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PubMed2003

Cancerous stem cells can arise from pediatric brain tumors.

Pediatric brain tumors are significant causes of morbidity and mortality. It has been hypothesized that they derive from self-renewing multipotent neural stem cells. Here, we tested whether different pediatric brain tumors, including medulloblastomas and gliomas, contain cells with properties similar to neural stem cells. We find that tumor-derived progenitors form neurospheres that can be passaged at clonal density and are able to self-renew. Under conditions promoting differentiation, individual cells are multipotent, giving rise to both neurons and glia, in proportions that reflect the tumor of origin. Unlike normal neural stem cells, however, tumor-derived progenitors have an unusual capacity to proliferate and sometimes differentiate into abnormal cells with multiple differentiation markers. Gene expression analysis reveals that both whole tumors and tumor-derived neurospheres express many genes characteristic of neural and other stem cells, including CD133, Sox2, musashi-1, bmi-1, maternal embryonic leucine zipper kinase, and phosphoserine phosphatase, with variation from tumor to tumor. After grafting to neonatal rat brains, tumor-derived neurosphere cells migrate, produce neurons and glia, and continue to proliferate for more than 4 weeks. The results show that pediatric brain tumors contain neural stem-like cells with altered characteristics that may contribute to tumorigenesis. This finding may have important implications for treatment by means of specific targeting of stem-like cells within brain tumors.

AC133 Antigen↗
PubMed2003

Genetic and functional differences between multipotent neural and pluripotent embryonic stem cells.

Stem cells (SCs) are functionally defined by their abilities to self-renew and generate differentiated cells. Although much effort has been focused on defining the common characteristics among various types of SCs, the genetic and functional differences between multipotent and pluripotent SCs have garnered less attention. We report a direct genetic and functional comparison of molecularly defined and clonally related populations of neural SCs (NSCs) and embryonic SCs (ESCs), using the Sox2 promoter for isolation of purified populations by fluorescence-activated cell sorting. A stringent expression profile comparison of promoter-defined NSCs and ESCs revealed a striking dissimilarity, and subsequent chimera analyses confirmed the fundamental differences in cellular potency between these populations. This direct comparison elucidates the molecular basis for the functional differences in pluripotent ESCs and multipotent NSCs.

Animals↗
PubMedDate not supplied

[Alternative sources of hepatocytes for cell therapy].

There is an urgent need to search for alternatives to whole organ transplantation. Several methods have been proposed. Among these strategies, cell transplantation is currently one of the most promising. To achieve this aim, in addition to highly differentiated adult hepatocytes, the use of stem cells is considered a highly attractive therapeutic method for the treatment of liver disease and for temporary support of hepatic function until a liver becomes available for organ transplantation. This strategy is based on the ability of stem cells to differentiate into different cellular types according to their environment. Therefore, stem cells could be an unlimited source of hepatic cells for transplantation and gene therapy. Bone marrow is considered the most promising source of adult stem cells, partly due to the versatility of the cells obtained in repairing damaged tissues of several lineages. Several different types of stem cells have been described in bone marrow: hematopoietic, mesenchymal, side population and multipotent adult stem cells. Bone marrow cells have been hypothesized as a third recruitment source in liver regeneration in addition to hepatocytes and endogenous liver stem cells. Consequently, attempts have been made to differentiate them into hepatic lineage for their subsequent use in hepatic cell therapy. The present article reviews the progress made in this field or research.

Animals↗
PubMed2005

Development of functional neurons from postnatal stem cells in vitro.

In order for stem cells to fulfill their clinical promise, we must understand their developmental transitions and it must be possible to control the differentiation of stem cells into specific cell fates. To understand the mechanism of the sequential restriction and multipotency of stem cells, we have established culture conditions that allow the differentiation of multipotential neural stem cells from postnatal stem cells. We used immunocytochemistry, fluorescence microscopy, and calcium imaging to demonstrate that progeny of adult rat neural stem cells develop into functional neurons that release excitatory neurotransmitters. We also found that the nontoxic heavy chain fragment of tetanus toxin, a toxin that targets neurons with high specificity, retained the specificity toward neural stem cell-derived neurons. These studies show that neural stem cells derived from adult tissues retain the potential to differentiate into functional neurons with morphological and functional properties of mature central nervous system neurons.

