Journal of hematotherapy & stem cell research最新文献

{"title":"A new concept of stem cell disorders and their new therapy.","authors":"Susumu Ikehara","doi":"10.1089/15258160360732678","DOIUrl":"https://doi.org/10.1089/15258160360732678","url":null,"abstract":"<p><p>The author previously proposed a new concept of categorizing stem cell disorders as: (1) stem cell aplasia (aplastic anemia), (2) monoclonal hematopoietic stem cell proliferative syndrome (leukemia and myelodysplastic syndrome), and (3) polyclonal hemopoietic stem cell proliferative syndrome (systemic and organ-specific autoimmune diseases). This review includes the following two stem cell disorders: mesenchymal stem cell disorders and organ-specific stem cell disorders. Age-associated diseases such as Alzheimer's disease, osteoporosis, and lung fibrosis belong to the former, whereas carcinosarcoma in the lung and adeno-endocrine cell carcinoma in the stomach belong to the latter. Recently, we have established a new method for allogeneic bone marrow transplantation using chimerism-resistant autoimmune-prone MRL/lpr mice. In this method, whole bone marrow cells containing a small number of T cells and mesenchymal stem cells are directly injected into the bone marrow cavity. MRL/lpr mice treated by injection of stem cells survived more than 2 years without showing symptoms of autoimmune disease. To apply this method to humans, we established a new method for bone marrow cell harvesting using cynomolgus monkeys. In this method, cells are harvested from the long bones using a perfusion method and are then injected directly into the bone marrow cavity of recipients. In this review, we show that this new method may become a powerful strategy for the treatment of various intractable diseases.</p>","PeriodicalId":80030,"journal":{"name":"Journal of hematotherapy & stem cell research","volume":"12 6","pages":"643-53"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/15258160360732678","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24405027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal differentiation of murine bone marrow Thy-1- and Sca-1-positive cells.","authors":"F Locatelli,&nbsp;S Corti,&nbsp;C Donadoni,&nbsp;M Guglieri,&nbsp;F Capra,&nbsp;S Strazzer,&nbsp;S Salani,&nbsp;R Del Bo,&nbsp;F Fortunato,&nbsp;A Bordoni,&nbsp;G P Comi","doi":"10.1089/15258160360732740","DOIUrl":"https://doi.org/10.1089/15258160360732740","url":null,"abstract":"<p><p>Recent evidence suggests that cells from bone marrow can acquire neuroectodermal phenotypes in cell culture or after transplantation in animal models and in the human brain. However, isolation of the bone marrow cell subpopulation with neuronal differentiation potential remains a challenge. To isolate and expand neural progenitors from whole murine bone marrow, bone marrow was obtained from hind limb bone of C57BL6 mice and plated in culture with neuronal medium with basic fibroblast growth factor and epidermal growth factor. After 5-7 days in culture, cellular spheres similar to brain neurospheres appeared either floating or attached to culture dishes. These spheres were collected, dissociated, and expanded. The bone marrow-derived spheres were positive for nestin as assessed by immunocytochemistry and by reverse transcriptase polymerase chain reaction. Thy-1- and Sca-1-positive bone marrow cells selected by magnetic cell sorting resulted in a higher yield of nestin-positive spheres. After exposure to neuronal differentiative medium retinoic acid with and without Sonic hedgehog, cells positive for neuronal markers tubulin III (TuJ-1) and neurofilament (NF) were detected. The mRNA profile of these cells included the expression of TuJ-1, neuronal-specific enolase (NSE), and NF-light chain. To evaluate the in vivo behavior of these cells, spheres derived from bone marrow-derived cells of transgenic green fluorescent protein (GFP) mice were transplanted into newborn mouse brain. Two months later, the mouse neural cortex contained a minor proportion of GFP(+) cells co-expressing neuronal markers (TuJ-1, NF, MAP-2, NeuN). Although cell fusion phenomena with the host cells could not be ruled out, bone marrow-derived neurosphere transplantation could be a strategy for cellular mediated gene therapy.</p>","PeriodicalId":80030,"journal":{"name":"Journal of hematotherapy & stem cell research","volume":"12 6","pages":"727-34"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/15258160360732740","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24405633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural stem cells in the adult nervous system.","authors":"Daniele Bottai,&nbsp;Roberta Fiocco,&nbsp;Fabrizio Gelain,&nbsp;Lidia Defilippis,&nbsp;Rossella Galli,&nbsp;Angela Gritti,&nbsp;L Angelo Vescovi","doi":"10.1089/15258160360732687","DOIUrl":"https://doi.org/10.1089/15258160360732687","url":null,"abstract":"<p><p>The concept of the immutability of the nervous tissue has recently been replaced with the new idea that a continuous neurogenic turnover does occur in some limited areas of the central nervous system (CNS). At least two neurogenic regions of the adult mammalian CNS are involved in this process: the subventricular zone of the forebrain and the dentate gyrus of the hippocampus, which are considered to be a reservoir of new neural cells. Neural stem cells (NSCs) are multipotential progenitors that have self-renewal capability. While in vivo endogenous NSCs seem able to produce almost exclusively neurons, a single NSC in vitro is competent to generate neurons, astrocytes, and oligodendrocytes. NSCs lack a specific morphology and unambiguous surface markers that could allow their identification. For this reason, one of the major difficulties in identifying stem cells is that they are defined in terms of their functional capabilities, the determination of which might alter the cells' nature. The purpose of this review is to describe the characteristics of the NSCs of the adult mammalian CNS, their potentiality in terms of proliferation and differentiation capabilities, as well as their stability in long-term culture, all attributes that make them a good tool for tissue replacement therapies.