Angiogenic Potential of Various Oral Cavity–Derived Mesenchymal Stem Cells and Cell-Derived Secretome: A Systematic Review and Meta-Analysis

Abstract Recent evidence suggests the immense potential of human mesenchymal stem cell (hMSC) secretome conditioned medium-mediated augmentation of angiogenesis. However, angiogenesis potential varies from source and origin. The hMSCs derived from the oral cavity share an exceptional quality due to their origin from a hypoxic environment. Our systematic review aimed to compare the mesenchymal stem cells (MSCs) derived from various oral cavity sources and cell-derived secretomes, and evaluate their angiogenic potential. A literature search was conducted using PubMed and Scopus from January 2000 to September 2020. Source-wise outcomes were systematically analyzed using in vitro , in vivo , and in ovo studies, emphasizing endothelial cell migration, tube formation, and blood vessel formation. Ninety-four studies were included in the systematic review, out of which 4 studies were subsequently included in the meta-analysis. Prominent growth factors and other bioactive components implicated in improving angiogenesis were included in the respective studies. The findings suggest that oral tissues are a rich source of hMSCs. The meta-analysis revealed a positive correlation between dental pulp–derived MSCs (DPMSCs) and stem cells derived from apical papilla (SCAP) compared to human umbilical cord–derived endothelial cell lines as a control. It shows a statistically significant positive correlation between the co-culture of human umbilical vein endothelial cells (HUVECs) and DPMSCs with tubule length formation and total branching points. Our meta-analysis revealed that oral-derived MSCs (dental pulp stem cells and SCAP) carry a better angiogenic potential in vitro than endothelial cell lines alone. The reviewed literature illustrates that oral cavity–derived MSCs (OC-MSCs) increased angiogenesis. The present literature reveals a dearth of investigations involving sources other than dental pulp. Even though OC-MSCs have revealed more significant potential than other MSCs, more comprehensive, target-oriented interinstitutional prospective studies are warranted to determine whether oral cavity–derived stem cells are the most excellent sources of significant angiogenic potential.


