1 Department of Dermatology, Tenon Hospital and UPRES EA2396, Saint-Antoine School of Medicine, Pierre et Marie Curie (Paris VI) University, 75020 Paris, France
2 Division of Genetics, Tufts-New England Medical Center, 750 Washington St, Boston, MA 02111, USA
* Author for correspondence (e-mail: dbianchi{at}tufts-nemc.org)
![]() |
Summary |
---|
Key words: Stem cells, Pregnancy, Fetus, Fetal cell microchimerism, Pregnancy-associated progenitor cells
![]() |
Introduction |
---|
Here we discuss recent findings that suggest that, in all pregnancies, fetal cells that have stem-cell-like properties are transferred into maternal blood. We hypothesize that these cells, which we term pregnancy-associated progenitor cells (PAPCs), persist after delivery in a maternal stem cell niche and, in the case of tissue injury, home to the damaged organ and differentiate as part of the maternal repair response.
![]() |
Fetal cells circulate during pregnancy |
---|
![]() |
Factors that influence the transfer of fetal cells during and after pregnancy |
---|
The number of fetal cells in the maternal circulation is affected by fetal and placental abnormalities. There is increased fetomaternal cell transfer in cases of fetal aneuploidy (Bianchi et al., 1997), maternal preeclampsia (Holzgreve et al., 1998
) or following terminations of pregnancy (Bianchi et al., 2001
). In the latter case, in the second trimester, the number of fetal cells in the maternal circulation before and after a termination increases from 19 to 1500/16 mL of maternal whole blood.
A woman's reproductive history is also important. By systematically analyzing all published cases of microchimerism that described the study subjects' individual reproductive histories, we observed that a prior history of fetal loss (either miscarriage or termination) significantly increases the chance that fetal cells can be detected in that woman's organs (Khosrotehrani et al., 2003a). Women who have a history of fetal loss are 2.4 times more likely to exhibit fetal cell microchimerism than are women with no history of fetal loss. Unfortunately, our meta-analysis cannot distinguish between natural and voluntary pregnancy loss in the published literature. There may be significant differences in the incidence of microchimerism between these scenarios. Other variables, such as the number of pregnancies, do not appear to influence the persistence of fetal cells significantly. The increased microchimerism following fetal loss is probably due either to increased transfusion of fetal cells at the time of loss or to the transfer of a cell type that is at an earlier developmental stage and thus more likely to engraft in the mother.
Another factor that might influence the presence of microchimerism is the length of time that has elapsed since completion of pregnancy. Several studies have suggested that fetal cells are not detectable in women with younger sons (Bianchi et al., 1996; Filho et al., 2002
).
![]() |
Fetal stem cells are transferred during pregnancy from the fetus to the mother |
---|
During the first trimester of pregnancy, fetal blood also contains mesenchymal stem cells (MSCs) (Campagnoli et al., 2001), which were initially described in adult bone marrow. Microchimeric fetal MSCs have been isolated from the peripheral blood of an adult woman following termination of pregnancy (O'Donoghue et al., 2003
). Fetal stem cells thus seem to enter the maternal circulation during pregnancy and persist in niches such as bone marrow.
![]() |
Do fetal cells cause autoimmune disease? |
---|
|
![]() |
Does the fetus `treat' its mother? |
---|
Similarly, a study of biopsy material from 29 women with thyroid disorders revealed fetal microchimeric cells in women with Hashimoto's disease as well as other non-immune thyroid disorders (Srivatsa et al., 2001). An unexpected result was the detection of large numbers of male fetal cells in an otherwise healthy woman who had a benign thyroid adenoma. DNA probes that map to the X and Y chromosomes showed that mature follicles from the woman's thyroid were partly male and partly female. She had no other potential sources of microchimeric cells: she had never been transfused, had never had an organ transplant, and was not a twin.