Adenosine Triphosphate↗
PubMed2004

SCL is required for normal function of short-term repopulating hematopoietic stem cells.

The stem cell leukemia (SCL) gene is essential for the development of hematopoietic stem cells in the embryo. Here, we used a conditional gene targeting approach to examine the function of SCL in adult hematopoietic stem cells (HSCs). Flow cytometry of bone marrow from SCL-deleted mice demonstrated a 4-fold increase in number of Lin(neg) c-kit(+) Sca-1(+) cells. Despite this increase in the number of phenotypic HSCs, competitive repopulation assays demonstrated a severe multilineage defect in repopulation capacity by SCL-deleted bone marrow cells. SCL-heterozygous cells also showed a mild repopulation defect, thus suggesting haploinsufficiency of SCL. The transplantation defect of SCL-deleted cells was observed within 4 weeks of transplantation, indicating a defect in a multipotent progenitor or short-term repopulating HSCs. Although the defect persisted in secondary transplants, it remained relatively stable, suggesting that SCL was not required for self-renewal of the HSCs. Generation of SCL-deleted cells within SCL-wild-type mice rescued the early repopulating defect. Together, our results suggest that SCL is required for the normal function of short-term repopulating HSCs.

Animals↗
PubMed2006

Multipotent, dedifferentiated cancer stem-like cells from brain gliomas.

In modern cancer biology, external factors and niches can act on differentiated tissue cells to cause cancer by inducing dedifferentiation of mature adult cells. Recently, we discovered that dedifferentiation of glioma cancer cells alters the expression of mature and neural stem cell (NSC)-related genes, in that cancer cells adjust to the serum-deprived environment and cell-to-cell interaction by down-regulating genes associated with neural mature markers and up-regulating genes that are primitive NSC markers. Neurogenesis of dedifferentiated glioma cancer cells also showed a highly increased neuronal marker associated with highly decreased glial and oligodendrocyte cell markers. After treatment with chemotherapeutic drugs, dedifferentiated cancer cells showed strong drug resistance and continued active cell growth. After grafting to severe combined immunodeficient (SCID) mouse brains, dedifferentiated cancer stem cells migrated and continued active proliferation for more than 4 weeks. We also performed microarray analysis and characterized the gene expression patterns in control cancer cells with dedifferentiated cancer stem-like cells. We delineated specific numbers of important proliferation signaling proteins, primitive neural lineage-related proteins, cancer genes, and transporter genes. In this report, we propose that the dedifferentiation process of brain tumor and normal tissue may contribute to the malignancy and aggressiveness of the brain cancer.

Animals↗
PubMed2005

Effects of age on the repair ability of mesenchymal stem cells in rabbit tendon.

Successful tissue engineered repair in the aging adult requires an abundant source of autologous, multipotent mesenchymal stem cells (MSCs). Although the number of bone marrow-derived MSCs declines dramatically with aging, their effectiveness in repair with increasing age has not been studied. We tested the hypothesis that MSCs harvested from geriatric rabbits would not repair patellar tendon defects as well as MSCs harvested from younger adult rabbits. In a novel within-subjects experiment, autologous MSCs were isolated from 1-year old rabbits, culture expanded, and cryogenically preserved. After housing the rabbits for 3 years, MSCs were re-harvested from the 4-year old rabbits and expanded. Five hundred thousand thawed and fresh MSCs were each separately mixed with type I collagen gel (333.3 x 10(3) cells/mg collagen) 24 h before surgery, and the resulting constructs implanted in bilateral full-length central third tendon defects. Twelve weeks post-surgery, the bone-tendon repair-bone units were failed in tension. Intra-animal (paired) comparisons between repair tissue treated with 1-year old MSCs and repair tissue treated with 4-year old MSCs resulted in no significant differences (alpha=0.05) in material properties including maximum stress (10.8 MPa vs. 9.9 MPa; p=0.762), modulus (139.8 MPa vs. 146.2 MPa; p=0.914), and strain energy density (0.52 N mm/mm(3) vs. 0.53 N mm/mm(3); p=0.966). Despite an age-related trend, there were also no significant differences in structural properties including maximum force (62.9 N vs. 27.0 N; p=0.070), stiffness (24.9 N/mm vs. 12.0 N/mm; p=0.111), and strain energy (87.2 N mm vs. 31.4 N mm; p=0.061). A subset of the rabbits (n=4 1 yrMSC, n=2 4 yrMSC) showed the presence of ectopic bone in the repair region and were not included in the mechanical analyses. We conclude that in the rabbit model MSCs do not lose their benefit as a tendon repair therapy with aging and that MSCs can be cryogenically stored for 3 years and still effectively repair soft tissue injuries.

