Selective loss of unmyelinated nerve fibers after extracorporeal shockwave application to the musculoskeletal system.

Application of extracorporeal shockwaves (ESW) to the musculoskeletal system may induce long-term analgesia in the treatment of chronic tendinopathies of the shoulder, heel and elbow. However, the molecular and cellular mechanisms behind this phenomenon are largely unknown. Here we tested the hypothesis that long-term analgesia caused by ESW is due to selective loss of nerve fibers in peripheral nerves. To test this hypothesis in vivo, high-energy ESW were applied to the ventral side of the right distal femur of rabbits. After 6 weeks, the femoral and sciatic nerves were investigated at the light and electron microscopic level. Application of ESW resulted in a selective, substantial loss of unmyelinated nerve fibers within the femoral nerve of the treated hind limb, whereas the sciatic nerve of the treated hind limb remained unaffected. These data might indicate that alleviation of chronic pain by selective partial denervation may play an important role in the effects of clinical ESW application to the musculoskeletal system.

Interleukin-11 expression: its significance in eutopic and ectopic human implantation.

Embryo implantation and subsequent decidualization, trophoblast invasion and formation of a functional placenta are crucial for establishment and maintenance of pregnancy. Interleukin-11 signalling has been shown to be obligatory for adequate decidualization and trophoblast invasion in mice. Defects in IL-11 signalling in mice result in trophoblast over-invasion and fetal loss. The pathological situation of human tubal pregnancy resembles that of IL-11Ralpha(-/-) mice concerning these symptoms. As our interest is focused on the human early pregnancy, we compared IL-11 expression at the implantation site of ectopic tubal pregnancy (EP) to 1st and 2nd trimester of normal intrauterine pregnancies (IP), and to the normal cycling endometrium. The mRNA expression of IL-11 and IL-11Ralpha was analysed by semiquantitative RT-PCR. Protein expression was detected by western blotting and immunohistochemistry. IL-11Ralpha is expressed constitutively in all tissue specimens analysed. IL-11 is expressed predominantly during follicular and early luteal phase of the menstrual cycle. In IP, IL-11 expression peaks during the 1st trimester and declines from the beginning of the 2nd trimester onwards. In tubal abortions, IL-11 expression is reduced in comparison to vital EP and IP. Cultured primary endometrial and decidual epithelial cells were analysed for hormonal regulation of IL-11 by enzyme-linked immunosorbent assay and RT-PCR. IL-11 is up-regulated by estrogen and down-regulated by progesterone. Overall, our results indicate that in humans, IL-11 signalling is significantly involved in regulation of trophoblast invasion. In the case of tubal abortion, inadequate IL-11 signalling may therefore result in dysregulation of trophoblast invasion.

Apoptosis of extravillous trophoblast cells limits the trophoblast invasion in uterine but not in tubal pregnancy during first trimester.

During the first trimester of pregnancy extravillous trophoblast cells (EVT) invade the maternal decidua. Invasion normally is reduced from the second trimester onwards and stops in the inner third of the myometrium. By contrast, in extrauterine tubal pregnancy, trophoblast invasion may even penetrate the tubal wall, which ultimately leads to the rupture of the fallopian tube. Induction of apoptosis of EVT cells, by maternal immune competent cells, may be an important mechanism to limit EVT invasion in uterine pregnancy. Tissue specimens from first and second trimester uterine pregnancy and first trimester tubal pregnancy were analyzed for apoptosis by TUNEL- and M30-staining. By immunohistochemical double labelling, maternal leukocyte subtypes were co-localized to apoptotic cells and in this context, the number of CD56(+)NK cells was analyzed. Our data show that apoptosis is confined to the decidua basalis. Most apoptotic cells are single cytokeratin-positive epithelial cells residing in the stromal compartment. Consequently these cells can only be EVT cells. Maternal leukocytes are not apoptotic. They are located in close contact to apoptotic cells. The number of apoptotic cells in the second trimester (1.8+/-0.7 per cent) is reduced compared to first trimester (5.6+/-0.7 per cent) of uterine pregnancy. In parallel, the number of NK cells declines from first (24.4+/-2.9) to second (12.4+/-1.8) trimester. Furthermore, apoptosis is significantly reduced in ectopic (0.9+/-0.3 per cent) compared to eutopic first trimester pregnancies. Consequently, we suggest that in first trimester uterine pregnancy, induction of EVT cell apoptosis by the maternal immune system is one mechanism to limit EVT invasion. During the second trimester, in parallel to declining numbers of NK cells, the mechanism changes. However, in tubal pregnancy due to differing immunological microenvironments at the ectopic implantation site, apoptosis induction fails, which deleteriously may result in uncontrolled invasion and penetration of the tubal wall.

