成体干细胞的横向分化及其可能的机制

传统的观点认为成体组织中的干细胞,只能定向分化为其所在组织中的某个或某些特定的细胞,其发育潜能具有限制性。近年来随着研究的深入,许多研究者对这一观点提出了质疑,认为成体干细胞的分化潜能远比先前认为的更为广泛,并将之称为干细胞的横向分化。本文综述了几种成体干细胞的横向分化及其可能的机制。     

Articular chondrocyte culturing for cell-based cartilage repair: needs and perspectives

Articular cartilage displays a limited capacity of self-regeneration after injury. Thus, the biology of this tissue and its cellular components - the chondrocytes - has become the focus of several investigations, driven by tissue engineering and the basic and clinical research fields, aiming to ameliorate the present clinical approaches to cartilage repair. In this work, we present a brief recapitulation of the events that lead to cartilage development during the skeletal embryonal growth. The intrinsic phenotypic plasticity of the mesenchymal precursors and the adult chondrocytes is evaluated, dependent on the cell source, its physiopathological state, and as a function of the donor's age. The phenotypic changes induced by the basic culturing techniques are also taken into account, thus highlighting the phenotypic plasticity of the chondrocyte as the main property which could couple the differentiation process to the repair process. Chondrocyte proliferation and the contemporary maintenance of the chondrogenic differentiation potential are regarded as the two primary goals to be achieved in order to fulfill the quantitative needs of the clinical applications and the qualitative requirements of a properly repaired tissue. In this light, the effects of several growth factors and medium supplements are investigated. Finally, the latest improvements in culturing conditions and their possible clinical applications are presented as well.     

Biological and clinical significance of T helper 17 cell plasticity

Mature T helper (Th) effector cells originate following antigen recognition by naive T precursors. The maturation process is accompanied by the acquisition of specific effector functions that distinguish at least three different T helper subsets: Th1, Th2 and Th17. In general, maturation of somatic cells is accompanied by terminal differentiation. However, accumulating evidence shows that effector T cells retain a certain degree of plasticity. This is especially true for Th17 cells, which have been shown to converge towards other phenotypes in response to specific microenvironmental pressure. In this review we will discuss the experimental evidence that supports the hypothesis of Th17 plasticity, with particular emphasis on the generation of Th17-derived ‘non-classic’ Th1 cells, and the molecular networks that control it. Moreover, we will consider why Th17 plasticity is important for host protection, but also why it can have pathogenic functions during chronic inflammation. Regarding the last point, we will discuss a possible role for biological drugs in the control of Th17 plasticity and disease course.     

4E-BP1 regulates the differentiation of white adipose tissue

4E Binding protein 1 (4E-BP1) suppresses translation initiation. The absence of 4E-BP1 drastically reduces the amount of adipose tissue in mice. To address the role of 4E-BP1 in adipocyte differentiation, we characterized 4E-BP1^−/− mice in this study. The lack of 4E-BP1 decreased the amount of white adipose tissue and increased the amount of brown adipose tissue. In 4E-BP1^−/− MEF cells, PPARγ coactivator 1 alpha (PGC-1α) expression increased and exogenous 4E-BP1 expression suppressed PGC-1α expression. The level of 4E-BP1 expression was higher in white adipocytes than in brown adipocytes and showed significantly greater up-regulation in white adipocytes than in brown adipocytes during preadipocyte differentiation into mature adipocytes. The amount of PGC-1α was consistently higher in HB cells (a brown preadipocyte cell line) than in HW cells (a white preadipocyte cell line) during differentiation. Moreover, the ectopic over-expression of 4E-BP1 suppressed PGC-1α expression in white adipocytes, but not in brown adipocytes. Thus, the results of our study indicate that 4E-BP1 may suppress brown adipocyte differentiation and PGC-1α expression in white adipose tissues.     

