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PubMed2005

Potential of mesenchymal stem cells in gene therapy approaches for inherited and acquired diseases.

The intriguing biology of stem cells and their vast clinical potential is emerging rapidly for gene therapy. Bone marrow stem cells, including the pluripotent haematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs) and possibly the multipotent adherent progenitor cells (MAPCs), are being considered as potential targets for cell and gene therapy-based approaches against a variety of different diseases. The MSCs from bone marrow are a promising target population as they are capable of differentiating along multiple lineages and, at least in vitro, have significant expansion capability. The apparently high self-renewal potential makes them strong candidates for delivering genes and restoring organ systems function. However, the high proliferative potential of MSCs, now presumed to be self-renewal, may be more apparent than real. Although expanded MSCs have great proliferation and differentiation potential in vitro, there are limitations with the biology of these cells in vivo. So far, expanded MSCs have failed to induce durable therapeutic effects expected from a true self-renewing stem cell population. The loss of in vivo self-renewal may be due to the extensive expansion of MSCs in existing in vitro expansion systems, suggesting that the original stem cell population and/or properties may no longer exist. Rather, the expanded population may indeed be heterogeneous and represents several generations of different types of mesenchymal cell progeny that have retained a limited proliferation potential and responsiveness for terminal differentiation and maturation along mesenchymal and non-mesenchymal lineages. Novel technology that allows MSCs to maintain their stem cell function in vivo is critical for distinguishing the elusive stem cell from its progenitor cell populations. The ultimate dream is to use MSCs in various forms of cellular therapies, as well as genetic tools that can be used to better understand the mechanisms leading to repair and regeneration of damaged or diseased tissues and organs.

Animals↗
PubMed2002

Emergence of hematopoietic stem cells in the human embryo.

We have previously identified a novel site of hematopoietic cell production within the human embryo, which is localised in the ventral wall of the dorsal aorta and vitelline artery. Cells emerging in that territory between 27 and 40 days of gestation exhibit the expected phenotypic, molecular, and functional properties of hematopoietic stem cells and are the first multipotent, lympho-myeloid progenitors that appear in human ontogeny. We have next demonstrated that vascular endothelial cells sorted stringently, by flow cytometry, from the human yolk sac and embryonic aorta exhibit dramatic blood-forming potential in culture. These results suggest a filiation between vascular endothelium and hematopoietic cells in the course of early human ontogeny. More preliminary data indicate that a subpopulation of vascular endothelial cells in the bone marrow may retain this hematogenous potential until adult stages.

Bone Marrow Cells↗
PubMed2004

The use of bone marrow stem cells for bone tissue engineering.

Bone marrow stem cells (BMSC), known for its multipotency to differentiate into various mesenchymal cells such as chodrocyte, osteoblasts, adipocytes, etc, have been actively applied in tissue engineering. BMSC have been successfully isolated from bone marrow aspirate and bone marrow scraping from patients of various ages (13-56 years) with as little as 2ml to 5ml aspirate. BMSC isolated from our laboratory showed the presence of a heterogenous population that showed varying prevalence of surface antigens and the presence of telomerase activity albeit weak. Upon osteogenic induction, alkaline phosphatase activity and mineralization activity were observed.

Bone Marrow Cells↗
PubMed1998

Insulin-like growth factor-I is a differentiation factor for postmitotic CNS stem cell-derived neuronal precursors: distinct actions from those of brain-derived neurotrophic factor.

Insulin-like growth factor-I (IGF-I) has been reported previously to promote the proliferation, survival, and maturation of sympathetic neuroblasts, the genesis of retinal neurons, and the survival of CNS projection and motor neurons. Here we asked whether IGF-I could promote the in vitro differentiation of postmitotic mammalian CNS neuronal precursors derived from multipotent epidermal growth factor (EGF)-responsive stem cells. In the absence of IGF-I, virtually no neurons were present in cultured stem cell progeny, whereas IGF-I increased neuron number by eight- to 40-fold. Brief exposures (2 hr) to IGF-I were sufficient to allow for neuronal differentiation without affecting proliferation or survival. IGF-I actions could be mimicked by insulin and IGF-II at concentrations that correspond to the pharmacology of the IGF-I receptor, the latter for which the mRNA was detected in undifferentiated stem cell progeny. Although ineffectual alone at low concentrations (10 nM) that would activate its own receptor, insulin was able to potentiate the actions of IGF-I by acting on mitotically active neural precursors. When neuronal precursor differentiation by IGF-I was examined in relation to brain-derived neurotrophic factor (BDNF), two important observations were made: (1) BDNF could potentiate the differentiating actions of IGF-I plus insulin, and (2) BDNF could act on a separate population of precursors that did not require IGF-I plus insulin for differentiation. Taken together, these results suggest that IGF-I and BDNF may act together or sequentially to promote neuronal precursor differentiation.

