Dental Apical Papilla as Therapy for Spinal Cord Injury

Abstract

Stem cells of the apical papilla (SCAP) represent great promise regarding treatment of neural tissue damage, such as spinal cord injury (SCI). They derive from the neural crest, express numerous neurogenic markers, and mediate neurite outgrowth and axonal targeting. The goal of the present work was to investigate for the first time their potential to promote motor recovery after SCI in a rat hemisection model when delivered in their original stem cell niche-that is, by transplantation of the human apical papilla tissue itself into the lesion. Control groups consisted of animals subjected to laminectomy only (shams) and to lesion either untreated or injected with a fibrin hydrogel with or without human SCAP. Basso-Beattie-Bresnahan locomotor scores at 1 and 3 d postsurgery confirmed early functional decline in all SCI groups. This significant impairment was reversed, as seen in CatWalk analyses, after transplantation of apical papilla into the injured spinal cord wound, whereas the other groups demonstrated persistent functional impairment. Moreover, tactile allodynia did not develop as an unwanted side effect in any of the groups, even though the SCAP hydrogel group showed higher expression of the microglial marker Iba-1, which has been frequently associated with allodynia. Notably, the apical papilla transplant group presented with reduced Iba-1 expression level. Masson trichrome and human mitochondria staining showed the preservation of the apical papilla integrity and the presence of numerous human cells, while human cells could no longer be detected in the SCAP hydrogel group at the 6-wk postsurgery time point. Altogether, our data suggest that the transplantation of a human apical papilla at the lesion site improves gait in spinally injured rats and reduces glial reactivity. It also underlines the potential interest for the application of delivering SCAP in their original niche, as compared with use of a fibrin hydrogel.

Stem Cells of Dental Origin: Current Research Trends and Key Milestones towards Clinical Application

“…DPSCs [51, 135–141], SHED [36, 57, 142, 143], and SCAP [4, 47, 125, 144–146] have shown enhanced potential for differentiation into a variety of neural lineages, including functionally active dopaminergic cells and glial cells, leading proposals for dental MSCs to be used for regenerative therapy of several neurodegenerative diseases [37]. Notably, dental MSCs, while still in an undifferentiated state, constitutively express markers of neural stem/progenitor, as well as mature neural cells, including SOX-2, tenascin C, ENO-2, MAP2ab, c-FOS, Nestin, Neurofilament (NEF-H and NEF-L), Glial Fibrillary Acidic Protein (GFAP), bIII-tubulin, Microtubule-Associated Protein 2 (MAP-2), and many others [143].…”

“…All of the above studies support that neural preinduction of undifferentiated MSCs before in vivo transplantation increases the expression of neural surface receptors and therefore the grafting efficiency into the nervous system, potentially improving clinical outcomes. In a very interesting recent study, the entire apical papilla was transplanted in a SCI (hemisection) model, in comparison to transplantation of human SCAP inside fibrin hydrogels [146]. Significantly, the delivery of SCAP in their original niche (entire apical papilla) improved gait and reduced glial reactivity, as compared to the classical TE approach of cell expansion and delivery in 3D scaffolds.…”

Extracellular matrix‐derived hydrogels for dental stem cell delivery

“…While several different populations of dental stem cells have been identified, stem cells of the apical papilla (SCAP) have been shown to possess greater proliferation potential than dental pulp stem cells and express a variety of neural markers including βIII tubulin, NeuN, nestin, neurofilament M, and glial fibrillary acidic protein . Recently, whole human apical papillae implanted into rat hemisected spinal cords induced a significant improvement of rat motor function . However, SCAP cells transplanted in a fibrin hydrogel in the same study did not have the same effect on motor function, highlighting the importance of delivering SCAPs in their original niche or a similarly supportive medium.…”

“…Stem cells derived from dental tissues are an attractive source for cell transplantation in the central nervous system (CNS) due to accessible supply, high proliferation rate and the potential for autologous transplantation . Human dental stem cells are of neural crest origin, display neural stem cell properties, and have recently been shown to induce functional recovery in SCI repair .…”

“…3 Stem cells derived from dental tissues are an attractive source for cell transplantation in the central nervous system (CNS) due to accessible supply, high proliferation rate and the potential for autologous transplantation. 4 Human dental stem cells are of neural crest origin, display neural stem cell properties, 5 and have recently been shown to induce functional recovery in SCI repair. 6 While several different populations of dental stem cells have been identified, stem cells of the apical papilla (SCAP) have been shown to possess greater proliferation potential than dental pulp stem cells 7 and express a variety of neural markers including bIII tubulin, NeuN, nestin, neurofilament M, and glial fibrillary acidic protein.…”