Heredity—Venturing Beyond Genetics

BIOLOGY OF REPRODUCTION 79, 2–8 (2008) Published online before print 9 April 2008. DOI 10.1095/biolreprod.107.065607

Minireview

Marie-Christine Maurel1,2 and Colette Kanellopoulos-Langevin3

Laboratoire de Biochimie de l’Evolution et Adaptabilite´ Mole´culaire2 and Laboratoire des Re´gulations Immunitaires et De´veloppement, Institut Jacques-Monod,3 UMR 7592, CNRS and Universite´s Paris 6 and 7, 75251 Paris Cedex 05, France

ABSTRACT Fertilization is the starting point for the hereditary transmission of the characteristics contained in the maternal Our knowledge of heredity has recently undergone major and paternal gametes. Recently, our knowledge regarding upheaval. Heredity transmits considerably more than just heredity has undergone major upheaval, particularly in light of genetic elements. First, the oocyte is full of maternal cytoplasmic recent studies concerning epigenetic phenomena [1, 2]. Clearly, components that subsequently are present in each new cell. neither the sequence nor the number of genes is sufficient to Second, maternal cells can pass to the progeny, where they explain the complexity of a living organism. One cannot remain active into adult life (microchimerism). Here, we examine the notion that the transmission of characters involves ‘‘calculate’’ the embryo. The term epigenetic, which was coined at least two processes in addition to that of mendelian heredity, in 1953 by Waddington [3], covers the interactions that exist long considered to be the only hereditary mechanism. These between genes and their environment and hereditary modifi- processes all involve epigenetic processes, including the cations other than those based on changes in the nucleotide transmission of macromolecules, subcellular organelles, and sequence. Waddington therefore placed epigenetics at the living cells solely from the mother to her offspring, whether junction between genetics, developmental biology, and ecol- female or male, during pregnancy and lactation. We postulate ogy—all based on evolutionary biology. The concept of that cytoplasmic heredity and maternal transmission of cells epigenetics itself has had ample time to evolve during the last leading to a long-term state of microchimerism in progeny are 50 years, but today, epigenetic studies are being focused on the two good examples of matrilineal, nonmendelian heredity. A influence of internal and external environments on genes and mother’s important contribution to the development and health their products and their effects on cells and organisms [4]. This of her progeny seems to possess many uncharted depths. significantly broadens the concept of heredity, moving it into cytoplasmic heredity, developmental biology, heredity, realms beyond that of the gene-centered neo-Darwinism. immunology, maternal-fetal exchanges, microchimerism, One consequence of the belief that everything is genetic is pregnancy illustrated by the disappearance of what was known previously as embryology, which today has been replaced by develop- INTRODUCTION mental biology. Along the lines of an idea put forward by Canguilhem et al. [5], the term development, which according The hereditary transmission of characters brings into play at to its etymology means the unrolling or unfolding of something least three types of processes. One, mendelian heredity, is well that is already present (i.e., preformed), does not, in fact, known. Two others involve transmission of characters from the correctly represent the process it is meant to describe. Today, mother to both male and female offspring. The first of these, developmental biology focuses on genes, with the environment cytoplasmic heredity, another well-established process, has being perceived as a background—that is, a context that made it possible to identify our common female ancestor. The provides the necessary conditions, just as a photographic film second and more recently examined, microchimerism, or is the background that expresses the latent image when dipped maternal-fetal exchange of cells, has been suggested to be into a chemical solution (i.e., developer). involved in tissue repair and/or immune dysregulation. The In the 17th century, the preformationists often depicted the present paper is not an extensive review of the state of the art in spermatozoon with a miniature, fully formed human (in a fetal any of these three domains; rather, it brings this knowledge into position) inside [6]. The preformationists considered that once a novel and wider perspective—namely, the until-now under- this homunculus had been deposited in a cavity (i.e., the evaluated role of the mother in the hereditary transmission of uterus), it simply had to increase in size, with the egg of the characters. mother merely supplying the nutrients necessary for its growth. This is why, if one takes a conceptual shortcut, the entire future 1Correspondence: Marie-Christine Maurel, Laboratoire de Biochimie organism could be said to be contained within the information de l’Evolution et Adaptabilite´ Mole´culaire, UMR 7592, CNRS and carried by the DNA. In this context, the egg grows and Universite´s Paris 6 and 7, Tour 43, 2 place Jussieu, 75251 Paris Cedex differentiates in the uterus, which thus becomes a passive 05,France.FAX:33144279916;e-mail: [email protected] repository—a theory that some scientists (and the novelist Aldous Huxley in Brave New World [7]) have used to imagine Received: 14 September 2007. the possibility of an artificial uterus. In his book The Selfish First decision: 8 October 2007. Accepted: 30 January 2008. Gene, Dawkins [8] theorizes that a self-sufficient gene has only Ó 2008 by the Society for the Study of Reproduction, Inc. one aim—namely, to locate the proper vehicle that will ensure ISSN: 0006-3363. http://www.biolreprod.org its perpetuation. Linking these ideas, many evolutionists 2 HEREDITY—VENTURING BEYOND GENETICS 3

FIG. 1. Three main paths of heredity.

