fibroblast-like MSC population with greater multipotent potency, faster proliferation, and longer life spans than adult bone marrow–derived MSCs.3 This is a result of reduced telomere length. Telomeres shorten with age, eventually resulting in cellular senescence. MSCs isolated from cord blood are much younger than adult MSCs and possess significantly longer telomeres.5
MSCs in WJ are an entity apart from cord blood MSCs and endothelial cells from the umbilical vein. The plentiful presence of MSCs in WJ is theorized to either be due to the trapping and retaining of fetal MSCs during the two waves of migration of fetal MSCs in early development or to the fact that the cells in WJ are actually primitive MSCs that originate from mesenchyme already present in the umbilical cord matrix. More research has been focused on not only the characterization and usage of these WJ-derived MSCs, but also on discrete differences of the stem cell populations depending on the anatomical region of the WJ.6
The most recent development is that what was once thought to be a single mass providing uniform MSCs is actually more anatomically distinct. There are six different zones of the cord with cells in various stages of differentiation: (1) the surface (amniotic) epithelium, (2) subamniotic stroma, (3) clefts, (4) intervascular stroma, (5) perivascular stroma, and (6) vessels. However, the descriptors separating these zones are not clear. It is thought that WJ is composed mainly of perivascular progenitors but may possibly include nonperivascular progenitors as they move away from the vasculature.6 In addition to the anatomical differences, there is concern that the MSCs may differ lengthwise and that the mother end of the umbilical cord may have different mesenchymal features than the fetus end of the umbilical cord.7
In addition to harvesting and potency advantages, cord blood and WJ-derived MSCs are also not limited to autologous use. Due to their excellent immunomodulatory properties and universally tolerated surface marker profiles, MSCs isolated from cord blood and WJ can be made available to patients as allografts.8,9 Using cells isolated from birth tissue as “off-the-shelf” allografts greatly simplifies the manufacturing process of MSCs for therapeutic use, providing a standardized, scalable method of producing cells that does not need to be personalized for each patient.
Importance of the secretome
The therapeutic effectiveness of MSCs is well documented, especially as it pertains to wound healing. However, the mechanisms of action are not well understood. Stem cells are partially defined as cells that are capable of differentiation into a variety of specialized somatic cells, and this knowledge has fueled speculation that cell differentiation upon engraftment is responsible for the observed therapeutic effects. On further investigation, it would appear that this is not the case.
Recent research has shown that MSCs introduced therapeutically primarily function through trophic and immunomodulatory signaling pathways, and the stem and progenitor cells of the host actually do most of the work.10 This is why the secretome, or the collection of bioactive molecules secreted from the cells, has been receiving more attention from researchers. Rich in growth factors and cytokines that are associated with modulating inflammation and promoting angiogenesis, the MSC secretome seems perfectly suited to enhance wound healing. This is evidenced in human physiology by the ability of MSCs to zero in on areas of inflammation and injury and secrete bioactive factors.11
The regenerative effects of growth factors and cytokines have been well documented in dentistry. Peptides in the transforming growth factor β (TGF-β), bone morphogenetic protein (BMP), fibroblast growth factor (FGF), and interleukin (IL) families are crucial components driving regeneration, especially as it relates to bone growth.12 These factors stimulate host cells in regenerative pathways, but it can be challenging to maintain dosing and ensure efficient cell uptake of these factors therapeutically. The MSC secretome is rich in many of these peptides, suggesting that the secretome could be responsible for some of the observed therapeutic effects.13
Stem Cells in Regenerative Endodontics
The potential utility of cord blood MSCs has not yet been fully realized in the relatively new field of regenerative endodontics. Since its development in 2004 by Banchs and Trope, regenerative endodontics has been employed as a root-preserving alternative to a root canal, utilized to eradicate pulp infections in immature permanent teeth, thus permitting further root development and preservation of teeth in patients who are still growing.14Liao et al15 revealed the presence of osteogenic MSCs in both inflamed pulp tissue and inflamed periapical tissues, and further investigation by Chrepa et al16 revealed that the evoked bleeding step demonstrated an increase in local accumulation of undifferentiated MSCs even in a mature tooth. Because of these revelations, the recommended American Association of Endodontists protocol was revised to use irrigants that are less toxic to stem cells and propose the use of platelet-rich plasma, platelet-rich fibrin, and autologous fibrin matrix in place of the simple blood clot.
However, there is no evidence in the literature of regeneration of the dentin pulp complex. The effect of noninflamed apical residual tissue in regeneration of pulp has been investigated recently in an animal model. Torabinejad et al17 conducted a study providing evidence that noninflamed apical residual pulp has the capability to regenerate the normal pulp. Given the discovery of the presence of stem cells involved in the restoration of the root, studies are now underway to assess if implantation of stem cells may in fact accelerate pulp tissue regeneration and healing and perhaps shorten the wait time. Tissue engineering permitted two strategies: (1) the direct implantation of freshly isolated stem cells with or without biodegradable scaffolds, and (2) implantation of preassembled tissue constructs containing in vitro cultured cells in the scaffold.18 Studies showed that the implantation of stem/progenitor cells isolated from a human root in a mouse model resulted in formation of a pulp-like tissue with a layer of dentin-like tissue along the canal wall.19
Unfortunately, retrieval of autologous dental stem cells is difficult, especially in the common case where all other teeth are healthy. It is even more difficult to obtain one of the five subtypes of dental stem cells: (1) dental pulp stem cells (DPSCs), (2) stem cells from human exfoliated deciduous teeth (SHEDs), (3) stem cells from apical papilla (SCAPs), (4) periodontal ligament stem cells (PDLSCs), and (5) tooth germ progenitor cells (TGPCs).20
As such, recent efforts have investigated the use of MSCs derived from other origins, such as human bone marrow–derived MSCs, which have potential for osteogenesis as a more multipotent stem cell than the differentiated dental stem cells. However, bone marrow–derived MSCs are associated with risks, mortality, and high cost of bone marrow harvesting and processing. Induced pluripotent stem cells have also been investigated,21,22