Introduction
Oral cavity-derived dental pulp stem cells (DPSCs) have gained attention due to their potential use in regenerative medicine.These stem cells are known for their unique characteristics that make them distinct from other stem cell sources.Some exceptional criteria of oral cavityderived DPSCs are their mesenchymal stem cell (MSC) characteristics, ease of accessibility, multilineage differentiation, regenerative capacity with high angiogenic potential, and immunomodulatory properties with low immunogenicity.Despite their potential advantages, using oral cavity-derived stem cells for oral cancer treatment and reconstruction poses several challenges.Oral cancer creates a hostile tumor microenvironment characterized by inflammation, hypoxia, and immune suppression.Stem cells may face difficulty surviving and exerting their regenerative properties in such an environment.There is a risk that the harvested stem cell population could be contaminated with cancer cells, which can lead to cancer recurrence if transplanted back into the patient.Moreover, oral carcinoma contains a population of neoplastic cells with aggressive stem cells that are difficult to distinguish from healthy cells.Angiogenesis or neovascularization is a dynamic process involving new blood vessels that form from existing blood vessels. 1 Oral cavity stem cells secrete various angiogenic factors, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and others.These factors attract endothelial cells and support the formation of new capillaries.
Oral cavity stem cells can trigger angiogenesis when introduced into a tissue requiring regeneration or healing.It is crucial during development, along with various physiological and pathological processes. 2Angiogenesis occurs lifelong, starting in the uterus and continuing into old age.Furthermore, capillaries are required to exchange nutrients and metabolites in all tissues. 3Angiogenesis is paramount concerning wound healing due to its critical role in growing a new capillary network from the granulation tissue, which plays a pivotal role in chronic inflammation. 3Wound healing is a complex procedure involving overlapping events, including inflammatory, proliferative, and remodeling phases.Many growth factors and cytokines participate in the proliferative phase, of which angiogenic growth factors hold a prime role. 4Revascularization is regulated by a complex interaction between various growth factors, including but not limited to VEGF, FGF, angiopoietins (ANG), PDGF, transforming growth factor-α (TGF-α), and transforming growth factor-β (TGF-β). 5Each factor plays a separate role in inducing, initiating, and amplifying cell proliferation, cell migration, stabilization, wound healing, inflammation, and suppression of angiogenesis. 1,6Several growth factors like VEGF, FGF-2, and PDGF have been used clinically to augment angiogenesis for various therapeutic applications.However, lack of spatiotemporal control over the release of these proangiogenic proteins has led to numerous complications, including leaky vasculature.Cell-based therapies are evolving therapeutic options for deranged angiogenesis. 7SCs derived from human placental tissue, bone marrow, or umbilical cord tissues provide a novel strategy for the induction of angiogenesis.Various studies have demonstrated the ability of MSCs to differentiate into endothelial cells and provide vascular stability.In addition, MSCs secrete an extended milieu of growth factors, cytokines, extracellular vesicles (EVs), and messenger ribonucleic acids (mRNAs) implicated in a wide range of biological processes.Interestingly, "secret factors" (secretomes) from MSCs promote angiogenesis and amend wound healing in virtue of potent paracrine signaling, yielding proangiogenic factors. 5Although hMSCs isolated from various sources have exhibited proangiogenic potential, knowledge about the ideal source (cells or secretomes, source-wise potential, and ease of sample collection) remains obscure.Oral tissues originate from mesenchymal and ectodermal germ layers that add to their value, making them the ideal source for isolation and therapeutic applications.Stem cells are influenced by their in vivo environment, which projects through their therapeutic properties. 8The stem cell niche includes cellular and extracellular matrix components, tissue location, innervation, and blood supply.The oral cavity is highly vascularized and yields better-quality stem cells with potent angiogenic potential.Rapid wound healing in the oral cavity can explain its unique potential.Their high proliferation and unique secretory profile can be attributed to their hypoxic condition.Oral cavity-derived cells are multipotent; primitive oral tissues such as dental follicles harbor oral cavity-derived MSCs (OC-MSCs).Therefore, MSCs isolated from various sources from the meta-analysis revealed that oral-derived MSCs (dental pulp stem cells and SCAP) carry a better angiogenic potential in vitro than endothelial cell lines alone.The reviewed literature illustrates that oral cavity-derived MSCs (OC-MSCs) increased angiogenesis.The present literature reveals a dearth of investigations involving sources other than dental pulp.Even though OC-MSCs have revealed more significant potential than other MSCs, more comprehensive, target-oriented interinstitutional prospective studies are warranted to determine whether oral cavity-derived stem cells are the most excellent sources of significant angiogenic potential.
oral cavity comprise a powerful weapon to battle numerous diseases. 9n recent decades, stem cell proliferation from various adult tissues has been a provoking tool in advanced sciences.Previous studies have revealed the role of dental pulp-derived MSCs (DPMSCs) and stem cells from human exfoliated deciduous teeth (SHED) in enhancing the cascade of angiogenesis.Our systematic review aimed to compare OC-MSCs and cell-derived secretomes and evaluate their angiogenic potential.The subsequent meta-analysis with compatible data analyses whether OC-MSCs (DPSC and stem cells derived from apical papilla [SCAP]) carry a better angiogenic potential in vitro than endothelial cell lines alone.Extensive collaborative research is required to conclude which oral-derived stem cells have the best angiogenic potential.This systematic review focuses on the potential of MSCs and their secretomes derived from various oral tissues such as gingival tissue, dental pulp, periodontal ligament (PDL), mandibular bone, and buccal fat, with particular emphasis on angiogenesis.