consider the body to be this vehicle for molecules to transmit heredity). Characters are transmitted to both male and female and reproduce the information they contain. If this is so, offspring by the mother, however, via at least two other however, what of the major concepts of evolution, such as processes, cytoplasmic heredity and microchimerism. coevolution, conjugation, symbiosis, and sexual reproduction, one of the major transitions in biological evolution? THE FIRST PATH: MENDELIAN (NUCLEAR) HEREDITY In their nucleus, human germinal cells contain 46 AT LEAST THREE TYPES OF HEREDITY chromosomes (22 pairs of autosomes and two sex chromo- The human body is composed of a million billion cells—at somes). Chromosomes contain DNA, the chemical component least a thousand times as many as the total number of stars in of genes. Often, DNA is compared to a book of instructions—a the galaxy. The 1015 cells all derive from one cell, the fertilized vast encyclopedia written in a coded language read by the cell, egg, which is formed by the encounter between a female oocyte which then transforms the material found in its environment to and the male spermatozoon. produce a living being. In each cell, within a pair of The fertilized egg divides into embryonic totipotent cells chromosomes, one chromosome comes from the mother and that are capable of participating in the formation of all types of one from the father. The pair of sex chromosomes is XX for the tissue, ultimately producing a complete, unique organism that female and XY for the male. Sex is determined genetically and, will bear the hereditary characteristics of its two parents. This in turn, determines the nature of the gonads—that is, the series of events reveals a transition between two periods—one primary sex characteristics (e.g., ovaries or testicles). In the that depends essentially on factors stored within the oocyte female, only one X chromosome is functional in somatic cells; (i.e., factors that make up the maternal heritage), followed by the other X chromosome remains a highly condensed, another that results from the activity of the newly formed heterochromatic seed, which is known as the Barr body [9]. genome built from the two parental genomes. This inactivation of the X chromosome is a genetically The fertilized egg possesses all the components of the controlled event that involves epigenetic regulation of sex translational apparatus in amounts sufficient to perform the first chromosome gene expression [10]. Interestingly, we now know rounds of protein synthesis. Thus, after fertilization, the that certain genes contained in this second X chromosome are cytoplasm of the oocyte itself is what constitutes the initial expressed and, therefore, that this chromosome is not cytoplasm of the embryo. completely silent. The transmission of characters brings into play several Genetically, the X and Y chromosomes are completely processes or paths (Fig. 1), one of which relies on the well- different from each other. A gene in an X chromosome has no known mechanism of mendelian inheritance (i.e., nuclear homologous counterpart in a Y chromosome, and vice versa. 4 MAUREL AND KANELLOPOULOS-LANGEVIN

The human X chromosome (165 Mb) harbors approximately during the first stages of development, our metabolic system, 1000 genes with a variety of functions [11]. In the ribbed newt which both allows and regulates nutritional, energetic, and (Pleurodeles sp.), the chromosomal composition is ZZ for respiratory exchanges, originates from that of the mother. At an males and ZW for females; the W chromosome bears the evolutionary level, Ohno [16] underlines the strictly maternal factors for female sex determination. In humans, numerous inheritance of the mitochondrial genome in each mammalian factors are responsible for genetic sex determination. Some are species. located in the autosomes, and the X chromosome contains sex- Moreover, by studying this mitochondrial DNA, we can and reproduction-related genes [12]. The equilibrium and level trace back some 150 000 years the origins of Man (Homo of expression of certain autosomal and/or heterochromosomal sapiens sapiens)—or, to be more precise, the origins of genes are believed to play an important role in sex Woman. The more stable mitochondrial DNA is less prone to determination. mutation, so it has been possible to identify our common At 60 Mb, the human Y chromosome is much smaller than ancestor by matrilineal descent, as demonstrated by the studies the human X chromosome, and it contains few genes. It of Cann et al. [17] as well as Cavalli-Sforza and Minch [18]. encodes 45 unique proteins with functions regarding sex or Oocytic factors other than mitochondria have been shown to fertility [13]. The presence of a Y chromosome (with its SRY have a transgenerational influence [19]. Roemer et al. [20] were gene) determines the masculinization of the embryonic gonad. the first to present evidence in mice for the epigenetic Ohno [14] proposes that sex chromosomes evolved from a pair inheritance of specific alterations of gene expression through of autosomes. The origin of the human XY pair can be traced the germline. These alterations are triggered by pronuclear back by comparison to related mammals and other vertebrates. transfer at the one-cell stage. Furthermore, the importance of As a result of the heterology of the X and Y chromosomes, cytoplasmic factors in the development of transplanted nuclei recessive characters coded by the X chromosome are expressed was demonstrated in elegant experiments carried out by Sun et differently in the two sexes. In males, a recessive allele