Human Wharton's Jelly-Cellular Specificity, Stemness Potency, Animal Models, and Current Application in Human Clinical Trials

Abstract

Stem cell therapies offer a great promise for regenerative and reconstructive medicine, due to their self-renewal and differentiation capacity. Although embryonic stem cells are pluripotent, their utilization involves embryo destruction and is ethically controversial. Therefore, adult tissues that have emerged as an alternative source of stem cells and perinatal tissues, such as the umbilical cord, appear to be particularly attractive. Wharton's jelly, a gelatinous connective tissue contained in the umbilical cord, is abundant in mesenchymal stem cells (MSCs) that express CD105, CD73, CD90, Oct-4, Sox-2, and Nanog among others, and have the ability to differentiate into osteogenic, adipogenic, chondrogenic, and other lineages. Moreover, Wharton's jelly-derived MSCs (WJ-MSCs) do not express MHC-II and exhibit immunomodulatory properties, which makes them a good alternative for allogeneic and xenogeneic transplantations in cellular therapies. Therefore, umbilical cord, especially Wharton's jelly, is a promising source of mesenchymal stem cells.

Keywords: Wharton’s jelly; stem cells; umbilical cord.

Figure 1

The schematic cross section of human umbilical cord covered with the umbilical cord lining, with an outer layer of umbilical epithelium, and three umbilical vessels embedded in Wharton’s jelly. Both umbilical vein and umbilical arteries are devoid of tunica adventitia. Between the latter, the residual allantois is located. Wharton’s jelly is a gelatinous connective tissue composed of extracellular matrix abundant in glycosaminoglycans (mostly hyaluronic acid), collagen fibers and myofibroblasts, and occasional mast cells. Stromal cells of Wharton’s jelly are most abundant in the proximity of the umbilical vessels in perivascular Wharton’s jelly, becoming less abundant in intervascular Wharton’s jelly, with the least amount of stromal cells in subamniotic Wharton’s jelly. The degree of stromal cells’ differentiation towards myofibroblasts is the highest near the vessels, gradually decreasing towards the umbilical epithelium.

Figure 2

Isolation of cells from Wharton’s jelly may be performed with the use of two different methods, namely, explant method or enzymatic digestion. In both cases, the umbilical epithelium and vessels are initially removed, while the residual tissue is mechanically fragmented. The tissue pieces are placed directly on the culture vessel in the explant method, which results in the cell outgrowth on the plastic surface. In the enzymatic method, the tissue pieces are first digested in the enzymatic solution, and after that the cells released from the tissue are centrifuged, suspended in the culture medium, and seeded in the culture vessels.

Figure 3

Stromal cells from Wharton’s jelly have a broad differentiation capacity and are able to transform into cells of all three primary germ layers: endoderm, ectoderm, and mesoderm. The endodermal lineages obtained from WJ-MSCs include hepatocytes or pancreatic islet-like cells. Differentiation of WJ-MSCs towards mesodermal lineages resulted in obtaining cells such as osteoblasts, chondroblasts, adipocytes, cardiomyocytes, skeletal muscle cells, or endothelial cells. Transformation of WJ-MSCs into neurons, which are of ectodermal origin, has also been achieved.