Cord lining

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Cord lining, cord tissue, or umbilical cord lining membrane, is the outermost layer of the umbilical cord. As the umbilical cord 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 cells (CLSCs): epithelial stem cells (from the amniotic layer) (CLECs) and mesenchymal stem cells (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.

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Cross-section of the umbilical cord

A histological cross section of the umbilical cord showing the umbilical cord lining membrane. Cross section of the umbilical cord.jpg
A histological cross section of the umbilical cord showing the umbilical cord lining membrane.
Dissection of the umbilical cord to demonstrate the cord lining membrane (held up with forceps). Umbilical cord vessels and Wharton's Jelly have been dissected free. Dissection of the umbilical cord.jpg
Dissection of the umbilical cord to demonstrate the cord lining membrane (held up with forceps). Umbilical cord vessels and Wharton's Jelly have been dissected free.

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 termed (CLMCs). [1] [2] These cells express MSC specific markers such as NT5E (cluster of differentiation73), endoglin (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. [3]

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. [4] 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. [5]

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. [6] 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. [7]

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. [8] They also express p63, a specific marker of epithelial progenitor cells. [9] [10] 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. [8] 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. [11]

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. [12] 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. [13]

Cord lining EpSC show similarities to limbal stem cells in terms of expression of ABCG2, HES1 and BMI1 in addition to p63. [10] When transplanted onto rabbit eyes with corneal defects on a human amniotic membrane scaffold, these stem cells could reconstitute the natural morphology of the corneal epithelium similar to that of a natural corneal surface. [14] The stem cells included a unique mucin-expressing cord lining epithelial stem cell (CLEC-muc) expressing (MUC1). [15] Such results were not seen when human amniotic membrane was used without the cells indicating the therapeutic value of the cord lining EpSC.

Related Research Articles

<span class="mw-page-title-main">Stem cell</span> Undifferentiated biological cells that can differentiate into specialized cells

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 of cell in a cell lineage. They are found in both embryonic and adult organisms, but they have slightly different properties in each. They are usually distinguished from progenitor cells, which cannot divide indefinitely, and precursor or blast cells, which are usually committed to differentiating into one cell type.

<span class="mw-page-title-main">Amnion</span> Innermost membranous sac that surrounds and protects the developing embryo

The amnion is a membrane that closely covers the human and various other embryos when first formed. It fills with amniotic fluid, which causes the amnion to expand and become the amniotic sac that provides a protective environment for the developing embryo. The amnion, along with the chorion, the yolk sac and the allantois protect the embryo. In birds, reptiles and monotremes, the protective sac is enclosed in a shell. In marsupials and placental mammals, it is enclosed in a uterus.

<span class="mw-page-title-main">Umbilical cord</span> Conduit between embryo/fetus and the placenta

In placental mammals, the umbilical cord is a conduit between the developing embryo or fetus and the placenta. During prenatal development, the umbilical cord is physiologically and genetically part of the fetus and normally contains two arteries and one vein, buried within Wharton's jelly. The umbilical vein supplies the fetus with oxygenated, nutrient-rich blood from the placenta. Conversely, the fetal heart pumps low-oxygen, nutrient-depleted blood through the umbilical arteries back to the placenta.

<span class="mw-page-title-main">Cornea</span> Transparent front layer of the eye

The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is approximately 43 dioptres. The cornea can be reshaped by surgical procedures such as LASIK.

Cord blood is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells, which can be used to treat hematopoietic and genetic disorders such as cancer. There is growing interest from cell therapeutics companies in developing genetically modified allogenic natural killer cells from umbilical cord blood as an alternative to CAR T cell therapies for rare diseases.

<span class="mw-page-title-main">Adult stem cell</span> Multipotent stem cell in the adult body

Adult stem cells are undifferentiated cells, found throughout the body after development, that multiply by cell division to replenish dying cells and regenerate damaged tissues. Also known as somatic stem cells, they can be found in juvenile, adult animals, and humans, unlike embryonic stem cells.

