Influence of maternal-fetal histocompatibility and MHC zygosity on maternal microchimerism

To investigate the relationship between maternal-fetal histocompatibility and maternal microchimerism, we developed a sensitive quantitative PCR assay for the neomycin resistance gene (neoR), and, in a mouse model system, used neoR as a noninherited maternal allele marker of maternal cells to detect and quantitate maternal microchimerism in tissues of neoR(-/-) N2 backcross progeny of (neoR(+/-))F(1) females mated with neoR(-/-) males. Using this approach, we obtained evidence for the presence of chimeric maternal cells in the brain, spleen, and thymus of all weanling and adult mice so tested. The numbers of chimeric maternal cells present in the spleen did not differ significantly from those in the thymus regardless of age or maternal-fetal histocompatibility. At all ages, brain tissue had higher level of maternal microchimerism than lymphoid tissue in mice MHC identical with their mothers, but the levels were similar in mice MHC disparate with their mothers. The levels of chimeric maternal cells in both brain and lymphoid tissue of mice with homozygous syngenicity and maternal allogenicity were similar, and tended to be higher than tissue-specific levels in mice with either combined maternal-fetal allogenicity or heterozygous syngenicity. Thus, MHC homozygous progeny had higher levels of maternal microchimerism than MHC heterozygous progeny. We conclude that normal mice possess small numbers of maternal cells in spleen, thymus, brain, and probably most other tissues, and that maternal-fetal histocompatibility influences the levels of these cells by mechanisms related to MHC zygosity of the progeny.     

Emergent roles of maternal microchimerism in postnatal development

Maternal microchimerism (MMc) is the phenomenon that a low number of cells from the mother persists within her progeny. Despite their regular presence in mammalian pregnancies, the overall cell type repertoire and roles of maternal cells, especially after birth, remain unclear. By using transgenic mouse strains and human umbilical blood samples, recent studies have for the first time characterized and quantified MMc cell type repertoires in offspring, identified the cross-generational influence on fetal immunity, and determined possible factors that affect their presence in offspring. This review summarizes new findings, especially on the maternal cell type repertoires and their potential role in utero, in postnatal life, and long after birth.     

Fetal microchimerism and maternal health: A review and evolutionary analysis of cooperation and conflict beyond the womb

The presence of fetal cells has been associated with both positive and negative effects on maternal health. These paradoxical effects may be due to the fact that maternal and offspring fitness interests are aligned in certain domains and conflicting in others, which may have led to the evolution of fetal microchimeric phenotypes that can manipulate maternal tissues. We use cooperation and conflict theory to generate testable predictions about domains in which fetal microchimerism may enhance maternal health and those in which it may be detrimental. This framework suggests that fetal cells may function both to contribute to maternal somatic maintenance (e.g. wound healing) and to manipulate maternal physiology to enhance resource transmission to offspring (e.g. enhancing milk production). In this review, we use an evolutionary framework to make testable predictions about the role of fetal microchimerism in lactation, thyroid function, autoimmune disease, cancer and maternal emotional, and psychological health. Also watch the Video Abstract .     

Fetal cells in mother rats contribute to the remodeling of liver and kidney after injury

Fetal microchimerism indicates a mixture of cells of maternal and fetal origin seen in maternal tissues during and after pregnancy. Controversy exists about whether persistent fetal microchimerism is related with some autoimmune disorders occurring during and after pregnancy. In the current experiment, an animal model in which EGFP positive cells were taken as fetal-origin cells was designed to detect the fetal microchimerism in various maternal organs. Ethanol drinking and gentamicin injection were adopted to induce liver and kidney injury simultaneously. EGFP positive cells were engrafted not only in the maternal circulation and bone marrow, but also in the liver and kidney as hepatocytes and tubular cells, respectively. These results indicate that fetal cells are engrafted to maternal hematopoietic system without apparent injury and they also contribute to the repairing process of maternal liver and kidney.     

Pregnancy, microchimerism, and the maternal grandmother

Background

A woman of reproductive age often harbors a small number of foreign cells, referred to as microchimerism: a preexisting population of cells acquired during fetal life from her own mother, and newly acquired populations from her pregnancies. An intriguing question is whether the population of cells from her own mother can influence either maternal health during pregnancy and/or the next generation (grandchildren).