More systematic studies have examined the phenotypes of fetal microchimeric cells from patients who have high numbers of such cells by combining in situ hybridization to detect the fetal cells and immunolabeling to identify their phenotype (Khosrotehrani et al., 2003b). In epithelial tissues such as thyroid, cervix, gallbladder or intestine, 14-60% of the fetal cells express epithelial markers such as cytokeratin (Fig. 1). In the liver, 4% of the fetal microchimeric cells have a hepatocytic phenotype (Khosrotehrani et al., 2004a
). Most of the other fetal microchimeric cells in these tissues express CD45, the common leukocyte antigen, indicating a likely hematopoietic origin. Similarly, 90% of the fetal cells detected in maternal hematopoietic tissues, such as spleen or lymph node, express CD45. In all cases, the morphology of the fetal cells suggests that they have differentiated. In addition, in sections containing diseased and healthy thyroid tissue, the fetal cells more frequently express cytokeratin if they are in the diseased area of the thyroid. These results suggest that fetal cells, possibly hematopoietic in origin, home to the site of injury and adopt the maternal local tissue phenotype. Whether the fetal cells actually differentiate or fuse with the damaged host cells remains an open question. However, using chromosome-specific probes and FISH analysis, we have never observed the tetraploid signals that would be consistent with such fusion. We therefore conclude that, among the fetal cells transferred to the mother during pregnancy, some have multi-lineage capacity. We term these PAPCs.
|
![]() |
Cellular origin of the PAPCs |
---|
Another possible origin of the PAPCs could be MSCs. Recently, O'Donoghue et al. found male (presumed fetal) MSCs in 100% of bone marrow samples obtained at thoracotomy from women with sons who ranged in age from 13 to 51 years (O'Donoghue et al., 2004). They characterized these cells phenotypically, as well as functionally, following culture. Under appropriate culture conditions, the cells differentiate into muscle, nerve, bone and fat.
![]() |
The need for animal models |
---|
Most studies of murine fetal cell microchimerism rely on the fetus and the mother being of different sex, or on the presence of a marker chromosome (T6) in the fetus. More recently, we have used male transgenic mice carrying unique paternal reporter transgenes to identify and track the fetal cells. The transgenic fetal cells can be easily detected in the wild-type maternal tissues. For example, when enhanced green fluorescent protein (GFP) under the control of the chicken ß-actin promoter and the cytomegalovirus (CMV) enhancer is used as the reporter (Okabe et al., 1997), cells from transgenic fetuses can be easily detected in wild-type females by fluorescence microscopy or immunohistochemistry. Furthermore, quantifying the number of gfp sequences by real-time PCR amplification of genomic DNA allows detection of the equivalent of one fetal cell in 105 maternal cells (Khosrotehrani et al., 2004b
). These methods allow fetal cells to be monitored in maternal blood and tissue during and after normal murine pregnancies (Khosrotehrani et al., 2005b
). In addition, we are currently developing injury models to assess the capabilities of fetal cells to home to maternal injured tissues and to differentiate. Animal models show great promise for determination of which types of maternal injury or disease are most likely to recruit fetal cells from their niche. Furthermore, new bioluminescent imaging techniques will allow study of the behavior of these cells in the living mouse (Contag et al., 1998
).
![]() |
Conclusions/Perspectives |
---|
Pregnancy results in the acquisition of cells that may have clinical applications and therapeutic potential. Whether the PAPCs are HSCs or MSCs, or a new population of stem cells, is an unresolved issue. It is also unknown whether PAPCs respond to all types of maternal injury or only those injuries that recruit stem cells. It is possible that these cells, since they are fetal in origin, have a higher proliferative capacity or more plasticity than their equivalent adult (maternal) cells. In the current debate over the use of embryonic stem cells for treatment of disease, the discovery of a population of fetal stem cells that apparently differentiate in the adult woman and can be acquired without harming the fetus may be significant. Future research will focus on animal models to determine the contribution of the fetal PAPCs to the repair of maternal injury.
![]() |
References |
---|
Adams, K. M., Lambert, N. C., Heimfeld, S., Tylee, T. S., Pang, J. M., Erickson, T. D. and Nelson, J. L. (2003). Male DNA in female donor apheresis and CD34-enriched products. Blood 102, 3845-3847.
