Olena Pogozhykh,corresponding author 1 , 2 Volodymyr Prokopyuk, 2 Constança Figueiredo, 1 and Denys Pogozhykh 1 ,
Recent research suggests that fetal and placental tissue have genetically different genotypes than maternal tissue creating a model of engraftment capable of producing a successful allogeneic transplantation of fetal and placental tissue. Clinicians and researchers have long been utilizing placental tissue for regenerative therapeutics. Characterization of the biological products in placental tissue can provide direction for future clinical developments.
Structure and Properties of the Placenta and Fetal Membranes
Development of the Placenta
” During pregnancy provides the key to understand its structural and functional peculiarities. At the stage of 8 blastomeres, the blastocyst divides into embryoblast and trophoblast. Trophoblast forms villi and first primary, containing only the trophoblast, then secondary, containing the stroma (embryonic mesenchyme), and later tertiary, containing the vessels (Figures 1(a) and 1(b)). At the same time, division of the trophoblast into syncytium and cytotrophoblast takes place. Implantation processes and trophoblast invasion occur through the enzymatic destruction of the endometrium and decidua of the uterus and layering of the resulting lacunae with trophoblast cells, replacing the choroid of the spiral arteries with trophoblast, which prevents thrombosis and makes the arteries refractory to vasopressor agents. After 6–8 weeks of pregnancy, the villi remain only on the placental site. The rest of the villi become atrophied and the smooth chorion, containing significant amounts of the trophoblast elements, is being formed [6, 7]. “
Trophoblast cells, mesenchymal cells, and endothelial cells of vessels make up the majority of the cell types within the placenta.
Controversy surrounds using tissue from the first two trimesters of pregnancy, so the majority of research is focused on the third trimester placenta (38-40 weeks of pregnancy). The mature placenta contains both fetal and maternal components. The fetal part of the placenta is composed of the chorionic plate, amnion, and umbilical cord.
” Fetal membranes (Figure 1(c)), amniotic and chorionic, are formed on the basis of the smooth chorion and can be easily separated at the intermediate layer. Thin, transparent, and smooth amniotic membrane is composed of a single layered epithelium and the amniotic mesenchyme, an avascular connective tissue. Chorionic membrane is composed of fibroblasts and a large number of trophoblast cells. The chorionic plate represents the fetal surface of the placenta, which is covered by the amnion. The umbilical cord enters the chorionic plate and connects the fetus to placenta. Umbilical cord is 50–70 cm in length and 1-2 cm in thickness. It is covered by the amniotic epithelium and contains two arteries and one vein that are immersed in the Wharton’s jelly (which contains a large amount of fibroblast cells and has an intercellular substance rich in hyaluronic acid) (Figures 1(d)–1(f)) [1, 6]. The maternal part, or so-called basal plate, is comprised of bed and walls of lacunae, formed by decidual endometrial tissue. Additionally, the maternal part contains NK cells, macrophages, and other immune cells. Therefore, postpartum placental cells possess mainly the fetal genotype with a certain amount of maternal cells [1, 7].”
The trophoblast cells in placental tissue are protected by the maternal immune system due to their biologic profile. A reduced expression of the major histocompatibility complex, apoptosis-inducing mechanisms, and a number of cytokines, and the influence of hormones make it hard for the maternal immune system to recognize these cells. Due to this suppression of the immune response, patients with autoimmune conditions tend to go into remission during pregnancy.
Trophoblasts produce a number of hormones that typically impact the reproductive and immune systems. Estradiol, progesterone, and chorionic gonadotropin regulate the development of the fetus throughout pregnancy.
Trophoblasts have the capability to exist long term in the maternal tissue, as well as outside of the placenta. There isn’t a current consensus as to the role of the trophoblast expulsion.
History of Clinical Application of Placental Components
Substantial research exists regarding the therapeutic and experimental use of placental tissue, however, little analysis and follow up has been conducted.
As seen in the figure above, ” conventional forms of application of placenta-derived biomaterial in clinics: placental extracts and lyophilizates, cord blood serum, various types of differentiated and stem cells, amniotic and chorionic membranes, and fragments of placental tissue. “
Cord Blood Cells
Umbilical cord blood contains a high concentration of hematopoietic stem cells and shows great efficacy when used as an allogenic transplant in patients with hematologic and metabolic pathologies.