Methodology/Principal Findings

Microchimerism from a woman''s (i.e. proband''s) own mother (mother-of-the-proband, MP) was studied in peripheral blood samples from women followed longitudinally during pregnancy who were confirmed to have uncomplicated obstetric outcomes. Women with preeclampsia were studied at the time of diagnosis and comparison made to women with healthy pregnancies matched for parity and gestational age. Participants and family members were HLA-genotyped for DRB1, DQA1, and DQB1 loci. An HLA polymorphism unique to the woman''s mother was identified, and a panel of HLA-specific quantitative PCR assays was employed to identify and quantify microchimerism. Microchimerism from the MP was identified during normal, uncomplicated pregnancy, with a peak concentration in the third trimester. The likelihood of detection increased with advancing gestational age. For each advancing trimester, there was a 12.7-fold increase in the probability of detecting microchimerism relative to the prior trimester, 95% confidence intervals 3.2, 50.3, p<0.001. None of the women with preeclampsia, compared with 30% of matched healthy women, had microchimerism (p = 0.03).

Conclusions/Significance

These results show that microchimerism from a woman''s own mother is detectable in normal pregnancy and diminished in preeclampsia, supporting the previously unexplored hypothesis that MP microchimerism may be a marker reflecting healthy maternal adaptation to pregnancy.     

Inheritance of Mitochondrial DNA and Plasmids in the Ascomycetous Fungus, Epichloe Typhina

We analyzed the inheritance of mitochondrial DNA (mtDNA) species in matings of the grass symbiont Epichloe typhina. Eighty progeny were analyzed from a cross in which the maternal (stromal) parent possessed three linear plasmids, designated Callan-a (7.5 kb), Aubonne-a (2.1 kb) and Bergell (2.0 kb), and the paternal parent had one plasmid, Aubonne-b (2.1 kb). Maternal transmission of all plasmids was observed in 76 progeny; two progeny possessed Bergell and Callan-a, but had the maternal Aubonne-a replaced with the related paternal plasmid Aubonne-b; two progeny lacked Callan-a, but had the other two maternal plasmids. A total of 34 progeny were analyzed from four other matings, including a reciprocal pair, and in each progeny the plasmid transmission was maternal. The inheritance of mitochondrial genomes in all progeny was analyzed by profiles of restriction endonuclease-cleaved mtDNA. In most progeny the profiles closely resembled those of the maternal parents, but some progeny had nonparental mtDNA profiles that suggested recombination of mitochondrial genomes. These results indicate that the fertilized stroma of E. typhina is initially heteroplasmic, permitting parental mitochondria to fuse and their genomes to recombine.     

The effect of pregnancy on production of maternal endogenous hematopoietic stem cells

Fetal microchimerism refers to the presence of fetal cells in maternal blood and tissues during pregnancy. This microchimerism may result from trafficking of fetal and maternal blood across the placenta during pregnancy. Physiological changes in the maternal blood cellular milieu are also recognized during pregnancy and in the early postpartum period. Earlier studies showed that maternal blood contains CD34⁺ hematopoietic stem cells (HSCs) that bear paternal genetic markers or male phenotype, suggesting that these cells circulated to the mother from male fetuses during pregnancy. Other studies showed that these maternal HSCs have significantly lower expansion potential than their fetal counterparts. We have recently shown increased percentages of CD34⁺ HSCs in peripheral blood of pregnant and parous women. Herein, we hypothesize that pregnancy stimulates the production of endogenous CD34⁺ HSCs of maternal origin, a phenomenon which potentially could favor postpartum regenerative capacity.     

New perspectives on the etiology of systemic sclerosis

Systemic sclerosis (SSc) is a disease of unknown origin. Although SSc is considered to be an autoimmune disease, recent studies have implicated cellular microchimerism in its pathogenesis. Microchimerism results from the persistence of fetal cells, from prior pregnancies, in the maternal circulation. The demonstration of the presence of fetal CD3+ T cells in the maternal circulation and of fetal cells in affected SSc tissues suggests that microchimerism might cause SSc in certain patients by initiating a graft-versus-host-like response.     

Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice

The influence of maternally transmitted immunoglobulins on the development of autoimmune diabetes mellitus in genetically susceptible human progeny remains unknown. Given the presence of islet beta cell-reactive autoantibodies in prediabetic nonobese diabetic (NOD) mice, we abrogated the maternal transmission of such antibodies in order to assess their influence on the susceptibility of progeny to diabetes. First, we used B cell-deficient NOD mothers to eliminate the transmission of maternal immunoglobulins. In a complementary approach, we used immunoglobulin transgenic NOD mothers to exclude autoreactive specificities from the maternal B-cell repertoire. Finally, we implanted NOD embryos in pseudopregnant mothers of a non-autoimmune strain. The NOD progeny in all three groups were protected from spontaneous diabetes. These findings demonstrate that the maternal transmission of antibodies is a critical environmental parameter influencing the ontogeny of T cell-mediated destruction of islet beta cells in NOD mice. It will be important to definitively determine whether the transmission of maternal autoantibodies in humans affects diabetes progression in susceptible offspring.     

Murine maternal cell microchimerism: analysis using real-time PCR and in vivo imaging

In humans, maternal cells are present in the affected tissues of children with inflammatory myopathy, scleroderma, and neonatal lupus. It is unknown if maternal cell microchimerism (MCM) contributes to the pathology of disease. We sought to understand the factors that affect MCM to serve as a baseline for future mechanistic studies. Using a mouse model, we bred female mice transgenic for the luciferase (Luc) reporter gene to wild-type (WT) males. The WT offspring were sacrificed at various postnatal ages. DNA was extracted from multiple organs, and real-time PCR amplification was used to quantify Luc transgene as a marker for maternally derived cells. Sensitivity was one to two transgenic cells per 100,000 WT cells. MCM was noted in 85% of mice and 45% of tissues assayed. The average quantity of MCM was 158 maternal cells per 100,000 neonatal cells. The organs displaying the highest frequency and quantity of MCM were heart and lung (P < 0.001). Postnatal age up to 21 days did not appear to affect levels of MCM (P = 0.47), whereas increasing parity may increase levels of MCM. The data show that MCM is a common occurrence in healthy newborn mice, that it is present in their major organs, and that there are organ specific differences. This may represent differential migration of maternal cells or varying receptivity of specific fetal organs to microchimerism. Pregnancy history appears to play a role in maternal cell trafficking. The role of MCM in pregnancy and disease pathogenesis remains to be elucidated.     

IS ORGANELLE DNA STRICTLY MATERNALLY INHERITED? POWER ANALYSIS OF A BINOMIAL DISTRIBUTION

Although numerous exceptions are well known, organelle DNA is often exclusively or predominantly maternally inherited. In such cases, maternal inheritance is often documented by the study of progeny derived from crosses between parents with distinguishable organelle genotypes. These studies generally detect a single type of progeny, those containing organelles derived from only one of the parents; no progeny containing organelles derived either from the opposite parent or from both parents are found. However, in most cases the number of progeny examined is quite small. I present a simple binomial model of organelle inheritance to determine the power of such experiments to distinguish between the hypothesis of strict maternal inheritance and a more complex hypothesis involving the presence of both organelle types within a progeny array. Extremely large sample sizes of progeny are required to distinguish these two hypotheses with reasonable confidence when organelle transmission is not strictly maternal. As a result, studies involving simple progeny testing may be misleading. Larger samples, more complex breeding designs, or more sensitive molecular methods are required to document adequately strict maternal inheritance of organelles.     

Coupled population dynamics of endosymbionts within and between hosts

Many insect species are infected with maternally transmitted endosymbionts, the most widely documented being Wolbachia . The rate of spread and equilibrium of prevalence of these infections depend on two parameters – maternal transmission fidelity and relative fitness of infected cytoplasmic lineages. Both transmission fidelity and the phenotypic effect of endosymbionts often increase with endosymbiont density within hosts. Thus, the dynamics of infection prevalence in host populations depends on processes affecting within-host density of endosymbionts. In theory, the equilibrium prevalence of infection by male-killing endosymbionts is much more sensitive to changes in transmission fidelity and relative fitness than is that of endosymbionts that cause cytoplasmic incompatibility. In natural populations, male-killers exhibit much greater temporal and spatial variation in the prevalence of infection than do endosymbionts that cause cytoplasmic incompatibility. Thus, the population dynamics of endosymbiont infections, especially those that cause male-killing, is likely to be governed by environmental and genetic variables that affect within-host density of these infections.     