Liver blood perfusion as a possible instrument for fetal growth regulation.

Placental and fetal liver blood perfusions are reduced in intrauterine growth-restricted human fetuses. We hypothesized that changes in fetal liver blood supply can alter fetal growth. In nine ewes with twin pregnancies at a gestational age of 119+/-2 days, a stent (4 mm) was placed into the ductus venosus of one twin (DV(stent) group). Alternatively, in 17 near term sheep with twin (n=11) or singleton (n=6) pregnancies, a DV was blocked with an embolization coil (DV(coil) group) for about one week. The cell proliferation rate (pKi-67) was determined in the liver, heart, skeletal muscle, kidneys and placenta. The dilatation or occlusion of the DV did not change placental perfusion on the first day or later after surgery. The liver blood supply was decreased in the DV(stent) group by more than half from 499+/-371 to 278+/-219 ml min(-1) (mean+/-s.d., n=4), and increased two-fold in the DV(coil) group (P< 0.05). The percentage of liver/body weight was decreased from 3.9+/-0.6 per cent in control twin to 3.0+/-0.2 per cent (n=3) in the DV(stent) group. Occlusion of the DV lead to an increase in the percentage of liver/body weight from 3.4+/-0.8 per cent to 4.3+/-0.8 per cent (n=11, P< 0.05). Reduced liver blood supply in the DV(stent) group was associated with a decrease of cell proliferation in the liver from 12.43+/-2.31 to 6.5+/-0.62 (nuclei microm(2) 10(-4), n=3, P=0.058), in heart from 1.14+/-0.03 to 0.93+/-0.02 (nuclei microm(2) 10(-4), P< 0.05), and in skeletal muscle from 0.82+/-0.05 to 0.54+/-0.01 (nuclei microm(2) 10(-4), P< 0.05). The increased liver blood perfusion following occlusion of the DV increased cell proliferation sixfold in the liver, (n=9, P< 0.005) and twofold in heart muscle, skeletal muscle and the kidneys (P< 0.05), whereas no significant difference was seen in the placenta. The expression of mRNA for IGF-I and IGF-II in the liver was increased in the DV(coil) group. In conclusion, these results suggest that liver blood perfusion can regulate fetal growth.

Effects of trophoblast invasion on the distribution of leukocytes in uterine and tubal implantation sites.

OBJECTIVE: To distinguish endocrine and paracrine influences on leukocyte subpopulations at uterine and tubal implantation sites. DESIGN: Retrospective immunohistochemical study. SETTING: Departments of Anatomy, and Obstetrics and Gynecology, School of Medicine, RWTH University of Aachen, Aachen, Germany. PATIENT(S): Ten women with a viable ectopic pregnancy (EP), 25 women who had undergone elective first-trimester termination of pregnancy, and 4 women who had undergone hysterectomy with adnexectomy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Quantitative analysis of leukocyte subpopulations at the implantation sites and their corresponding noninvaded tissues, decidual tissue from patients with EP, and tubal mucosa from normal menstrual cycle. RESULT(S): Similar numbers and characteristic distribution patterns of macrophages, T cells, and B cells were found at both normal intrauterine and tubal implantation sites. Natural killer (NK) cells were always absent from tubal mucosa. The number and distribution of leukocytes within decidual tissue from women with EP corresponded to those in the noninvaded decidual compartment in intrauterine pregnancy (IUP). CONCLUSION(S): Leukocyte populations present in the tubal and uterine mucosa are an intrinsic characteristic of these tissues. The distinct leukocyte distribution pattern at the implantation sites suggests that the invading trophoblast exerts a paracrine influence on endometrial and endosalpingeal leukocytes. The absence of natural killer cells from the tubal wall may be one reason for the higher degree of invasiveness of the trophoblast at the tubal implantation site.

Obstruction of ductus venosus stimulates cell proliferation in organs of fetal sheep.