Methods
This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.The research proposal has been registered in PROSPERO (registration no: CRD42021282497).
Based on the PRISMA criteria, the research question for this review was framed in the PICO format as the following: Which is the best oral source of MSCs for augmenting angiogenesis at the implanted site?
The terms used to identify studies based on the elements of the PICO format were as follows: • Population: in vitro studies, in vivo studies, and ex vivo studies.• Intervention: OC-MSCs.
• Outcome: angiogenesis at the desired site of implantation.
The inclusion criteria of the study were the following: • Articles published in the English language.
• Studies relevant to the topic published from January 1, 2000 to March 2023.• Studies showing in vitro, in vivo, and in ovo results for angiogenesis of OC-MSCs.• Studies having well-defined information regarding the angiogenic potential of OC-MSCs.
The exclusion criteria of the review included the following: • Articles in languages other than English.
Systematic computer searches were performed on two electronic databases: PubMed and Scopus.The following keyword combinations were used to search articles: • "Dental stem cells AND Angiogenesis AND conditioned media."• "Dental stem cells AND Angiogenic potential AND conditioned media."• "Dental stem cells AND Angiogenesis." • "Dental stem cells AND Angiogenic potential." Along with the electronic search, a hand search was also performed to find the missed articles.Articles published between January 1, 2000 and March 1, 2023 were included in the survey.Two reviewers (M.S. and S.K.) independently evaluated the titles and abstracts of the retrieved publications pertaining to the covered research topic during the initial screening.If material relevant to the inclusion criteria was provided in the abstract, or if the title was relevant but the abstract was unavailable, a full-text report was acquired.
The complete text of the articles was then screened to find those that matched the inclusion criteria.If the work appeared to meet the inclusion criteria, the authors were contacted to seek further information.Articles with full-text reports only were evaluated in this systematic review.Studies that only published abstracts were removed because evidence revealed differences between data given in abstracts and those supplied in the final published complete report.Two review authors (M.S. and S.K.) separately collected data using a specifically designed data extraction sheet (►Table 1).A third (S.D.) and a fourth (Y.M.) reviewer handled any disagreements about the inclusion of publications or data extraction.
The following data items were extracted: authors and year of publication; source of stem cells used; type of study; model used for evaluating angiogenesis; growth factors assessed for angiogenesis; method used for analysis of angiogenesis; use of stem cells/conditioned media; use of preconditioning; use of co-culture with MSCs; and results obtained.
To evaluate an article's quality, we used the Joanna Briggs Institute appraisal checklist for a case-control study.Based on 10 prespecified questions in the tool, two researchers independently examined all case reports.Each question received one of the following statuses based on judgment: "yes," "no," "maybe," or "unclear."A quality grade was assigned to the listed studies, with scores over 70% deemed excellent.Scores between 40 and 70% were considered to be of moderate quality, while those under 40% were considered to be of low quality.The reviewers agreed on these criteria in order to provide a thorough and objective assessment of the research quality.Egger's regression test was used to identify publication bias in the selected articles for quantitative analysis.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.A quantitative analysis was possible only for comparing studies with an individual oral-derived source of MSCs.The DPMSCs and SCAPs were individually compared with the endothelial cell lines used to control in vitro analysis of blood vessel formation.Thus, the best source of oral-derived MSCs is not projected through the meta-analysis performed.Instead, the present meta-analysis shows that oral tissuederived stem cells have more potential for augmenting angiogenesis than endothelial cell lines alone.The studies compared the in vitro tubule formation or total branching points between cases and controls.Out of the 94 studies in the systematic review, only four had data compatible with a meta-analysis. 34,61,84,90These studies referred to tubular formation's mean and total branch points in the case and control groups.The difference between the mean with standard deviation and the corresponding confidence interval was calculated for each study.Forest plots were created with RevMan software (version 5.4.1) using the calculated mean differences shown in ►Figs. 3-5.
The meta-analysis (►Fig. 3) shows a positive correlation of the co-culture of human umbilical vein endothelial cells (HUVECs) and DPMSCs with tubule length formation, which was statistically significant (p ¼ 0.04), with a mean difference of 0.20 and a 95% confidence interval of 0.01-0.40.Succeeding meta-analysis (►Figs.4 and 5) showed a positive correlation with the co-culture of HUVEC and the SCAP group with tubule length formation (►Fig.4) and total branching points (►Fig. 5)with a mean difference of 5.20 and 20.78 and a 95% confidence interval of -2.05 to 12.45 and -6.66 to 48.21, respectively.Thus, the overall results from the meta-analysis revealed that oral-derived MSCs (DPSC and SCAP) carry a better angiogenic potential in vitro than the endothelial cell lines used alone, as depicted in the forest plot in ►Figs.3-5.

