Perinatal Derivatives: Where Do We Stand? A Roadmap of the Human Placenta and Consensus for Tissue and Cell Nomenclature

Abstract

Progress in the understanding of the biology of perinatal tissues has contributed to the breakthrough revelation of the therapeutic effects of perinatal derivatives (PnD), namely birth-associated tissues, cells, and secreted factors. The significant knowledge acquired in the past two decades, along with the increasing interest in perinatal derivatives, fuels an urgent need for the precise identification of PnD and the establishment of updated consensus criteria policies for their characterization. The aim of this review is not to go into detail on preclinical or clinical trials, but rather we address specific issues that are relevant for the definition/characterization of perinatal cells, starting from an understanding of the development of the human placenta, its structure, and the different cell populations that can be isolated from the different perinatal tissues. We describe where the cells are located within the placenta and their cell morphology and phenotype. We also propose nomenclature for the cell populations and derivatives discussed herein. This review is a joint effort from the COST SPRINT Action (CA17116), which broadly aims at approaching consensus for different aspects of PnD research, such as providing inputs for future standards for the processing and in vitro characterization and clinical application of PnD.

Keywords: cells; consensus nomenclature; derivatives; fetal annexes; perinatal; placenta; tissues.

FIGURE 1

Architecture of the human term placenta. General overview of the relationship between the basal decidua (maternal side/component of the human placenta) and the fetal side/component of the human placenta represented by the chorion frondosum, the chorionic plate and the fused amniotic membrane (placental portion). The residual portion of the amniotic membrane (reflected portion) adheres to the chorion laeve (so called because it is devoid of villi) which is in touch with the capsular decidua. The amniotic membrane surrounds the amniotic cavity containing amniotic fluid with different types of detached cells. The magnified scheme shows the different parts of the term placental architecture. hBD-MSC, human basal decidua-mesenchymal stromal cells; hAFC, human amniotic fluid cells; hAFSC, human amniotic fluid stem cells; hAF-MSC, human amniotic fluid-mesenchymal stromal cells.

FIGURE 2

Stages of placental development. (A) Implantation at 6 to 7 days (d) after conception; (B) prelacunar period (7 to 8 days); (C) beginning of lacunar period (8 to 9 days); (D) transition from lacunar period to primary villus stage (12 to 15 days); (E) secondary villus stage (15 to 21 days); and (F) tertiary villus stage (18 days to week 12). BP, basal plate; BV, blood vessel; CP, primary chorionic plate; CT, cytotrophoblast; D, decidua; E, endometrial epithelium; EB, embryoblast; EG, endometrial gland; EM, extraembryonic mesoderm; EVT, extravillous trophoblast; IVS, intervillous space; M, myometrium; NF, Nitabuch fibrinoid; PB, placental bed; RF, Rohr fibrinoid; SA, spinal artery; ST, syncytiotrophoblast; T, trabeculae; TS, trophoblastic shell; UV, umbilical vein. (Redrawn and modified from Kaufmann, 1981).

FIGURE 3

Schematic representation of a human placenta during the first trimester of pregnancy. The chorionic plate represents the embryonic side of the placenta from which placental villi grow into the intervillous space. Anchoring villi are connected to the uterine wall by trophoblast cell columns from which extravillous trophoblasts invade into uterine tissues. From these sites interstitial trophoblast invades into the uterine stroma, differentiating into endoglandular trophoblast invading uterine glands, endovenous trophoblast, invading uterine veins and endoarterial trophoblast invading into uterine spiral arteries Histological images of (A) first trimester chorionic plate with a placental villus extending into the intervillous space, (B) first trimester mesenchymal villus with the cover of villous trophoblast and the mesenchymal villous stroma, (C) anchoring villus that is attached to the uterine wall by a trophoblast cell column, (D) first trimester placenta showing a number of anchoring villi attached to the uterine wall by trophoblast cell columns. Within the uterine wall a huge amount of interstitial trophoblast invades towards vessels, glands and the myometrium. A, uterine spiral artery; AV, anchoring villus; CC, trophoblast cell column; CP, chorionic plate; G, uterine gland; GA, gestational age; IT, interstitial trophoblast; IVS, intervillous space; PM, placental macrophage (Hofbauer cell); PV, placental villus; STB, syncytiotrophoblast; V, uterine vein; VCTB, villous cytotrophoblast; VS, villous stroma.

FIGURE 4

Schematic representation of a human placenta at term. The amniotic membrane is the layer closest to the fetus and is attached to the chorionic plate mesenchyme from which large stem villi reach into the intervillous space. The villous trees are fully differentiated and have a large number of terminal villi where enlarged capillaries, sinusoids, allow a higher exchange rate between maternal and fetal blood. Anchoring villi are still connected to the uterine wall, while trophoblast cell columns are exhausted. Spiral arteries invaded by endoarterial trophoblast and uterine veins invaded by endovenous trophoblast can still be found in the placental bed allowing the constant flow of maternal blood into the placenta and the drainage back into the maternal circulation (red arrows in artery and vein). Histological images of (A) term amniotic membrane with epithelium and avascular mesenchyme, (B) term chorionic plate covered by the amniotic membrane, (C) placental villi of a term placenta with a sinusoid in a terminal villus and a neighboring mature intermediate villus, (D) anchoring villus that is attached to the uterine wall where interstitial trophoblast can be found, (E) vessel in the basal plate of a term placenta. The vessel is surrounded by interstitial trophoblast. A, uterine spiral artery; AM, amniotic membrane; AV, anchoring villus; CP, chorionic plate; GA, gestational age; IT, interstitial trophoblast; MIV, mature intermediate villus; SI, sinusoid; STB, syncytiotrophoblast; TV, terminal villus; V, uterine vein.

