Cord lining, cord tissue, or umbilical cord lining membrane, is the outermost layer of the

umbilical cord In placental mammals, the umbilical cord (also called the navel string, birth cord or ''funiculus umbilicalis'') is a conduit between the developing embryo or fetus and the placenta. During prenatal development, the umbilical cord is physiologi ...

. As the

itself is an extension of the placenta, the umbilical cord lining membrane is an extension of the amniotic membrane covering the placenta. The umbilical cord lining membrane comprises two layers: the amniotic (or epithelial) layer and the sub-amniotic (or mesenchymal) layer. The umbilical cord lining membrane is a rich source of two strains of

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

s (CLSCs): epithelial stem cells (from the amniotic layer) (CLECs) and

mesenchymal stem cell Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage c ...

s (from the sub-amniotic layer) (CLMCs). Discovered by Singapore-based CellResearch Corporation in 2004, this is the best known source for harvesting human stem cells.

Cross-section of the umbilical cord

Source of mesenchymal stem cells

The sub-amniotic region of the umbilical cord lining has been reported to be a source of

mesenchymal stem cells Mesenchymal stem cells (MSCs) also known as mesenchymal stromal cells or medicinal signaling cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes (cartilage ce ...

termed (CLMCs). These cells express MSC specific markers such as

NT5E 5′-nucleotidase (5′-NT), also known as ecto-5′-nucleotidase or CD73 (cluster of differentiation 73), is an enzyme that in humans is encoded by the ''NT5E'' gene. CD73 commonly serves to convert AMP to adenosine. Transcription factor bindin ...

(

cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...

73),

endoglin Endoglin (ENG) is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1. It has a crucial role in angiogenesis, therefore, ...

(CD105) as well as Oct 3/4 and NANOG. Furthermore, these CLMCs can also be differentiated in-vitro into osteogenic, chondrogenic and adipogenic lineages. MSC from the sub-epithelial region of the cord lining can be expanded in-vitro for more than 30 passages or 90 population doublings without losing their multi-lineage differentiation capability or going into senescence. MSC isolated from the cord lining membrane have been reported to be immune-privileged. Compared with MSC from the bone marrow, cord lining MSC showed more effective immune suppression presumably due to lower expression of HLA Class I on their surfaces and also higher expression of immune suppressive cytokines. Compared with MSC from cord blood, placenta and Wharton’s Jelly, cord lining MSC showed the highest proliferation and migration potential. Furthermore, they expressed lower levels of HLA Class I and II, contributing to their lower immunogenicity. Pre-clinical studies performed on the cord lining MSC have revealed their potential in repairing heart muscle damage due to ischemia. A study performed in the rat model showed improved heart function and reduction of damaged myocardium when cord lining MSC combined with a fibrin gel carrier and a vascularized graft were introduced to the ischaemic area. A similar study combining the cord lining MSC with carrier endothelial cells within a fibrin matrix in-vivo also revealed improvement in cardiac function, reduction in scar tissue formation and better vascularization.

Source of epithelial stem cells

The amniotic layer of the umbilical cord lining has been shown to contain a large population of epithelial stem cells (EpSC). These cord lining EpSC exhibit classical pluripotent stem cell markers such as SSEA-4, Oct-4, SOX2 and Nanog.Huang, L. (2011). Stem cell-like properties of human umbilical cord lining epithelial cells and the potential for epidermal reconstitution. Cytotherapy, 13(2), 145-155. They also express p63, a specific marker of epithelial progenitor cells.Reza, H. M. (2011). Characterization of a novel umbilical cord lining cell with CD227 positivity and unique pattern of P63 expression and function. Stem Cells Reviews and Reports, 7(3), 624-638. In-vitro organotypic culture of cord lining EpSC using the air-liquid interface method resulted in stratified epithelium being formed with expression of various forms of cytokeratins. Furthermore, due to their similarity in terms of phenotypic expression of keratins compared to normal human epidermal keratinocytes, cord lining EpSC have the potential to be an alternative source of cells for skin repair and regeneration. Animal studies on cord lining EpSC have shown that genetic modifications using the proinsulin gene allowed transplanted stem cells to lower blood glucose levels in diabetic animals. These cells also express HLA-G in the transmembrane and soluble form, aiding in their immunosuppressive behavior. In vitro studies also indicated that cord lining EpSC can be differentiated biochemically to become hepatocyte-like cells (liver cells) as shown by the expression of hepatic-specific markers such as â-fetoprotein, albumin and hepatocyte-specific cytokeratins.Cheong, H. H. (2013). Metabolically functional hepatocyte-like cells from human umbilical cord lining epithelial cells. Assay Drug Development and Technologies, 11(2), 130-138. Cord lining EpSC show similarities to limbal

s in terms of expression of ABCG2, HES1 and BMI1 in addition to p63. When transplanted onto rabbit eyes with corneal defects on a human amniotic membrane scaffold, these

s could reconstitute the natural morphology of the corneal epithelium similar to that of a natural corneal surface. The stem cells included a unique mucin-expressing cord lining epithelial stem cell (CLEC-muc) expressing (

MUC1 Mucin short variant S1, also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen (EMA), is a mucin encoded by the ''MUC1'' gene in humans. Mucin short variant S1 is a glycoprotein with extensive O-linked glycosylation of its e ...

). Such results were not seen when human amniotic membrane was used without the cells indicating the therapeutic value of the cord lining EpSC.

References

{{Extraembryonic and fetal membranes Stem cells Vertebrate developmental biology Embryology