Placenta - Villi Development

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Placental villi cartoon

This page introduces an overview of aspects of the basic fetal subunit of the placenta, the placental villi development. In early placentation, each villi proceeds through a similar initial program of development. In later placentation, villi morphologically differentiate into a limited range of villi functional changes reflecting their specialization. The major initial contribution is from the trophoblast shell that surrounds the conceptus and later by the development of extraembryonic mesoderm and blood vessel differentiation.

There are three main types of trophoblast cells that differentiate:

  1. villous cytotrophoblasts
  2. extravillous cytotrophoblasts
  3. syncytiotrophoblasts that form by fusion of villous cytotrophoblasts

Placenta Links: placenta | Lecture - Placenta | Lecture Movie | Practical - Placenta | implantation | placental villi | trophoblast | maternal decidua | uterus | endocrine placenta | placental cord | placental membranes | placenta abnormalities | ectopic pregnancy | Stage 13 | Stage 22 | placenta histology | placenta vascular | blood vessel | cord stem cells | 2013 Meeting Presentation | Placenta Terms | Category:Placenta
Historic Embryology - Placenta 
1883 Embryonic Membranes | 1907 Development Atlas | 1909 | 1910 Textbook | 1917 Textbook | 1921 Textbook | 1921 Foetal Membranes |1921 human | 1921 Pig implantation | 1922 Single placental artery | 1923 Placenta Review | 1939 umbilical cord | 1943 human and monkey | 1944 chorionic villus and decidua parietalis | 1946 placenta ageing | 1960 first trimester placenta | 1960 monkey | 1972 Placental circulation | Historic Disclaimer

Some Recent Findings

  • Image processing methods for the structural detection and gradation of placental villi[1] "The context-based examination of stained tissue specimens is one of the most important procedures in histopathological practice. The development of image processing methods allows for the automation of this process. We propose a method of automatic segmentation of placental structures and assessment of edema present in placental structures from a spontaneous miscarriage. The presented method is based on texture analysis, mathematical morphology, and region growing operations that are applicable to the heterogeneous microscopic images representing histological slides of the placenta. The results presented in this study were obtained using a set of 50 images of single villi originating from 13 histological slides and was compared with the manual evaluation of the pathologist. In the presented experiments, various structures, such as villi, villous mesenchyme, trophoblast, collagen, and vessels have been recognized. Moreover, the gradation of villous edema for three classes (no villous edema, moderate villous edema, and massive villous edema) has been conducted. Villi images were correctly identified in 98.21%, villous mesenchyme was correctly identified in 83.95%, and the villi evaluation was correct in 74% for the edema degree and 86% for the number of vessels."
More recent papers  
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Search term: Placental Villi | Hofbauer cells

Older papers  
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  • Gene markers of normal villous maturation and their expression in placentas with maturational pathology[2] "The placenta demonstrates a recognized sequence of histomorphologic maturation throughout pregnancy, and in some cases, shows abnormally advanced (AVM) or delayed (DVM) villous maturation. While AVM and DVM have important clinical implications, it is unknown whether they truly represent a state of accelerated/delayed normal maturation or a state of pathological maldevelopment. The purpose of our study is, therefore, to address this challenge via a genome-wide search for expression markers of normal villous maturation (NM) and the assessment of these genes in cases of maturational pathology. DISCUSSION: We have found evidence of advanced molecular GA in AVM placentas, while molecular alterations in DVM placentas were merely suggestive of delayed maturation. In the future, these findings will need to be validated with additional techniques such as in situ hybridization or immunohistochemistry."

Cytotrophoblast Layer

There is a new interpretation of the changes that are occuring in the cytotrophoblast (CTB) layer during early to full-term human placenta development. Traditionally the interpretation was that the cytotrophoblast layer thinned and became discontinuous towards term. The thinning is thought due to the epithelium surface expanding at a faster rate than its volume. Two recent studies suggest that while the cytotrophoblast layer does indeed thin, it does not become discontinuous.

Syncytiotrophoblast Layer

The syncytiotrophoblast (STB) layer forms the epithelial covering of the entire villous tree. These cells are multinucleated, terminally-differentiated syncytium formed by the fusion of the underlying progenitor cytotrophoblast (CTB) cells. The process is described as "syncytialization" and is mediated by syncytin-1, an envelope protein of a human endogenous retrovirus W (HERV-W). The differentiation is regulated by chorionic gonadotropin (hCG) and the fusion of cytotrophoblast cells is ongoing during placental development.

