Chapter 7
Villous Development
General Considerations . . . 96
Mesenchymal Villi . . . 98
Immature Intermediate Villi . . . 99
Stem Villi . . . 100
Mature Intermediate Villi . . . 102
Terminal Villi . . . 103
Anatomy of the Intervillous Space . . . 105
Selected References . . . 106
General Considerations
The ramifications of the villous trees can be subdivided into five villous types based on caliber, stroma, vasculature, position within the villous tree, and development (Figures 7.1 A–E). The five types are these:
• Mesenchymal villi,
• Immature intermediate villi,
• Mature intermediate villi,
• Stem villi, and
• Terminal villi.
The mesenchymal villi are the first generation of the tertiary villi and
are the precursors from which all other villous types arise. Immature inter-
mediate villi develop from maturation of mesenchymal villi during the
first two trimesters and are later transformed into stem villi (Figure
7.2 A). The mature intermediate villi derive from mesenchymal villi
during the third trimester and are later transformed into terminal villi
(Figure 7.2 B). Thus, both types of “intermediate” villi are transitions
from mesenchymal to mature villi. These intermediate villi topo-
graphically lie between the centrally located stem villi and the most
peripheral terminal villi.
General Considerations 97
A
B
D C
E
A
C
D E
B
Figure 7.1. Simplified representation of the mature placental villous tree (A) and cross sections of the various villous types (B–E). For further details see text. (From Kaufman P, Scheffen I. I. Placental devel- opment. In: Neonatal and Fetal Medicine: Physiology and Pathophysiology. Vol. I. R.A. Polin and W.W.
Fox, eds., Orlando, FL: Saunders, 1992; 7–55, with permission.)
Mesenchymal Villi
Mesenchymal villi are the forerunners of all other villous types. They develop beginning in the fifth week PM (from last menstrual period) at the onset of villous vascularization. From the fifth to the sixth week PM they develop from the tertiary villi via primary and secondary villi.
After the sixth week PM, the primary and secondary villi are exhausted and new mesenchymal villi develop by a different method. First, the villous surface of the mesenchymal villi develops syncytial outgrowths called syncytial sprouts. Ingrowth of cytotrophoblast forms tro- phoblastic sprouts and then ingrowth of connective tissue forms villous sprouts. Finally, fetal capillaries form in the connective tissue core. From early gestation through the second trimester, mesenchymal villi differentiate into immature intermediate villi, which ultimately form stem villi. In the third trimester, mesenchymal villi primarily dif- ferentiate into mature intermediate villi, which are the forerunners of the terminal villi (Figures 7.1, 7.2, Table 7.1).
Villous Sprout
Trophoblastic Sprout
Mesenchymal Villi
Immature Intermediate Villi
Stem Villi
Villous Sprout
Trophoblastic Sprout
Mesenchymal Villi
Mature Intermediate Villi
Terminal Villi
Stem Villi Remaining
Immature Intermediate Villi
Figure 7.2. Routes of villous development during the first and second trimester (A) and third trimester (B). (A) Trophoblastic sprouts are produced along the surfaces of mesenchymal and immature inter- mediate villi. Via villous sprouts, they are transformed into mesenchymal villi. The latter differentiate into immature intermediate villi, which produce new sprouts before they are transformed into stem villi. (B) Throughout the third trimester, the mesenchymal villi differentiate into mature intermediate villi, which then may produce terminal villi. Mesenchymal villi no longer produce immature interme- diate villi, but those still remaining continue to differentiate into stem villi. Thus, their number decreases with increasing gestational age. The source of new sprouts is also then reduced, and there- fore the growth capacity of the villous trees gradually slows.
A
B
Mesenchymal villi have a thick trophoblastic cover with prominent Langhans’ cells. They have the most Langhans’ cells and the highest mitotic index of all villous types. There is a primitive stromal core with loosely arranged collagen, fibroblasts and a few Hofbauer cells (Figures 7.1 C, 7.3). Fetal capillaries are poorly developed and do not show sinu- soidal dilatation. Occasionally, the capillaries are occluded at the villous tips. During the first weeks of pregnancy, mesenchymal villi are not only the source of villous proliferation but also the site of maternofe- tal exchange and endocrine activity. With advancing pregnancy and the development of more advanced villous types, their functional impor- tance is reduced to villous growth. At term, they are generally only found in small numbers on the surfaces of immature intermediate villi in the center of the villous trees and comprise less than 1% of the pla- cental volume.