Assessment of Quality and Publication Bias
Ten of the 94 studies considered obtained ratings less than 70%, categorizing them as intermediate in quality.In contrast, the other 84 studies were classed as high quality given that their overall score surpassed 70%.The studies included for meta-analysis were high quality with score greater than 70%.
The Egger test showed a potential publication bias with 50% studies closer to the intercept line and 50% of studies away from the intercept line (►Table 2, ►Fig.6).Such skewed results could be attributed to small sample of studies that were analyzed quantitatively.

Discussion
After a detailed scrutiny of the literature, 94 articles meeting our inclusion criteria were included in the review, investigating the influence of MSCs or their secretomes derived from oral sources.Of these, 54 studies involved dental pulp, 10 articles investigated MSCs from SHED, and 9 investigated the PDL stem cells.The SCAPs were studied in 10 articles, and gingival MSCs (GMSCs) were explored in a single study.DPMSCs were relatively more explored for their angiogenic potential, as evidenced by the number of articles published.The critical parameters investigated to assess the effect of OC-MSCs and their secretomes on angiogenesis were tube capillary length and diameter, branching points, number of loops, expression of angiogenic proteins, endothelial cell proliferation in in vitro studies and capillary formation, enhanced wound healing, and generation of neovascularization in in ovo and in vivo studies.Postnatal MSCs (DPMSCs, PDL-derived stem cells [PDLSCs], SHED, GMSCs, and SCAP) retain the unique ability to form new functional blood vessels through angiogenesis. 97g. 2 Graphical representation of the source-wise articles included in the review.DPSC, dental pulp stem cell; GMSC, gingival mesenchymal stem cell; PDLSC, periodontal ligament-derived mesenchymal stem cell; SCAP, stem cells from apical papilla; SHED, stem cells from human exfoliated deciduous teeth.