Alvarez-Silva, M., Belo-Diabangouaya, P., Salaun, J. and Dieterlen-Lievre, F. (2003). Mouse placenta is a major hematopoietic organ. Development 130, 5437-5444.
Aractingi, S., Sibilia, J., Meignin, V., Launay, D., Hachulla, E., Le Danff, C., Janin, A. and Mariette, X. (2002). Presence of microchimerism in labial salivary glands in systemic sclerosis but not in Sjogren's syndrome. Arthritis Rheum. 46, 1039-1043.[CrossRef][Medline]
Ariga, H., Ohto, H., Busch, M. P., Imamura, S., Watson, R., Reed, W. and Lee, T. H. (2001). Kinetics of fetal cellular and cell-free DNA in the maternal circulation during and after pregnancy: implications for noninvasive prenatal diagnosis. Transfusion 41, 1524-1530.[CrossRef][Medline]
Artlett, C. M., Smith, J. B. and Jimenez, S. A. (1998). Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N. Engl. J. Med. 338, 1186-1191.
Artlett, C. M., Cox, L. A., Ramos, R. C., Dennis, T. N., Fortunato, R. A., Hummers, L. K., Jimenez, S. A. and Smith, J. B. (2002). Increased microchimeric CD4+ T lymphocytes in peripheral blood from women with systemic sclerosis. Clin. Immunol. 103, 303-308.[CrossRef][Medline]
Artlett, C. M., O'Hanlon, T. P., Lopez, A. M., Song, Y. W., Miller, F. W. and Rider, L. G. (2003). HLA-DQA1 is not an apparent risk factor for microchimerism in patients with various autoimmune diseases and in healthy individuals. Arthritis Rheum. 48, 2567-2572.[CrossRef][Medline]
Bianchi, D. W., Zickwolf, G. K., Weil, G. J., Sylvester, S. and DeMaria, M. A. (1996). Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc. Natl. Acad. Sci. USA 93, 705-708.
Bianchi, D. W., Williams, J. M., Sullivan, L. M., Hanson, F. W., Klinger, K. W. and Shuber, A. P. (1997). PCR quantitation of fetal cells in maternal blood in normal and aneuploid pregnancies. Am. J. Hum. Genet. 61, 822-829.[Medline]
Bianchi, D. W., Farina, A., Weber, W., Delli-Bovi, L. C., Deriso, M., Williams, J. M. and Klinger, K. W. (2001). Significant fetal-maternal hemorrhage after termination of pregnancy: implications for development of fetal cell microchimerism. Am. J. Obstet. Gynecol. 184, 703-706.[CrossRef][Medline]
Bonney, E. A. and Matzinger, P. (1997). The maternal immune system's interaction with circulating fetal cells. J. Immunol. 158, 40-47.[Abstract]
Campagnoli, C., Roberts, I. A., Kumar, S., Bennett, P. R., Bellantuono, I. and Fisk, N. M. (2001). Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 98, 2396-2402.
Christner, P. J., Artlett, C. M., Conway, R. F. and Jimenez, S. A. (2000). Increased numbers of microchimeric cells of fetal origin are associated with dermal fibrosis in mice following injection of vinyl chloride. Arthritis Rheum. 43, 2598-2605.[CrossRef][Medline]
Contag, P. R., Olomu, I. N., Stevenson, D. K. and Contag, C. H. (1998). Bioluminescent indicators in living mammals. Nat. Med. 4, 245-247.[CrossRef][Medline]
Corpechot, C., Barbu, V., Chazouilleres, O. and Poupon, R. (2000). Fetal microchimerism in primary biliary cirhhosis. J. Hepatol. 33, 690-695.[CrossRef][Medline]
Evans, P. C., Lambert, N., Maloney, S., Furst, D. E., Moore, J. M. and Nelson, J. L. (1999). Long-term fetal microchimerism in peripheral blood mononuclear cell subsets in healthy women and women with scleroderma. Blood 93, 2033-2037.