Immature Intermediate Villi
The immature intermediate villi appear around the 8th week PM and comprise the majority of villi from the 14th to the 20th week. At term, only rare clusters are present in the center of the villous trees where they comprise less than 5% of the placental volume. They mature into stem villi, a transformation that is a gradual process resulting in many intermediate forms. Morphologically, immature intermediate villi are bulbous in shape with a thick tropohoblastic cover and a distinctive retic- ular stroma containing fluid-filled stromal channels (Figures 7.1 D, 7.4). The stroma contains Hofbauer cells, and there are prominent Langhans’ cells
Immature Intermediate Villi 99
Table 7.1. Villous characteristics
When When % volume Characteristic
Villous type present maximum at term Size features
Mesenchymal Throughout 0 to 8 <1 120–250mm Primitive stroma,
villi gestation weeks (0–8 weeks) thick trophoblastic
60–100 (8 weeks cover, few vessels to term)
Immature 8 weeks to 14 to 20 5 to 10 Usually Reticular stroma
intermediate term weeks 100–200mm; with fluid-filled
villi may be up to stromal channels
400mm
Stem villi 12 weeks to Term 20 to 25 150–300mm Dense fibrotic stroma
term and myofibroblastic
perivascular sheath, large vessels
Mature Third Third 25 80–150mm Dense, cellular
intermediate trimester trimester stroma with >50%
villi capillaries
Terminal Third Term 40 to 50 60mm >50% capillaries
villi trimester
interposed between the syncytium and the tropohoblastic basal lamina.
Fetal capillaries are poorly developed. The reticular stroma may cause diagnostic problems as it has a weak affinity for conventional stains and may simulate villous edema. Starting at about the 8th week PM, the immature intermediate villi act as growth centers of the villous trees by forming new mesenchymal villi. This is accomplished by villous sprouting, as described above. Thus, new mesenchymal villi are formed from both old mesenchymal villi and immature intermediate villi.
Stem Villi
Stem villi are derived from immature intermediate villi by a gradual
process (Figures 7.1 A, 7.4, 7.5). They begin to appear at about the
eighth week PM. The large “trunks” and “branches” of the villous trees
(trunci chorii, rami chorii, ramuli chorii) and the anchoring villi are all
stem villi and differ only in caliber and position within the hierarchy
Figure 7.3. Mesenchymal villi. Eighth week PM. As can be seen from the diffuse stromal structure, the villi still belong to the mesenchymal type. ¥125. (From Kaufmann P. Entwicklung der Plazenta. In: Die Plazenta des Menschen. V Becker, ThH Schiebler, F Kucli, eds. Stuttgart: Thieme, 1981; 13–50, with permission.)Figure 7.4. Immature intermediate villi and stem villi. Fifteenth week PM. The larger immature inter- mediate villi exhibit the first signs of central stromal fibrosis, originating from the larger fetal vessels, thus establishing the first stem villi (SV). Several typical immature intermediate villi (IV) and mes- enchymal villi (MV) can be seen. As is typical for mesenchymal villi of the second and third trimester, they are associated with degenerating villi and are becoming transformed into intravillous fibrinoid.
¥125.
Figure 7.5. Cross section of a large stem villus. Note that the adventitias of the artery (right) and vein (left) directly continue into the surrounding dense fibrous stroma of the villus. Superficially, numerous smaller vessels of the paravascular capillary net are seen. As is typical for stem villi of the mature pla- centa, the trophoblastic covering has been replaced by fibrinoid in many places. ¥115. (From Leiser R, Luckhardt M, Kaufmann P, Winterhager E, Bruns U. The fetal vascularisation of term human placen- tal villi. I. Peripheral stem villi. Anat Embryol 1985;173:71–80, with permission.)
of villous branching. At term, they make up 20% to 25% of the placen- tal volume but, because of the typical branching pattern, their “volu- metric” share is highest in the central subchorionic area of the placenta.