Animals↗
PubMed1997

Use of stem cell factor to mobilize hematopoietic progenitors.

Stem cell factor (SCF) is a multipotent growth factor that plays a role in the growth and development of hematopoietic cells, spermatocytes, melanocytes, and mast cells. SCF alone has little direct stimulatory activity on hematopoietic progenitors but acts synergistically with other colony-stimulating factors to potentiate their effects on colony growth. SCF also potentiates the mobilization of hematopoietic progenitor cells into the peripheral blood in response to granulocyte colony-stimulating factor (G-CSF), with or without chemotherapy. The combination of SCF plus G-CSF appears to be a particularly effective mobilization regimen for patients who have been heavily pretreated. Whether engraftment of peripheral blood progenitor cells mobilized by SCF plus G-CSF is superior to that of cells mobilized by G-CSF alone remains unclear. SCF appears to be a necessary requirement for ex vivo expansion of hematopoietic progenitors in both liquid and bioreactor culture systems and will be an important component of future cellular therapies, such as expansion of placental cord blood progenitors and retroviral-mediated gene transfer into hematopoietic target cells.

Animals↗
PubMed2006

Stem cell factor expression, mast cells and inflammation in asthma.

The Kit ligand SCF or stem cell factor (SCF) is a multipotent growth factor, acting as an important growth factor for human mast cells. SCF induces chemotaxis and survival of the mast cell, as well as proliferation and differentiation of immature mast cells from CD34(+) progenitors. Additionally, SCF enhances antigen-induced degranulation of human lung-derived mast cells, and induces a mast cell hyperplasia after subcutaneous administration. SCF expression increases in the airways of asthmatic patients, and this is reversed after treatment with glucocorticoids. A role for SCF may thus be hypothesized in diseases associated with a local increase in the number and/or activation of mast cells, as occurring in the airways in asthma. SCF will be reviewed as a potential therapeutic target in asthma, to control the regulation of mast cell number and activation. We here report the main pathways of SCF synthesis and signalling, and its potential role on airway function and asthma.

Animals↗
PubMed2003

Cell context-specific effects of the BCR-ABL oncogene monitored in hematopoietic progenitors.

Acute BCR-ABL expression during in vitro hematopoietic development of embryonic stem (ES) cells causes expansion of multipotent and myeloid progenitors with a concomitant reduction in differentiation toward erythroblasts. Progenitor cell expansion is due to a rapid, cell autonomous, suppression of programmed cell death with an increase in expression of the antiapoptotic molecule BCL-X(L). Other antiapoptotic effectors, including AKT, STAT5, and BCL-2 are not up-regulated by BCR-ABL in this system. In addition, the proapoptotic p38 mitogen-activated protein kinase (MAPK) pathway is suppressed by BCR-ABL expression in ES-derived hematopoietic progenitors. Inhibition of p38 MAPK by the small molecule inhibitor SB203580 expanded ES-derived hematopoietic progenitors by an antiapoptotic mechanism and is sufficient to expand ES-derived hematopoietic progenitors to levels approaching 80% of that seen following BCR-ABL expression. In the cellular context of ES-derived hematopoietic progenitors, BCR-ABL expression expands cells by suppressing programmed cell death with a set of antiapoptotic pathways distinct from those previously reported in continuous cell line studies.

Animals↗
PubMed2002

Genetic perpetuation of in vitro expanded human neural stem cells: cellular properties and therapeutic potential.

Long-term propagated human neural stem cells (self-renewing and multipotent) allow for the unlimited and predictable generation of different types of human neural cells in vitro. In addition, these cell lines may be of help for the elucidation of basic neuro-developmental issues, and also for the development of innovative therapeutic strategies for nervous system disorders (through cell replacement and/or gene transfer-based therapies). In this article we summarize our current knowledge about these long-term cultured cells, particularly that of immortalized cells, with the aim of critically addressing their usefulness and potential for therapeutic use. Perpetuation methods and in vitro properties of immortalized cells are analyzed. Although reports on in vivo studies are scarce, present data on survival, integration, migration, and differentiation of the cells indicate that they may be useful for the development of cellular and genetic therapies, in various models of neurodegeneration. A great deal of basic and applied research remains to be done in order to fully explore, understand, and exploit the therapeutic potential of human neural precursor cells.