Incipient Reproductive Isolation between Geographic Populations of Ophryotrocha labronica (Polychaeta, Dorvilleidae)

Åkesson, B. (Department of Zoology, University of Gothenburg, Göteborg, Sweden.) Incipient reproductive isolation between geographic populations of Ophryotrocha labronica (Polychaeta, Dorvilleidae). Zocl. Scripta 1 (5): 207–210, 1972.–The mechanism of sex determination and the incipient reproductive isolation between geographic populations of Ophryotrocha labronica are studied in intra- and interpopulation crosses. Two populations from the Naples area and one from Leghorn are employed in the crosses. The considerable genetic difference between the Leghorn population and any of the Naples populations is reflected in some crossing combinations by changes in sex ratios, by occurrence of individuals with a reduced viability in the progeny, by a decreased mating propensity, and by discrimination of mates from alien populations. It is stated that the changes in sex ratios, the decreased mating propensity, the dwarfed individuals in the progeny, and the preferential mating all reflect the incompatibility of gene complexes. The differences between reciprocal crosses are not fully explained. The occurrence of extranuclear DNA, as well as the existence of a maternal heredity in intrapopulation crosses, indicate that cytoplasmic inheritance may be one of the factors behind these reciprocal differences.     

Y-chromosome DNA Is Present in the Blood of Female Dogs Suggesting the Presence of Fetal Microchimerism

Fetal microchimerism has been suggested to play contradictory roles in women’s health, with factors including age of the recipient, time elapsed since microchimerism occurred, and microchimeric cell type modulating disease. Both beneficial and harmful effects have been identified in wound healing and tissue regeneration, immune mediated disease, and cancer. This area of research is relatively new, and hindered by the time course from occurrence of fetal microchimerism to the multi-factorial development of disease. Dogs represent an excellent model for study of fetal microchimerism, as they share our environment, have a naturally condensed lifespan, and spontaneously develop immune-mediated diseases and cancers similar to their human counterparts. However, fetal microchimerism has not been described in dogs. These experiments sought preliminary evidence that dogs develop fetal microchimerism following pregnancy. We hypothesized that Y chromosomal DNA would be detected in the peripheral blood mononuclear cells of female dogs collected within two months of parturition. We further hypothesized that Y chromosomal DNA would be detected in banked whole blood DNA samples from parous female Golden Retrievers with at least one male puppy in a prior litter. Amplification of DNA extracted from five female Golden Retrievers that had whelped within the two months prior to collection revealed strong positive bands for the Y chromosome. Of banked, parous samples, 36% yielded positive bands for the Y chromosome. This is the first report of persistent Y chromosomal DNA in post-partum female dogs and these results suggest that fetal microchimerism occurs in the canine species. Evaluation of the contributions of fetal microchimeric cells to disease processes in dogs as a model for human disease is warranted.     

FERTILIZATION IN PLUMBAGO ZEYLANICA: GAMETIC FUSION AND FATE OF THE MALE CYTOPLASM

Developmental phases surrounding the processes of gametic delivery and fusion were examined ultrastructurally in the reduced megagametophyte of Plumbago zeylanica, which lacks synergids. Gametic delivery occurs at the end of pollen tube growth and results in deposition of two male gametes, a vegetative nucleus, and a limited amount of pollen cytoplasm between the egg and central cell. Discharge of these materials from the tube is accompanied by loss of inner and outer pollen tube plasma membranes, loss of sperm-associated cell wall components, and disruption of the formerly continuous cell wall between the egg and central cell. The dispersion of egg cell wall components directly exposes female reproductive cell membranes to the unfused male gametes and pollen tube without disrupting gametic cell plasma membranes. Presence of unfused sperms within the female gametophyte appears to be a transitory phenomenon, lasting less than 5 min at the end of over 8½ hr of pollen tube growth. At the time of gametic deposition, plasma membranes of unfused sperm cells become directly appressed to plasma membranes of both the egg and central cell. Gametic fusion is initiated by a single fusion event between membranes of participating male and female cells, which is rapidly followed by subsequent, secondary fusion events between the same two cells at different locations along their surface. Gametic fusion results in the transmission of male gamete nuclei with co-transmission of nearly the entire sperm cytoplasmic volume and organellar complement, and it is possible to identify heritable male cytoplasmic organelles within both the incipient zygote and endosperm. Paternally originating plastids may be distinguished from maternal plastids by differences in morphology and staining characteristics, whereas paternal mitochondria may be distinguished from maternal mitochondria by populational differences in mitochondrial size which are statistically significant. Such observations further indicate that transmitted paternal mitochondria seem to remain viable, as judged by their ultrastructural appearance, and are transmitted exclusively by sperm cytoplasm rather than discharged pollen cytoplasm. The presence of anucleate, membrane-bounded cytoplasmic bodies between the egg and central cell are identifiable on the basis of their enclosed organelles and indicate that fragmentation of a small amount of the sperm cytoplasm associated with the vegetative nucleus commonly occurs. The presence and identification of sperm cytoplasmic organelles and associated membranes within female reproductive cells following gametic transmission represents strong evidence in support of the cellular basis of nuclear and cytoplasmic transmission during sexual reproduction in Plumbago.     

