Song WP, Jin LY, Zhu MD, Wang H, Xia DS. Clinical trials using dental stem cells: 2022 update. World J Stem Cells 2023; 15(3): 31-51 [PMID: 37007456 DOI: 10.4252/wjsc.v15.i3.31]
Corresponding Author of This Article
Deng-Sheng Xia, DDS, Assistant Professor, Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, No. 4 Tiantan Xili, Dongcheng District, Beijing 100050, China. dsxia@mail.ccmu.edu.cn
Research Domain of This Article
Dentistry, Oral Surgery & Medicine
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Wen-Peng Song, Hao Wang, Department of Stomatology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
Lu-Yuan Jin, Meng-Di Zhu, Deng-Sheng Xia, Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing 100050, China
Author contributions: Song WP and Zhu MD contributed to the data collection and manuscript writing; Song WP and Jin LY contributed to the data analysis; Xia DS, Wang H, and Jin LY contributed to the study design and supervision; all authors have read and approved the final manuscript.
Supported bythe National Natural Science Foundation of China, No. 82071073 and No. 82270951.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Deng-Sheng Xia, DDS, Assistant Professor, Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, No. 4 Tiantan Xili, Dongcheng District, Beijing 100050, China. dsxia@mail.ccmu.edu.cn
Received: December 5, 2022 Peer-review started: December 5, 2022 First decision: January 11, 2023 Revised: January 20, 2023 Accepted: March 8, 2023 Article in press: March 8, 2023 Published online: March 26, 2023 Processing time: 107 Days and 21.9 Hours
Abstract
For nearly 20 years, dental stem cells (DSCs) have been successfully isolated from mature/immature teeth and surrounding tissue, including dental pulp of permanent teeth and exfoliated deciduous teeth, periodontal ligaments, dental follicles, and gingival and apical papilla. They have several properties (such as self-renewal, multidirectional differentiation, and immunomodulation) and exhibit enormous potential for clinical applications. To date, many clinical articles and clinical trials using DSCs have reported the treatment of pulpitis, periapical lesions, periodontitis, cleft lip and palate, acute ischemic stroke, and so on, and DSC-based therapies obtained satisfactory effects in most clinical trials. In these studies, no adverse events were reported, which suggested the safety of DSC-based therapy. In this review, we outline the characteristics of DSCs and summarize clinical trials and their safety as DSC-based therapies. Meanwhile, we also present the current limitations and perspectives of DSC-based therapy (such as harvesting DSCs from inflamed tissue, applying DSC-conditioned medium/DSC-derived extracellular vesicles, and expanding-free strategies) to provide a theoretical basis for their clinical applications.
Core Tip: Since dental pulp stem cells were first isolated and identified in 2000, a variety of dental stem cells (DSCs) have been reported. DSCs have shown satisfactory clinical effects in the treatment of a variety of diseases and have great potential for clinical application. This paper will summarize DSC-based clinical trials and put forward the current limitations and perspectives to accelerate and extend the clinical application of DSCs.
Citation: Song WP, Jin LY, Zhu MD, Wang H, Xia DS. Clinical trials using dental stem cells: 2022 update. World J Stem Cells 2023; 15(3): 31-51
Mesenchymal stem cells (MSCs) are a population of unspecialized cells characterized by the properties of self-renewal and multidirectional differentiation[1,2]. Currently, MSCs are currently being explored for the treatment of many diseases, such as cardiovascular disease, neurodegenerative diseases, dental diseases, and metabolic diseases[1].
Dental SCs (DSCs) were reported to have similar features to MSCs[3]. Since dental pulp SCs (DPSCs) were first successfully isolated from the extracted third molar in 2000[4], multiple DSC types have been harvested from mature and immature teeth and their surrounding tissues, including periodontal ligament stem cells (PDLSCs), stem cells from apical papilla (SCAP), stem cells from exfoliated deciduous teeth (SHED), gingiva-derived mesenchymal SCs (GMSCs), and dental follicle progenitor cells (DFPCs)[5-7] (Figure 1). DSCs develop from the neural crest and express both stem cell markers and neural markers[8,9]. It was reported that DSCs have the potential for multipotent differentiation into osteogenic, chondrogenic, adipogenic, neurogenic, odontogenic, dentinogenic cells, and so on[10]. In addition to their self-renewal and differentiation properties, DSCs have also been reported to be involved in secretion, immunomodulation, and tumor processes[3,11]. Based on the characteristics of DSCs, many clinical articles and clinical trials have used DSCs in tissue regeneration and the treatment of various diseases, such as pulpitis, periapical lesions, and periodontitis[12].