Dental Pulp-Derived Mesenchymal Stem Cells
The dental pulp is a rich source of MSCs that exhibit a selfrenewal multilineage differentiation potential and secrete multiple proangiogenic factors.Thus, among the several therapeutic applications under investigation, the ability of DPMSCs to enhance angiogenesis has been the subject of active investigation.
Interestingly, the co-culture of DPMSCs with HUVECs exhibited a thick vessel-like structure, a characteristic feature of angiogenesis.The formation of vessel-like structures was absent in untreated HUVECs, confirming the angiogenic role of DPMSCs. 55,61DPMSCs could induce angiogenesis in a chicken chorioallantoic membrane model, as shown by the increased capillaries that observe a typical spoke wheel pattern around the DPMSCs Matrigel. 58DPMSCs mediated noticeable repair of the infarcted myocardium in the animal model of myocardial infarction as an increase in the total number of blood vessels and an overall reduction in the infarct size was apparent.Therefore, the authors suggested DPMSCs as a potential alternative to bone marrow-derived MSCs to treat myocardial infarction. 59,102DPMSC-derived cells could promote neovasculogenesis in the mouse brain. 39ecretomes derived from DPMSCs have been actively investigated for their proangiogenic role.DPMSC secretomes    also potentially enhance the proliferation of HUVECs. 24PMSC secretomes promoted angiogenesis in endothelial cell progenitors and terminally differentiated endothelial cells, as evidenced by the formation of tubelike structures in the Matrigel assay.In addition, DPMSC secretomes have been shown to improve the capillary density of skeletal muscles through improved angiogenesis, which can be attributed to the VEGF content in the secretomes.In the transwell migration assay performed on HUVECs, DPMSC secretomes promote better migration of HUVECs and microvascular network formation than the endothelial growth medium (EGM), suggesting a profound angiogenic role of DPMSC secretomes. 42Under serum-free conditions, DPMSC secretomes have been shown to enhance the capillary tubelike formation from preexisting blood vessels, ultimately assisting angiogenesis. 29n a co-culture of secretomes derived from DPMSCs and bone marrow-derived MSCs, substantial proangiogenic changes were observed in the chorioallantoic membrane. 22urthermore, local intramuscular injection of DPMSC secretomes in the hindlimb ischemic mice model showed enhanced neovascularization and marked improved blood perfusion at the ischemic site. 54,60,62Similar results were found in a mice model of ectopic tooth transplantation wherein enhanced expression of VEGF was noted, promoting pulp regeneration. 30,77Furthermore, DPMSC secretomes could promote pulplike vascularization in a scaffold implanted in a mouse model. 45ne of the added therapeutic benefits of MSCs is their ability to secrete EV containing various nucleic acids, lipids, and proteins into the extracellular space.Many studies have suggested that EVs from MSCs can be employed for therapeutic applications in recent times.Interestingly, fibrin gel loaded with DPMSC-derived EVs enhanced cell migration and vascular tube formation in in vitro culture. 27A mouse model was used to assess wound healing over the skin, where EVs derived from DPMSCs of healthy and periodontally compromised teeth were included.The results showed that EVs from DPMSCs from periodontally compromised teeth (P-DPMSCs) accelerated wound healing in mice compared to those derived from DPMSCs from healthy teeth.
Moreover, it showed enhanced blood vessel formation/angiogenesis, which forms the basis of wound healing, suggesting that the inflammatory microenvironment enhances the proangiogenic effects of DPMSCs.A comparative analysis between the DPMSCs derived from regular and deep carious teeth revealed that the expression levels of angiogenesis markers (VEGF, PDGF, stromal cellderived growth factor-1) were higher in MSCs derived from deep carious pulp compared to the MSCs of the normal pulp.This suggests that an inflammatory microenvironment would instead work well for cell proliferation and further angiogenesis. 25A combination of VEGF and IGF-1 enhances the angiogenic proliferation of DPMSCs from the carious environment synergistic effect. 32Chronic inflammation-mediated tumor necrosis factor alpha induced initial apoptosis emerges DPSC into an angiogenic phenotype. 40,56The role of DPMSC EVs in angiogenesis is evident as miR-424 plays a regulatory role in angiogenesis. 57Recently, modulation of the proangiogenic potential of DPMSCs by preconditioning, altering the culture conditions, and using novel biomaterials yielded promising results.Hypoxic preconditioning could enhance the proangiogenic capacity of DPMSCs. 43,53The expression of HIF-1α and SENP1 formed a positive feedback loop in angiogenesis promoted by DPMSCs under hypoxic conditions.HUVECs cultured with DPMSC secretomes treated with baicalein, 51 calcium phosphate cement (CPC), and CPC-bioactive glass nanoparticles (CPC-BGNs), 50 insulinlike growth factor binding protein 5 (IGFBP5) 10 exhibited higher expression of angiogenic markers in DPMSCs.DPMSCs treated with mineral trioxide aggregate (MTA), calcium hydroxide (Ca [OH]2), Biodentine (BD) and Emdogain, 23 EphrinB2-Fc, or EphB4-Fc 37 enhanced the expression of VEGF, which plays a crucial role in angiogenesis. 52n contrast, treatment with triethylene glycol dimethacrylate (TEGDMA) alone at a concentration of 0.25 mM downregulated the expression of angiogenic factors, 38 clindamycin and minocycline 35 ; complete endothelial medium 2 (EGM-2) improved vessel formation; and angiogenic cell differentiation was achieved. 36Aksel and Huang observed similar findings. 47Treatment with 20% human platelet lysate under lipopolysaccharide-induced inflammatory environment in DPMSCs showed increased expression of proangiogenic markers. 6Furthermore, the concentrated growth factor scaffold potentially enhanced endothelial cell proliferation and migration for DPMSCs. 41Lipoprotein receptorrelated protein signaling is required to express VEGF-promoting angiogenesis. 46Decellularized matrix hydrogel derived from human dental pulp effectively promoted DPMSCs in a multidirectional differentiation. 31em Cells Obtained from Exfoliated Deciduous Teeth SHED is a potent source of MSCs due to their higher proliferation potential, plasticity, and unique secretory profile.Few studies have explored the ability of SHED to enhance angiogenesis.Co-culture of the SHED with HUVECs promoted increased angiogenesis. 68Furthermore, the SHED-HDMEC co-culture enhanced proangiogenic factor expression via NF-κB-dependent pathways. 65Interestingly, SHED was subjected to shear stress-induced arterial endothelial differentiation. 4HED supplemented with an EGM showed augmented angiogenesis in vivo. 71When subjected to a hypoxic environment, SHED augmented angiogenesis with improved function. 70hese studies suggest that SHED can be used as a perivascular source to form functional vascularlike structures in vivo. 76