Functionally, stem villi serve to mechanically support the structure of the villous trees. Their share in the function of maternofetal exchange is negligible.
Histologically, stem villi have a thick trophoblastic cover. Cytotro- phoblastic cells are easily identified below the syncytiotrophoblast on about 20% of the villous surfaces (Figure 7.1 A). In the mature placenta, the surfaces of the villi are often degenerative and partially replaced by fibrinoid. This is more prominent in large caliber stem villi. The stroma consists of condensed bundles of collagen fibers with occasional fibroblasts and rare macrophages (Figures 7.4, 7.5). Mast cells are occa- sionally seen. In the larger stem villi, there is a central artery and cor- responding vein along with smaller arterioles, venules, and superficial paravascular capillaries (Figure 7.5). These structures are comparable to the vasa vasorum of large vessels in other organs. The adventitia of the vessels continues without sharp demarcation into the surrounding fibrous stroma. Centrally, the connective tissue cells are myofibroblasts, whereas peripherally they are noncontractile fibroblasts. The central myofibroblasts around the stem vessels form the perivascular sheath.
The transition from immature intermediate villi to stem villi is gradual. Initially, the vessels acquire a distinct media and adventitia, which expands to include the entire villus. Concurrently, an increase in the connective tissue leads to compression and finally disappearance of the stromal channels. In “immature” stem villi, there is a superficial rim of reticular stroma separating the fibrous stroma from the trophoblastic cover, which represents a differentiation gradient, the most central layer showing the highest degree of differentiation. Stem villi are established when the superficial reticular stroma beneath the trophoblast is thinner than the fibrous tissue surrounding the stem vessels.
Mature Intermediate Villi
In the third trimester, the mesenchymal villi switch from forming immature intermediate villi to forming mature intermediate villi, the precursors of the terminal villi. Mature intermediate villi are long and slender. When their surfaces bear developing terminal villi, they form a zigzag configuration as the terminal villi branch off. At 32 to 34 weeks gestation, there are many groups of mature intermediate villi with round to oval cross sections alternating with slender longitudinal sec- tions (Figure 7.6). The stroma consists of seemingly unoriented, loose bundles of connective tissue fibers and connective tissue cells (Figure 7.1 E).
Rudimentary narrow stromal channels may also be found. There are
numerous capillaries, small terminal arterioles, and collecting venules without
a media. Cross sections contain less than 50% vascular lumens and thus
they participate significantly in fetomaternal exchange. Approximately
25% of the placental volume at term consists of this villous type.
Terminal Villi
Terminal villi are the final ramifications of the villous tree. They are grapelike outgrowths of the mature intermediate villi and appear as single villi or poorly ramified side branches (see Figures 7.1 B, 7.6). The peripheral end of the mature intermediate villus normally branches into an aggregate of terminal villi and is connected to them by a narrow neck region. There are scant connective tissue fibers and rare macrophages with a thin trophoblastic cover in intimate contact with sinusoidally dilated capillaries (Figures 7.6, 7.7). Strictly speaking, terminal villi are those villi in which the vascular lumens comprise at least 50% of the stromal volume and which contain no vessels other than capillaries and sinusoids.
The sinusoids of terminal villi are not comparable to the sinusoids of the liver, spleen, and bone marrow as they possess a continuous endothelium and complete basal lamina. Contrary to the development of other villous types, the terminal villi are not formed by cellular out- growths but rather are formed passively by capillary growth and coiling.
This results in stretching of trophoblast and thinning of the vasculo- syncytial membranes. Accordingly, maldevelopment of the terminal villi is a consequence of abnormal fetoplacental angiogenesis (see Chapter 18). These villi are the primary site of fetomaternal exchange
Terminal Villi 103
Figure 7.6. Mature intermediate villi. Twenty-ninth week PM. During this period, the mature inter- mediate villi and the stem villi (lower left) are the prevailing villous types. Immature intermediate villi with typical reticular stroma (lower right) are less common. ¥125.