In growth restricted fetuses, hepatic blood flow is reduced. This suggests the hypothesis that liver blood flow controls fetal growth. In 11 near term sheep the ductus venosus was blocked with an embolization coil in one fetus (experimental) and left patent in the twin (control). Arterial catheters were placed in both fetuses. After termination [mean (s.d.) 5 days (2) after surgery] the fetal body and organs were weighed. The cell proliferation rate (pKi-67) was determined in tissue samples of the liver, heart, skeletal muscle, kidneys and placenta (n=6). Blood flow through the umbilical vein measured by Doppler ultrasound did not differ in control and experimental fetuses [experimental: 600 (101) ml/min; control: 626 (89) ml/min]. In experimental fetuses, blood flow through the ductus venosus was negligible (colour Doppler), and thus hepatic blood flow was increased. Absolute and relative (percentage of body weight) liver weights were increased in experimental fetuses [liver weight: 119 (34) g versus 84 (17) g; relative liver weight: 4.3 (0.8) per cent versus 3.4 (0.8) per cent;P=0.002, n=11]. The cell proliferation rate was increased significantly (twofold) in heart muscle, skeletal muscle and kidneys, and sixfold in liver. It is concluded that increases of hepatic blood flow stimulate cell proliferation in major organs of the ovine fetus.

Distensible transtrophoblastic channels in the rat placenta.

Paracellular pathways in the haemotrichorial placenta of the rat were studied by electron microscopy using lanthanum hydroxide as an electron dense marker. Near term placentae were dually perfused in situ, adding lanthanum to the fetal perfusate. In some placentae outflow pressure on the fetal side was elevated (between 10 and 25 cm H(2)O) to promote filtration of fluid in a fetomaternal direction. Under normal pressure conditions lanthanum particles lined the subendothelial spaces and tubular structures in the inner, syncytial layer of trophoblast. Further penetration of lanthanum into the tubules was blocked by coarse lanthanum aggregates. Elevated fetal hydrostatic pressure resulted in a fluid shift across the placenta (filtration rate 50+/-16 per cent of fetal arterial inflow rate), distending the tubules in the inner trophoblast layer. Lanthanum particles gradually appeared in tubular structures in the middle (syncytial) layer and in the lateral intercellular spaces in the outer (cellular) layer. Finally lanthanum reached the maternal surface of the trophoblast. These pressure effects were only partially reversible. When the fetal pressure was returned to control values, some distension of the tubules persisted and the entire length of the paracellular pathways remained accessible to lanthanum. It is concluded that the placental barrier in the rat contains pressure dependent paracellular pathways connecting the maternal and fetal extracellular compartments.

Different placentation patterns in viable compared with nonviable tubal pregnancy suggest a divergent clinical management.

OBJECTIVE: In contrast to tubal abortions, viable ectopic pregnancies in color Doppler ultrasonography exhibit a signal-intensive ring around the gestational sac. We investigated the underlying differences in implantation and placentation. STUDY DESIGN: Histologic sections of fallopian tubes carrying viable tubal pregnancies (13 patients) and tubal pregnancies that aborted (8 patients) were immunostained for cytokeratin, MIB-1, CD-34, and CD-68. The data were studied by computer-aided image analysis followed by statistical evaluation (Student t test, P <.05). RESULTS: In contrast to tubal abortions, viable tubal pregnancies are characterized by implantation at the mesosalpingial rather than at the antimesosalpingial side of the organ. They exhibit deeper trophoblast invasion into the thickened tubal wall, more intense trophoblast proliferation (P <.001), and increased villous vascularization (P <.001). CONCLUSION: The morphologic findings correlate with preoperative Doppler ultrasonography. They suggest that trophoblast invasion, placental growth, and the fate of tubal pregnancies depend on the implantation site. They encourage a conservative management of anti-mesosalpingially implanted, nonviable ectopic pregnancies in clinically stable patients.

Immunohistochemistry of matrix metalloproteinases (MMP), their substrates, and their inhibitors (TIMP) during trophoblast invasion in the human placenta.