carried al. [21] with two different species of fish. by the X chromosome has no homologous counterpart in the Y Subsequently, nuclear transfer experiments have empha- chromosome and, therefore, is expressed. In females, this allele sized the significant role of the maternal cytoplasmic is only expressed in homozygotes. The frequently quoted environment in the reprogramming of the sperm, but not the examples, such as daltonism (i.e., color blindness) and oocyte, genome [22, 23]. Moreover, recent studies that hemophilia (i.e., defective blood coagulation), result from analyzed the effects of environment (e.g., maternal lifestyle mutations in genes carried by the X chromosome. All or low food supply) on early embryonic development have heterozygous females who carry these mutated genes will shown that these effects can last for several generations (for have a normal phenotype and be apparently healthy, but one in review, see Gluckman and Hanson [24]). two of their sons will carry the mutated phenotype, regardless of whether the father’s chromosome is normal. Indeed, the X THE THIRD PATH: MOSAIC HEREDITY chromosome of a male is always inherited from the mother; consequently, the disease only appears in sons. In vision, for Microchimerism corresponds to the presence of two instance, a protein pigment, rhodopsin, enables the rod cells in genetically distinct cell populations within one organism. In the retina to distinguish black and white, whereas cone cells are other words, low concentrations of the cells of one individual responsible for color vision thanks to three rhodopsins that are are contained in a given organ of another individual. sensitive to red, green, and blue light, respectively. In humans, Although the fetal and maternal blood circulations are this trichromatic vision makes it possible to distinguish separate, numerous studies have demonstrated the passage of approximately 200 different colors. The genes coding for the cells across the maternal-fetal interface, in both directions, in green and red opsins are located in one region of the X both humans and mice (Fig. 2). Other sources of micro- chromosome. Thus, abnormalities in this region of the chimerism include blood transfusions and organ transplants chromosome will be transmitted with the X chromosome, (i.e., grafts). In humans, the passage of fetal cells or DNA into leading to daltonism. On the positive side, however, various the maternal circulation was first detected by procedures evolutionary stages of the genetic system of rhodopsins exist in originally designed to provide noninvasive methods for primates, which suggests that genetic recombinations on the X prenatal genetic diagnosis [25–28]. Transfer of fetal cells to chromosome one day might constitute the starting point for the mother occurs in most, if not all, normal pregnancies and quadrichromatic vision (i.e., blue, red, green, and red/green) in can be observed from the fourth month of pregnancy onward. humans, which at present is inconceivable. Fetal cells have been detected in all types of maternal tissues, including the spinal cord, skin, lungs, thyroid gland, liver, intestine, lymph nodes, and blood vessels [29]. Interestingly, THE SECOND PATH: CYTOPLASMIC HEREDITY fetal cells have even been detected in maternal blood up to 27 In addition to the nucleus, the oocyte contains the years after the birth of the last child [30]. Such microchimerism cytoplasm, in which organelles, such as mitochondria, are persists throughout life [31], and a role in the development of located. Mitochondria are the factories that produce the energy adult autoimmune diseases in the female has been proposed of the cells through aerobic respiration. They possess their own [32–35]. genome, which is circular and single-stranded, like those of Conversely, the transfer of maternal DNA [36, 37], prokaryotes with asexual reproduction. They are themselves antibodies [38], or nucleated cells [39–42] into the fetal derived from an ancient, aerobic, purple eubacterium that today circulation and organs [43] also has been described. If maternal lives endosymbiotically with a larger cell [15]. Consequently, antibodies are important to confer protective immunity on the they possess their own matrix and their own DNA. They newborn, it appears that in some cases, specific maternal multiply by rapid divisions (;1 min), and their volume antibodies might induce in the progeny diseases such as occupies 10–40% of the cell. autoimmune ovarian disease or autoimmune diabetes [44, 45]. It is important to emphasize that the 250 000 mitochondria Therefore, maternal microchimerism seems to have benefits as contained in the egg all originate from the oocyte and are well as potentially harmful repercussions. The presence of transmitted directly to the fetus, whether female or male. Thus, maternal leukocytes in the fetal circulation might be a HEREDITY—VENTURING BEYOND GENETICS 5

FIG. 2. Maternal-fetal interface and migration of maternal cells to placenta in mouse pregnancy. Tg(ACTB-EGFP)1Osb (Tg) B6 females were mated with non-Tg B6 males. Placentas from non-Tg offspring were harvested at 10–12 days postcoitum (dpc; A–C), 13–16 dpc (D–F), or 17–19 dpc (G–I) and then cryosectioned (6 lm sec- tions) and stained with Hoechst (Sigma). Arrowheads show maternal cells present in the fetal part of the placenta. D, Decidua; F, fetal part of the placenta; gc, giant cells (secondary); lab, labyrinth; M, maternal decidua and uterus; sp, spongiotrophoblast. Bar ¼ 100 lm(A, D, and G) and 50 lm(B, C, E, F, H, and I). (Reprinted from Vernochet et al. [55]. Copyright 2007, with permission from Elsevier.)