</p>","PeriodicalId":80030,"journal":{"name":"Journal of hematotherapy & stem cell research","volume":"12 6","pages":"655-70"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/15258160360732687","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24405028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Growth factor deprivation induces an alternative non-apoptotic death mechanism that is inhibited by Bcl2 in cells derived from neural precursor cells.","authors":"María del Carmen Cárdenas-Aguayo,&nbsp;Jesús Santa-Olalla,&nbsp;José-Manuel Baizabal,&nbsp;Luis-Miguel Salgado,&nbsp;Luis Covarrubias","doi":"10.1089/15258160360732759","DOIUrl":"https://doi.org/10.1089/15258160360732759","url":null,"abstract":"<p><p>Although apoptosis has been considered the typical mechanism for physiological cell death, presently alternative mechanisms need to be considered. We previously showed that fibroblast growth factor-2 (FGF2) could act as a survival factor for neural precursor cells. To study the death mechanism activated by the absence of this growth factor, we followed the changes in cell morphology and determined cell viability by staining with several dyes after FGF2 removal from mesencephalic neural-progenitor-cell cultures. The changes observed did not correspond to those associated with apoptosis. After 48 h in the absence of FGF2, cells began to develop vacuoles in their cytoplasm, a phenotype that became very obvious 3-5 days later. Double-membrane vacuoles containing cell debris were observed. Vacuolated cells did not stain with either ethidium bromide or trypan Blue, and did not show chromatin condensations. Nonetheless, during the course of culture, vacuolated cells formed aggregates with highly condensed chromatin and detached from the plate. Neural progenitor cells grown in the presence of FGF2 did not display any of those characteristics. The vacuolated phenotype could be reversed by the addition of FGF2. Typical autophagy inhibitors such as 3-MA and LY294002 inhibited vacuole development, whereas a broad-spectrum caspase inhibitor did not. Interestingly, Bcl-2 overexpression retarded vacuole development. In conclusion, we identified a death autophagy-like mechanism activated by the lack of a specific survival factor that can be inhibited by Bcl2. We propose that anti-apoptotic Bcl2 family members are key molecules controlling death activation independently of the cell degeneration mechanism used.</p>","PeriodicalId":80030,"journal":{"name":"Journal of hematotherapy & stem cell research","volume":"12 6","pages":"735-48"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/15258160360732759","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24405634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neural stem cell therapy in the aging brain: pitfalls and possibilities.","authors":"Tobi L Limke,&nbsp;Mahendra S Rao","doi":"10.1089/15258160360732641","DOIUrl":"https://doi.org/10.1089/15258160360732641","url":null,"abstract":"<p><p>As aging progresses, there is a decline in the brain's capacity to produce new neurons in the two neurogenic regions, the subventricular zone surrounding the lateral ventricles and the subgranular layer of the hippocampal dentate gyrus. The underlying cause of the declining neurogenesis is unknown, but is presumably related to age-related changes that occur during normal aging of the brain. It is exacerbated by age-related neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Stem cell-based therapy to replace lost and/or damaged cells in the aging brain is currently the focus of intense research. The two most promising approaches involve transplantation of exogenous tissue and promoting proliferation of endogenous cells. However, age-related changes in the brain environment, including elevated oxidative stress and accumulation of protein and lipid by-products, present several unique challenges that must be addressed before cell-based therapy can be used as a viable option. Although progress has been made toward replacement of lost cells and recovery of lost function, there are fundamental issues that need to be addressed for stem cell therapy to be successful in the aging brain. In this review, we focus on recent progresses made toward understand the biology of neural stem cells in the aging brain, as well as progress toward using stem cells to replace cells lost during disease.