxylase and DAT (dopamine transporter). Furthermore, they also expressed other midbrain DA markers, including Nurr1 and Pitx3, and released significant amounts of DA. We also found that these ES NPs can be cryopreserved without losing their proliferative and developmental potential. Finally, we tested the in vivo characteristics of the expanded NPs derived from J1 ES cells with low passage number. When transplanted into the mouse striatum, the expanded NPs as well as control NPs efficiently generated DA neurons expressing mature DA markers, with approximately 10% tumor formation in both cases. We conclude that ES NPs maintain their developmental potential during in vitro expansion, whereas mouse E12.5 VM NPs do not.

Animals↗
PubMedDate not supplied

Hepatocytic gene expression in cultured rat mesenchymal stem cells.

The origin of liver cells from distinct bone marrow stem cells, eg, hematopoietic stem cells or multipotent adult progenitor cells has been recently described using in vitro studies. Cell culture experiments revealed the key role of growth factors and the organ-specific environment for the induction of liver-specific genes. We investigated the in vitro potential of rat mesenchymal stem cells to differentiate into hepatocytic cells in cocultures with isolated rat liver cells. Rat mesenchymal stem cells (MSCs) propagated in culture, and transduced with green fluorescent protein (GFP) were cloned. Cells from selected clones were either cultured under liver-stimulating conditions, using serum free medium supplemented with HGF, EGF, SCF, and FGF-4 alone on fibronectin-coated surfaces, or cocultured with freshly isolated rat liver cells. Cocultured cells were harvested after two weeks and sorted into GFP-positive (GFP+) and GFP-negative (GFP-) cells. RT-PCR for liver specific markers CK-18 and albumin were performed on the different cell populations. After 2 weeks, the specified culture conditions led to the expression of albumin and CK-18 RNA in GFP-positive sorted MSCs from the cocultures, whereas MSCs cultured without liver cells did not express the studied genes. The results indicate, that when cocultured with liver cells MSCs from the bone marrow have the potential to differentiate toward hepatocytic cells in vitro. We conclude that MSC may possess an enhanced capacity to differentiate into functional liver cells. Additionally, environmental factors seem to be crucial for specific and directed differentiation.

Animals↗
PubMed2003

Multipotential mesenchymal stem cells from femoral bone marrow near the site of osteonecrosis.

Stem cell-based therapies for degenerative disorders and injuries are promising in the new era. Multipotential mesenchymal stem cells (MSCs) from bone marrow (BM) are on the leading edge because they are easy to expand in culture while maintaining their multilineage potential. In vitro assessment of the chondrogenic and osteogenic potentials of cultured MSCs has been established, and the BM used in those experiments was exclusively from healthy donors via iliac crest aspiration. It is unknown whether human marrow obtained from femurs also contains these multipotential MSCs. We collected marrow from proximal femurs of two patients undergoing total hip replacement surgery for femoral head osteonecrosis and isolated and culture expanded MSCs to about 20 population doublings. These cells were homogeneously positive for beta1-integrin. When pelleted into aggregates and cultured in a medium containing transforming growth factor-beta3 for 14 days, the cells began to express mRNA for aggrecan and collagen type II and to deposit immunoreactive collagen type II and sulfated proteoglycans in the matrix, hallmarks of chondrogenic differentiation. These MSCs could also be differentiated into osteocytic lineage in vitro, as shown by increased expression of alkaline phosphatase activity and deposition of mineral content onto culture plates. These results indicate that femoral BM obtained during hip surgeries also contained multipotential MSCs. These data imply that direct replacement therapy using MSCs from in situ marrow may be possible in the future and that an MSC bank may be established by using marrow from this approach, bypassing the necessity for iliac marrow aspiration from healthy donors.

Age Factors↗
PubMed2005

Prox1 activity controls pancreas morphogenesis and participates in the production of "secondary transition" pancreatic endocrine cells.