significant risk when umbilical cord blood is used for bone In 1988, Claas et al. [62] observed that 50% of highly marrow transplantation [31, 46, 47]. The transmission of sensitized patients, waiting for a renal allograft and producing maternal cells also could be responsible for the vertical transfer anti-human leukocyte antigen (HLA) antibodies that react to of infectious agents, such as human immunodeficiency virus virtually all donors, do not form antibodies to NIMAs. In 1998, type 1 [48, 49]. Engraftment of maternal cells has been Burlingham et al. [63] studied the outcome of kidney reported in immunodeficient children [50, 51] as well as transplantations between haplo-identical siblings. Those au- normal offspring, in whom maternal cells can persist for thors found that the graft survival of kidneys donated by haplo- decades [52]. It has been postulated that these maternal cells play a role in the pathogenesis of juvenile inflammatory myopathies [53]. Microchimerism can have various origins. It can derive from cells that have already been passed on to the mother by the grandmother or by the fetuses of previous pregnancies. Transfer of maternal cells also can occur during breast-feeding; in this case, maternal cells can infiltrate the progeny via the digestive tract. The organism therefore contains genetically different cells that consequently express foreign antigens [54, 55]. In most cases, microchimeric cells are tolerated perfectly well and produce no illnesses [56] for reasons we are just beginning to understand: Most probably, in vivo regulatory mechanisms prevent cells from being activated and harming the host [57–59]. The migration of maternal cells into the fetus can induce a state of tolerance to its noninherited maternal antigens (NIMAs) and contribute to the partial immunological tolerance observed in the adult [60]. Regarding hemolytic anemia of the newborn because of Rh incompatibility, approximately 5% of Rh-negative women carrying Rh-positive fetuses produce anti-Rh antigen antibodies that induce the destruction or lysis of fetal red blood cells. FIG. 3. NIMA effect on transplantation tolerance: graft survival in Among the Rh-negative women who do not produce hemolytic recipients of kidney transplants from HLA-identical sibling donors and antibodies, many have an Rh-positive mother. Consequently, from sibling donors mismatched for one HLA haplotype. The donors mismatched for one HLA haplotype expressed either maternal (NIMA) or these mothers do not cause the disease in their offspring, paternal (NIPA) HLA antigens not inherited by the recipient. (Reprinted because they have become unresponsive or tolerant to the Rh from [57] van den Boogaardt et al. [57]. Copyright 2005, with permission antigen, which is a NIMA [61]. from the Massachusetts Medical Society. All rights reserved.) 6 MAUREL AND KANELLOPOULOS-LANGEVIN identical siblings mismatched for the NIMA haplotype was as infections caught during childhood shape the immune similar to that of kidneys donated by HLA-identical siblings. system and, possibly, steer it away from allergic reactions. A more recent study by Andrassy et al. [64] showed that These maternal cells, which are present in small numbers (on mice exposed to noninherited maternal H2-D1 alloantigens the order of one or fewer maternal cell per 105 cells), might tolerated heart or skin grafts bearing H2-D1 alloantigens much have beneficial as well as harmful effects in the progeny, such longer than control animals that were not exposed to NIMA as the induction of tolerance to specific transplantation antigens H2-D1 (Fig. 3) [64]. Those authors suggested that exposure to (i.e., NIMAs) or a shift in the balance toward autoimmunity, NIMAs during gestation and suckling inhibited anti-NIMA T- respectively. cell responses in the offspring, thus predisposing to NIMA- Second, this type of microchimerism affects the progeny’s specific transplantation tolerance as an adult. This hypothesis immune system and may have participated in the evolution of implies that the progeny’s immune repertoire and reactivity are the mammalian immune system. Before