Animals↗
PubMed2006

Stem cells as a source of regenerative cardiomyocytes.

The realization of regenerative cardiac medicine depends on the availability of cardiomyocytes in sufficient numbers for transplantation of cardiac tissue and the accompanying blood vessels. Embryonic stem (ES) cells, bone marrow (BM) stem cells, and tissue-derived stem cells are all potential cell sources. Although ES cells are highly proliferative and suitable for mass production, an efficient protocol is yet to be established to ensure selective cardiomyocyte induction using these cells. Recent advances in developmental biology have clarified the involvement of critical factors in cardiomyocyte differentiation, including bone morphogenic protein and Wnt signaling proteins, and such factors have the potential to improve the efficiency of stem cell induction. Initial studies of the intracoronary administration of BM mononuclear cells after myocardial infarction has yielded promising results; however, intensive investigation of the underlying molecular mechanisms at play as well as double-blinded clinical trials will be necessary to establish the extent of both migration of the BM stem cells into the damaged cardiac tissue and their differentiation into cardiomyocytes. Several types of cardiac tissue stem cells have also been reported, but an accurate and extensive comparison of these cells with regard to their characteristics and multipotency remains to be done. An integrative study involving developmental biology, stem cell biology, and tissue engineering is required to achieve the full potential of cardiac regeneration.

Animals↗
PubMed2001

Multipotent hematopoietic progenitor cells immortalized by Lhx2 self-renew by a cell nonautonomous mechanism.

OBJECTIVE: Direct molecular and cellular studies of hematopoietic stem cells (HSCs) are hampered by the low levels of HSCs in hematopoietic tissues. To address these issues, we generated immortalized multipotent hematopoietic precursor cell (HPC) lines by expressing the LIM-homeobox gene Lhx2 (previously LH2) in hematopoietic progenitors derived from embryonic stem cells differentiated in vitro. MATERIALS AND METHODS: To validate further the relevance of the HPC lines as a model for normal HSCs, we analyzed in detail the growth requirements of HPC lines in vitro. RESULTS: Lhx2 immortalized the HPC lines by a putatively novel and cell nonautonomous mechanism. Self-renewal of the HPC lines is dependent on functional Lhx2 expression. Most early-acting hematopoiesis-related growth factors show synergistic effects on the HPC lines, whereas late-acting factors do not induce differentiation by themselves. Transforming growth factor-beta(1) is a potent inhibitor of proliferation of the HPC lines. HPC lines form cobblestone areas with high efficiency when seeded onto stromal cell lines, and the cobblestone area-forming cell can be maintained in these cultures for several months. CONCLUSIONS: Our data show that, in many respects, HPC lines are similar to normal hematopoietic progenitor/stem cells on the cellular level, in contrast to most previously described multipotent hematopoietic cell lines. The cell nonautonomous mechanism for immortalization of the HPC lines suggests that Lhx2 regulates, directly or indirectly, soluble mediators involved in self-renewal of the HPC lines.

Animals↗
PubMed2005

Loss of gene expression in lentivirus- and retrovirus-transduced neural progenitor cells is correlated to migration and differentiation in the adult spinal cord.

Gene transfer into multipotent neural progenitor cells (NPC) and stem cells may provide for a cell replacement therapy and allow the delivery of therapeutic proteins into the degenerating or injured nervous system. Previously, murine leukemia virus-based retroviral vectors expressing GFP from an internal EF-1alpha promoter and lentiviral vectors expressing GFP from a hybrid CMV/beta-actin promoter have been described to be resistant to stem cell specific gene silencing. Therefore, we investigated whether these viral vectors allow stable in vivo gene expression in genetically modified NPC isolated from the adult rat spinal cord. In vitro, NPC genetically modified to express GFP using the described retroviral vector showed strong GFP expression in undifferentiated NPC. However, in vitro differentiation resulted in the loss of GFP expression in 50% of cells. Grafting of BrdU-prelabeled NPC to the spinal cord resulted in a loss of GFP expression in 70% and 95% of surviving NPC at 7 and 28 days post-grafting, respectively. The loss in gene expression was paralleled by the differentiation of NPC into a glial phenotype. Transgene downregulation although less profound was also observed in cells modified with lentiviral vectors, whereas in vivo lentiviral gene transfer resulted in stable transgene expression for up to 16 months. Thus, in vivo gene expression in genetically engineered neural progenitor cells is temporally limited and mostly restricted to undifferentiated NPC using the viral vectors tested.