</p>","PeriodicalId":80030,"journal":{"name":"Journal of hematotherapy & stem cell research","volume":"12 6","pages":"615-23"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/15258160360732641","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24405024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Embryonic stem cells for neural replacement therapy: prospects and challenges.","authors":"Su-Chun Zhang","doi":"10.1089/15258160360732650","DOIUrl":"https://doi.org/10.1089/15258160360732650","url":null,"abstract":"<p><p>Injury or degeneration of the vertebrate central nervous system often disrupts neuronal circuitry that is built by projection neurons during early embryonic life. Repair of neural network through regeneration of these early-born projection neurons in adult life often fails since stem cells residing in the adult brain are generally programmed to give rise to late-born interneurons. Thus, exogenous cells are needed to rebuild the neural circuitry. Nevertheless, cell replacement in the brain remains a challenging goal because of the lack of safe and effective donor cells, as well as difficulty in remodeling the nonneurogenic adult CNS environment. Here I will concentrate on the donor side and discuss how recent advancement in stem cell technology offers hope for transplant therapy, with a focus on the potentials and hurdles of human embryonic stem cells as a sustainable source.</p>","PeriodicalId":80030,"journal":{"name":"Journal of hematotherapy & stem cell research","volume":"12 6","pages":"625-34"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/15258160360732650","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24405025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Postnatal astrocytes promote neural induction from adult human bone marrow-derived stem cells.","authors":"Alexis Joannides,&nbsp;Phil Gaughwin,&nbsp;Mike Scott,&nbsp;Suzanne Watt,&nbsp;Alastair Compston,&nbsp;Siddharthan Chandran","doi":"10.1089/15258160360732704","DOIUrl":"https://doi.org/10.1089/15258160360732704","url":null,"abstract":"<p><p>Neural stem cells (NSCs) have generated considerable interest because of their potential as a source of defined cells for drug screening or cell-based therapies for neurodegenerative diseases. Ethical and practical considerations limit the availability of human fetal-derived neural tissue and highlight the need to consider alternative sources of human NSCs. Because of their ready availability, their ability to be easily expanded, and reports of neural potential, bone marrow-derived populations have become the focus of intense study with regard to their potential clinical utility. However, recent identification of spontaneous cell fusion and limited neuronal differentiation has tempered initial optimism. In this study, we demonstrate the monoclonal neural and mesodermal potential of adult human bone marrow mesenchymal cells. Critically, we show that sequential treatment with the mitogens epidermal growth factor (EGF) and fibroblast growth factor-2 (FGF-2) followed by postnatal hippocampal astrocyte conditioned medium significantly promotes the generation of neurofilament(+)/beta-tubulin(+) cells from bone marrow precursors. The ability to generate almost limitless numbers of neural precursors from a readily accessible autologous adult human source provides a platform for further studies and potentially has important therapeutic implications.</p>","PeriodicalId":80030,"journal":{"name":"Journal of hematotherapy & stem cell research","volume":"12 6","pages":"681-8"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/15258160360732704","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24405629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Embryonic neural progenitor cells: the effects of species, region, and culture conditions on long-term proliferation and neuronal differentiation.","authors":"R Smith,&nbsp;V Bagga,&nbsp;R A Fricker-Gates","doi":"10.1089/15258160360732731","DOIUrl":"https://doi.org/10.1089/15258160360732731","url":null,"abstract":"<p><p>One of the major obstacles to the use of neural stem/progenitor cells in neuronal replacement therapy is the limited ability of these cells to generate sufficient numbers of specific neuronal phenotypes either in the culture dish or after transplantation in animal models of neurodegenerative disease. It is not yet fully understood whether embryonic neural stem and progenitor cells show species-specific or regional identities, or if current culture paradigms select for a particular subset of stem cells/progenitors with similar proliferation and differentiation capacities. To investigate this issue, we isolated embryonic neural progenitors derived from the developing rat and mouse central nervous system for in vitro culture to assess the regional, species-specific, and temporal effects on both cell proliferation and generation of neurons. Neurosphere cultures were derived from E13-15 mouse or rat developing striatum (medial, lateral, or whole ganglionic eminence), ventral mesencephalon, and cortex. We compared basic fibroblast growth factor and epidermal growth factor for their influence on cell proliferation and neuronal differentiation under defined differentiation paradigms. Seeding density and conditioned media were also tested for their effects on maintenance of cell proliferation over protracted time periods. Results showed that embryonic neural stem/progenitor cells maintained defined patterns of proliferation and neuronal differentiation, with both declining with time in vitro. Proliferation rate was more dependent on species and region than the neurotrophins or conditions used for culture. These results suggest that the appropriate selection of embryonic neural stem cells and culture conditions may be crucial for the optimization of their neurogenic potential.