one can speculate on shaped not only via genetically inherited maternal and paternal its overall importance from an evolutionary point of view, major histocompatibility complex antigens but also via NIMAs however, microchimerism needs to be studied in several borne by maternal cells entering the offspring during life in different species and its physiological roles better understood. utero or through milk during suckling. Genetically modified Third, a somatic maternal form of heredity exists, the mice provide useful experimental models to dissect the cellular functional and evolutionary traces of which are to be found in and molecular mechanisms underlying the induction and mitochondria and in maternal-fetal transfers. This concept maintenance of the so-called NIMA effect [53, 64]. needs to be further studied and developed to establish the These observations should have beneficial clinical applica- conceptual and conceptional contributions of maternal heredity tions in the field of organ transplants. For instance, once the to genealogical transmission. mechanisms involved are elucidated, one could conceivably To conclude, we are now in a position to challenge the mimic the NIMA effect in a recipient about to receive a dogma according to which everything is genetic and the transplant to induce a specific unresponsiveness to the donor transmission of the ‘‘selfish’’ gene is monolithic and vertical. antigens, thus leaving the other protective immune responses Heredity transmits considerably more than just genetic unaffected. elements; it also entails mitochondrial inheritance, cytoplasmic Finally, microchimerism might be involved in tissue repair. influences, and maternal cell transmission which leads to a The presence of maternal cells in tissues of the offspring raises long-term state of microchimerism. We would like to important questions concerning the benefits of such micro- emphasize that all the mechanisms of hereditary transmission chimerism during both development and adult life. Certain discussed in the present paper can be strongly influenced by authors suggest that these maternal cells might help in tissue epigenetic processes. These considerations shed new light on repair and with resistance to infections. For instance, Nelson et the relevance of recent, highly publicized scientific projects al. [65] reported that maternal microchimerism contributes to involving the transplantation of human nuclei into animal (i.e., functional and tissue repair processes in the pancreas. bovine) cytoplasms. Such embryonic chimeras are likely to be Rinkevich [66] proposed that microchimerism participates in significantly different from whole human embryos—and their growth, development, and immunological ‘‘apprenticeship.’’ study to be less useful than expected. Such phenomena also might explain, in part, how maternal The novel view of heredity presented in this paper opens immunization against oxidized, low-density lipoproteins before exciting horizons in many fields, and the potential applications pregnancy protects the progeny from atherosclerosis in adult are numerous. Perhaps in the future, the fantasy of physiolog- life [67]. Consequently, to the well-studied concept regarding ical self-repair might even become a reality. transfer of protective immunity from mother to child, one should add that of a maternal contribution to the regulation of ACKNOWLEDGMENTS immune functions in the progeny, a phenomenon that is We are indebted to Dr. Anne-Lise Haenni, Dr. Giuseppe Zaccai, Prof. overlooked at present. Michel Vervoort, and Dr. Evani Viegas-Pequignot for helpful discussions, Martine Dombrosky for Figure 1, and to Antonia Kropfinger for revising CONCLUSION the manuscript. We are grateful to our past and present collaborators for their work and stimulating exchanges. Our working hypothesis is based on evidence that heredity transmits considerably more than just genetic elements and that REFERENCES the cytoplasm of the oocyte is full of maternal cytoplasmic components subsequently present in each new cell. Interest- 1. Pigliucci M. Epigenetics is back! Hsp90 and phenotypic