The invasion of extravillous trophoblast cells into the maternal endometrium is one of the key events in human placentation. The ability of these cells to infiltrate the uterine wall and to anchor the placenta to it as well as their ability to infiltrate and to adjust utero-placental vessels to pregnancy depends, among other things, on their ability to secrete enzymes that degrade the extracellular matrix. Most of the latter enzymes belong to the family of matrix metalloproteinases. Their activity is regulated by the tissue inhibitors of matrix metalloproteinases. We have studied the distribution patterns of matrix metalloproteinases-1, -2, -3, and -9 and their inhibitors TIMP-1 and TIMP-2 as compared to the distribution of their substrates along the invasive pathway of extravillous trophoblast of 1st, 2nd, and 3rd trimester placentas by means of light microscopy on paraffin and cryostat sections as well as at the ultrastructural level (only 3rd trimester placenta). The comparison of different methods proved to be necessary, since the immunohistochemical distribution patterns of these soluble enzymes are considerably influenced by the pretreatment of tissues. All three methods revealed immunoreactivities of both, proteinases and their inhibitors, not only intracellularly in the extravillous trophoblast but also extracellularly in its surrounding matrix, the distribution patterns depending on the stage of pregnancy and on the degree of differentiation of trophoblast cells along their invasive pathway. Within the extracellular matrix, immunolocalization of matrix metalloproteinases as well as their inhibitors showed a specific relation to certain extracellular matrix molecules.

Classification of human placental stem villi: review of structural and functional aspects.

The stem villi of the human placenta represent the central branches of the villous trees. They are characterized by a condensed fibrous stroma in which the fetal arteries and veins as well as the arterioles and venules are embedded. Functionally they are accepted as the mechanically supporting structures of the villous trees, and they are supposed to control fetal blood flow to the maternofetal exchange area, which is located in the peripheral villi. To obtain further insights into the functions of the stem villi, the recent literature has been reviewed, and some immunohistochemical, ultrastructural, and reconstruction studies have been added. These new studies were aimed at identifying immunohistochemically different subtypes of stem villi, their branching patterns, the distribution of macrophages, the stromal proliferation patterns, and the differentiation of extravascular stromal cells. Our findings demonstrate that the stem villi and their precursors, the immature intermediate villi, can selectively be identified by anti-gamma-smooth muscle (sm) actin staining. Furthermore, the existence of three different subtypes of stem villi is shown; these differ regarding the presence and distribution of gamma-sm actin-positive cells. These cells were immunohistochemically and ultrastructurally identified as smooth muscle cells and myofibroblasts. Increasingly complex coexpression patterns of cytoskeletal proteins reflect a clearly defined differentiation gradient of extravascular stromal cells, which covers the whole range of an undifferentiated germinative layer beneath the trophoblast to highly differentiated myofibroblasts surrounding the medias of the stem vessels. Possible functions of the extravascular contractile system include the regulation of villous turgor and the control of intervillous blood flow impedance.

Pressure dependence of so-called transtrophoblastic channels during fetal perfusion of human placental villi.

To test the influence of perfusion pressures on structural preservation of human placental villi and on the dilatation of the so-called transtrophoblastic channels, cotyledons of 32 term human placentas have been perfused in vitro. Periods of perfusion with isotonic Ringer solution under various arterial and venous hydrostatic pressures were followed by perfusion fixation. In some experiments, lanthanum hydroxide as an extracellular marker was added to the fixative. Distention of the fetal vascular system, stromal edema and continuity, as well as trophoblastic vacuolization were studied via electron microscopy with subsequent morphometry. The findings suggest that arterial hydrostatic pressures in the perfusion system of about 80 cm H2O are needed to guarantee homogeneous perfusion of the fetal vascular system. To avoid stromal edema and trophoblastic vacuolization, venous hydrostatic pressures of 4 cm H2O and arterial hydrostatic pressures of 80 cm H2O should not be exceeded. It is concluded that the trophoblastic vacuoles are dilated segments of the so-called transtrophoblastic channels. The functional importance of in vivo variations of fetal intravascular hydrostatic pressure for the dilatation of transtrophoblastic channels and for fetal water balance is discussed.

The ultrastructure of the trophoblastic layer of the degu (Octodon degus) placenta: a re-evaluation of the 'channel problem'.

