ABSTRACT
Hematopoietic stem cells (HSC) show heterogeneous behavior even when isolated as phenotypically homogeneous populations. The cellular and molecular mechanisms that control the generation of diversity (GOD) in the HSC compartment are not well understood, but have been the focus of much debate. There is increasing evidence that the most important HSC functions, self-renewal and differentiation, are epigenetically preprogrammed and therefore predictable. Indeed, recent data show that the adult HSC compartment consists of a limited number of functionally distinct subsets of HSC. This contradicts older models of HSC behavior, which postulated a single type of HSC that can be continuously molded into different subtypes of HSC. We propose a clonal diversity model where the adult HSC compartment consists of a fixed number of different types of HSC, each with epigenetically preprogrammed behavior. Aging or disease may change the overall function of the HSC population. The model predicts that these changes reflect the relative composition of the HSC subsets, rather than changes in individual HSC. This view has implications for using HSC in experimental and clinical settings. Selection for the appropriate subsets of HSC, rather than attempts to force HSC to adjust, should improve their utility in transplantation and gene transfer applications.
Subject(s)
Cell Compartmentation , Cell Differentiation , Cell Lineage , Clone Cells/cytology , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Animals , Cell Differentiation/genetics , Epigenesis, Genetic , Models, BiologicalABSTRACT
Previously we reported that the size of the stem cell compartment (measured as LTC-IC) is 11-fold greater in DBA/2 than in C57BL/6 mice, and we identified genes that regulate the size of the stem cell pool. To determine whether stem cell intrinsic or extrinsic events account for these differences, we created chimeras by aggregating morulae from the strains C57BL/6 and DBA/2. In these chimeras stem cells of both genotypes are exposed to a common mixed environment. Thus, an equalization of stem cell frequencies is expected if stem cell extrinsic effects dominate. Conversely, the parental ratio of LTC-IC should be preserved if the regulation is stem cell autonomous. For each chimera, individual LTC-IC were genotyped on the clonal levels by analyzing their progeny. We found that most of the difference that regulates the size of the stem cell compartment was intrinsic.
Subject(s)
Genotype , Hematopoietic Stem Cells/cytology , Animals , Cells, Cultured , Chimera , Female , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Polymerase Chain Reaction , Species Specificity , Stromal CellsABSTRACT
Myeloperoxidase (MPO) is a myeloid-specific enzyme that generates hypochlorous acid and other reactive oxygen species. MPO is present at high levels in circulating neutrophils and monocytes but is not detectable in microglia, brain-specific macrophages, in normal brain tissue. However, an earlier study indicated that MPO is present in macrophage-microglia at multiple sclerosis lesions, suggesting that reactivation of MPO gene expression may play a role in neurodegenerative diseases involving macrophage-microglia. In the present study, MPO is shown to colocalize with amyloid beta (Abeta) in senile plaques in cerebral cortex sections from Alzheimer's disease (AD) brain tissue. Microglia costaining for MPO and CD68 are closely associated with plaques, suggesting that plaque components induce MPO expression in microglia. In support of this interpretation, treatment of rodent microglia with aggregated Abeta(1-42) was shown to induce MPO mRNA expression. Also, the ApoE4 allele, the major AD risk factor associated with increased Abeta deposition, was shown to correlate with increased MPO deposition in plaques (P = 0.01, ANOVA). Finally, a genetic polymorphism links MPO expression to Alzheimer's risk, in that a higher expressing SpSp MPO genotype was associated with increased incidence of AD in females, and decreased incidence in males (P = 0.006). These findings suggest that the MPO polymorphism is a gender-specific risk factor for Alzheimer's disease.
Subject(s)
Alzheimer Disease/genetics , Genetic Predisposition to Disease/genetics , Peroxidase/genetics , Polymorphism, Genetic/physiology , Sex Characteristics , Aged , Aged, 80 and over , Alleles , Amyloid beta-Peptides/metabolism , Animals , Apolipoprotein E4 , Apolipoproteins E/genetics , Cells, Cultured , Female , Gene Expression/drug effects , Genotype , Humans , Male , Microglia/metabolism , Microglia/pathology , Middle Aged , Peroxidase/metabolism , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathology , Rats , Risk FactorsABSTRACT
We describe a discrete dynamical systems approach to exploring the hypothesis-trees associated with wetlab experiments. On-going applications of the method to experimental research using a genetically engineered mouse animal model with severe combined immune deficiency (SCID) in the area of HIV infection are outlined as an example. In conclusion, we survey how this method can be used to engineer an informational murine, called Cybermouse [Mus Cyberspacea], that can be experimented upon using current immersion technologies.
Subject(s)
Artificial Intelligence , Computer Simulation , Animals , Disease Models, Animal , Genetic Engineering , HIV Infections/virology , Humans , Information Systems , Macrophages/immunology , Macrophages/virology , Mice , Mice, SCID , Programming Languages , SoftwareABSTRACT
Human immunodeficiency virus (HIV) occurs as a number of genetic and biological variants. Of these, transmission of macrophage-tropic HIV variants appears to be favored, although most infected individuals also harbor T-cell-tropic cytopathic viruses and macrophage-tropic non-cytopathic viruses. Recent evidence regarding CD4+ T-cell depletion in vivo suggests that macrophage-tropic HIV isolates may be necessary and sufficient for the development of AIDS. This review summarizes the recent findings on macrophage-tropic viruses, and compares matched sets of experiments in HIV-infected humanized severe combined immunodeficiency (SCID) mice with a computer simulation of the lymph node microenvironment. This may help to understand why HIV infection of macrophages may have profound effects on the immune system.
Subject(s)
Acquired Immunodeficiency Syndrome/microbiology , HIV/growth & development , Macrophages/microbiology , Animals , CD4-Positive T-Lymphocytes/immunology , Computer Simulation , Humans , Lymph Nodes/immunology , Lymph Nodes/microbiology , Lymph Nodes/pathology , Lymphocyte Depletion , Mice , Mice, SCID , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/microbiology , Severe Combined Immunodeficiency/pathologyABSTRACT
The natural and medical sciences have strongly benefitted from technological advances that help to create and store more raw information than can be effectively processed. In particular, this rapid growth has created a strong need for a flexible and far-reaching approach to cross-database simulation. The paper uses a highly simplified example, called the 'TinyMouse' simulator, to explain the design and functioning of interactive cross-database simulators that can be applied to prototype experiments with animal models of human disease, such as the hu-SCID mouse model for the Acquired Immune Deficiency Syndrome (AIDS). Work in progress is discussed to extend 'TinyMouse' into 'CyberMouse', an informational organism that synthesizes factual databases of the murine neuroendocrine-immune system.