</p>","PeriodicalId":80030,"journal":{"name":"Journal of hematotherapy & stem cell research","volume":"12 6","pages":"713-25"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/15258160360732731","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24405632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Could the functional expression of HLA-G be exploited for successful stem cell transplantation and engraftment?","authors":"Marc A Williams","doi":"10.1089/15258160360732777","DOIUrl":"https://doi.org/10.1089/15258160360732777","url":null,"abstract":"757 AS ASSERTED BY Drs. Agrawal and Pandey in their paper in this issue, “The Potential Role of HLA-G Polymorphism in Maternal Tolerance to the Developing Fetus,” the mechanism of maternal tolerance to the developing fetus has remained a major medical puzzle for more than fifty years. Since the fetal genome is half-paternal and half-maternal, how is it that the fetus escapes the maternal immune system? A number of modified hypotheses have been proposed to account for the apparent maternal tolerance of the fetus. However, there is no consensus hypothesis, nor has any compelling data been offered. The answer is indeed important for understanding this unique if not unprecedented response. This may in turn provide clues to devise methods to prevent haplotype disparate transplants from the inevitable and devastating immunological rejection. Every recipient would then have a willing donor whose organs and tissues would not consequently be rejected. This in the absence of immuno-suppression almost appears to be too good to be a viable approach. But, if evolution did not provide a simple, albeit hitherto undefined mechanism for the fetus to escape maternal killer T cells, the species would not have developed by maternal gestation. Was this design an evolutionary exception, or is the answer somewhat simpler? I take this opportunity to respond to the thought-provoking points raised by Drs. Agrawal and Pandey with the objective of not being critical but to seek additional answers to this question of profound importance. Many hypotheses have been advanced to account for maternal tolerance of the antigenically foreign fetus (1,2). Some, perhaps most, of these have been rejected following years of extensive research. Of particular interest are the possibilities that the fetus lacks immunogenicity, that there is a marked attenuation of immune reactivity during pregnancy, or that there exists a status of immunological privilege afforded by the uterus. As Agrawal and Pandey, as well as others, point out, the role of HLA-G expression by the trophoblast and the potential role of HLA-G gene polymorphisms in maternal tolerance to the developing fetus have attracted much attention (3–8). HLA-G can be expressed as seven distinct protein isoforms, each encoded by a specific, alternatively spliced transcript from the HLA-G gene (3). Three isoforms are in soluble form (HLA-G5, -G6, and G-7), while four isoforms are membrane-associated proteins (HLA-G1, -G2, -G3, and G4). Soluble HLA-G isoforms are abundant in the maternal circulation throughout pregnancy. HLA-G is unique among the HLA class I molecules due in part to its quasimonomorphic nature and restricted tissue distribution. However, it remains controversial whether tolerance to HLA-G develops during fetal life. Moreover, proof of tolerance to HLA-G has hitherto not been shown although the expression of HLA-G is present in fetal thymic epithelial cells and in amniotic fluid. This suggests that classical thymic select","PeriodicalId":80030,"journal":{"name":"Journal of hematotherapy & stem cell research","volume":"12 6","pages":"757-8"},"PeriodicalIF":0.0,"publicationDate":"2003-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/15258160360732777","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24405636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional evaluation of proliferative T cell responses in patients with severe T lymphopenia: characterization of optimal culture conditions and standardized activation signals for a simple whole blood assay.","authors":"Øystein Wendelbo,&nbsp;Øystein Bruserud","doi":"10.1089/152581603322448231","DOIUrl":"https://doi.org/10.1089/152581603322448231","url":null,"abstract":"<p><p>In this methodological study, we describe an assay for analysis of proliferative T cell responses in patients with severe leukopenia. Severe treatment-induced cytopenia is observed in patients with malignant disorders who receive conventional intensive chemotherapy or autologous stem cell transplantation. The quantitative T cell defect can then be characterized by flow cytometric analysis of membrane molecule expression, whereas the functional status of the remaining T cell population is more difficult to evaluate. In the present study, we describe a standardized whole blood assay that requires small sample volumes and can be used for repeated analysis even in severely ill patients. The assay is based on the following strategy: (i) blood samples are diluted with the serum-free medium X-vivo 10, (ii) T cells are activated either with monoclonal immunoglobulin E (IgE) anti-CD3 or anti-CD3 plus anti-CD28; (iii) T cell proliferation is assayed by [(3)H]thymidine incorporation after 4 days of in vitro culture. These proliferative responses are not affected by the plasma levels of interleukin-2 (IL-2), sIL-2-R alpha, IL-7 and IL-15, and the kinetics of the response are not altered by the presence of exogenous cytokines. Detectable proliferation is observed for most patients with treatment-induced cytopenia. We conclude that the assay can be used for functional characterization of remaining T lymphocytes in patients with severe T lymphopenia.</p>","PeriodicalId":80030,"journal":{"name":"Journal of hematotherapy & stem cell research","volume":"12 5","pages":"525-35"},"PeriodicalIF":0.0,"publicationDate":"2003-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1089/152581603322448231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"24055047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}