Previous studies on immersion-fixed specimens of the haemomonochorial labyrinthine chorioallantoic placenta of the degu have made visible channels or pores which completely crossed the trophoblastic layer; for the first time hints for an open connection between maternal blood spaces and fetal interstitium were demonstrated in a placenta. This important finding was re-evaluated by means of transmission electron microscopy paying particular attention to the influence of the mode of fixation and of ischaemic periods prior to fixation. Thirty placentae from seven near-term degu (estimated gestational age 80-90 days) were fixed at various times (5-45 min) after maternal death. Placentae were perfused in situ via the aorta/uterine arteries or the umbilical vein with 2.2 per cent phosphate-buffered glutaraldehyde (n = 7, ischaemic periods < 5-45 min) or lanthanum hydroxide/osmium tetroxide (n = 7, ischaemic periods < 5 min), or were immersion-fixed in 2.2 per cent phosphate-buffered glutaraldehyde (n = 16, ischaemic periods 10-45 min). In material with brief ischaemic periods (n = 3, 5-10 min) no open connections between the maternal blood lacunae and fetal interstitium could be detected. Instead, occasional foci of trophoblast reduced to a thickness of 0.1 micron were found. After ischaemic periods exceeding 10 min, the thin trophoblastic diaphragms had partly disappeared resulting in complete transtrophoblastic pores. It is likely, therefore, that visible trophoblastic pores or channels in the degu placenta are ischaemic artefacts. Application of lanthanum hydroxide from the fetal circulation showed that a branching system of membrane-lined tubules (15-50 nm wide) intruded the trophoblast from its basal side, as has been reported for the guinea-pig and human placenta. It remains to be investigated whether these invaginations belong to a continuous transtrophoblastic channel system.

Extracellular matrix components of the placental extravillous trophoblast: immunocytochemistry and ultrastructural distribution.

Invasive extravillous trophoblast cells of the human placenta are embedded in a self-secreted extracellular matrix, the matrix-type fibrinoid. The ultrastructure and molecular composition of the matrix-type fibrinoid of the term human placenta were studied by transmission electron microscopy and immunogold labelling. We used antibodies directed against different matrix proteins such as collagen type IV, laminin, vitronectin, heparan sulfate, various fibronectin isoforms, and against the oncofetal blood group antigen, "i". Immunogold labelling patterns of matrix proteins are the basis for the subdivision of the trophoblast-derived matrix-type fibrinoid into mosaic-like patches of structurally and immunocytochemically different compartments. Firstly, fine granular patches with structural similarities to basal lamina material are composed solely of collagen type IV and laminin. Secondly, an ultrastructurally amorphous glossy substance shows reactivity with antibodies against heparan sulfate and vitronectin. A third type of patches, fine fibrillar networks embedded in the above-mentioned glossy matrix, are reactive with antibodies against normal fibronectin isoforms (IST-4, IST-6, IST-9) and oncofetal isoforms (BC-1, FDC-6). The blood group precursor antigen "i" was not only expressed on the surfaces of the extravillous trophoblast cells but was associated with the fibronectin-positive fibrils. In conclusion, within this extracellular matrix, clear compartments of different composition can be distinguished from each other. Glycosylation with "i" in this matrix may be involved in immunological masking, thus preventing rejection of placenta and fetus.

Placental villous stroma as a model system for myofibroblast differentiation.

Different subtypes of myofibroblasts have been described according to their cytoskeletal protein patterns. It is quite likely that these different subtypes represent distinct steps of differentiation. We propose the human placental stem villi as a particularly suitable model to study this differentiation process. During the course of pregnancy, different types of placental villi develop by differentiation of the mesenchymal stroma surrounding the fetal blood vessels. In order to characterise the differentiation of placental stromal cells in the human placenta, the expression patterns of the cytoskeletal proteins vimentin, desmin, alpha- and gamma-smooth muscle actin, pan-actin, smooth muscle myosin, and the monoclonal antibody GB 42, a marker of myofibroblasts, were investigated on placental tissue of different gestational age (7th-40th week of gestation). Proliferation patterns were assessed with the proliferation markers MIB 1 and PCNA. Additionally, dipeptidyl peptidase IV distribution was studied in term placenta and the ultrastructure of placental stromal cells was assessed by electron microscopy. Different subpopulations of extravascular stromal cells were distinguished according to typical co-expression patterns of cytoskeletal proteins. Around the fetal stem vessels in term placental villi they were arranged as concentric layers with increasing stage of differentiation. A variable layer of extravascular stromal cells lying beneath the trophoblast expressed vimentin (V) or vimentin and desmin (VD). They were mitotically active. The next layer co-expressed vimentin, desmin, and alpha-smooth muscle actin (VDA). More centrally towards the fetal vessels, extravascular stromal cells co-expressed vimentin, desmin, alpha- and gamma-smooth muscle actin, and GB 42 (VDAG). Cells close to the fetal vessels additionally co-expressed smooth muscle myosin (VDAGM). Ultrastructurally, V cells resembled typical mesenchymal cells. VD cells corresponded to fibroblasts, while VDA and VDAG cells developed features of myofibroblasts. Cells of the VDAGM-type revealed a smooth muscle cell-related ultrastructure. In earlier stages of pregnancy, stromal cell types with less complex expression patterns prevailed. The media smooth muscle cells of the fetal vessels showed a mixture of different co-expression patterns. These cells were separated from extravascular stromal cells by a layer of collagen fibres. The results obtained indicate a clearly defined spatial differentiation gradient with increasing cytoskeletal complexity in human placental stromal cells from the superficial trophoblast towards the blood vessels in the centre of the stem villi. The spatial distribution of the various stages of differentiation suggests that human placental villi could be a useful model for the study of the differentiation of myofibroblasts.