Cellular parts derived from the syncytiotrophoblasts (apoptotic nuclei and microparticulate debris) can be shed into the maternal blood in which they are bathed. The apototic process appears to be part of the fusion mechanism between cytotrophoblast and the overlying multinucleate syncytiotrophoblast layer.

Studies have suggested that these cells are transcriptionally inactive. A recent study using a number of different detection techniques now suggests that at least some of the cells nuclei may still be transcriptionally inactive.

Mesenchymal Villi

Mesenchymal villi generate all other villous types:

  • immature intermediate villi
  • stem villi
  • mature intermediate villi
  • terminal villi

Mesenchymal villi continuously form out of the trophoblastic sprouts throughout pregnancy and have been considered the basis for growth and differentiation of the villous trees.

Villi Stages

Early chorionic (placental) villi development is defined by the contribution number and type of layers. In early embryonic placental development, villi proceed through each of these stages, while later fetal development consists mainly of branching of existing villi.

Primary Villi

Week 2 - (GA week 4) first stage of chorionic villi development, trophoblastic shell cells (syncitiotrophoblasts and cytotrophoblasts) form finger-like extensions into maternal decidua. Gray0036.gif

Secondary Villi

Week 3 - (GA week 5) second stage of chorionic villi development, extraembryonic mesoderm grows into villi, covers entire surface of chorionic sac.

Basal region will form chorionic plate. Gray0037.gif

Tertiary Villi

Week 4 - (GA week 6) third stage of chorionic villi development, mesenchyme differentiates into blood vessels and cells, forms arteriocapillary network, fuse with placental vessels, developing in connecting stalk.


Villi Types

Later villi development has additional morphological and functional descriptions.

  • stem villi - or anchoring villi, cytotrophoblast cells attached to maternal tissue.
  • branched villi - grow from sides of stem villi, region of main exchange, surrounded by maternal blood in intervillous spaces.
  • terminal villi - not active outgrowths caused by proliferation of the trophoblast. Passive protrusions induced by capillary coiling due to growth of the fetal capillaries within the mature intermediate villi (third trimester).
  • chorionic plate - region of membrane at the base of the villi through which placental arteries and vein passes.

Hofbauer Cells

Placental villi Hofbauer cells[3]

The placental macrophages known as Hofbauer cells[4] can be seen located within the villi and may have different origins depending on gestational age.[5]

  • early pregnancy - may differentiate from villous mesenchymal stem cells of the stroma or monocyte progenitor cells from the hypoblast-derived yolk sac
  • later pregnancy - may originate from fetal hematopoietic stem cells. For example, fetal monocytes that were recruited to the placenta.

Hofbauer Cell features:

  • highly vacuolated cells
  • located the core stroma of placental villi and cord
  • macrophages with micropinocytotic activity and phagocytosis ability
  • possible paracrine role for early stages of placental vasculogenesis

Human placental villi cartoon 01.jpg

A figure showing the changes in placental villi between early (first trimester) and late (third trimester) placental development.

The Hofbauer cells can also be a site of placental transmitted pathogen infection and act as a reservoir for fetal infection.

Villi Trimester Development

Trimester 1 and 2

In the first two trimesters they are the forerunners of the immature intermediate villi, whereas in the last trimester the mesenchymal villi are transformed into mature intermediate villi. Immature intermediate villi formed during the first two trimesters are developmental steps towards the stem villi.

Trimester 3

Mature intermediate villi develop during the last trimester, produce numerous terminal villi. Terminal villi are not active outgrowths caused by proliferation of the trophoblast, but rather passive protrusions induced by capillary coiling due to excessive longitudinal growth of the fetal capillaries within the mature intermediate villi. The arrangement of the capillary bed in the terminal villi can vary from simple U-like loops to a richly branched network due to capillary elongation and sprouting.

Some text modified from[6], see also[7]

Placental Villi Blood Vessels

Some of the following data is from a histological study of human placental villi.[8]

  • macrophage-like cells first cells to differentiate at day 21 (post-conception) from mesenchymal precursors.
  • haemangioblastic cell cords (angiogenic cell cords, ACC) at day 21 (post-conception) also from mesenchymal cells, are the precursors of the capillary endothelium and haematopoietic stem cells
  • pericytes form later and are a third cell population derived from the mesenchymal cells
  • first main vascular patterns grow towards the longitudinal axis of the developing villi
  • capillary basal lamina cannot be detected earlier than in the third trimester
  • third trimester - fetal villous angiogenesis occurs by proliferation of the existing endothelium and pericytes rather than through haemangioblastic cells.