A Genetic Analysis of Hermaphrodite, a Pleiotropic Sex Determination Gene in Drosophila Melanogaster

Sex determination in Drosophila is controlled by a cascade of regulatory genes. Here we describe hermaphrodite (her), a new component of this regulatory cascade with pleiotropic zygotic and maternal functions. Zygotically, her(+) function is required for female sexual differentiation: when zygotic her(+) function is lacking, females are transformed to intersexes. Zygotic her(+) function may also play a role in male sexual differentiation. Maternally, her(+) function is needed to ensure the viability of female progeny: a partial loss of her(+) function preferentially kills daughters. In addition, her has both zygotic and maternal functions required for viability in both sexes. Temperature sensitivity prevails for all known her alleles and for all of the her phenotypes described above, suggesting that her may participate in an intrinsically temperature-sensitive process. This analysis of four her alleles also indicates that the zygotic and maternal components of of her function are differentially mutable. We have localized her cytologically to 36A3-36A11.     

Mechanisms of activation of maternal behaviour in mammals

In mammals, the activation of maternal behaviour depends on internal maternal factors related with parturition. The nature of these factors may vary between species, although oestradiol, foetus expulsion and intracerebral oxytocin are the most commonly encountered. They induce a period of specific receptivity to some sensory cues provided by the neonate. These cues (tactile, olfactory, auditory, ...) also vary between species. The interactions between the mother and her progeny during this period, known as the sensitive period, facilitate the maintenance of maternal responsiveness beyond the initial phase of activation by the factors internal to the mother. The ability of mothers to display a well-adapted maternal behaviour is also modulated by maternal experience gained at the first parturition. Furthermore, this capacity is also influenced by the nature of the interactions experienced in infancy with the own mother of the female, which can lead to a non-genomic transmission of some individual characteristics of maternal behaviour or sensitivity to stress across generations.     

Genetic and Phenogenetic Studies on the Dynamic Nature of the Cytoplasmic Inheritance System in CULEX PIPIENS

Analysis by a progeny test system has permitted the selection for different cytoplasmic sterility factors in two strains of mosquitoes derived from the progeny of a single female. Reciprocal interstrain crosses show full fertility and viability. However, testcrosses to a third cytoplasmic type show highly significant, reproducible differences in the cytoplasmic systems of the selected strains. A direct relationship between teratological growth patterns and the degree of heterozygosity of cytoplasmic factors was observed. In testcrosses, cytoplasmic sterility factors, when selected to homozygosity, produce non-teratological inviable haploid, or exceptional viable gynogenetic diploid larvae. Heterozygosity in the cytoplasmic system in testcrosses produced a broad spectrum of teratological growth patterns related to the degree of heterozygosity of the multiple factors present in the cytoplasm. Formal genetic crosses involving the selected strains show that teratological growth and cytoplasmic sterility, both partial and complete, are inherited through the germ plasm of the maternal parent. This work suggests that the interactions of cytoplasmic factors that result in teratological growth and cytoplasmic sterility may not be restricted to Culex pipiens, where in some cases it is prominent and obvious, but may be a much more general hereditary mechanism of major significance in other eukaryotic animals.