Periodontal Ligament-Derived Stem Cells
The PDL contains a population of progenitor cells, recently recognized as PDLSCs, capable of multilineage differentiation to produce tissues rich in collagen type I. Coadministration of PDLSCs and HUVECs showed anastomosis and enhanced blood vessel formation.It was seen that CXCR4 (an alpha-chemokine receptor specific for stromal-derived factor 1) antagonist inhibited blood vessel formation.This explains the role of PDLSCs in augmenting angiogenesis and blood vessel formation. 80Furthermore, PDLSCs seeded on machined titanium disk surfaces showed increased VEGF expression, and RUNX2 (a gene inducing pluripotent stem cell differentiation to immature osteoblasts) plays a potential role in exhibiting angiogenesis. 74In contrast, cyclosporine A-treated MSCs derived from PDL negatively impacted angiogenesis. 76urthermore, prostacyclin pretreated PDL stem cells negatively impacted iloprost enhanced angiogenic marker expression. 78PDLSCs derived from healthy and inflamed tissue (periodontally compromised teeth) were subjected to proliferation and angiogenesis.The results depicted that the inflammatory microenvironment provided better augmentation for angiogenesis, which agrees with the findings on DPMSCs. 73,79

Stem Cells Derived from Apical Papilla
A unique population of SCAP of the growing tooth root tips with embryoniclike properties is readily accessible in dental clinical practice from extracted wisdom teeth.Exposure of SCAP to various stress microenvironments and their respective secretomes has promoted angiogenesis. 89EphrinB2 (a transmembrane ligand of EphB receptor tyrosine kinases expressed explicitly in arteries) could stabilize the vessellike structure generated by the co-culture of SCAPs and HUVECs in vitro. 87Co-culture of HUVECs and SCAPs under hypoxic conditions promoted the formation of endothelial tubules and a blood capillary network, which was in agreement with those obtained by Nam et al. 49 VEGF-loaded fibers can be considered a viable option for stimulating SCAP angiogenesis and new histogenesis during the endodontic procedure. 86EphrinB2-transduced SCAPs could express VEGF marker in numerous amounts compared to the control group; its co-culture with HUVECs showed enhanced blood vessel formation in a Matrigel plug assay. 84Treatment of SCAP cells with recombinant human erythropoietin-alpha (rhEPOa) elicits a proangiogenesis program by activating the Erythropoetin Receptor pathway. 85Exposure of SCAP to MTA and BD (root-end filling material used in endodontic therapy of root canals) stimulated angiogenic gene expression and VEGF release inducing similar expression patterns in both MTA and BD.However, they appear to inhibit the expression of specific genes, including ANGPT1 and FGF2. 88SCAP-derived secretomes improved osteogenic and neurogenic differentiation of dental pulp cells, but angiogenic differentiation did not significantly improve. 83