Aging↗
PubMed2001

Phenotypic differentiation of TGF-beta1-responsive pluripotent premesenchymal prehematopoietic progenitor (P4 stem) cells from murine bone marrow.

On the horizon of modern molecular medicine is the requisite technology to capture multipotent human stem cells that are capable of self-renewal and to direct these stem cells along defined lineages for therapeutic purposes. In this article, we describe the hematopoietic and mesenchymal differentiation potential of a unique population of transforming growth factor-beta1 (TGF-beta1)-responsive stem cells derived from murine bone marrow. Stringent selection of the stem cells was accomplished under low serum conditions by virtue of an inherent survival response to a TGF-beta1-vWF fusion protein that was bound to collagen matrices. The TGF-beta1-responsive stem cells initially exhibited a non-adherent and uniformly blastoid morphology, underwent expansion into colonies upon serum reconstitution, and were capable of overt cytodifferentiation along fibrogenic, osteogenic, chondrogenic, or adipogenic lineages upon growth factor stimulation. Remarkably, these stem cells also underwent rapid expansion in the presence of either hematopoietic stem cell factor (SCF) or interleukin3 (IL-3), and differentiated into myeloid and lymphoid phenotypes upon exposure to the latter. Taken together, these results support the hypothesis that pluripotent premesenchymal prehematopoietic progenitor cells, designated P4 stem cells, are present postnatally in murine bone marrow and, thus, may be summarily isolated for various cell-based experimental therapies.

Adipocytes↗
PubMed2003

Adult stem cell therapy for heart failure.

Evidence indicates that bone marrow and many other somatic tissues contain pluripotent or multipotent adult stem cells as well as progenitor cells which can differentiate into cells of various phenotypes. Experimental studies strongly suggest that the normal function of the marrow derived adult stem cells is for tissue repair, and that they can be recruited by signals originating from injured tissue, traffic through the circulation and home into the injured site to undergo milieu dependent differentiation in situ. In the heart, these cells may differentiate into cardiomyocytes, vascular cells and scar tissue, thus participating in vasculogenesis, scar maturation and modulation of the remodelling process of the myocardium. To augment such a healing process, cell therapy using such cells, which may be preprogrammed if desired, may have donor cells implanted by direct injection, coronary infusion and, in some cases, by systemic intravenous administration. Improved ventricular function has been reported in myocardial infarct animal models. Although early Phase I clinical trials have been initiated for both autologous myoblast and autologous marrow cell transplants with favourable reported outcomes, the data are still too preliminary to draw definitive conclusions regarding their safety and efficacy. Additional mechanistic and translational preclinical investigations are essential, and well designed clinical studies are required before the great potential of adult stem cell therapy can be fully realised and benefit the vast number of heart failure patients.

Animals↗
PubMed2005

Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism.