Animals↗
PubMed2002

Regulation of neurogenesis by neurotrophins in developing spinal sensory ganglia.

Neurons and glia in spinal sensory ganglia derive from multipotent neural crest-derived stem cells. In contrast to neural progenitor cells in the central nervous system, neural crest progenitors coexist with differentiated sensory neurons all throughout the neurogenic period. Thus, developing sensory ganglia are advantageous for determining the possible influence of cell-cell interactions in the regulation of precursor proliferation and neurogenesis. Neurotrophins are important regulators of neuronal survival in the developing vertebrate nervous system and, in addition, they appear to influence precursor behavior in vitro. Studies in mice carrying mutations in neurotrophin genes provide a good system in which to analyze essential actions of these factors on the different developing neural populations.

Animals↗
PubMed2002

Diverse expression of ErbB receptor proteins during rat liver development and regeneration.

BACKGROUND & AIMS: The protein expression and interactions of the ErbB receptors were examined in different liver proliferation models in vivo and in vitro, including ontogeny and regeneration following partial hepatectomy. METHODS: Expression and tyrosine phosphorylation status of specific ErbB proteins were studied by immunologic methods. RESULTS: The epidermal growth factor receptor, ErbB2, and ErbB3 were the only ErbB proteins detected in the liver parenchyma on embryonic day 19. ErbB2 disappeared by the third week after birth and could not be appreciably induced in the adult animal by partial hepatectomy. ErbB2 was also detected in multipotent stem (RLE) and hepatoma (H4IIe) cell lines as well as in fetal, but not adult, hepatocyte cultures. Only epidermal growth factor receptor and ErbB3 were detected in adult liver, and both showed circadian variation in protein expression. ErbB4 was not detected in any model. Patterns of ligand-induced ErbB phosphorylation differed between fetal and adult hepatocytes. CONCLUSIONS: Complex and independent programs regulate the ErbB receptors, with implications for differential cell signaling in hepatic development and regeneration.

Aging↗
PubMed2004

Robust in vivo gene transfer into adult mammalian neural stem cells by lentiviral vectors.

Stable genetic modification of adult stem cells is fundamental for both developmental studies and therapeutic purposes. Using in vivo marking studies, we showed that injection of lentiviral vectors (LVs) into the subventricular zone of the adult mouse brain enables efficient gene transfer into long-term self-renewing neural precursors and steady, robust vector expression in their neuronal progeny throughout the subventricular zone and its rostral extension, up to the olfactory bulb. By clonal and population analysis in culture, we proved that in vivo-marked neural precursors display self-renewal and multipotency, two essential characteristics of neural stem cells (NSCs). Thus, LVs efficiently target long-term repopulating adult NSCs, and the effect of the initial transduction is amplified by the continuous generation of NSC-derived, transduced progeny. LVs may thus allow novel studies on NSCs' physiology in vivo, and introduction of therapeutic genes into NSCs may allow the development of novel approaches for untreatable CNS diseases.

Animals↗
PubMed2006

Potent induction of chondrocytic differentiation of human adipose-derived adult stem cells by bone morphogenetic protein 6.

OBJECTIVE: Recent studies have identified an abundant source of multipotent progenitor cells in subcutaneous human adipose tissue, termed human adipose-derived adult stem cells (ADAS cells). In response to specific media formulations, including transforming growth factor beta1 (TGFbeta1), these cells exhibit significant ability to differentiate into a chondrocyte-like phenotype, expressing cartilage-specific genes and proteins such as aggrecan and type II collagen. However, the influence of other growth factors on the chondrogenic differentiation of ADAS cells is not fully understood. This study was undertaken to investigate the effects of TGFbeta1, TGFbeta3, insulin-like growth factor 1, bone morphogenetic protein 6 (BMP-6), and dexamethasone, in various combinations, on the chondrogenic potential of ADAS cells in alginate beads. METHODS: The chondrogenic response of alginate-encapsulated ADAS cells was measured by quantitative polymerase chain reaction, 3H-proline and 35S-sulfate incorporation, and immunolabeling for specific extracellular matrix components. RESULTS: Significant differences in chondrogenesis were observed under the different culture conditions for all outcomes measured. Most notably, BMP-6 up-regulated AGC1 and COL2A1 expression by an average of 205-fold and 38-fold, respectively, over day-0 controls, while down-regulating COL10A1 expression by approximately 2-fold. CONCLUSION: These findings suggest that BMP-6 is a potent inducer of chondrogenesis in ADAS cells, in contrast to mesenchymal stem cells, which exhibit increased expression of type X collagen and a hypertrophic phenotype in response to BMP-6. Combinations of growth factors containing BMP-6 may provide a novel means of regulating the differentiation of ADAS cells for applications in the tissue-engineered repair or regeneration of articular cartilage.