variation. Cell Cycle 2003; 2:34–35. ingly, maternal cytoplasmic components play an important role 2. Queitsch C, Sangster TA, Lindquist S. Hsp90 as a capacitor of phenotypic in the reprogramming of the sperm genome [22]. Moreover, variation. Nature 2002; 6:618–624. Sun et al. [21] emphasized the significant influence that the egg 3. Waddington CH. Epigenetics and evolution. In: Brown R, Danielli JF cytoplasm can have on the development of transplanted nuclei. (eds.), Evolution. SEB Symposium VII. Cambridge, UK: Cambridge Those authors produced cross-genus cloned fish by transferring University Press; 1953:186–199. carp nuclei into goldfish enucleated eggs. Subsequently, these 4. Jablonka E, Lamb MJ. The changing concept of epigenetics. Ann N Y Acad Sci 2002; 981:82–96. cloned fish presented somite development and numbers 5. Canguilhem G, Lapassade G, Piquemal J, Ulmann J. Du de´veloppement a` consistent with those of the goldfish recipient species, but l’e´volution au XIXe`me sie`cle. Paris: Presses Universitaires de France, not with those of the carp nucleus donor. Considerable 1962. quantities of enzymes, ribosomes, RNA, and so on are 6. Hartsoeker N. Essai de Dioptrique. Paris: J. Anisson, 1694. transmitted intact from one generation to the next, and 7. Huxley A. Brave New World. London: Harper Perennial Modern Classics; increasing clinical and experimental evidence supports the 1932. following hypotheses. 8. Dawkins R. The Selfish Gene. New York: Oxford University Press; 1989. 9. Ng K, Pullirsch D, Leeb M, Wutz A. Xist and the order of silencing. First, the presence of maternal cells in the embryo, fetus, or EMBO Rep 2007; 8:34–39. neonate—cells that later are found in the descendants—plays a 10. Clerc P, Avner P. Random X-chromosome inactivation: skewing lessons role in the acquisition of a variety of immune mechanisms, just for mice and men. Curr Opin Genet Dev 2006; 16:246–253. HEREDITY—VENTURING BEYOND GENETICS 7

11. Graves JAM. Sex chromosome specialization and degeneration in amplification of the noninherited maternal HLA gene. Blood 1996; 88: mammals. Cell 2006; 124:901–914. 1494–1500. 12. Saifi GM, Chandra HS. An apparent excess of sex- and reproduction- 38. Adeniyi-Jones SC, Ozato K. Transfer of antibodies directed to paternal related genes on the human X chromosome. Proc R Soc Lond B Biol Sci major histocompatibility class I antigens from pregnant mice to the 1999; 266:203–209. developing fetus. J Immunol 1987; 138:1408–1415. 13. Lahn BT, Page DC. Four evolutionary strata on the human X 39. Shimamura M, Ohta S, Suzuki R, Yamazaki K. Transmission of maternal chromosome. Science 1999; 286:964–967. blood cells to the fetus during pregnancy: detection in mouse neonatal 14. Ohno S. Sex chromosomes and sex linked genes. New York: Springer- spleen by immunofluorescence flow cytometry and polymerase chain Verlag; 1967. reaction. Blood 1994; 83:926–930. 15. John P. Mitochondrial regulation of cell surface components in relation to 40. Piotrowski P, Croy BA. Maternal cells are widely distributed in murine carcinogenesis. J Theor Biol 1984; 110:377–381. fetuses in utero. Biol Reprod 1996; 54:1103–1110. 16. Ohno S. The one ancestor per generation rule and three other rules of 41. Zhou L, Yoshimura Y, Huang Y, Suzuki R, Yokoyama M, Okabe M, mitochondrial inheritance. Proc Natl Acad Sci U S A 1997; 94:8033– Shimamura M. Two independent pathways of maternal cell transmission 8035. to offspring: through placenta during pregnancy and by breastfeeding after 17. Cann RL, Stoneking M, Wilson AC. Mitochondrial DNA and human birth. Immunology 2000; 101:570–580. evolution. Nature 1987; 325:31–36. 42. Marleau AM, Greenwood JD, Wei Q, Singh B, Croy BA. Chimerism of 18. Cavalli-Sforza LL, Minch E. Paleolithic and neolithic lineages in the murine fetal bone marrow by maternal cells occurs in late gestation and European mitochondrial gene pool. Am J Hum Genet 1997; 61:247–251. persists into adulthood. Lab Invest 2003; 83:673–681. 19. Heasman J. Maternal determinants of embryonic cell fate. Semin Cell Dev 43. Srivatsa B, Srivatsa S, Johnson KL, Bianchi DW. Maternal cell Biol 2006; 17:93–98. microchimerism in newborn tissues. J Pediatr 2003; 142:31–35. 