In this study, the current status of clinical articles and clinical trials using DSCs in the treatment of various diseases and conditions are reviewed. In addition, current limitations and perspectives, including harvesting DSCs from inflamed tissue, applying DSC-conditioned medium (CM) and DSC-derived extracellular vesicles (EVs), and expanding-free strategies, are also discussed.
CHARACTERISTICS OF DSCS
Based on their various sources, DSCs are divided into DPSCs, SHED, PDLSCs, SCAP, GMSCs, and DFPSCs (Figure 1). DSCs are known to express not only mesenchymal and embryonic stem cell markers (such as CD44, STRO-1, and Nanog) but also neuronal markers because they originate from embryonic neural crests[8,9] (Table 1). However, they do not express CD34, CD45, or CD11b, which are defined as hematopoietic markers[7].
Table 1 Characteristics of different types of dental stem cells.
Similar to mesenchymal stem cells, DSCs showed the ability of self-renewal and multidirectional differentiation, such as osteogenic, chondrogenic, adipogenic, neurogenic, odontogenic, dentinogenic, cementogenic, and myogenic differentiation[13-16] (Table 1). In addition, even in the undifferentiated state, DSCs were able to secrete several angiogenic and neurotrophic factors, including vascular endothelial growth factor (VEGF), ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), glia-derived neurotrophic factor (GDNF), and β-nerve growth factor (β-NGF), to promote angiogenesis and tissue regeneration[17,18].
In addition, the immunomodulatory features of DSCs have also been the focus of a number of studies. First, it was reported that DSCs, like mesenchymal stem cells, faintly express the MHC class II antigen HLA-DR and maintain low immunogenicity[19-21]. Second, local tissue regeneration and inflammation could be influenced by the secretome of DSCs (including the production of inflammatory and anti-inflammatory cytokines and the regulation of immune cells), which is also regulated by the local inflammatory microenvironment[21-24]. Finally, the inflammatory microenvironment could impact the behaviors of DSCs, such as proliferation potential, migration, homing, and differentiation[22].
Based on the characteristics of DSCs, they have been widely studied in regenerative medicine and tissue engineering and have shown an amazing therapeutic effect on oral-facial, neurologic, corneal, cardiovascular, hepatic, diabetic, renal, muscular, tenogenic, dystrophic and autoimmune conditions in both animal and human models[21,25-27]. For example, the proliferation, paracrine effect, and multidirectional differentiation potential of DSCs support the application of DSCs in regenerative medicine (e.g., dental pulp and bone tissue regeneration)[28,29]. The anti-inflammatory, immunomodulatory, and immunoevasive properties of DSCs also help in the treatment of plaque psoriasis[30] (Figure 1). DSC-based therapies have broad prospects for clinical application.
It is worth noting that the naming of mesenchymal stem cells and mesenchymal stromal cells remains controversial. Based on the position paper issued by The International Society for Cell & Gene Therapy (ISCT) Mesenchymal Stromal Cell (ISCT MSC) in 2005, mesenchymal stem cells are not equivalent or interchangeable with mesenchymal stromal cells[31]. Mesenchymal stem cells refer to progenitor cell populations with obvious self-renewal and differentiation functions, while mesenchymal stromal cells refer to large populations with significant secretion, immune regulation, and homing properties[32-34]. As we have just summarized, dental stem cells share some of the characteristics of both mesenchymal stem cells and mesenchymal stromal cells, and more consensus articles may be needed to further define the naming of dental stem cells.