Filho, M. A., Pavarino-Bertelli, E. C., Alvarenga, M. P., Fernandes, I. M., Toledo, R. A., Tajara, E. H., Savoldi-Barbosa, M., Goldmann, G. H. and Goloni-Bertollo, E. M. (2002). Systemic lupus erythematosus and microchimerism in autoimmunity. Transplant. Proc. 34, 2951-2952.[CrossRef][Medline]
Guetta, E., Gordon, D., Simchen, M. J., Goldman, B. and Barkai, G. (2003). Hematopoietic progenitor cells as targets for non-invasive prenatal diagnosis: detection of fetal CD34+ cells and assessment of post-delivery persistence in the maternal circulation. Blood Cells Mol. Dis. 30, 13-21.[CrossRef][Medline]
Holzgreve, W., Ghezzi, F., di Naro, E., Ganshirt, D., Maymon, E. and Hahn, S. (1998). Disturbed feto-maternal cell traffic in preeclampsia. Obstet. Gynecol. 9, 669-672.
Jimenez, D. F. and Tarantal, A. F. (2003). Quantitative analysis of male fetal DNA in maternal serum of gravid rhesus monkeys (Macaca mulatta). Pediatr. Res. 53, 18-23.
Jimenez, D. F., Leapley, A. C., Lee, C. I., Ultsch, M. N. and Tarantal, A. F. (2005). Fetal CD34+ cells in the maternal circulation and long-term microchimerism in Rhesus monkeys (Macaca mulatto). Transplantation 79, 142-146.[CrossRef][Medline]
Johnson, K. L., Nelson, J. L., Furst, D. E., McSweeney, P. A., Roberts, D. J., Zhen, D. K. and Bianchi, D. W. (2001a). Fetal cell microchimerism in tissue from multiple sites in women with systemic sclerosis. Arthritis Rheum. 44, 1848-1854.[CrossRef][Medline]
Johnson, K. L., McAlindon, T. E., Mulcahy, E. and Bianchi, D. W. (2001b). Microchimerism in a female patient with systemic lupus erythematosus. Arthritis Rheum. 44, 2107-2111.[CrossRef][Medline]
Johnson, K. L., Samura, O., Nelson, J. L., McDonnell, M. and Bianchi, D. W. (2002). Significant fetal cell microchimerism in a nontransfused woman with hepatitis C: evidence of long-term survival and expansion. Hepatology 36, 1295-1297.[CrossRef][Medline]
Khosrotehrani, K. and Bianchi, D. W. (2003). Fetal cell microchimerism: helpful or harmful to the parous woman? Curr. Opin. Obstet. Gynecol. 15, 195-199.[CrossRef][Medline]
Khosrotehrani, K., Johnson, K. L., Lau, J., Dupuy, A., Cha, D. H. and Bianchi, D. W. (2003a). The influence of fetal loss on the presence of fetal cell microchimerism: a systematic review. Arthritis Rheum. 48, 3237-3241.[CrossRef][Medline]
Khosrotehrani, K., Stroh, H., Bianchi, D. W. and Johnson, K. L. (2003b). Combined FISH and immunolabeling on paraffin-embedded tissue sections for the study of microchimerism. Biotechniques 34, 242-244.[Medline]
Khosrotehrani, K., Johnson, K. L., Cha, D. H., Salomon, R. N. and Bianchi, D. W. (2004a). Transfer of fetal cells with multilineage potential to maternal tissue. JAMA 292, 75-80.
Khosrotehrani, K., Wataganara, T., Bianchi, D. W. and Johnson, K. L. (2004b). Fetal cell-free DNA circulates in the plasma of pregnant mice: relevance for animal models of fetomaternal trafficking. Hum. Reprod. 19, 2460-2464.
Khosrotehrani, K., Mery, L., Aractingi, S., Bianchi, D. W. and Johnson, K. L. (2005a). Absence of fetal cell microchimerism in cutaneous lesions of lupus erythematosus. Ann. Rheum. Dis. 64, 159-160.
