Phenotypically, dental stem cells express a range of surface markers (including CD49a/CD29, CD44, STRO-1, CD90, CD105, CD106, CD146, CD140b, CD166 and CD27). This suggests a common link between different cell types because most of these markers are expressed by all MSCs. ²,¹⁸,¹⁹,²⁰ Immunophenotyping is a technique used to study the protein expressed by cells. This technique is commonly used in basic science research and laboratory diagnostic purposes. This can be carried out on tissue section (fresh or fixed tissue), cell suspension, etc. The tests used to detect immunophenotypes are: ²¹

Fluorescent microscopy - identifies stem cell surface markers using the fluorescent tags Figure 2 that are attached to a cell receptor on the stem cell. Each specific stem cell marker can be identified on the cell surface by viewing under the fluorescent microscope by their fluorescence in a particular wavelength of light. An e.g., is the expression of pluripotent markers identified on DPSCs and PDLSCs such as Vimentin, Oct-4 and Nanog ²² Figure 3.Figure 2

Identifying stem cell surface marker by indirect immunoflourescence by tagging with fluorescent antibodies

A few relevant surface and intracellular stem cell markers are described in Table 1. ³⁰,³¹,³²,³³,³⁴,³⁵,³⁶,³⁷,³⁸,³⁹ These markers presence or absence can help to establish phenotypes of MSCs.{Table 1}

The DPSCs represent less than 1% of the total cell population present in dental pulp. ⁴⁰ The presence of stem cells in dental pulp was proposed by Fitzgerald et al. ⁴¹ However, the identification and isolation of DPSCs in the adult dental pulp was first reported by Gronthos et al. in 2000 ² after which they identified stromal stem cells in the bone marrow ⁴² and found that DPSCs have similar characteristics as that of BMMSCs. They extensively studied the stem cell properties of human DPSCs and observed that DPSCs are also capable of differentiation into adipocytes and neural - like cells. ⁴³ Heterogeneous populations of DPSCs exist in the dental pulp, which is capable of multilineage differentiation. ⁴⁴ It is believed that these cells reside in the various regions inside the dental pulp. In adult dental tissue, the stem cell niches are usually quiescent and become activated only after injury. ⁴⁵ Various labeling studies have shown that notch signaling plays a vital role in DPSCs differentiation and proliferation. ⁴⁶,⁴⁷ It has been observed that DPSCs produced bone instead of dentin when these cells were implanted into subcutaneous sites in immunocompromised mice with hydroxyapatite tricalcium phosphate powder as their carrier. ⁴⁸ DPSCs thus belong to a novel population of post-natal somatic stem cells.

Immunophenotype of DPSCs

Although there is no specific marker for identifying DPSCs, it has been noted that they express a range of mesenchymal and bone marrow stem cell markers such as STRO-1, CD146 and CD31. ⁴³ They also express embryonic stem cell markers such as Oct-4, Nanog and mesenchymal marker Vimentin. ²² Recently, SSEA4, an embryonic stem cell marker has been shown to be useful in identifying DPSCs and it was observed that 46% of the DPSCs were SSEA-4 positive. ⁴⁹ It has been observed that the there are two populations of DPSCs, one of neural crest origin and other of mesenchymal origin. ⁴⁵ Both populations express the markers STRO-1 and CD31.

SHED

It was first isolated by Miura et al. in 2003 ⁶ from dental pulp of exfoliated deciduous teeth and observed to be highly proliferative and clonogenic. The isolation technique was similar to that used for DPSCs. Although, there were some differences compared with DPSCs.

SHED formed sphere-like cell-cluster formation, which could be separated and grown as individual fibroblast - like cells.

Higher proliferation rate than DPSCs and high number of colony forming cells.

SHED were thought to represent a more immature multipotent stem cells than DPSCs.

Immunophenotype of SHED

These cells express the cell surface molecules STRO-1 and CD146, two early MSC markers also known to be expressed by BMMSCs and DPSCs. These STRO-1 and CD146 positive cells are located around blood vessels suggesting that SHED possibly originate from a perivascular environment. ⁶ It has also been observed that SHED express embryonic stem cells markers oct4, nanog, stage specific embryonic antigens (SSEA-3, SSEA-4). ⁵⁰,⁵¹ Owing to their higher proliferation rate and their osteogenic potential they are considered a more immature form than DPSCs.