20. Roemer I, Reik W, Dean W, Klose J. Epigenetic inheritance in the mouse. 44. Setiady YY, Samy ET, Tung KS. Maternal autoantibody triggers de novo Curr Biol 1997; 7:277–280. T cell-mediated neonatal autoimmune disease. J Immunol 2003; 170: 21. Sun YH, Chen SP, Wang YP, Hu W, Zhu ZY. Cytoplasmic impact on 4656–4664. cross-genus cloned fish derived from transgenic common carp (Cyprinus 45. Greeley SA, Katsumata M, Yu L, Eisenbarth GS, Moore DJ, Goodarzi H, carpio) nuclei and goldfish (Carassius auratus) enucleated eggs. Biol Barker CF, Naji A, Noorchashm H. Elimination of maternally transmitted Reprod 2005; 72:510–515. autoantibodies prevents diabetes in nonobese diabetic mice. Nat Med 22. Jaenisch R. Human cloning—the science and ethics of nuclear 2002; 8:399–402. transplantation. N Engl J Med 2004; 351:2787–2791. 46. Hall JM, Lingenfelter P, Adams SL, Lasser D, Hansen JA, Bean MA. 23. Yang X, Smith SL, Tian XC, Lewin HA, Renard J-P, Wakayama T. Detection of maternal cells in human umbilical cord blood using Nuclear reprogramming of cloned embryos and its implications for fluorescence in situ hybridization. Blood 1995; 86:2829–2832. therapeutic cloning. Nat Genet 2007; 39:296–302. 47. Socie G, Gluckman E, Carosella E, Brossard Y, Lafon C, Brison O. Search 24. Gluckman PD, Hanson MA. Living with the past: evolution, development, for maternal cells in human umbilical cord blood by polymerase chain and patterns of disease. Science 2004; 305:1733–1736. reaction amplification of two minisatellite sequences. Blood 1994; 83: 25. Bianchi DW, Flint AF, Pizzimenti MF, Knoll JH, Latt SA. Isolation of 340–344. fetal DNA from nucleated erythrocytes in maternal blood. Proc Natl Acad 48. Sprecher S, Soumenkoff G, Puissant F, Degueldre M. Vertical Sci U S A 1990; 87:3279–3283. transmission of HIV in 15-week fetus. Lancet 1986; ii:288–289. 26. Herzenberg LA, Bianchi DW, Schroder J, Cann HM, Iverson GM. Fetal 49. Schwartz DH, Sharma UK, Perlman EJ, Blakemore K. Adherence of cells in the blood of pregnant women: detection and enrichment by human immunodeficiency virus-infected lymphocytes to fetal placental fluorescence-activated cell sorting. Proc Natl Acad Sci U S A 1979; 76: cells: a model of maternal fetal transmission. Proc Natl Acad Sci U S A 1453–1455. 1995; 92:978–982. 27. Little MT, Langlois S, Wilson RD, Lansdorp PM. Frequency of fetal cells 50. Geha RS, Reinherz E. Identification of circulating maternal T and B in sorted subpopulations of nucleated erythroid and CD341 hematopoietic lymphocytes in uncomplicated severe combined immunodeficiency by progenitor cells from maternal peripheral blood. Blood 1997; 89:2347– HLA typing of subpopulations of T cells separated by the fluorescence- 2358. activated cell sorter and of Epstein Barr virus-derived B cell lines. J 28. Lo YM, Tein MS, Lau TK, Haines CJ, Leung TN, Poon PM, Wainscoat Immunol 1983; 130:2493–2495. JS, Johnson PJ, Chang AM, Hjelm NM. Quantitative analysis of fetal 51. Knobloch C, Goldmann SF, Friedrich W. Limited T cell receptor diversity DNA in maternal plasma and serum: implications for noninvasive prenatal of transplacentally acquired maternal T cells in severe combined diagnosis. Am J Hum Genet 1998; 62:768–775. immunodeficiency. J Immunol 1991; 146:4157–4164. 29. Nguyen Huu S, Oster M, Uzan S, Chareyre F, Aractingi S, Khosrotehrani 52. Maloney S, Smith A, Furst DE, Myerson D, Rupert K, Evans PC, Nelson K. Maternal neoangiogenesis during pregnancy partly derives from fetal JL. Microchimerism of maternal origin persists into adult life. J Clin Invest endothelial progenitor cells. Proc Natl Acad Sci U S A 2007; 104:1871– 1999; 104:41–47. 1876. 53. Artlett CM, Ramos R, Jiminez SA, Patterson K, Miller FW, Rider LG. 30. Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, DeMaria MA. Male Chimeric cells of maternal origin in juvenile idiopathic inflammatory fetal progenitor cells persist in maternal blood for as long as 27 years myopathies. Childhood Myositis Heterogeneity Collaborative Group. postpartum. Proc Natl Acad Sci U S A 1996; 93:705–708. Lancet 2000; 356:2155–2156. 