In degenerative disorders of the central nervous system (CNS), transplantation of neural multipotent (stem) precursor cells (NPCs) is aimed at replacing damaged neural cells. Here we show that in CNS inflammation, NPCs are able to promote neuroprotection by maintaining undifferentiated features and exerting unexpected immune-like functions. In a mouse model of chronic CNS inflammation, systemically injected adult syngeneic NPCs use constitutively activated integrins and functional chemokine receptors to selectively enter the inflamed CNS. These undifferentiated cells survive repeated episodes of CNS inflammation by accumulating within perivascular areas where reactive astrocytes, inflamed endothelial cells and encephalitogenic T cells produce neurogenic and gliogenic regulators. In perivascular CNS areas, surviving adult NPCs induce apoptosis of blood-borne CNS-infiltrating encephalitogenic T cells, thus protecting against chronic neural tissue loss as well as disease-related disability. These results indicate that undifferentiated adult NPCs have relevant therapeutic potential in chronic inflammatory CNS disorders because they display immune-like functions that promote long-lasting neuroprotection.

Animals↗
PubMed1999

Fibroblast growth factor-2 activates a latent neurogenic program in neural stem cells from diverse regions of the adult CNS.

During development of the mammalian brain, both neurons and glia are generated from multipotent neural stem cells. Although neurogenesis ceases in most areas at birth, stem cells continue to generate neurons within the subventricular zone and hippocampal dentate gyrus throughout adult life. In this work, we provide the first demonstration that precursors native to regions of the adult brain that generate only glia can also generate neurons after exposure to FGF-2 in vitro. When progenitors isolated from hippocampal tissue were directly compared with cells isolated from the neocortex, both populations were able to initiate a program of proliferative neurogenesis. Genetic marking and lineage analysis showed that a majority of the cells able to generate neurons were multipotent precursors; however, progeny from these precursors acquired the competence to differentiate into neurons only after exposure to FGF-2. The recruitment of similar FGF-2-responsive cells from the adult optic nerve, a structure well isolated from the neurogenic zones within the brain, confirmed that neuron-competent precursors naturally exist in widely divergent tissues of the adult brain.

Animals↗
PubMed2005

Evidence that osteogenic progenitor cells in the human tunica albuginea may originate from stem cells: implications for peyronie disease.

Tissue ossification in Peyronie disease (commonly known as Peyronie's disease [PD]), a localized fibrotic lesion within the tunica albuginea (TA) of the penis, may result from osteogenic differentiation of fibroblasts, myofibroblasts, and/or adult stem cells in the TA, and may be triggered by chronic inflammation, oxidative stress, and profibrotic factors like transforming growth factor beta 1 (TGFB1). In this study, we have investigated whether cultures of cells from normal TA and PD plaques undergo osteogenesis, express markers for stem cells, and originate other cell lineages via processes modulated by TGFB1. We found that TA and PD cells in osteogenic medium (OM) expressed osteogenic markers, alkaline phosphatase, and osteopontin and underwent calcification. PD cells, but not TA cells, formed foci in soft agar that were positive for alkaline phosphatase and calcification and expressed the mRNAs for osteoblast-specific factors pleiotrophin and periostin and bone morphogenic protein 2. Both cultures expressed stem cell marker CD34 antigen but not protein tyrosine phosphatase, receptor type c. TA and PD cells expressed smooth-muscle cell markers smoothelin and transgelin. None of the cultures underwent adipogenesis in adipogenic medium. Incubation with TGFB1 increased osteogenesis and myofibroblast differentiation and reduced CD34 antigen expression in both cultures. TA and PD cells modulated the differentiation of the multipotent C3H 10T(1/2) cells in dual cultures, into osteoblasts and myofibroblasts. In conclusion, both TA and PD cultures contain cells, presumably stem cells, that undergo osteogenic and myofibroblast differentiation, and may induce these processes by paracrine interactions. This may explain progression of fibrosis in the PD plaque and its eventual calcification.

Adipose Tissue↗
PubMed2004

[Isolation, culture and multipotent differentiation of mesenchymal stem cells from human fetal livers].