The development of the mammalian pancreas is governed by various signaling processes and by a cascade of gene activation events controlled by different transcription factors. Here we show that the divergent homeodomain transcription factor Prox1 is a novel, crucial regulator of mouse pancreas organogenesis. Loss of Prox1 function severely disrupted epithelial pancreas morphology and hindered pancreatic growth without affecting significantly the genesis of endocrine cells before E11.5. Conversely, the lack of Prox1 activity substantially decreased the formation of islet cell precursors after E13.5, during a period known as the "secondary transition". Notably, this defect occurred concurrently with an abnormal increment of exocrine cells. Hence, it is possible that Prox1 contributes to the allocation of an adequate supply of islet cells throughout pancreas ontogeny by preventing exocrine cell differentiation of multipotent pancreatic progenitors. Prox1 thus appears to be an essential component of a genetic program destined to produce the cellular complexity of the mammalian pancreas.

Animals↗
PubMed2003

Xrx1 controls proliferation and multipotency of retinal progenitors.

We investigated the function of Xrx1 during Xenopus retinogenesis. Xrx1 overexpression lengthens mitotic activity and ectopically activates the expression of markers of undifferentiated progenitors in the developing retina. We assayed Xrx1 ability to support proliferation with a cell-autonomous mechanism by in vivo lipofection of single retinal progenitors. Xrx1 overexpression increases clonal proliferation while Xrx1 functional inactivation exerts the opposite effect. We also compared the effects of Xrx1 with those of the cyclin-dependent kinase cdk2, a strong mitotic promoter. Despite the similar increase in clonal proliferation displayed by both factors, Xrx1 and cdk2 act differently on retinal cell fate determination. cdk2/cyclinA2 lipofected retinas show a decrease in early-born cell types as ganglion cells and cones and an increase in late-born types such as bipolar neurons. On the contrary, Xrx1 lipofected retinas show no changes in the proportions of the different cell types, thus suggesting a role in supporting multipotency of retinal progenitors.

Amacrine Cells↗
PubMed2006

[Adipose tissue stromal cells -- multipotent cells with therapeutic potential for stimulation of angiogenesis in tissue ischemia].

Results of studies of properties of adipose tissue stromal cells are summarized in this review. It contains data on separation and cultivation of these cells as well as description of their antigenic characteristics, ability to differentiate into cells of mesenchymal and nonmesenchymal origin, angiogenic potential, and potential for transfection and transfer of therapeutic genes. Analysis of perspectives of clinical use of adipose tissue stromal cells in therapy of cardiovascular and other diseases is also presented.

Adipose Tissue↗
PubMed1996

[Neuroendocrine differentiated carcinoma of the uterine cervix].

Cervical neuroendocrine carcinomas (CNC) are rare tumors. The term includes the cervical carcinoid, the small cell (oat-cell) carcinoma and the primitive neuroectodermal tumor (PNET). Between 1979 and 1993 eight CNC out of 788 cervical carcinomas were identified by conventional light microscopy and immunohistochemistry. Three tumors were small cell carcinomas with positive staining for NSE (6/8 tumors) and chromogranin A (2/8). In one case a PNET was diagnosed by identifying rosette like structures and negative immunohistochemistry for neuroendocrine markers. Two patients (including PNET) died of disease 3.1 (1.3 to 4.8) years after diagnosis. The others showed no evidence of disease after a mean follow up to 4.4 years. Three of them got pelvic radiation postoperatively. Four tumors showed foci of squamous cell carcinoma [3] and adenocarcinoma [2]. There is no evidence, that these foci influence the prognosis on CNC. Therefore, it is important to recognize the neuroendocrine component, as this type of carcinoma requires special therapeutic considerations. The authors favour the metaplastic origin of CNC from a multipotent (endocervical) stem cell.

Adenocarcinoma↗
PubMed2003

Functional motor neurons differentiating from mouse multipotent spinal cord precursor cells in culture and after transplantation into transected sciatic nerve.