31. Lo YMD, Lo ESF, Watson N, Noakes L, Sargent IL, Thilaganathan B, 54. Vernochet C, Caucheteux SM, Gendron MC, Wantyghem J, Kanellopou- Wainscoat JS. Two-way cell traffic between mother and fetus: biological los-Langevin C. Affinity-dependent alterations of mouse B cell develop- and clinical implications. Blood 1996; 88:4390–4395. ment by noninherited maternal antigen. Biol Reprod 2005; 72:460–469. 32. Kuroki M, Okayama A, Nakamura S, Sasaki T, Murai K, Shiba R, 55. Vernochet C, Caucheteux SM, Kanellopoulos-Langevin C. Bidirectional Shinohara M, Tsubouchi H. Detection of maternal-fetal microchimerism in cell trafficking between mother and fetus in mouse placenta. Placenta the inflammatory lesions of patients with Sjogren’s syndrome. Ann Rheum 2007; 28:639–649. Dis 2002; 61:1041–1046. 56. Nelson JL. Microchimerism in human health and disease. Autoimmunity 33. Evans PC, Lambert N, Maloney S, Furst DE, Moore JM, Nelson JL. Long- 2003; 36:5–9. term fetal microchimerism in peripheral blood mononuclear cell subsets in 57. van den Boogaardt DE, van Miert PP, Koekkoek KM, de Vaal YJ, van healthy women and women with scleroderma. Blood 1999; 93:2033–2037. Rood JJ, Claas FH, Roelen DL. No in vitro evidence for a decreased 34. Artlett CM, Smith JB, Jimenez SA. Identification of fetal DNA and cells in alloreactivity toward noninherited maternal HLA antigens in healthy skin lesions from women with systemic sclerosis. N Engl J Med 1998; individuals. Hum Immunol 2005; 66:1203–1212. 338:1186–1191. 58. Ichinohe T, Teshima T, Matsuoka K, Maruya E, Saji H. Fetal–maternal 35. Klintschar M, Schwaiger P, Mannweiler S, Regauer S, Kleiber M. microchimerism: impact on hematopoietic stem cell transplantation. Curr Evidence of fetal microchimerism in Hashimoto’s thyroiditis. J Clin Opin Immunol 2005; 17:546–552. Endocrinol Metab 2001; 86:2494–2498. 59. Matsuoka K, Ichinohe T, Hashimoto D, Asakura S, Tanimoto M, Teshima 36. Lo YM, Lau TK, Chan LY, Leung TN, Chang AM. Quantitative analysis T. Fetal tolerance to maternal antigens improves the outcome of allogeneic of the bidirectional fetomaternal transfer of nucleated cells and plasma bone marrow transplantation by a CD4þ CD25þ T-cell-dependent DNA. Clin Chem 2000; 46:1301–1309. mechanism. Blood 2006; 107:404–409. 37. Scaradavou A, Carrier C, Mollen N, Stevens C, Rubinstein P. Detection of 60. van Rood JJ, Claas F. Both self and noninherited maternal HLA antigens maternal DNA in placental/umbilical cord blood by locus-specific influence the immune response. Immunol Today 2000; 21:269–273. 8 MAUREL AND KANELLOPOULOS-LANGEVIN

61. Owen RD, Wood HR, Foord AG, Sturgeon P, Baldwin LG. Evidence for Burlingham WJ. Tolerance to noninherited maternal MHC antigens in actively acquired tolerance to Rh antigens. Proc Natl Acad Sci U S A mice. J Immunol 2003; 171:5554–5561. 1954; 40:420–424. 65. Nelson JL, Gillepsie KM, Lambert NC, Stevens AM, Loubiere LS, 62. Claas FH, Gijbels Y, van der Velden-de Munck J, van Rood JJ. Induction Rutledge JC, Leisenring WM, Erickson TD, Yan Z, Mullarkey ME, of B cell unresponsiveness to noninherited maternal HLA antigens during Boespflug ND, Bingley PJ. Maternal microchimerism in peripheral blood fetal life. Science 1988; 241:1815–1817. in type 1 diabetes and pancreatic islet (beta) cell microchimerism. Proc 63. Burlingham WJ, Grailer AP, Heisey DM, Claas FH, Norman D, Natl Acad Sci U S A 2007; 104:1637–1642. Mohanakumar T, Brennan DC, de Fijter H, van Gelder T, Pirsch JD, Sollinger HW, Bean MA. The effect of tolerance to noninherited maternal 66. Rinkevich B. Human natural chimerism: an acquired character or a vestige HLA antigens on the survival of renal transplants from sibling donors. N of evolution? Hum Immunol 2001; 62:651–657. Engl J Med 1998; 339:1657–1664. 67. Yamashita T, Freigang S, Eberle C, Pattison J, Gupta S, Napoli C, Palinski 64. Andrassy J, Kusaka S, Jankowska-Gan E, Torrealba JR, Haynes LD, W. Maternal immunization programs postnatal immune responses and Marthaler BR, Tam RC, Illigens BM, Anosova N, Benichou G, reduces atherosclerosis in offspring. Circ Res 2006; 99:51–64.