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Dental Stem Cells: An Intriguing Treatment for Corneal Blindness?

Review of “Dental Pulp Stem Cells: A New Cellular Resource for Corneal Stromal Regeneration” from Stem Cells TM by Stuart P. Atkinson

Trauma to the outermost tissue of the eye, the cornea, can result in blindness due to the deposition of unorganized scar tissue [1]. The stroma is normally maintained by the action of keratocytes, a neural crest-derived cell type, and treatment for corneal trauma commonly uses penetrating keratoplasty with allogeneic cadaveric tissue. This however has a failure rate of around 38% after 10 years, mainly due to tissue rejection [2], and so alternative cell therapies are being actively sought after. The laboratory of James L. Funderburgh (University of Pittsburgh, Pennsylvania, USA) now propose that neural crest-derived, multipotent mesenchymal stem cells [3] from the dental pulp (Dental pulp stem cells or DPCs) may be a feasible source of cells for differentiation into keratin producing cells and corneal repair, and they now report on their findings in Stem Cells TM [4].

Neural crest-derived DPCs, derived from tissue digestion of dental pulp extracted from third molars, expressed various pluripotency associated genes, neural crest genes, and also ABCG2, a gene associated with corneal stromal progenitors [5]. The authors then successfully demonstrated keratocyte differentiation of DPCs [6], with resultant cells expressing very high levels of keratocan mRNA, a unique component of the stromal matrix, while also expressing a range of proteins associated with keratocytes (corneal keratan sulfate proteoglycans, type I collagen, and keratocan).

To act as an appropriate tissue replacement in the cornea, engineered tissue must faithfully recapitulate the highly organized structure of corneal stromal tissue. In order to attain this level of organisation, the group cultured DPCs on aligned nanofibers to direct cell orientation and matrix deposition, and by 4 weeks of growth a 30-mm-thick corneal stromal-like construct formed. This construct presented parallel alignments of collagen which changed direction at different depths and expressed collagen type 1 and keratocan, similar to the native corneal stroma.

Finally, the authors assessed the construct after implantation into the mouse corneal stroma, finding the presence of DPCs and clear corneas at 1 and 5 weeks after injection (See Figure). Optical coherence tomography (OCT), used to measure light scattering in the murine corneas, found that mouse eyes with and without injected DPCs remained similar, suggesting that transparency was not significantly altered by human DPCs. The group also found no evidence of a change in stromal volume, suggesting that DPCs injection did not lead to edema, and that DPCs in the mouse cornea expressed human type I collagen and human keratocan, suggesting that these cells still had the ability to express stromal matrix components after injection in to the cornea.

In summation, DPCs appear to be an attractive cell source for corneal repair; they are easy to isolate from any given patient, which would minimise any risk of immune rejection, and they derive from a neural crest source, similar to the corneal stroma. Furthermore, DPCs demonstrate multiple advantages over previously assessed cells types, such as primary human keratocytes, corneal fibroblasts, ESC-derived keratocytes and bone marrow- and adipose-derived mesenchymal stem cells (see article for extensive references), and so may represent the future cell of choice in this field. This is further strengthened by two other reports that show promising results using stem cells from exfoliated deciduous teeth (SHED) for corneal epithelium regeneration [7, 8].

References

  1. Fini ME Keratocyte and fibroblast phenotypes in the repairing cornea. Prog Retin Eye Res 1999;18:529-551.
  2. Williams KA, Esterman AJ, Bartlett C, et al. How effective is penetrating corneal transplantation? Factors influencing long-term outcome in multivariate analysis. Transplantation 2006;81:896-901.
  3. Liu H, Zhang J, Liu CY, et al. Cell therapy of congenital corneal diseases with umbilical mesenchymal stem cells: lumican null mice. PLoS One 2010;5:e10707.
  4. Syed-Picard FN, Du Y, Lathrop KL, et al. Dental Pulp Stem Cells: A New Cellular Resource for Corneal Stromal Regeneration. Stem Cells Translational Medicine 2015;4:276-285.
  5. Du Y, Funderburgh ML, Mann MM, et al. Multipotent stem cells in human corneal stroma. Stem Cells 2005;23:1266-1275.
  6. Du Y, Sundarraj N, Funderburgh ML, et al. Secretion and organization of a cornea-like tissue in vitro by stem cells from human corneal stroma. Investigative ophthalmology & visual science 2007;48:5038-5045.
  7. Gomes JA, Geraldes Monteiro B, Melo GB, et al. Corneal reconstruction with tissue-engineered cell sheets composed of human immature dental pulp stem cells. Investigative ophthalmology & visual science 2010;51:1408-1414.
  8. Monteiro BG, Serafim RC, Melo GB, et al. Human immature dental pulp stem cells share key characteristic features with limbal stem cells. Cell proliferation 2009;42:587-594.