Stem Cells Derived from Gingiva
The gingiva of human dentition is blessed with a remarkable contribution of neural crest ectomesenchyme, perifollicular mesenchyme, and partly the dental follicle proper.The origin of this tissue and its close approximation with the tooth give the GMSCs an exclusive position to stand apart from the rest of the oral cavity-derived cells.A study by Jin et al showed that when GMSCs were transfected with FGF-2, their expression potential for VEGF and TGF-β increased.Also, the secretomes derived from untreated GMSCs enhanced the gene and protein expression of angiogenic-related factors, endothelial tube formation, and cell migration capacity.However, the results obtained had an inferior efficacy than those obtained by the transfected GMSCs and their secretomes. 91everal researchers have investigated the comparative potential of OC-MSCs to explore the ideal source of MSCs in the augmentation of angiogenesis.In a study by Angelopoulos et al, GMSCs potentially proliferate, migrate, and form angiogenic tubules better than DPMSCs in vitro and in vivo. 94nother study performed by Xu et al compared SHED and DPMSCs in enhancing angiogenesis.Their findings revealed that SHED possesses better angiogenic potential than the DPMSCs. 95Furthermore, SHED showed a more substantial angiogenesis differentiation and proliferation potential than DPMSCs.Furthermore, PDLSCs exhibited better angiogenic potential than DPMSCs. 96However, very few studies have reported the comparative potential of OC-MSCs.
In yet another study, a co-culture of DPMSCs and SCAPs exhibited improved blood vessel formation in vivo. 99urthermore, in an in ovo angiogenesis assay, the co-culture of DPMSCs and SCAPs showed better angiogenesis than the single source. 101A root canal obturating material, Well-Root ST stimulated neovascularization during endodontic regeneration procedures.Furthermore, Well-Root ST showed better efficacy than BD or ProRoot MTA for stimulation in various oral-derived MSCs (DPMSCs, SHED, PDLSCs, GMSCs, and SCAP). 98he field of oral cavity-derived stem cells, particularly MSCs from dental pulp and apical papilla, has garnered interest due to their unique characteristics and potential applications in regenerative medicine.The finding that these stem cells have strong angiogenic potential holds several clinical implications and suggests promising directions for future research that could benefit the population in various ways.
• Tissue regeneration: The angiogenic potential of oral cavity-derived stem cells suggests their capability to stimulate the formation of new blood vessels.This can be extremely valuable in regenerating damaged tissues, such as those affected by injury, disease, or degeneration.These stem cells could aid in promoting blood supply and nutrients to the regenerating tissue, enhancing the overall healing process.• Wound healing: The ability of these stem cells to promote angiogenesis can significantly accelerate wound healing in various clinical scenarios.For instance, they could be employed in chronic wound management, diabetic ulcer treatment, and postsurgical wound healing to expedite tissue repair and reduce complications.• Bone regeneration: Oral-derived MSCs have shown potential for bone tissue regeneration.Enhancing angiogenesis could aid in developing more effective treatments for bone defects, fractures, and conditions like osteoporosis.• Dental applications: The dental pulp and apical papilla are easily accessible sources of MSCs.This accessibility could make these stem cells valuable for various dental applications, such as periodontal tissue regeneration, dental implant support, and treatment of oral diseases.• Cardiovascular disorders: Given their angiogenic properties, these stem cells might hold promise in treating cardiovascular diseases.They could stimulate the growth of new blood vessels in ischemic heart tissue, potentially reducing the impact of heart attacks.

Limitations
The current literature shows a paucity of studies involving sources other than dental pulp.Even though OC-MSCs have proved their enhanced potential compared to other MSCs, further target-oriented comprehensive research is required to conclude which oral-derived stem cells have the most significant angiogenic potential.The systematic review involves different oral sources for MSCs, where maximum studies include dental pulp, and data for other sources (SHED, PDLSC, SCAP, and GMSC) are limited; therefore, a comparative evaluation could not be done.This systematic review incorporates in vitro, ex vivo, and in vivo trials and the data appear to be skewed.One specific type of research design might be advocated for better outcomes.