Human Villi Timeline

Human Villi Timeline
Fertilization Age


Gestational Age


Vessel Lumen Diameter

(range in microns, µm)

3 to 4 5 and 6 10 - 15
  • a complex network of cords and vessels with redundant connections
  • network comprises mainly cords, already connected together
  • vessels and cords are connected to each other without any interruptions
  • chorionic villus dominated by this network of vascular elements
  • vessels and cords are located centrally as well as peripherally and as a consequence contact the overlying trophoblastic layer
5 to 6 7 and 8 10 - 26
  • villi dominated by capillary network of vessels and cords
  • capillary network contains more vessels than cords
  • chorionic villus tip - regular small branched off (mesenchymal) chorionic villi are present containing CD31 positive cells
7 to 8 9 and 10 60 - 75 two central vessels

26 - 34 capillary network

  • villi have two large centrally located vessels
  • surrounded by and connected to a peripheral capillary network
  • capillary network contains vessels with a lumen in tight contact with overlying trophoblastic layer
  • villous projections also contain blind ending capillary sprouts
9 to 10 11 and 12 70 - 90 two central vessels

26 - 34 capillary network

  • immature intermediate villi characterized by two large vessels surrounded by a capillary network
  • capillary network has few cords
  • blind ending capillary sprouts off the capillary network
Vill development data based upon immunochemistry confocal laser scanning microscope (CLSM) study[9] with clinical gestational age (GA) from last menstrual period (LMP) and has been corrected for post-conception (fertilization) age, approximately 14 days later.

CD31 - (PECAM-1, Platelet Endothelial Cell Adhesion Molecule) is a cluster of differentiation molecule found on endothelial and other blood cells.

Extravillous Trophoblast Outgrowth

During the first trimester of human pregnancy, extravillous trophoblasts (EVT) from placental villi invade the decidua temporarily occluding the spiral arteries. This occusion prevents maternal blood flow and creates a low-oxygen environment, that may play a role in the regulation of extravillous trophoblast outgrowth.

A study has shown that the early placenta ( under 11 weeks of gestation) responds to oxygen concentration, whereas villi from older placentae (11 or 12 weeks) show no differential response.[10]


  1. Swiderska-Chadaj Z, Markiewicz T, Koktysz R & Cierniak S. (2018). Image processing methods for the structural detection and gradation of placental villi. Comput. Biol. Med. , 100, 259-269. PMID: 28797713 DOI.
  2. Leavey K, Benton SJ, Grynspan D, Bainbridge SA, Morgen EK & Cox BJ. (2017). Gene markers of normal villous maturation and their expression in placentas with maturational pathology. Placenta , 58, 52-59. PMID: 28962696 DOI.
  3. Lorenzi T, Turi A, Lorenzi M, Paolinelli F, Mancioli F, La Sala L, Morroni M, Ciarmela P, Mantovani A, Tranquilli AL, Castellucci M & Marzioni D. (2012). Placental expression of CD100, CD72 and CD45 is dysregulated in human miscarriage. PLoS ONE , 7, e35232. PMID: 22606231 DOI.
  4. Wynn RM. (1967). Derivation and ultrastructure of the so-called Hofbauer cell. Am. J. Obstet. Gynecol. , 97, 235-48. PMID: 6017029
  5. Reyes L, Wolfe B & Golos T. (2017). Hofbauer Cells: Placental Macrophages of Fetal Origin. Results Probl Cell Differ , 62, 45-60. PMID: 28455705 DOI.
  6. Castellucci M, Scheper M, Scheffen I, Celona A & Kaufmann P. (1990). The development of the human placental villous tree. Anat. Embryol. , 181, 117-28. PMID: 2327595
  7. Castellucci M, Kosanke G, Verdenelli F, Huppertz B & Kaufmann P. (2000). Villous sprouting: fundamental mechanisms of human placental development. Hum. Reprod. Update , 6, 485-94. PMID: 11045879
  8. Demir R, Kaufmann P, Castellucci M, Erbengi T & Kotowski A. (1989). Fetal vasculogenesis and angiogenesis in human placental villi. Acta Anat (Basel) , 136, 190-203. PMID: 2481376
  9. Lisman BA, van den Hoff MJ, Boer K, Bleker OP, van Groningen K & Exalto N. (2007). The architecture of first trimester chorionic villous vascularization: a confocal laser scanning microscopical study. Hum. Reprod. , 22, 2254-60. PMID: 17545656 DOI.
  10. James JL, Stone PR & Chamley LW. (2006). The effects of oxygen concentration and gestational age on extravillous trophoblast outgrowth in a human first trimester villous explant model. Hum. Reprod. , 21, 2699-705. PMID: 16807282 DOI.



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