OBJECT: One of the current challenges in neurobiology is to ensure that neural precursor cells differentiate into specific neuron types, so that they can be used for transplantation purposes in patients with neuron loss. The goal of this study was to determine if spinal cord precursor cells could differentiate into motor neurons both in culture and following transplantation into a transected sciatic nerve. METHODS: In cultures with trophic factors, neurons differentiate from embryonic precursor cells and express motor neuronal markers such as choline acetyltransferase (ChAT), Islet-1, and REG2. Reverse transcription-polymerase chain reaction analysis has also demonstrated the expression of Islet-1 in differentiated cultures. A coculture preparation of neurospheres and skeletal myocytes was used to show the formation of neuromuscular connections between precursor cell-derived neurons and myocytes both immunohistochemically and electrophysiologically. Following various survival intervals, precursor cells transplanted distal to a transection of the sciatic nerve differentiated into neurons expressing the motor neuron markers ChAT and the alpha1 1.2 (class C, L-type) voltage-sensitive Ca++ channel subunit. These cells extended axons into the muscle, where they formed cholinergic terminals. CONCLUSIONS: These results demonstrate that motor neurons can differentiate from spinal cord neural precursor cells grown in culture as well as following transplantation into a transected peripheral nerve.

Animals↗
PubMed2002

[Small cell carcinoma of the bladder. Report of 3 cases and review of the literature].

Primary small cell carcinoma of the urinary bladder is a highly aggressive disease and accounts for less than 0.5% of all primary bladder tumors. Quite often, clinical presentation is related to local and/or systemic involvement of the disease. Histogenesis is still unknown, but investigators consider the tumor originating from a multipotent undifferentiated stem cell of the bladder urothelium. Hematuria is the first and most frequent symptom that patients complain at the clinical presentation of the disease. The primary local tumor is treated by radical surgery or radiation therapy, while systemic involvement requires polychemotherapy according to the M-VAC protocol. Prognosis is worse and related to the pathological stage of the disease and to chemotherapy reply. Herein we report on 3 cases of primary small cell carcinoma of the urinary biadder. We also review and update the literature concerning this topic.

Aged↗
PubMed2004

[Therapeutic implications of the differentiation of adult stem cells into other cell types].

During last years stem cells have generated a great interest because its potential therapeutic use. These are unspecialised cells, with ability to self-renewal and to differentiate into other cell types, being embryo cells totipotent and of restrictive use for ethical reasons, while adult stem cells are multipotent and of potential clinical use . Between the latter the best studied are the cells of the bone marrow: hematopoietic producing blood cell lines and mesenchymal that may be transformed into hepatocytes, chondrocytes, osteocytes, adipocytes, cardiocytes and neural cells. Although these facts are promising many studies must be done until to get stem cells therapies, as well as verify these treatments in animal models. It is believed that in this century besides traditional therapies we will have to take into account cell therapies with stem cells, in whose development will be very important the scientific, clinical and ethical parameters.

Age Factors↗
PubMed2000

Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep.

Mesenchymal stem cells are multipotent cells that can be isolated from adult bone marrow and can be induced in vitro and in vivo to differentiate into a variety of mesenchymal tissues, including bone, cartilage, tendon, fat, bone marrow stroma, and muscle. Despite their potential clinical utility for cellular and gene therapy, the fate of mesenchymal stem cells after systemic administration is mostly unknown. To address this, we transplanted a well-characterized human mesenchymal stem cell population into fetal sheep early in gestation, before and after the expected development of immunologic competence. In this xenogeneic system, human mesenchymal stem cells engrafted and persisted in multiple tissues for as long as 13 months after transplantation. Transplanted human cells underwent site-specific differentiation into chondrocytes, adipocytes, myocytes and cardiomyocytes, bone marrow stromal cells and thymic stroma. Unexpectedly, there was long-term engraftment even when cells were transplanted after the expected development of immunocompetence. Thus, mesenchymal stem cells maintain their multipotential capacity after transplantation, and seem to have unique immunologic characteristics that allow persistence in a xenogeneic environment. Our data support the possibility of the transplantability of mesenchymal stem cells and their potential utility in tissue engineering, and cellular and gene therapy applications.

Adipocytes↗