Gum-Based Stem Cells For Regenerative Medicine


The gums are also known as the gingivae, and this soft tissue serves as a biological barrier that covers the oral cavity of the maxillae and mandible (upper and lower jawbones). The gingivae also harbor a stem cell population known as gingival mesenchymal stem cells or GMSCs.

“Oh that’s a big surprise,” you say, “another mesenchymal stem cell population found in the body.” Well this one is a big deal because of its tissue of origin. Most MSCs are formed during embryonic development from cells that originate from the mesoderm, the embryonic tissue that lies between the skin of the embryo and the gut. Mesoderm forms the muscles, bones, connective tissue, adrenal glands, circulatory system, kidneys, gonads, and some other vitally important tissues.

Mesoderm

However, in the head, a large number of tissues are formed from “neural crest cells.” Neural crest cells hail from the top of the neural tube, which is the beginnings of the spinal cord. The dorsal-most portion of the neural tube contains a population of cells that move out of the neural tube and colonize the embryo to form a whole host of tissues. These include: Neurons, including sensory ganglia, sympathetic and parasympathetic ganglia, and plexuses, Neuroglial cells, Schwann cells, Adrenal medulla, Calcitonin-secreting cells, Carotid body type I cells, Epidermal pigment cells, Facial cartilage and bone Facial and anterior ventral skull cartilage and bones, Corneal endothelium and stroma, Tooth papillae, Dermis, smooth muscle, and adipose tissue of skin of head and neck, Connective tissue of salivary, lachrymal, thymus, thyroid, and pituitary glands, Connective tissue and smooth muscle in arteries of aortic arch origin. Wow, that’s a lot of stuff. I think you can see that these neural crest cells are important players during embryonic development.

Neural_Crest

Songtao Shi, from the Ostrow School of Dentistry, University of Southern California and his co-workers demonstrated that approximately 90% of GMSCs are derived from cranial neural crest cells and 10% are derived from mesoderm. This is important because neural crest-based stem cells seem to have greater plasticity.

Shi and his team compared mesodermally derived MSCs with GMSCs and the neural crest derived MSCs have a greater ability to differentiate into neural cells and cartilage-making cells.

In a mouse model of colitis in which mice are fed dextran sulfate sodium, which induces colitis in the mice, the neural crest derived MSCs did a better job of relieving the inflammation associated with colitis than their mesodermally derived counterparts.

Shi admits that further research on these stem cells must be done in order to better understand them and their functional roles. Shi is especially interested in the functional interaction between the neural crest derived MSCs in the gum and the mesodermally derived MSCs. Also, their potential for suppressing inflammation in particular diseases of the immune system and wound healing needs to be examined in some detail.

Genomic Imprinting Maintains A Reserve Pool of Blood-Forming Stem Cells


Hematopoietic stem cells or HSCs reside in the bone marrow and give rise to the wide variety of specialized blood cells that inhabit our bloodstreams. Within the bone marrow, HSCs come in two varieties: an active arm of HSCs that proliferate continually to replace our blood cells and a reserve arm that sits and quietly waits for their time to come.

New research from the Stowers Institute at Kansas City, Mo, in particular a research team led by Linheng Li, discovered a mechanism that helps maintain the balance between those HSCs kept in reserve and those on active duty.

According to Dr. Li, genomic imprinting, a process that specifically shuts off one of the two gene copies found in each mammalian cell , prevents the HSCs held in reserve from being switched to active duty prematurely.

Li explained: “Active HSCs form the daily supply line that continually replenishes worn-out blood and immune cells while the reserve pool serves as a backup system that replaces damaged active HSCs and steps in during times of increased need. In order to maintain a long-term strategic reserve of hematopoietic stem cells that lasts a lifetime it is very important to ensure that the back-up crew isn’t mobilized all at once. Genomic imprinting provides an additional layer of regulation that does just that.”

Sexual reproduction produces progeny that have once set of chromosomes from the mother and one set of chromosomes from the father. The vast majority of genes are expressed from both sets of chromosomes. However, in placental mammals and marsupial mammals a small subset of genes are imprinted, which means that they receive a mark during the development of eggs and sperm and these marks shut down expression of those genes in either the sperm pronucleus or the egg pronucleus. Therefore, after the fusion of the sperm and the egg and the eventual fusion of the egg and sperm pronuclei, these imprinted genes are only expressed from one copy of genes. Some are only expressed from the paternal chromosomes and others are only expressed from the maternal chromosome. Imprinting is essential for normal development in mammals.

The importance of genetic imprinting is shown if an egg loses its pronucleus and is then fertilized by two sperms. The resulting zygote has two copies of paternal chromosomes and no copies of the maternal chromosomes. Such an embryo is called an andogenote, and the embryo fails to form but the placenta overgrows. If this occurs during human development, it can lead to a so-called “molar pregnancy” or “hydatiform mole.” This fast growing placental tissue can become cancerous and lead to uterine cancer. For that reason, molar pregnancies are usually dealt with expeditiously.

However, if the sperm that fertilizes the egg is devoid of a pronucleus, and the egg pronucleus duplicates, then the resulting zygotes can two copies of the maternal chromosomes, and this entity is known as a gynogenote, and it develops with a poorly formed placenta that dies early in development.

In previous experiments in mice, Li and his colleagues indicated that the expression of several imprinted genes changes as HSCs transition from quiescent reserve cells to multi-lineage progenitor cells.

In their current study, Li and other Stowers Institute researchers examined a differentially imprinted control region, which drives the reciprocal expression of a gene called H19 from the maternal chromosome and IGF2 (insulin-like growth factor-2) from the paternal chromosome.

The first author of this study, Aparna Venkatraman developed a mouse model that allowed her to specifically delete the imprinted copy from the maternal chromosome. Thus, in these mice, H19, which restricts growth, was no longer active and Igf2,, which promotes cell division, was now active from the paternal and the maternal chromosome. To access the effect of this loss of imprinting on the maintenance of HSCs, Venkatraman examined the numbers of quiescent HSCs and active HSCs. in mouse bone marrow.

Venkatraman explained: “A large number of quiescent HSCs was activated simultaneously when the epigenetic control provided by genomic imprinting was removed. It created a wave of activated stem cells that moved through different maturation stages.”

She followed this experiment with a closer look at the Igf2 gene. Misregulation of Igf2 leads to overgrowth syndromes such as Beckwith-Wiedmann Syndrome. It exerts its growth promoting effects through the Igf1 receptor, which induces an intracellular signaling cascade that stimulates cell proliferation.

IGF signaling pathway
IGF signaling pathway

The expression of the Igf1 receptor itself is regulated by H19, which encodes a regulatory microRNA (miR-675) that represses translation of the Igf1 receptor gene and therefore prevents production of Igf1 receptor protein. Venkatraman explained that once the “imprinting block is lifted, the Igf2-Igf1r signaling pathway is activated.” Venkatraman continued: “The resulting growth signal triggers the inappropriate activation and proliferation of quiescent HSCs, which eventually leads to the premature exhaustion of the reserve [HSC] pool.”

Interestingly, the roundworm, Caenorhabditis elegans, provided the first clues that diminished insulin/IGF signaling can increase lifespan and delay aging. Li again: “Here the IGF pathway is conserved by subject to imprinting, which inhibits its activation in quiescent reserve stem cells. This ensures the long-term maintenance of the blood system, which in turn supports the longevity of the host.”