Terminal differentiation of lymphocytes depends on Blimp-1

B lymphocyte induced maturation protein 1 (Blimp-1) has long been considered a master regulator of the terminal differentiation of B cells into antibody-secreting plasma cells. Gene-targeting experiments have now demonstrated that quantitative changes in Blimp-1 expression define plasma cell ontogeny--a process that requires the continual function of Blimp-1. Recently, new roles for Blimp-1 have been revealed, as a suppressor of diffuse large B cell lymphoma and as a key regulator of T-cell differentiation. Blimp-1 is expressed in differentiated effector T cells and controls their homeostasis. These new findings suggest that Blimp-1 has a conserved function in the final differentiation of both the cellular and the humoral arm of the adaptive immune response.     

Adipose tissue development: The role of precursor cells and adipogenic factors

Summary Obesity is regarded as a heterogeneous syndrome, which may appear in different forms. Various causes have been found to contribute to its pathogenesis. During recent years investigations of adipose tissue cellularity and its dynamic changes have gained growing interest. An important progress was the discovery of adipose tissue precursor cells. These cells have not yet been precisely identified by morphological and biochemical methods in intact tissue. However, due to methodological developments such precursor cells can be cultured both as primary cultures and as established cell lines. These culture systems have proven to be valuable models for the study of the processes involved in the formation of new fat cells.Abbreviations cAMP Cyclic adenosine monophosphate - cDNA Complementary desoxyribonucleic acid - DHAP Dihydroxy-acetone phosphate - GPDH Glycero-3-phosphate dehydrogenase - IGF-I Insulin-like growth factor I - MIX 1-Methyl-3-isobutylxanthine - mRNA Messenger ribonucleic acid - TNF Tumor necrosis factor Experiments carried out in the authors' laboratories and published in this review were supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 43 Terms: A number of terms have been used to describe the process of adipocyte development. These are defined as follows [11]:Adipoblast: the pluripotent mesenchymal stem cell of the adipose tissue, which at present is still putative and has not been identified biochemically and morphologicallyPreadipocyte: the cell already committed or determined to become a fat cell with the ability to synthesize lipogenic enzymes and to store lipids; these cells may even contain small lipid droplets or become quickly filled with triglyceridesAdipocyte precursor cells: a precise distinction between adipoblast and preadipocyte is usually not possible and therefore this term is frequently used to describe both differentiation phases, particularly in primary cultureAdipocyte: a cell with a central large lipid vacuole, showing the characteristic signet-ring form, with high activities for enzymes of triglyceride synthesis and releaseDetermination or commitment: the irreversible recruitment of the pluripotent stem cell to a preadipocyte, which may be preceded by one or more cell divisionsAdipogenic conversion: the development of a preadipocyte to the morphological and biochemical appearance of an adipocyte by the expression of a genetic programAdipogenic (adipose) differentiation: the continuous gradual development of an adipoblast to a mature fat cell     

Peritoneal immune system in patients with advance epithelial ovarian cancer

The development of epithelial ovarian cancer is associated with changes in the peritoneal cavity microenvironment. Tumor cells produce different factors, which impairs differentiation, maturation, and function of antigen-presenting cells. In this review, we focus on selected cell populations in the peritoneal cavity immune system and their potential role in epithelial ovarian cancer immunopathogenesis. We devote most attention to dendritic cells because they are considered to be superior in their antigen-presenting ability, compared with both macrophages and B lymphocytes. We also present a brief characterization of tumor-infiltraiting cells in epithelial ovarian cancer patients.     

Peritoneal Immune System in Patients with Advance Epithelial Ovarian Cancer

The development of epithelial ovarian cancer is associated with changes in the peritoneal cavity microenvironment. Tumor cells produce different factors, which impairs differentiation, maturation, and function of antigen-presenting cells. In this review, we focus on selected cell populations in the peritoneal cavity immune system and their potential role in epithelial ovarian cancer immunopathogenesis. We devote most attention to dendritic cells because they are considered to be superior in their antigen-presenting ability, compared with both macrophages and B lymphocytes. We also present a brief characterization of tumor-infiltraiting cells in epithelial ovarian cancer patients.     

