Pulp Regeneration by Harnessing Dental Pulp Stem Cells - New Trends in Tissue Engineering and Regenerative Medicine - page 42

pulp is connecting to the inferior alveolar nerve (Figure 3D)(Iohara et al., 2011). The trans‐
planted pulp stem cells expressed angiogenic/neurotrophic factors, and localized in the
vicinity of newly formed capillaries (Iohara et al., 2011; Ishizaka et al., 2012), suggesting
potential trophic effects on angiogenesis. The odontoblast-like cells attached to the dentinal
wall in the root canal, and produce dentin-like mineralized tissue extending their processes
into dentinal tubules (Figure 3F). The enlarged apical portion following pulpectomy is filled
by additional formation of dentin and cementum. On the other hand, transplantation of stem/
progenitor cells alone (Figure 3G), or SDF-1 alone (Figure 3H), yield significantly less pulp
tissue. When unfractionated total pulp cells are implanted in place for the fractionated pulp
stem cells, the regenerated tissue is significantly less in volume and undergo mineralization
(Figure 3I) (Iohara et al., 2011). The regenerated tissue induced by the pulp stem/progenitor
cells and SDF-1 is identical to be normal functional pulp tissue as demonstrated similar
expression of the pulp tissue markers, Syndecan and TRH-DE mRNA. It is noteworthy that the
qualitative and quantitative protein and mRNA expression patterns obtained by two dimen‐
sional electrophoretic analyses and microarray analyses are virtually identical (Iohara et al.,
2011; Ishizaka et al., 2012). Furthermore, in a canine experimental model of periapical disease,
which root canal is kept open for more than three weeks, pulp regeneration has been demon‐
strated after transplantation of pulp stem cells and SDF-1 as demonstrated in case of pulpitis.
The possible mechanisms of pulp regeneration may involve the CXCR4/SDF-1 axis functioning
as a migration/homing factor for CXCR4-positive endogenous stem cells to migrate to the
coronal portion of the root canal, proliferate, and differentiate into endothelial cells for
angiogenesis and re-innervation by angiogenic and neurotrophic factors secreted by trans‐
planted stem cells. These findings suggest potential clinical translation of complete pulp
regeneration by harnessing pulp stem/progenitor cells with high angiogenic/neurogenic
potential and additional migration/homing factors in endodontic treatment. The mechanisms
of recruitment and crucial molecules for cell migration are still unclear. Chemokines and their
receptors which play critical roles need further scrutiny.
2.4. Other sources of tissue stem cells for pulp regeneration
Supply of autologous pulp tissue declines with age, and alternative sources of MSCs to pulp
stem cells are necessary for clinical application in endodontic treatment. Some transcriptional
and epigenetic analyses have revealed very similar profiles among a variety of MSCs from
bone marrow, adipose tissue, placenta, umbilical cord and amnion (Aranda etal., 2009; Boeuf
and Richter, 2010). Different expression profile of trophic factors and growth factors, however,
has also been reported among MSC populations (Noël et al., 2008; Boeuf and Richter, 2010;
Philippe et al., 2010). Thus, it is necessary to investigate the requirements and preconditions
of MSCs for effective induction of pulp regeneration (Ishizaka, et al., 2012). A candidate of an
alternative cell source for pulp regeneration is autologous bone marrow and adipose tissue-
derived MSCs due to neither ethical nor immunoreactive considerations. Transplantation of
adipose CD31 - SP cells resulted in formation of a similar amount of regenerated tissue com‐
pared with that of pulp CD31 - SP cells (Figure 4A, C). Bone marrow CD31 - SP cell transplanta‐
tion induce significantly less amount of regenerated tissue compared with other two (Figure
4B, D). Those regenerated tissues, however, are all identical to pulp tissue confirmed by