The Gift of Life: Stem Cells in the Umbilical Cord

The acquisition of the umbilical cord has natural advantages. Both the umbilical cord and the placenta are medical waste in my country, and there is no additional trauma to the donor (donor), and there is no medical ethics. From this perspective, compared with adipose tissue, extracted bone marrow, dental pulp and other sources, the isolation and culture of mesenchymal stem cells (MSCs) from the umbilical cord has certain advantages in industrialization. Worldwide, umbilical cord MSC has carried out hundreds of clinical studies, treating diseases including arthritis, stroke, liver disease, diabetes, cardiovascular disease, etc., as shown in the figure below:

The umbilical cord develops from the yolk sac and is formed in the fifth week of fetal development. It connects the mother through the placenta, delivers nutrients to the fetus and excretes metabolites. The tissue structure of the umbilical cord is relatively simple, 40-60 cm long, 1-2 cm in circumference, surrounded by a layer of amnion, and 3 blood vessels (1 vein and 2 arteries) in the stroma.

The whole umbilical cord contains a variety of cell types, including mesenchymal stem cells, hematopoietic stem cells, epithelial stem cells, vascular endothelial cells, etc.

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The mucoid or mucous connective tissue is abundant in the stroma. In 1656, Thomas Wharton was the first to describe the jelly-like properties of the umbilical cord matrix, so the mucus connective tissue in the umbilical cord matrix is ​​also called "Wharton's jelly" (abbreviated as WJ). But Thomas Wharton did not realize that these jelly-like matrices contained cells, because Hooke discovered cells in 1665, nine years after Thomas Wharton first described the properties of the matrices.

Wharton's jelly is rich in type I collagen, as well as the small molecule chondroitin sulfate proteoglycan [1]. In addition to proteins and glycoproteins, the matrix contains hyaluronic acid, sulfated glycosaminoglycans, diffuse plasma proteins, but does not contain nerve cells and lymphatic vessels. According to HE staining, the matrix is ​​clearly divided into pink matrix and white matrix. Although studies have shown that there are certain differences in fibroblasts in these two parts of matrix, the origin of embryonic development may be different, but the specific matrix function has not yet been studied clearly.

In 1970, Parry used an electron microscope to discover the presence of fibroblast-like cells in the umbilical cord Wharton's jelly[2].

In 1978, Meyer used an electron microscope to reveal the structure of the umbilical artery [3]. The umbilical artery has two layers of cells, the inner layer is irregularly arranged loose endothelial cells, and the outer layer is smooth muscle cells, and the artery is not surrounded by adventitia, and directly contacts and connects with the matrix[3, 4].

In 1991, McElreavey isolated and cultured fibroblast-like cells from umbilical cord Wharton's jelly for the first time by using the tissue block culture method [5]. To this day, many laboratories still use McElreavey's method to isolate and culture umbilical cord mesenchymal stem cells by tissue block culture method.

Then in 1993, Takechi found that these fibroblast-like cells could secrete collagen fibers and express actin, vimentin, and desmin, which had the characteristics of myofibroblastic cells, but were obviously different from muscle cells [6]. It was not until 2003 that it was recognized that these fibroblast-like cells in Wharton's jelly were mesenchymal stem cells with the ability of adipogenic and osteogenic differentiation [7]. Since 2005, different laboratories have reported the existence of such umbilical cord mesenchymal stem cells, which have similar functional properties to bone marrow mesenchymal stem cells [8-10].

Studies have shown that the umbilical cord stroma is divided into three regions[11]. In addition to the pink stroma and white stroma discussed above, there is a thin layer of stroma under the amniotic membrane of the umbilical cord, as indicated by the Cord Lining WJ layer or the number 3 or sa in the figure below refers to a layer. That is, Wharton's jelly (WJ) is divided into 3 layers: Cord Lining WJ, Intermediate WJ, and Perivascular WJ from outside to inside (see the picture below). Mesenchymal stem cells can be isolated and cultured from Wharton's jelly (Cord Lining WJ, Intermediate WJ, Perivascular WJ) in different regions [12-17].

From Figure F above, the blue dye DAPI bound to the cell nucleus shows that the cell density around the umbilical cord vessels is the largest, and then radially outwards gradually become less. We can see that the cell density in the white arrow area is higher than other areas. The white arrow area is the Perivascular WJ area. The cells in the Perivascular WJ area account for 45% of all cells in the entire WJ area [18]. Why is there a gradient of decreasing cell density in the umbilical cord stroma? There is a theory that amniotic fluid contains PDGF-AB factor [19] and amnion epithelial cells express PDGF-B factor [20, 21], which attracts cells expressing this factor receptor (PDGF-R) in the matrix to migrate outward, resulting in cell The density is distributed in a gradient decreasing from the inside to the outside, and this group of migrating cells highly expresses CD146[4]. But this theory cannot explain why the cells in the stroma need to migrate from the perivascular to the adventitia, what is the significance?

Umbilical cord and placental blood are rich in hematopoietic stem cells, and these hematopoietic stem cells are suitable for transplantation treatment of blood diseases. It can be seen from the schematic diagram and the real picture of the umbilical cord and placenta that the venous blood of the umbilical cord and the venous blood of the placenta are connected; similarly, the arterial blood of the umbilical cord and the placental artery are also connected. The usual cord blood collection actually also collects placental blood, because the operator did not block the blood flow at the junction of the placenta and the umbilical cord when the blood was collected.

When the umbilical cord blood is collected, the placenta can be in the uterus (such as caesarean section), or it can be taken out of the mother’s uterus and placed on a sterile operating table (such as vaginal delivery). For the latter operation, please refer to the following video (from youtube) .