Figure 7.7. (A, B) Terminal villi. Thirty-eighth week PM. Dominating villous types are mature inter- mediate villi and terminal villi, both of small caliber. Several stem villi of varying caliber can also be seen in between. As is typical for term placentas, the trophoblastic cover of the stem villi is partly replaced by fibrinoid. The stromal core is completely fibrotic. Reticular stroma or cellular connective tissue (a typical sign of immaturity that is usually visible below the trophoblast in earlier stages) throughout the last few weeks is absent. ¥125.
B
for the transfer of oxygen, carbon dioxide, and water. In the term pla- centa, they comprise 45% or more of the placental volume and approx- imately 60% of the cross section.
Anatomy of the Intervillous Space
After leaving the spiral arteries, maternal blood circulates through the intervillous space, flowing directly around the villi outside the confines of the maternal vascular system. At delivery, much of this blood is lost and, therefore, on histologic examination the usual appearance of the intervillous space is that of a system of narrow clefts. The inlets of the spiral arteries are near the centers of the villous trees while the venous outlets are arranged around the periphery. Therefore, each fetomaternal circulatory unit is composed of one villous tree with a corresponding, cen- trifugally perfused portion of the intervillous space (Figure 7.8). This unit has been called a “placentone.” Most of the 40 to 60 placentones are in contact with each other and overlap. The peripheral placentones are more clearly separated from one another than the central units.
Anatomy of the Intervillous Space 105
Figure 7.8. Typical spatial relations between villous trees and the maternal bloodstream. According to the placentone theory, a placentone is one villous tree together with the related part of the intervillous space. In the case of typical placentones, which prevail in the periphery of the placenta, the maternal blood (arrows) enters the intervillous space near the center of the villous tree and leaves near the clefts between neighboring villous trees. One or only a few villous trees occupy one placental lobule (cotyle- don). In the central parts of the placenta, the villous trees, because of size and nearby location, may partly overlap so that the zonal arrangement of the placentone disappears.
Maternal venous blood is collected in the “perilobular zone,” which is the portion of most densely packed terminal villi. The remaining immature intermediate villi and sprouts of mesenchymal villi are concentrated in the center of the placentone. The placentone ranges in diameter from 1 to 4 cm, and therefore the entire unit may not be well represented in histologic sections. In addition, placentones from different locations may show varying degrees of maturation. Thus, even careful study of several sections from a given placenta may be difficult to interpret without knowledge of this anatomy.
Selected References
PHP4, Chapter 7, pages 116–154.
Castellucci M, Scheper M, Scheffen I, et al. The development of the human placental villous tree. Anat Embryol (Berl) 1990;181:117–128.
Demir R, Kosanke G, Kohnen G, et al. Classification of human placental stem villi: review of structural and functional aspects. Microsc Res Technique 1997;38:29–41.
Graf R, Schönfelder G, Mühlberger M, et al. The perivascular contractile sheath of human placental stem villi; its isolation and characterization. Placenta 1995;16:57–66.
Kaufmann P. Entwicklung der Plazenta. In: Becker V, Schiebler TH, Kubli F (eds) Die Plazenta des Menschen. Sturrgart: Thieme, 1981:13–50.
Kaufmann P. Basic morphology of the fetal and maternal circuits in the human placenta. Contrib Gynecol Obstet 1985;13:5–17.
Kaufmann P, Scheffen I. Placental development. In: Polin RA, Fox WW (eds) Neonatal and fetal medicine. Physiology and pathophysiology, vol I.
Orlando: Saunders, 1992:47–55.
Kaufmann P, Sen DK, Schweikhart G. Classification of human placental villi. I.
Histology and scanning electron microscopy. Cell Tissue Res 1979;
200:409–423.
Krantz KE, Parker JC. Contractile properties of the smooth muscle in the human placenta. Clin Obstet Gynecol 1963;6:26–38.
Leiser R, Luckhardt M, Kaufmann P, et al. The fetal vascularisation of term human placental villi. I. Peripheral stem villi Anat Embryol 1985;173:71–80.
Wigglesworth JS. Vascular organization of the human placenta. Nature (Lond) 1967;216:1120–1121.