Articular cartilage, most notably that which is found in the knee joint, is generally characterized by very low friction, high wear resistance, and poor regenerative qualities. It is responsible for much of the compressive resistance and load bearing qualities of the knee joint and, without it, walking is painful to impossible. Osteoarthritis is a common condition of cartilage failure that can lead to limited range of motion, bone damage and invariably, pain. Due to a combination of acute stress and chronic fatigue, osteoarthritis directly manifests itself in a wearing away of the articular surface and, in extreme cases, bone can be exposed in the joint. Some additional examples of cartilage failure mechanisms include cellular matrix linkage rupture, chondrocyte protein synthesis inhibition, and chondrocyte apoptosis. There are several different repair options available for cartilage damage or failure.

An amniotic epithelial cell is a form of stem cell extracted from the lining of the inner membrane of the placenta. Amniotic epithelial cells start to develop around 8 days post fertilization. These cells are known to have some of the same markers as embryonic stem cells, more specifically, Oct-4 and nanog. These transcription factors are the basis of the pluripotency of stem cells. Amniotic epithelial cells have the ability to develop into any of the three germ layers: endoderm, mesoderm, and ectoderm. They can develop into several organ tissues specific to these germ layers including heart, brain, and liver. The pluripotency of the human amniotic epithelial cells makes them useful in treating and fighting diseases and disorders of the nervous system as well as other tissues of the human body. Artificial heart valves and working tracheas, as well as muscle, fat, bone, heart, neural and liver cells have all been engineered using amniotic stem cells. Tissues obtained from amniotic cell lines show promise for patients with congenital diseases or malformations of the heart, liver, lungs, kidneys, and cerebral tissue.

<span class="mw-page-title-main">Human embryonic development</span> Development and formation of the human embryo

Human embryonic development, or human embryogenesis, is the development and formation of the human embryo. It is characterised by the processes of cell division and cellular differentiation of the embryo that occurs during the early stages of development. In biological terms, the development of the human body entails growth from a one-celled zygote to an adult human being. Fertilization occurs when the sperm cell successfully enters and fuses with an egg cell (ovum). The genetic material of the sperm and egg then combine to form the single cell zygote and the germinal stage of development commences. Embryonic development in the human, covers the first eight weeks of development; at the beginning of the ninth week the embryo is termed a fetus. The eight weeks has 23 stages.

Amniotic stem cells are the mixture of stem cells that can be obtained from the amniotic fluid as well as the amniotic membrane. They can develop into various tissue types including skin, cartilage, cardiac tissue, nerves, muscle, and bone. The cells also have potential medical applications, especially in organ regeneration.

<span class="mw-page-title-main">Fetal membranes</span> Amnion and chorion which surround and protect a developing fetus

The fetal membranes are the four extraembryonic membranes, associated with the developing embryo, and fetus in humans and other mammals. They are the amnion, chorion, allantois, and yolk sac. The amnion and the chorion are the chorioamniotic membranes that make up the amniotic sac which surrounds and protects the embryo. The fetal membranes are four of six accessory organs developed by the conceptus that are not part of the embryo itself, the other two are the placenta, and the umbilical cord.

miR-203

In molecular biology miR-203 is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several mechanisms, such as translational repression and Argonaute-catalyzed messenger RNA cleavage. miR-203 has been identified as a skin-specific microRNA, and it forms an expression gradient that defines the boundary between proliferative epidermal basal progenitors and terminally differentiating suprabasal cells. It has also been found upregulated in psoriasis and differentially expressed in some types of cancer.

<span class="mw-page-title-main">Mesenchymal stem cell</span> Multipotent, non-hematopoietic adult stem cells present in multiple tissues

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, chondrocytes, myocytes and adipocytes.

Dermal fibroblasts are cells within the dermis layer of skin which are responsible for generating connective tissue and allowing the skin to recover from injury. Using organelles, dermal fibroblasts generate and maintain the connective tissue which unites separate cell layers. Furthermore, these dermal fibroblasts produce the protein molecules including laminin and fibronectin which comprise the extracellular matrix. By creating the extracellular matrix between the dermis and epidermis, fibroblasts allow the epithelial cells of the epidermis to affix the matrix, thereby allowing the epidermal cells to effectively join together to form the top layer of the skin.