Conclusion
The specific objectives of our study were to explore whether easily accessible OC-MSCs from dental pulp and apical papilla had good angiogenic potential.The reviewed literature shows that all the OC-MSCs augmented angiogenesis in various experiments.In the studies comparing DPMSCs and PDLSC, GMSCs, or SHED, the latter sources have shown increased significant potential for angiogenesis compared to that of the DPMSCs.MSCs obtained from different places show close phenotypic characteristics.However, it is still unclear how similar they are since proliferation and differentiation capabilities in the presence of different growth factor stimuli differ depending on the source of origin.For instance, bone marrow MSCs tend to lose their proliferative potential with age.DPSCs, on the other hand, have a higher proliferation index and growth potential.DPSCs show the highest odontogenic capability under the same inductive microenvironment in comparison to bone marrow stromal stem cells. 103venues that can be explored further in the research realm are angiogenesis mechanisms, optimal delivery methods, combination therapy, and personalized medicine.This knowledge of precise molecular and cellular mechanisms underlying the angiogenic potential of oral-derived MSCs could lead to the development of targeted therapies.Future research could focus on identifying the most effective methods for delivering oral-derived MSCs to target tissues.This could involve investigating various delivery vehicles, such as scaffolds or hydrogels, to ensure the stem cells reach their intended destination.Furthermore, research might delve into tailoring treatments based on individual patient characteristics to maximize the regenerative potential.Exploring combination therapies, such as coupling oral-derived MSCs with growth factors or other regenerative agents, could enhance their angiogenic potential and effectiveness in various applications.Regenerative medicine and stem cells will usher in a renaissance in therapy in the near future.
The manuscript has been checked with the Fi-index tool and obtained a scrore of 0.60 for the first author on September 3, 2023 according to the Scopus database.The Fi-index tool aims to ensure the quality of the reference list and limit autocitations. 104,105 Dentistry © 2023.The Author(s).
the qualitative and quantitative analysis is illustrated using the PRISMA flowchart.The results of database searches were carefully maintained using Mendeley software (version 1803).Mendeley software (version 1803) for Windows (Elsevier, London, UK) was used in the initial phase of the screening process to remove duplicate articles.Five hundred and twenty-nine articles from both databases were excluded due to overlapping data.After scrutiny of the titles, 284 articles were selected.Abstracts and full texts of the remaining articles were further screened for relevance, and 80 articles were excluded.In addition, 70 reviews and letters to editors were excluded.Of the remaining 134 articles, 40 were excluded due to data being in languages other than English or irrelevance.Hence, a total of 94 articles were selected for data extraction.The data extracted from the included studies are summarized in ►Table 1. ►Fig. 1 summarizes and depicts the PRISMA flowchart.Source-wise number of articles included in the review are depicted in the graph in ►Fig. 2.

Fig. 1
Fig. 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) chart illustrating the research methodology used in the review.

Fig. 3
Fig. 3 Summary of the meta-analysis assessing the effect of DPMSCs on the tubular length in an in vitro Matrigel assay showing a positive correlation of the co-culture of HUVEC and DPMSCs with the tubule length formation, which was statistically significant (p ¼ 0.04).CI, confidence interval; DPMSCs, dental pulp-derived mesenchymal stem cells; DPSC, dental pulp stem cell; HUVEC, human umbilical vein endothelial cell; SD, standard deviation.

Fig. 4
Fig.4Summary of the meta-analysis assessing the effect of SCAP on the tubular length in an in vitro Matrigel assay showing a positive correlation of the co-culture of HUVEC and SCAPs with the tubule length formation, which was not statistically significant (p ¼ 0.16).CI, confidence interval; HUVEC, human umbilical vein endothelial cell; SCAP, stem cells from apical papilla; SD, standard deviation.

Fig. 5
Fig.5Summary of the meta-analysis assessing the effect of SCAP on the total branching points in an in vitro Matrigel assay showing a positive correlation of the co-culture of HUVEC and SCAPs with the total branching point number, which was not statistically significant (p ¼ 0.14).CI, confidence interval; HUVEC, human umbilical vein endothelial cell; SCAP, stem cells from apical papilla; SD, standard deviation.

Table 1
Tabular representation of qualitative data obtained from literature search for included studies

Table 1 (
Continued) European Journal of Dentistry © 2023.The Author(s).Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive LiteratureReview Shekatkar et al.Table 1 (Continued) Sl. no.

Table 1 (
Continued) Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.Comparison of Oral Cavity-Derived Mesenchymal Stem Cells through a Comprehensive Literature Review Shekatkar et al.

Table 2
Tabular representation of Egger's regression test