Adipose Tissue↗
PubMedDate not supplied

Human adipose-derived adult stem cells produce osteoid in vivo.

Adult subcutaneous fat tissue is an abundant source of multipotent cells. Previous studies from our laboratory have shown that, in vitro, adipose-derived adult stem (ADAS) cells express bone marker proteins including alkaline phosphatase, type I collagen, osteopontin, and osteocalcin and produce a mineralized matrix as shown by alizarin red staining. In the current study, the ADAS cell ability to form osteoid in vivo was determined. ADAS cells were isolated from liposuction waste of three individual donors and expanded in vitro before implantation. Equal numbers of cells (3 x 10(6)) were loaded onto either hydroxyapatite/tricalcium phosphate (HA-TCP) cubes or the collagen/HA-TCP composite matrix, Collagraft, and then implanted subcutaneously into SCID mice. After 6 weeks, implants were removed, fixed, and demineralized and sectioned for hematoxylin and eosin staining. Osteoid formation was observed in 80% of HA-TCP implants loaded with ADAS cells. Only 20% of Collagraft implants were positive for the presence of osteoid matrix. Whereas 100% of HA-TCP implants loaded with hFOB 1.19 cells formed osteoid, Collagraft loaded with hFOB 1.19 cells displayed a high degree of adipose tissue within the matrix. Immunostaining of serial sections for human nuclear antigen demonstrated that the osteoid contained human cells. Osteoid formation was not observed in control HA-TCP or Collagraft matrices implanted without cells. In summary, the data demonstrate the ability of ADAS cells to form osteoid matrix in vivo. Because of their abundance and accessibility, ADAS cells may prove to be a novel cell therapeutic for bone repair and regeneration.

Adipose Tissue↗
PubMed2003

Muscle-derived stem cells: potential for muscle regeneration.

Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle disease characterized by progressive muscle weakness caused by the lack of dystrophin expression at the sarcolemma of muscle fibers. Although various approaches to delivering dystrophin in dystrophic muscle have been investigated extensively (e.g., cell and gene therapy), there is still no treatment that alleviates the muscle weakness in this common inherited muscle disease. The transplantation of myoblasts can enable transient delivery of dystrophin and improve the strength of injected dystrophic muscle, but this approach has various limitations, including immune rejection, poor cellular survival rates, and the limited spread of the injected cells. The isolation of muscle cells that can overcome these limitations would enhance the success of myoblast transplantation significantly. The efficiency of cell transplantation might be improved through the use of stem cells, which display unique features, including (1) self-renewal with production of progeny, (2) appearance early in development and persistence throughout life, and (3) long-term proliferation and multipotency. For these reasons, the development of muscle stem cells for use in transplantation or gene transfer (ex vivo approach) as treatment for patients with muscle disorders has become more attractive in the past few years. In this paper, we review the current knowledge regarding the isolation and characterization of stem cells isolated from skeletal muscle by highlighting their biological features and their relationship to satellite cells as well as other populations of stem cells derived from other tissues. We also describe the remarkable ability of stem cells to regenerate skeletal muscle and their potential use to alleviate the muscle weakness associated with DMD.

Animals↗
PubMedDate not supplied

[Behavior and differentiation of the neural stem cells in vivo].

We studied the behavior and differentiation of human and rat neural stem cells after transplantation in the adult rat brain without immunosuppression. The rat stem cells were isolated from the presumptive neocortex of 15-day-old embryos. The human cells were isolated from the ventricular brain zone of 9-week-old embryos and cultivated for two weeks before transplantation. The results of histomorphological studies suggest that the microenvironment factors did not suppress the growth or development of transplanted stem cells. Both rat and human embryonic multipotent neural cells showed similar behavior and differentiation into neurons and glial cells. After transplantation, they continued to mitotically divide and migrated from the graft area to the surrounding tissue of a recipient brain. The presumptive glial cells migrated preferentially along the capillaries and fibrous structures of the recipient brain. Similar behavior of the rat and human neural stem cells in the microenvironment of the recipient adult rat brain and the absence of immune reaction suggest that the transplantation into the rat brain may serve as a model for studying the developmental biology of the human stem cells.

Animals↗