Umbilical cord blood contains erythrocytes and platelets. Fetal cord blood contains 90% erythrocytes and fetal hemoglobin has a higher affinity to oxygen. The transplant of fetal blood erythrocytes into adults can result in better recovery of “neutrophils and slower recovery of platelets in comparison to transfusion of erthrocytes.”
Placental extracts are used in a wide range of therapies , most commonly in “surgery, neurology, gynecology, and dermatology.” They “possess anti-inflammatory, analgesic , antioxidant [50, 51], cyto- and radioprotective , and anti-allergic properties and express hormonal activity [16, 53, 54], as well as stimulate proliferation and reparative processes [14, 55, 56].”
The mechanism of action in wound healing utilizing placental extracts has been defined as an increase in TGF-B in early regeneration, VEGF in late stage regeneration, the presence of FGF and CD31, and the amplification of angiogenesis.
The mechanism of action in neurological regeneration has been defined as an increase in the synthesis of GAP-43 and Cdc2.
Cord Blood Serum
Cord blood serum has shown to be effective as a regenerative therapy in ophthalmology, neurology, diabetes, obstetrics, and wound healing.
In ophthalmology, cord blood serum has been utilized on chemically and thermally damaged corneas and corneal erosion.
In diabetics, cord blood serum can be used to stimulate pancreas cells for insulin synthesis.
In obstetrics, the “application of cord blood serum in obstetrical antiphospholipid syndrome improves the readiness of preimplantation endometrium and reduces the number of antiphospholipid antibodies.  “
The efficacy of cord blood serum in wound healing has been defined by the presence of EGF, FGF, HGH, fibronectin, NGF, and IGF-1.
Isolated Placental Cells
Mesenchymal stromal cells isolated from placental cells express ” CD105, CD90, CD73, CD29, CD13, CD10, and to a minor extent HLA-A, B, and C, while not expressing CD14, CD34, CD45, and HLA-DR.  Importantly, the cells obtained by the mentioned protocols retain the ability to synthesize chorionic gonadotropin and express cytokeratin-7 and CD200 . Moreover, placental MSCs possess the capability of differentiation not only into three classical mesodermal lineages (adipogenic, osteogenic, and chondrogenic) but were also shown to be able to differentiate in myogenic, angiogenic, pancreatic, cardiogenic, and neurogenic cell types [6, 21]. “
Amniotic and Chorionic Membranes
The amniotic membrane is primarily used as a biological coating in surgery.
“The mechanism of action of placental membranes is explained by the effect of biological dressings, activation of epithelialization and neovascularization, suppression of inflammation, and scarring, as well as by antimicrobial properties [19, 109]. “
Placental fragments can be used as a biosorbent for the treatment of chronic inflammation. It has been shown to reduce the number of bacteria in the blood and endotoxemia, and can strengthen the central and peripheral blood flow in patients with chronic inflammatory diseases.
Efficacy has been shown when using amniotic fluid as a therapy in neurology, “bone healing , regeneration of nerve tissue , and prevention of epidural fibrosis .”
Current Research and Clinical Trials
The highest number of studies are dedicated to umbilical cord blood cells. Although, the amount of studies being conducted on placental MSCs is substantially smaller than what is being done on cord blood, the range of pathologies that can be addressed is greater.
Studies on amniotic membranes tend to revolve around nourishment and protection of “wounds, surgical defects, ulcers, and burns.”
Studies on placental extracts tend to focus on “degenerative diseases and disorders of the reproductive system.”
Cord blood serum studies are mainly related to ophthalmology.
Bio-banking of Placental Components
Bio-banking refers to the long term storage of placental material for clinical application or scientific research. Chemical preservation of placental components can be done in a multitude of ways through “high temperature sterilization, hypothermic storage, low temperature storage, and cryosublimation.” Sterilization of placental components consists of filtration or devitalization. Devitalization can significantly reduce immunogenicity and extends longevity.