Khosrotehrani, K., Johnson, K. L., Guegan, S., Stroh, H. and Bianchi, D. W. (2005b). Natural history of fetal cell microchimerism during and following murine pregnancy. J. Reprod. Immunol. (in press).
Krabchi, K., Gros-Louis, F., Yan, J., Bronsard, M., Masse, J., Forest, J. C. and Drouin, R. (2001). Quantification of all fetal nucleated cells in maternal blood between the 18th and 22nd weeks of pregnancy using molecular cytogenetic techniques. Clin. Genet. 60, 145-150.[CrossRef][Medline]
Lambert, N. C., Evans, P. C., Hashizumi, T. L., Maloney, S., Gooley, T., Furst, D. E. and Nelson, J. L. (2000). Cutting edge: persistent fetal microchimerism in T lymphocytes is associated with HLA-DQA1*0501: implications in autoimmunity. J. Immunol. 164, 5545-5548.
Lambert, N. C., Lo, Y. M., Erickson, T. D., Tylee, T. S., Guthrie, K. A., Furst, D. E. and Nelson, J. L. (2002). Male microchimerism in healthy women and women with scleroderma: cells or circulating DNA? A quantitative answer. Blood 100, 2845-2851.
Liégeois, A., Escourrou, J., Ouvre, E. and Charreire, J. (1977). Microchimerism: a stable state of low-ratio proliferation of allogeneic bone marrow. Transplant. Proc. 9, 273-276.[Medline]
Liégeois, A., Gaillard, M. C., Ouvre, E. and Lewin, D. (1981). Microchimerism in pregnant mice. Transplant. Proc. 13, 1250-1252.[Medline]
Mosca, M., Curcio, M., Lapi, S., Valentini, G., D'Angelo, S., Rizzo, G. and Bombardieri, S. (2003). Correlations of Y chromosome microchimerism with disease activity in patients with SLE: analysis of preliminary data. Ann. Rheum. Dis. 62, 651-654.
Nelson, J. L. (1996). Maternal-fetal immunology and autoimmune disease: is some autoimmune disease auto-alloimmune or allo-autoimmune? Arthritis Rheum. 39, 191-194.[Medline]
Nelson, J. L., Furst, D. E., Maloney, S., Gooley, T., Evans, P. C., Smith, A., Bean, M. A., Ober, C. and Bianchi, D. W. (1998). Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 351, 559-562.[CrossRef][Medline]
O'Donoghue, K., Choolani, M., Chan, J., de La Fuente, J., Kumar, S., Campagnoli, C., Bennett, P. R., Roberts, I. A. and Fisk, N. M. (2003). Identification of fetal mesenchymal stem cells in maternal blood: implications for non-invasive prenatal diagnosis. Mol. Hum. Reprod. 9, 497-502.
O'Donoghue, K., Chan, J., de La Fuente, J., Kennea, N., Sandison, A., Anderson, J. R., Roberts, I. A. and Fisk, N. M. (2004). Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet 364, 179-182.[CrossRef][Medline]
Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. and Nishimune, Y. (1997). `Green mice' as a source of ubiquitous green cells. FEBS Lett. 407, 313-319.[CrossRef][Medline]
Osada, H., Doi, S., Fukushima, T., Nakauchi, H., Seki, K. and Sekiya, S. (2001). Detection of fetal HPCs in maternal circulation after delivery. Transfusion 41, 499-503.[CrossRef][Medline]
Srivatsa, B., Srivatsa, S., Johnson, K. L., Samura, O., Lee, S. L. and Bianchi, D. W. (2001). Microchimerism of presumed fetal origin in thyroid specimens from women: a case-control study. Lancet 358, 2034-2038.[CrossRef][Medline]
Wang, Y., Iwatani, H., Ito, T., Horimoto, N., Yamato, M., Matsui, I., Imai, E. and Hori, M. (2004). Fetal cells in mother rats contribute to the remodeling of liver and kidney after injury. Biochem. Biophys. Res. Commun. 325, 961-967.[CrossRef][Medline]