Anti-adhesive glycosylation of fibronectin-like molecules in human placental matrix-type fibrinoid.

Recently, fibrinoid of the human placenta has been described as being composed of two main types differing in origin and chemical composition. Fibrin-type fibrinoid is mostly a blood clot product. Matrix-type fibrinoid was defined as the extracellular matrix secreted by extravillous trophoblast cells. The structure and composition of matrix-type fibrinoid was addressed in this study, focusing on fibronectins as one major constituent. A panel of antibodies directed against different fibronectin isoforms generated by different mRNA splicing, as well as antibodies recognizing oncofetal carbohydrate epitopes, were used on cryostat, paraffin and Lowicryl sections of placental tissue from different stages of pregnancy. The oncofetal carbohydrate epitopes studied comprised the blood group precursor antigens i and I. We identified the blood group-related antigen i as an additional marker for matrix-type fibrinoid. The antigen was detected on a glycoprotein that was also recognized by the fibronectin antibodies in western blots. Immunohistochemically this i-glycosylated oncofetal fibronectin-like molecule of about 55 kDa is expressed only by the invasive phenotype of extravillous trophoblast. Long chain carbohydrate moieties with a structure fulfilling the criteria for i reactivity on human placental fibronectin are known to have antiadhesive properties and to enhance resistance of the protein chain to proteolysis. These properties underline the functional relevance of glycosylation of fibronectins in matrix-type fibrinoid and suggest matrix-type fibrinoid is a typical matrix of invasive cells. In contrast, the more mature blood group precursor I could be detected after sialidase pretreatment of sections. This antigen was expressed by villous, non-invasive trophoblast.

Immunohistochemistry of two different types of placental fibrinoid.

The structure and composition of human placental fibrinoid were studied on cryostat and paraffin sections and by transmission electron microscopy as well as immunohistochemistry using antibodies directed against fibrin, fibronectin isoforms, collagens IV and VI, laminin and tenascin. The findings suggest two structurally and immunohistochemically different subtypes of fibrinoid: fibrin-type fibrinoid and matrix-type fibrinoid. Fibrin-type fibrinoid was characterized by immunoreactivity for fibrin and cellular fibronectin, including the ED-A sequence. Immunostaining for all other extracellular matrix molecules was negative. Ultrastructurally, this fibrinoid subtype consisted of a meshwork of fibers with 20-nm cross striation typical of fibrin. Fibrin-type fibrinoid never contained extravillous trophoblast cells. It is therefore primarily a blood clot product derived from maternal and fetal blood. In contrast, matrix-type fibrinoid showed virtually no evidence of fibrin; it was immunopositive for extracellular matrix molecules such as the fibronectins, particularly oncofetal fibronectin (containing the ED-B sequence), collagen IV, laminin and tenascin. Oncofetal fibronectin, which was neither expressed in fibrin-type fibrinoid nor in the villous stromal core, seemed to be a specific marker for matrix-type fibrinoid. Single or clustered nonproliferative extravillous trophoblast cells were embedded within the matrix molecules. It is very likely that these cells secrete the matrix in a non-polarized fashion. Fibrin-type fibrinoid would appear to be involved in shaping the intervillous space and in replacing damaged syncytiotrophoblast acting as a transport and immune barrier. Matrix-type fibrinoid, as a secretory product of the extravillous trophoblast, should be discussed in context with the invasive properties of this cell population.