Age- and stage-specific regulation patterns in the hematopoietic stem cell hierarchy

Understanding of the genetic basis of normal and abnormal development of the immune response is an enormous undertaking. The immune response, at the most minimal level, involves interactions of antigen presenting cells (APCs), T and B cells. Each of these cells produce cell surface and soluble factors (cytokines) that affect both autocrine and paracrine functions. A second level of complexity needs to consider the development of the macrophage/monocyte lineage as well as the production of the common lymphoid precursor which undergoes distinct maturation steps in the thymus and periphery to form mature T cells as well as in BM (BM) and lymphoid organs to form mature B cells. A third level of complexity involves the immune response to infectious agents including viruses and also the response to tumour antigens. In addition, there are imbalances that predispose to decreased responses (immunodeficiencies) or increased responses (autoimmunity). A fourth level of complexity involves attempts to understand the differences in the immune response that occurs at a very young age, in adults, and at a very old age. This review will focus on the use of C57BL/6 J X DBA/2 J (BXD) recombinant inbred (RI) strains of mice to map genetic loci associated with the production of lymphoid precursors in the BM, development of T cells in the thymus, and T-cell responses to stimulation in the peripheral lymphoid organs in adult and in aged mice. Strategies to improve the power and precision in which complex traits such as the age-related immune response can be mapped is limited with the current set of 35 strains of BXD mice. Strategies to increase these strains by generating recombinant intercross (RIX) strains of mice are being developed to enable this large set of lines to detect quantitative trait loci (QTLs) with a much higher consistency and statistical power. More importantly, the resolution with which these QTLs can be mapped would be greatly improved and, in many cases, adequate to carry out direct identification of candidate genes. It is likely that, given the complexity of the immune system development, the number of cells involved in an immune response, and especially the changes in the immune system with ageing, mapping hundreds of genes will be required to fully understand age-related changes in the immune response. This review outlines ongoing and future strategies that will enable the mapping and identification of these genes.

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“…the QTL affecting proliferation, regulate the numbers of early progenitor cells in young animals [18]. Lastly, a locus on Chr.…”

Section: Quantitative Trait Loci (Qtls) Affecting the Haematopoietic mentioning

confidence: 99%

“…Lastly, a locus on Chr. 2 affects the stem and progenitor cell number only in old animals and thus qualifies as an`ageing gene' [18]. The latter is one of very few examples of loci that specifically affect an old age phenotype.…”

Section: Quantitative Trait Loci (Qtls) Affecting the Haematopoietic mentioning

confidence: 99%

Genetic Dissection of Age‐Related Changes of Immune Function in Mice

et al. 2001

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“…The long-term culture initiating cell (LTC-IC) and Cobblestone Area Forming Cells (day 35 CAFC) have been shown to be related to the bone marrow repopulating stem cell in BXD RI mice (Ploemacher et al 1991;Muller-Sieburg and Riblet, 1996;Sutherland et al 1990;Petzer et al 1996;Breems et al 1994). As described in Table 1, the initial study using LTC-IC identified QTL on chromosome 1 (Muller-Sieburg and Riblet, 1996) and although this was missed in an initial CAFC Day 35 study (QTL on chromosome 18 only; de Haan and Van Zant, 1997), a more recent CAFC Day 35 study identified both QTL on chromosomes 1 and 18 (Geiger et al 2001). …”

Section: Introductionmentioning

confidence: 99%

QTL analyses of lineage-negative mouse bone marrow cells labeled with Sca-1 and c-Kit

et al. 2008

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Differences in the number of functionally and/or phenotypically defined bone marrow cells in inbred mouse strains have been exploited to map quantitative trait loci (QTL) that determine the variation in cell frequency. To extend this approach to the differences in the stem/progenitor cell compartment in CBA/H and C57BL/6 mice, we have exploited the resolution of flow cytometry and the power of QTL analyses in 124 F2 mice to analyse lineage negative (Lin -) bone marrow cells according to the intensity of labelling with Sca-1 and c-Kit. In the Lin -Sca-1 + c-Kit + enriched population six quantitative trait loci (QTL) were identified -one significant and five suggestive. Whereas previous in vitro clonogenic, LTIC-IC, CAFC day 35, and flow cytometry each identified different QTL, our approach identified the same or very similar QTL at all three loci (Chromosome 1, 17 and 18) as well as QTL on chromosomes 6 and 10. In silico analyses implicate haematopoietic stem cell homing involving Cxcr4 and Cxcl12 as being the determining pathway. The mapping of the same or very similar QTLs in independent studies using different assay(s) suggests a common genetic determinant, and thus reinforces the biological and genetic significance of the QTL. These data also suggest that mouse bone marrow cell subpopulations can be functionally, phenotypically and genetically defined.3

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“…[20][21][22][23][24] Further, in mice, the extent of the aging of HSCs is strain dependent, highlighting the importance of genetic influences on the aging process. [25][26][27][28] In addition to the genetic factors regulating stem cell aging, it is likely that epigenetic changes in chromatin structure play important roles in regulating gene transcription and thus influence the aging process.…”

Section: Introductionmentioning

confidence: 99%

Unraveling the complex regulation of stem cells: implications for aging and cancer

Oakley

Zant

2007

Leukemia

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Substantial progress in embryonic and adult stem cell research in the past several years has yielded a wealth of information regarding the mechanisms regulating self-renewal and differentiation, two processes often used to define stem cells. Recent evidence suggests that epigenetic as well as genetic processes maintain stem cells in a pluripotent state as well as dictate their transition to more restricted stages of development. In this review, we discuss two emerging themes in stem cell biology, epigenetic control of gene expression and post-transcriptional regulation via microRNAs. We summarize how these regulatory mechanisms facilitate various aspects of normal stem cell biology and extend the discussion to their involvement in aging and tumorigeneisis, two biological phenomena intimately tied to stem cells. We speculate that aberrant epigenetic events and altered miRNA expression profiles in aged stem cell populations play important roles in carcinogenesis.

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Age- and stage-specific regulation patterns in the hematopoietic stem cell hierarchy

Cited by 97 publications

References 49 publications

Genetic Dissection of Age‐Related Changes of Immune Function in Mice

Genetic Dissection of Age‐Related Changes of Immune Function in Mice

QTL analyses of lineage-negative mouse bone marrow cells labeled with Sca-1 and c-Kit

Unraveling the complex regulation of stem cells: implications for aging and cancer

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