| 1. |
- Beerman, Isabel, et al.
(författare)
-
Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion
- 2010
-
Ingår i: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:12, s. 5465-5470
-
Tidskriftsartikel (refereegranskat)abstract
- Aging of the hematopoietic stem cell compartment is believed to contribute to the onset of a variety of age-dependent blood cell pathophysiologies. Mechanistic drivers of hematopoietic stem cell (HSC) aging include DNA damage accumulation and induction of tumor suppressor pathways that combine to reduce the regenerative capacity of aged HSCs. Such mechanisms do not however account for the change in lymphoid and myeloid lineage potential characteristic of HSC aging, which is believed to be central to the decline of immune competence and predisposition to myelogenous diseases in the elderly. Here we have prospectively isolated functionally distinct HSC clonal subtypes, based on cell surface phenotype, bearing intrinsically different capacities to differentiate toward lymphoid and myeloid effector cells mediated by quantitative differences in lineage priming. Finally, we present data supporting a model in which clonal expansion of a class of intrinsically myeloid-biased HSCs with robust self-renewal potential is a central component of hematopoietic aging.
|
|
| 2. |
- Månsson, Robert, et al.
(författare)
-
B-lineage commitment prior to surface expression of B220 and CD19 on hematopoietic progenitor cells
- 2008
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 112:4, s. 1048-1055
-
Tidskriftsartikel (refereegranskat)abstract
- Commitment of hematopoietic progenitor cells to B-lymphoid cell fate has been suggested to coincide with the development of PAX5-expressing B220 +CD19+ pro-B cells. We have used a transgenic reporter mouse, expressing human CD25 under the control of the B-lineage- restricted IgII1 (λ5) promoter to investigate the lineage potential of early progenitor cells in the bone marrow. This strategy allowed us to identify a reporter expressing LIN-B220- CD19-CD127 +FLT3+ SCA1lowKITlow population that displays a lack of myeloid and a 90% reduction in in vitro T-cell potential compared with its reporter-negative counterpart. Gene expression analysis demonstrated that these lineage-restricted cells express B- lineage-associated genes to levels comparable with that observed in pro-B cells. These data suggest that B-lineage commitment can occur before the expression of B220 and CD19. © 2008 by The American Society of Hematology.
|
|
| 3. |
- Månsson, Robert, et al.
(författare)
-
Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity
- 2010
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 115:13, s. 2601-2609
-
Tidskriftsartikel (refereegranskat)abstract
- To investigate molecular events involved in the regulation of lymphoid lineage commitment, we crossed lambda 5 reporter transgenic mice to Rag1-GFP knockin mice. This allowed us to subfractionate common lymphoid progenitors and pre-pro-B (fraction A) cells into lambda 5(-)Rag1(low), lambda 5(-)Rag1(high), and lambda 5(+)Rag1(high) cells. Clonal in vitro differentiation analysis demonstrated that Rag1(low) cells gave rise to B/T and NK cells. Rag1(high) cells displayed reduced NK-cell potential with preserved capacity to generate B- and T-lineage cells, whereas the lambda 5(+) cells were B-lineage restricted. Ebf1 and Pax5 expression was largely confined to the Rag1high populations. These cells also expressed a higher level of the surface protein LY6D, providing an additional tool for the analysis of early lymphoid development. These data suggest that the classic common lymphoid progenitor compartment composes a mixture of cells with relatively restricted lineage potentials, thus opening new possibilities to investigate early hematopoiesis.
|
|
| 4. |
- Zandi, Sasan, 1976-, et al.