Dendritic cell based tumor vaccines

Dendritic cells (DC) constitute a unique system of cells that induce, sustain and regulate immune responses. Distributed as sentinels throughout the body, DC are poised to capture antigen (Ag), migrate to draining lymphoid organs, and, after a process of maturation, select Ag-specific lymphocytes to which they present the processed Ag, thereby inducing immune responses. DC present Ag to CD4(+) T cells which in turn regulate multiple effectors, including CD8(+) cytotoxic T cells, B cells, NK cells, macrophages and eosinophils, all of which contribute to the protective immune responses. Several key features of the DC system may be highlighted: (1) the existence of different DC subsets that share biological functions, yet display unique ones such as polarization of T cell responses towards Type 1 or Type 2 or regulation of B cell responses; (2) the functional specialization of DC according to their differentiation/maturation stages; and (3) the plasticity of DC which is determined by the microenvironment (e.g. cytokines) and may manifest as (i) the final differentiation into either DC (enhanced antigen presentation) or macrophage (enhanced antigen degradation); (ii) the induction of immunity or tolerance; and (iii) the polarization of T cell responses. Because of these unique properties, DC represent both vectors and targets for immunological intervention in numerous diseases and are optimal candidates for vaccination protocols both in cancer and infectious diseases.     

Nuclear fusion-independent smooth muscle differentiation of human adipose-derived stem cells induced by a smooth muscle environment

Human adipose-derived stem cells hASC have been isolated and were shown to have multilineage differentiation capacity. Although both plasticity and cell fusion have been suggested as mechanisms for cell differentiation in vivo, the effect of the local in vivo environment on the differentiation of adipose-derived stem cells has not been evaluated. We previously reported the in vitro capacity of smooth muscle differentiation of these cells. In this study, we evaluate the effect of an in vivo smooth muscle environment in the differentiation of hASC. We studied this by two experimental designs: (a) in vivo evaluation of smooth muscle differentiation of hASC injected into a smooth muscle environment and (b) in vitro evaluation of smooth muscle differentiation capacity of hASC exposed to bladder smooth muscle cells. Our results indicate a time-dependent differentiation of hASC into mature smooth muscle cells when these cells are injected into the smooth musculature of the urinary bladder. Similar findings were seen when the cells were cocultured in vitro with primary bladder smooth muscle cells. Chromosomal analysis demonstrated that microenvironment cues rather than nuclear fusion are responsible for this differentiation. We conclude that cell plasticity is present in hASCs, and their differentiation is accomplished in the absence of nuclear fusion.     

Wnt signaling in somite development.

During vertebrate embryogenesis, specialized mesodermal structures, called somites, give rise to a variety of mesodermal tissues including skeletal muscles, vertebrae and dermis. Development of the somites is a rhythmic process that involves a series of steps including segmentation of the paraxial mesoderm, epithelialization, somite formation, somite maturation, somite patterning and differentiation of somitic cells into different lineages. Wnt signaling has been found to play crucial roles in multiple steps of somite development. In this review, we present a brief overview of current knowledge on Wnt signaling events during the development of somites and their derivatives.     

B cell maturation in chronic lymphocytic leukemia. II. Clonal heterogeneity in the response to various B cell activators and recombinant cytokines (rIFN-gamma, rIFN-alpha, rIL2)

Maturation of B cells into immunoglobulin (Ig)-secreting cells is influenced by antigen-nonspecific growth and differentiation factors. In the present study, we have analyzed the effect of several recombinant cytokines (rIL2, rIFN-alpha, rIFN-gamma) on the terminal differentiation of B cells from 10 patients with chronic lymphocytic leukemia (CLL) stimulated with three different B cell activators (phorbolester TPA, staphylococcus aureus Cowan I bacteria, or pokeweed mitogen). Secretion of IgM, as determined by heavy-chain specific ELISA, varied widely among different CLL cell populations, but was induced in all cases by one or several of these activators. Importantly, this response was enhanced 2-10-fold in all patients by at least one of the tested recombinant cytokines alone, or a combination of rIL2 with rIFN-alpha or rIFN-gamma. The results illustrate the clonal heterogeneity of CLL B cell maturation in vitro and demonstrate that rIL2, rIFN-alpha or rIFN-gamma can act as a B cell differentiation factor, depending on the responsiveness (stage of differentiation) of the individual clonal B cell population.