SCAP

During tooth development, the dental papilla evolves into the dental pulp and contributes to the development of the root. The apical part of the dental papilla is loosely attached to the developing root and is separated from the differentiated pulp tissue by a cell rich zone. It contains less blood vessels and cellular components than the pulp tissue and separating rich zone. ⁸,¹² In 2006, Sonoyama et al. isolated a new population of dental stem cells and called them SCAP. ⁵²

Immunophenotype of SCAP

SCAP are clonogenic fibroblast-like cells, but have a higher proliferation rate than DPSCs. ⁵² As other dental stem cells, SCAP express the early mesenchymal surface markers, STRO-1 and CD146. However, SCAP also express CD24, which could be a unique marker for this cell population as it is not detected on DPSCs or BMMSCs. ⁸ The expression of CD24 by SCAP is down regulated in response to osteogenic stimulation. However, the biological significance of this finding needs to be investigated. SCAP show a two- to threefold higher proliferation rate than do DPSCs and are more committed to osteo/dentinogenicity. SCAP exhibit a heterogeneous nature by showing:

Co-expression of STRO-1 with a variety of osteo/dentinogenic markers and

A low percentage of STRO-1 - positive cells while a high percentage of cells positive with osteo/dentinogenic markers in cultures.

PDLSCs

The periodontal ligament (PDL) is a specialized connective tissue derived from the DF and originates from neural crest cells. ⁵³,⁵⁴ Seo et al. identified stem cells in human PDL and found that PDLSCs implanted into nude mice generated cementum/PDL-like structures that resemble the native PDL as a thin layer of cementum that interfaced with dense collagen fibers, similar to Sharpey′s fibers. These cells can also differentiate into adipocytes, odontoblasts, myotubes, NFM-positive neuron-like cells, glial fibrillary acidic protein-positive astrocyte-like cells and CNPase-positive oligodendrocyte-like cells. ⁴,⁵⁵,⁵⁶

Immunophenotype of PDLSCs

PDLSCs and DPSCs both showed similar characteristics as compared with BMMSCs. All cell types were strongly positive for CD44, CD90 (cell surface markers associated with stromal cells), CD105 and CD166 (cell surface markers associated with stromal cells and endothelial cells), but negative for CD40, CD80 and CD86 (cell surface markers of hematopoietic cells). ⁵⁷ PDLSCs and DPSCs expressed HLA-ABC (MHC class I antigen) similar to BMMSCs, while HLA-DR (MHC class II antigen) expression was not detected in these cell populations. ²² PDLSCs express a variety of stromal cell markers like CD90, CD29, CD44, CD105, CD166 and CD13. ¹⁴ PDLSCs also express STRO-1 and CD146 and scleraxis (tendon specific transcription factor). Scleraxis is found to be highly expressed in PDLSCs than in DPSCs and BMMSCs. This finding supports the fact that periodontal ligament has similar structural characteristics as that of a tendon and can withstand mechanical stress during physiological activity. ³ The possibility of obtaining stem cells from cryopreserved adult human PDL ⁴ indicates that samples from tissue banks could be viable for future applications.

DFPCs

In 2005, Morsczeck et al. isolated stem cells from the DF of the human impacted third molar, using the same methodology of DPSCs isolation and culture. DFPCs are localized in the DF, a mesenchymal tissue that surrounds the tooth germ and can be easily isolated after wisdom tooth extraction. ⁷,⁵⁸ The DF is a loose connective tissue of an ectomesenchymal origin and it is present as a sac surrounding the unerupted tooth. ⁵⁹ During tooth development, it has been found that DF plays a significant role in the eruption process by controlling the osteoclastogenesis and osteogenesis needed for eruption. ⁶⁰,⁶¹ It is also believed that DF differentiates into the periodontium as the tooth is erupting and becomes visible in the oral cavity. ⁶² However, these cells are available only from patients during wisdom tooth eruption, usually between 15 years and 28 years of age. ⁶³

Immunophenotype of DFPCs

The cells are observed to be fibroblast-like and expressed putative stem cell markers such as Nestin, Notch-1 and STRO-1. ⁷,⁵⁸,⁶⁴ Compared with bone marrow-derived stem cells, DFPCs express higher amounts of IFF-2 transcripts. In addition, these cells have also been found to be positive for Vimentin, a typical marker for mesenchymal cells. ⁵⁸ DFPCs were also able to differentiate and express cementoblast markers (cementum attachment protein and cementum protein-23) after being induced with enamel matrix derivatives, or bone morphogenetic protein-1 (BMP-1) and BMP-7. ⁶⁴

GING SCs

The presence of stem cells in gingival connective tissue was investigated by Mitrano et al.. ¹⁰ Consequently, the identification of MSCs in human gingiva was carried out and they were characterized phenotypically and functionally. The gingiva derived MSCs also had the potential to differentiate into osteocytes, chondrocytes and adipocytes.