FIGURE 5

Structure of the human amniotic membrane. (A) Schematic representation of the structure of the human amniotic membrane and tissues underneath (chorion laeve and capsular decidua). Human amniotic membrane epithelial cells (hAEC) form, for the most part, a monolayer facing the amniotic fluid. The basement membrane underneath separates the epithelial layer from the avascular amniotic mesoderm including the compact layer devoid of cells in touch with the basement membrane and the fibroblast layer below it containing human amniotic membrane mesenchymal stromal cells (hAMSC). Between amniotic membrane and the vascular chorionic mesoderm there are slender, fluid filled clefts forming an intermediate spongy layer. A basement membrane separates chorionic mesoderm from extravillous trophoblast (hCL-EVT) (embedded in self-secreted matrix-type fibrinoid) which is in touch with maternal capsular decidua (hCD). (B) Histological image of human amniotic membrane stained with haematoxylin-eosin staining solution. Magnification: 40x. (C) Transmission electron microscopy image showing the ultrastructure of hAEC belonging to the central region of hAM (left panel) or the peripheral region of hAM. Green arrows point at surface microvilli; pale blue arrows point at nuclei; blue arrows point at the basement membrane below hAEC; red asterisks point at different types of granules; orange asterisks point at nucleoli; yellow triangle points at extracellular matrix of the compact layer. Magnification: 3000x.

FIGURE 6

Cell populations from chorionic plate and chorionic villi. Histological images of human chorionic plate (hCP) and chorionic villi (hCV). Haematoxylin-eosin staining. (A) At low magnification (10x) the structure of hCP and hCV is appreciable. hCP-MSC: human chorionic plate mesenchymal stromal cells; hCP-EC: human chorionic plate endothelial cells. (B,C) At higher magnification (20x) cell populations present in the chorionic villi are more appreciable. hCVC, human chorionic villi cells; hCV-EC, human chorionic villi endothelial cells: hCV-MSC, human chorionic villi mesenchymal stromal cells; hCV-TC, human chorionic villi trophoblast cells.

FIGURE 7

Structure of the chorion laeve. Histological images of human amnio-chorionic membrane (hACM) in correspondence of the chorion laeve (hCL) and the capsular decidua (hCD). Haematoxylin-eosin staining. (A) At low magnification (20x) a general overview of this portion of the amnio-chorionic membrane, which has a smooth appearance due to the absence of chorionic villi, is appreciable. (B) At higher magnification (40x) it is possible to appreciate more cell populations present in the chorion laeve including extravillous trophoblast (hCL-EVT) and mesenchymal stromal cells (hCL-MSC).

FIGURE 8

Structure and cell populations from the umbilical cord. (A) Schematic structure of the human umbilical cord showing the presence on the surface of the amniotic membrane (hUC-AM) made of hUC-AEC and hUC-AMSC and the different regions of Wharton’s jelly (subamniotic, intermediate and perivascular). hUC-WJ-MSC, human umbilical cord Wharton’s jelly mesenchymal stromal cells; hUC-PVC, human umbilical cord perivascular cells; hUC-V, human umbilical cord vascular region; hUC-VSMC, human umbilical cord vascular smooth muscle cells. Histological images (Haematoxylin-eosin) of (B) hUC at low magnification (10x) showing the presence of two umbilical arteries (light blue arrows) surrounded by human umbilical cord Wharton’s jelly (hUC-WJ), (C) umbilical artery at higher magnification (20x) showing the presence of human umbilical cord perivascular cells (hUC-PV), (D) intermediate region of Wharton’s jelly showing at higher magnification (40x) the presence of numerous mesenchymal stromal cells (hUC-iWJ-MSC).

FIGURE 9

Cells from blood vessels of human umbilical cord. Histological sections of human umbilical vein (A) and artery (B) at low magnification (20x). Haematoxylin-eosin staining. hUC-MF, human umbilical cord myofibroblasts; HUAEC, human umbilical artery endothelial cells surrounding a lumen containing blood cells; HUVEC, human umbilical vein endothelial cells surrounding an empty lumen.

FIGURE 10

Decidua stromal cells. Histological images of human basal decidua (hBD). Haematoxylin-eosin staining. (A) A general overview of the uterine wall containing human basal decidua decidualized stromal cells (hBD-dDSC) representing the maternal component of the human placenta facing the fetal component represented by human chorionic villi (hCV) of the chorion frondosum is appreciable at low magnification (20x). (B) At higher magnification (40x) it is possible to appreciate the cell populations present in the human decidua including hBD-dDSC.