Tissue engineering of oral mucosa combines cells, materials and engineering to produce a three-dimensional reconstruction of oral mucosa. It is meant to simulate the real anatomical structure and function of oral mucosa. Tissue engineered oral mucosa shows promise for clinical use, such as the replacement of soft tissue defects in the oral cavity. These defects can be divided into two major categories: the gingival recessions which are tooth-related defects, and the non tooth-related defects. Non tooth-related defects can be the result of trauma, chronic infection or defects caused by tumor resection or ablation. Common approaches for replacing damaged oral mucosa are the use of autologous grafts and cultured epithelial sheets.

A Muse cell is an endogenous non-cancerous pluripotent stem cell. They reside in the connective tissue of nearly every organ including the umbilical cord, bone marrow and peripheral blood. They are collectable from commercially obtainable mesenchymal cells such as human fibroblasts, bone marrow-mesenchymal stem cells and adipose-derived stem cells. Muse cells are able to generate cells representative of all three germ layers from a single cell both spontaneously and under cytokine induction. Expression of pluripotency genes and triploblastic differentiation are self-renewable over generations. Muse cells do not undergo teratoma formation when transplanted into a host environment in vivo. This can be explained in part by their intrinsically low telomerase activity, eradicating the risk of tumorigenesis through unbridled cell proliferation. They were discovered in 2010 by Mari Dezawa and her research group. Clinical trials for acute myocardial infarction, stroke, epidermolysis bullosa, spinal cord injury, amyotrophic lateral sclerosis, acute respiratory distress syndrome (ARDS) related to novel coronavirus (SARS-CoV-2) infection, are conducted by Life Science Institute, Inc., a group company of Mitsubishi Chemical Holdings company. In february 2023, however, Mitsubishi Chemical Group decided to discontinue the development of a regenerative medicine product (CL2020) using Muse Cells. Physician-led clinical trial for neonatal hypoxic-ischemic encephalopathy was also started. The summary results of a randomized double-blind placebo-controlled clinical trial in patients with stroke was announced.

<span class="mw-page-title-main">Cordlife</span> Consumer health company

Incorporated in May 2001, Cordlife Group Limited, is a consumer health company and one of the leading providers of cord blood and cord lining banking services in Asia. Cordlife has been listed on the mainboard of SGX since March 2012.

<span class="mw-page-title-main">Limbal stem cell</span>

Limbal stem cells, also known as corneal epithelial stem cells, are unipotent stem cells located in the basal epithelial layer of the corneal limbus. They form the border between the cornea and the sclera. Characteristics of limbal stem cells include a slow turnover rate, high proliferative potential, clonogenicity, expression of stem cell markers, as well as the ability to regenerate the entire corneal epithelium. Limbal stem cell proliferation has the role of maintaining the cornea; for example, by replacing cells that are lost via tears. Additionally, these cells also prevent the conjunctival epithelial cells from migrating onto the surface of the cornea.

Pregnancy-specific biological substances, which include the placenta, umbilical cord, amniotic fluid, and amniotic membrane are being studied for a number of health uses. For example, Placental-derived stem cells are being studied so they can serve as a potential treatment method for cell therapy. Hepatocyte-like cells (HLC) are generated from differentiated human amniotic epithelial cells (hAEC) that are abundant in the placenta. HLC may replace hepatocytes for hepatocyte transplantation to treat acute or chronic liver damage.

CellResearch Corporation is a biotechnology company with a primary focus on skin cell and cord lining stem cell research. CellResearch has one of the world's largest private skin-, scar-, and keloid-cell libraries which have been used for research by cell culture laboratories worldwide, including those at Harvard University, Procter & Gamble and Johnson & Johnson. It owns 39 patents worldwide with intellectual property for the isolation of stem cells from the umbilical cord lining membrane of all mammals, which also includes the banking and cultivation of these cells, as well as the therapeutic applications of these cells.

References

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