Immunophenotype of GING SCs

The immunophenotype characterization was evaluated from culture at the third through fifth passages. A positive immunostaining was consistently obtained for gingival MSCs including CD90, CD105, CD73, CD44 and CD13. They were weakly positive or negative for typical hematopoietic markers such as CD45, CD34, CD54 and CD38. ¹⁰

OPSCs

OPSCs were first isolated by characteristic surface markers in 2005. ⁶⁵ Their osteogenic properties were compared with stem cells of different origin such as bone marrow and alveolar process. The percentage of mineralization observed with OPSCs at 12 weeks was equal to 58.2% versus 26.9% of BMMSCs and 41.1% of those in origin from the alveolar process. ⁶⁶ The mesengenic multipotency of cryopreserved OPSCs was evaluated for chondrogenesis, osteogenesis and adipogenesis. They were found to differentiate into mesodermal lineages and maintained growth until passage 15. ⁶⁷

Immunophenotype of OPSCs

Using FACS, it was observed that OPSCs expressed CD 9, CD90, CD105 and CD166. ⁶⁶

The distinct phenotypes of dental stem cells can be ascertained by analyzing differences in expression of various cell-surface markers used to identify putative MSCs. ² The present review attempts to gain insight into their "phenotypic fingerprint" by analyzing whether these stem cells depict distinct immunophenotypes. The in vitro phenotypes of various dental stem cell populations observed until date compared to BMMSCs is summarized in Table 2.{Table 2}

It can be observed that PDLSCs have a unique phenotype compared to DPSCs Table 2. The DPSCs are positive for SSEA4 and Notch-1 embryonic stem cell markers and PDLSCs are negative for it. This suggests that DPSCs are a more primitive population of stem cells.

CD29 on the other hand is negative in DPSCs and positive in PDLSCs. CD106, which is negative in both DPSCs and PDLSCs is positive in OPSCs. Nanog, which is a marker for pluripotency is absent in PDLSCs, SCAP and DFPCs suggesting they are multipotent stem cells.

Understanding that different stem cells express distinct phenotypes may have further implications in understanding the factors that regulate the formation of mineralized matrices and other associated connective tissues. Different levels of expression of certain stem cell markers will help in understanding the multi lineage differentiation potential of these dental stem cells and which population can be utilized for regeneration of specific tissues such as bone, periodontal ligament, cementum and even neurogenic tissues. For e.g., CD9, a protein highly expressed in cells that differentiate into osteogenic precursors, is expressed more in OPSCs ⁶⁶ and PDLSCs ²² compared to other dental stem cells. The difference in expression of CD9 suggests that these stem cells are more likely to differentiate into osteogenic precursors. This knowledge in a clinical scenario will lead to novel tissue engineering strategies in future utilizing stem cells. A tissue engineering approach using stem cells for bone augmentation is depicted, which can be carried out as a chair side method or using bio engineered matrices. Figure 5. ⁶⁸Figure 5

Depicting current clinical approaches to stem-cell-based bone augmentation. The chair-side cellular grafting approach (orange arrow) uses patient-derived freshly processed bone marrow (mononuclear cell population), which contains mesenchymal stem/stromal cells, hematopoietic stem cells and angiogenic cells, mixed with a scaffold and growth factors, like platelet-rich plasma as a grafting material

Figure 5

The craniofacial/dental complex is continuously remodeling and subject to wear and tear. ⁵⁵ This lends credence to the fact there are many populations of stem cells within this complex located in unique niches and it has been observed there is more than one population of stem cells even within the periodontal ligament. ²² This suggests the heterogeneous nature of stem cells in the dental complex.

The present review provides an insight into the understanding of how MSCs from related tissue could depict distinct characteristics. Understanding that different stem cells express distinct phenotypes may have further implications in understanding the factors that regulate the formation of mineralized matrices and other associated connective tissues. Different levels of expression of certain stem cell markers will help in understanding the multi lineage differentiation potential of these dental stem cells and which population can be utilized for regeneration of specific tissues such as bone, periodontal ligament, cementum and even neurogenic tissues.

However, definitive experiments like in situ hybridization of specific markers and further clonal studies need to be performed to highlight the heterogeneous nature of stem cells from dental tissues. However, identifying the unique phenotypic fingerprints of dental stem cells provides streamlined regenerative therapies with predictable outcomes.

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