OBJECTIVE: To isolate and culture mesenchymal stem cells (MSCs) from human fetal livers and describe their biological characteristics. METHODS: MSCs were acquired using an optimized method. Cell cycles and the immunophenotype of the cells were analyzed by flow cytometry. The osteogenic and adipogenic differentiations were induced and identified by specific stainings, and hepatic differentiation by morphology and RT-PCR. RESULTS: The target cells derived from human fetal livers adhered to the plate with fibroblast-like morphology, whose surface markers were CD90, CD44, CD147 positive, and CD34, CD45, HLA-DR negtive. In the differentiation study, these cells could be induced to differentiate into osteogenic, adipogenic and hepatocyte-like cells. CONCLUSION: Multipotent MSCs can be isolated and cultured from human fetal livers.

Cell Differentiation↗
PubMed2003

Pax5 determines B- versus T-cell fate and does not block early myeloid-lineage development.

Progenitor B cells deficient in Pax5 are developmentally multipotent, suggesting that Pax5 is necessary to maintain commitment to the B-cell lineage. Commitment may be mediated, in part, by Pax5 repression of myeloid-specific genes. To determine whether Pax5 expression in multipotential cells is sufficient to restrict development to the B-cell lineage in vivo, we enforced expression of Pax5 in hematopoietic stem cells using a retroviral vector. Peripheral blood analysis of all animals reconstituted with Pax5-expressing cells indicated that more than 90% of Pax5-expressing cells were B220+ mature B cells that were not malignant. Further analysis showed that Pax5 completely blocked T-lineage development in the thymus but did not inhibit myelopoiesis or natural killer (NK) cell development in bone marrow. These results implicate Pax5 as a critical regulator of B- versus T-cell developmental fate and suggest that Pax5 may promote commitment to the B-cell lineage by mechanisms that are independent of myeloid gene repression.

Animals↗
PubMed1998

Antigenic phenotype of early intra-embryonic lymphoid progenitors in the chicken.

The stem cells for the definitive haematopoiesis are derived from intra-embryonic sources originally described in an avian model and later also in mammals. However, the molecular make-up of the early embryonic haematopoietic progenitors is not yet clearly defined. We have recently characterized the phenotype of prethymic intra-embryonic progenitors capable of thymic colonization. Here we studied the ontogeny of cell-surface antigens HEMCAM, alpha2beta1 integrin, thrombomucin, chL12 and c-kit and their co-expression on prethymic T-cell progenitors. The early intra-embryonic expression of avian B-cell antigen chB6 was also demonstrated on cells derived from the intra-embryonic areas. We suggest that in the chicken, embryonic B-cell progenitors segregate earlier than T-cell progenitors in the differentiation of multipotent haematopoietic stem cells to committed progenitors.

Animals↗
PubMed2004

Stem and precursor cells in the nervous system.

The early-formed neural tube consists of proliferating, morphologically homogeneous cells, termed "neuroepithelial (NEP) stem cells" which generate neurons, astrocytes, and oligodenrocytes through a series of intermediate precursor cells. In addition to NEP cells, a second class of stem cells-the neurosphere-forming cell-can be isolated at later stages of development. NEP cells can differentiate into neural crest stem cells, which in turn generate PNS derivatives. NEP cells and neurosphereforming stem cells and more restricted precursors express a characteristic spectrum of markers that can be used to characterize them. Each of these cell types can be isolated from embryonic stem (ES) cell cultures, and their behavior appears similar to cells isolated at later developmental ages. The relative advantages and disadvantages of these cells for cell replacement therapy are discussed.

Animals↗
PubMed1984

A cell line secreting stimulating factors for CFU-GEMM culture.

The multipotent hemopoietic stem cell has fastidious growth requirements in vitro. Traditionally, phytohemagglutinin-stimulated leukocyte conditioned medium has been used to supply the undefined growth factors required for culture of the human multipotent hemopoietic progenitor. We describe the use of medium conditioned by the bladder carcinoma cell line, 5637, to replace PHA-LCM in CFU-GEMM cultures and show that the properties of this conditioned medium closely mimic those of PHA-LCM in two separate CFU-GEMM culture systems.

Cell Line↗