(författare)
-
EBF1 is essential for B-lineage priming and establishment of a transcription factor network in common lymphoid progenitors
- 2008
-
Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 181:5, s. 3364-3372
-
Tidskriftsartikel (refereegranskat)abstract
- Development of B-lymphoid cells in the bone marrow is a process under strict control of a hierarchy of transcription factors. To understand the development of a B-lymphoid-restricted functional network of transcription factors, we have investigated the cell autonomous role of the transcription factor EBF1 in early B cell development. This revealed that even though transplanted EBF1-deficient fetal liver cells were able to generate common lymphoid progenitors (CLPs) as well as B220(+)CD43(+)AA4.1(+) candidate precursor B cells, none of these populations showed signs of B lineage priming. The isolated CLPs were able to generate T lymphocytes in vitro supporting the idea that the phenotype of EBF1-deficient mice is restricted to the development of the B lineage. Furthermore, EBF deficient CLPs displayed a reduction in Ig H chain recombination as compared with their wild-type counterpart and essentially lacked transcription of B-lineage-associated genes. Among the genes displaying reduced expression in the EBF1 deficient CLPs were the transcription factors Pax5, Pou2af1 (OcaB), and FoxO1 that all appear to be direct genetic targets for EBF1 because their promoters contained functional binding sites for this factor. This leads us to suggest that EBF1 regulates a transcription factor network crucial for B lineage commitment.
|
|
| 5. |
- Zandi, Sasan, et al.
(författare)
-
Load and lock: the molecular mechanisms of B-lymphocyte commitment
- 2010
-
Ingår i: IMMUNOLOGICAL REVIEWS. - : Blackwell Publishing Ltd. - 0105-2896. ; 238:1, s. 47-62
-
Forskningsöversikt (refereegranskat)abstract
- The maturation of B-lymphoid cells from hematopoietic stem cells in the bone marrow is a complex process under control of interplay between extrinsic and intrinsic factors. In addition to serving as a model for normal cell differentiation, disturbances in this process results in immunodeficiencies and malignancies, such as leukemia and lymphoma, making the subject of high relevance for modern medicine. Although the process of B lymphopoiesis has been under intense investigation, recent methodological developments within the area of cell sorting, genome-wide expression, and DNA-binding analysis has allowed for a rapid development of the understanding of B-lymphocyte differentiation. This has suggested that the path to B-lymphoid cell fate may be initiated by lineage priming reflected in the expression of lymphoid associated genes already in multipotent hematopoietic progenitors. Upon differentiation, the gene expression profile is changed to involve an increasing number of B-lineage-restricted genes linked to loss of alternative developmental potentials and B-lineage commitment. This review focuses on the molecular regulation of early B-lymphoid development and aims to provide an up to date summary of the current status of the research area.
|
|
| 6. |
- Zetterblad, Jenny, et al.
(författare)
-
Genomics based analysis of interactions between developing B-lymphocytes and stromal cells reveal complex interactions and two-way communication
- 2010
-
Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 11:108
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The use of functional genomics has largely increased our understanding of cell biology and promises to help the development of systems biology needed to understand the complex order of events that regulates cellular differentiation in vivo. One model system clearly dependent on the integration of extra and intra cellular signals is the development of B-lymphocytes from hematopoietic stem cells in the bone marrow. This developmental pathway involves several defined differentiation stages associated with specific expression of genes including surface markers that can be used for the prospective isolation of the progenitor cells directly from the bone marrow to allow for ex vivo gene expression analysis. The developmental process can be simulated in vitro making it possible to dissect information about cell/cell communication as well as to address the relevance of communication pathways in a rather direct manner. Thus we believe that B-lymphocyte development represents a useful model system to take the first steps towards systems biology investigations in the bone marrow. Results: In order to identify extra cellular signals that promote B lymphocyte development we created a database with approximately 400 receptor ligand pairs and software matching gene expression data from two cell populations to obtain information about possible communication pathways. Using this database and gene expression data from NIH3T3 cells (unable to support B cell development), OP-9 cells (strongly supportive of B cell development), pro-B and pre-B cells as well as mature peripheral B-lineage cells, we were able to identify a set of potential stage and stromal cell restricted communication pathways. Functional analysis of some of these potential ways of communication allowed us to identify BMP-4 as a potent stimulator of B-cell development in vitro. Further, the analysis suggested that there existed possibilities for progenitor B cells to send signals to the stroma. The functional consequences of this were investigated by co-culture experiments revealing that the co-incubation of stromal cells with B cell progenitors altered both the morphology and the gene expression pattern in the stromal cells. Conclusions: We believe that this gene expression data analysis method allows for the identification of functionally relevant interactions and therefore could be applied to other data sets to unravel novel communication pathways.
|
|
