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Citterio et al. Plast Aesthet Res 2020;7:41 I http://dx.doi.org/10.20517/2347-9264.2020.29 Page 9 of 20

Grade III furcation, bone regeneration was not complete. When tested in intrabony defects, BMMSCs
provided conflicting results for PL regeneration. One study reported that BMMSCs without bone
[82]
substitutes did not promote an increased PL regeneration . Another study reported that the combination
of BMMSCs and bone substitutes provided significantly higher formation of new cementum and PL
[68]
compared to bone substitutes alone . A study which compared the performance of bone graft with
PDLSCs or BMMSCs in intrabony defects reported less perpendicularly oriented newly inserted fibers in
the BMMSCs group. Conflicting results were also reported in the use of BMMSCs that had undergone ex
vivo osteogenic differentiation before use. Osteogenically differentiated BMMSCs (oBMMSCs) promoted
increased bone formation but not cementum and PL regeneration.

Adipose-derived stem cells
ASCs and DPSCs appeared to have similar genetic expression patterns. ASCs transplanted in periodontal
defects have been shown to favor cementum and PL fibers regeneration and to increase periodontal
vascularization [83,84] . Finally, ASCs in extraction sockets in a rabbit model showed potential for the
[85]
regeneration of the alveolar bone structure .

DENTAL STEM CELLS IN ANIMAL STUDIES
Periodontal ligament stem cells
As for PDLSCs, the majority of the studies showed the positive effect of the use of this type of cells
[92]
for periodontal regeneration [86-91] , as reported in a recent systematic review of pre-clinical studies .
Importantly, PDLSCs have unique properties to form a cementum/PL complex-like structure when
ectopically transplanted in animals [93,94] .

In fenestration defects (applied with hyaluronic acid sheet), they showed significantly greater formation of
[95]
cementum, bone, and periodontal ligament than in control group . When PDLSCs were associated with
e-PTFE membranes on fenestration defects, it was observed that cementum formation was increased in
the test group; however, no difference in bone formation was observed between test and control (e-PTFE
[96]
membranes alone) . In fact, data on bone regeneration with PDLSCs are conflicting, even though their
effect on cementum and PL is promising. Another study reported that PDLSCs improved bone formation
[90]
in circumferential and fenestration defects, but not in three-wall defects treated without bone substitutes .
In intrabony defects, they provided improved periodontal regeneration with a nearly complete recovery
of bone, cementum, and ligament when used in combination with beta tri-calcium phosphate [86,97] . The
benefits were less pronounced but still maintained when used with non-supportive biomaterials [90,98] .
PDLSCs’ protocols without manipulation before direct implantation have been tested and proven effective,
thus making the use of this cell type more sustainable .
[95]

Dental pulp stem cells
DPSCs are another well studied lineage in the animal model. These cells were isolated almost 20 years
[35]
ago and found to be capable of forming lamellar bone after grafting [43,99] . Their use in different ways
[67]
(injected, organized in sheet, and on different carriers) showed potential in regenerative procedure . In
the majority of the studies, the regeneration of all periodontal tissues was increased when DPSCs were
used. Regenerated cementum was thicker in the group receiving bone substitutes plus DPSCs than in the
[67]
control group treated with bone substitute alone, and it covered a larger surface of the root , even though
no noticeable difference in bone formation between the two groups was observed.

Dental follicle precursor cells
DFPCs may improve periodontal regeneration by PDLSCs in vivo. DFPCs appear to enhance the self-
renewal and multi-differentiation capacity of PDLSCs, which indicates that DFPCs could provide a
beneficial microenvironment for periodontal regeneration by using PDLSCs [100] .