DSC-BASED CLINICAL TRIALS FROM PUBLISHED ARTICLES
Pulpitis and pulp necrosis
Four studies were reported to treat pulp necrosis or irreversible pulpitis using autologous DPSCs or SHED, including a randomized controlled trial (RCT), two case series, and a case report[28,35-37] (Table 2). Xuan et al[28] applied SHED in the treatment of pulp necrosis caused by trauma and observed dental pulp tissue regeneration at 12 mo and 24 mo after transplantation. Meanwhile, the results also showed increased dental root length and decreased apical foramen width compared with traditional apexification treatment. Two case series reported by Nakashima et al[35,37] indicated that DPSCs transplanted with granulocyte colony-stimulating factor and gelatin sponges could increase pulp sensitivity and mineralization and recover the signal intensity (SI) of regenerated pulp tissue on MRI examination. Meza et al[36] transplanted DPSCs and leukocyte platelet-rich fibrin (L-PRF) harvested from autologous inflamed dental pulp and blood, respectively, to the root canal of irreversible pulpitis teeth and observed dentin bridge formation and a response to the cold test and electric pulp test.
Table 2 Dental stem cell-based clinical trials from published articles.
In a case report and two case series, SCAP/SHED combined with a polyethylene glycol polylactic-polyglycolic acid (PEG-PLGA) scaffold and SHED combined with bioglass were used for the treatment of periapical lesions[38-40] (Table 2). Periapical tissue healing was found in the follow-up examinations of all three studies. It was reported a positive response in the test of dental pulp activity after SHED transplantation, suggesting the regeneration of pulp or pulp-like tissue, which does not occur in traditional root canal therapy[39,40].
Periodontal intrabony defects
There are two RCTs, a controlled clinical trial (CCT), three case series, and two case reports of DSC-based treatment for periodontal intrabony defects[29,41-46] (Table 2). The RCT of Ferrarotti et al[41] indicated that pulp micrografts applied with collagen sponges could significantly reduce PD and CAL and promote the regeneration of bone defects when compared with collagen sponges alone. Three case series and a case report using pulp micrografts/DPSCs and collagen sponges also reported similar results of periodontal benefits[46-49]. It was reported a novel approach using periodontal ligament soft tissue, gelatin sponges, and cementum scrapings, which reduced the CAL and PD of periodontitis teeth in their case report[45].
Although two case series demonstrated the periodontal benefits of PDLPs and PDL-derived cell sheets[43,44], significant differences in periodontal indices (including PD and CAL) were not observed between the test groups and control groups in the other two CCTs that applied PDLSC and PDLSC sheets[29,42]. Several factors might have contributed to the lack of significant differences in the outcomes, such as satisfactory scaffold material properties and small sample sizes. In these four studies, β-TCP, HA/TCP, and deproteinized bovine bone mineral (Bio-oss®) were applied as scaffold materials. Although some studies reported abilities to provide support for PDLSCs on osteogenic differentiation of these scaffoldsin vitro and in vivo[50-53], only using these scaffolds also achieved great clinical benefits in the treatment of periodontitis[54-56]. The excellent performance of the scaffold may have overshadowed the contribution by PDLSCs. More clinical studies at multiple centers with different amounts and types of DSCs, more follow-up time points, and larger sample sizes are necessary, and the results of such studies would be meaningful.
Bone defects caused by other conditions
In addition to periodontal intrabony defects, DSCs were also used for the treatment of post-extraction sockets, mandibular osteoradionecrosis, bone defects after ameloblastoma resection, and sinus lifting[57-61] (Table 2). Two split-mouth RCTs reported by Barbier et al[57] and Cubuk et al[62] did not find significant differences in BD or interdental septum height between the pulp micrograft + scaffold (collagen matrix/L-PRF) group and the scaffold (collagen matrix/L-PRF) group after implantation into post-extraction sockets. However, in another split-mouth CCT designed for regenerating post-extraction sockets, DPSCs combined with collagen sponges promoted the rate of mineralization, the levels of cortical bone, and the expression of bone morphogenetic protein-2 (BMP-2) and VEGF when compared with collagen sponge treatment alone[58]. Tanikawa et al[63] reported a historical control study comparing the effects of SHED, rhBMP, and iliac crest bone grafts in treating cleft lip and palate. The SHED group showed similar satisfactory performance in bone healing compared with iliac crest bone grafts and a higher bone filling percentage compared with the rhBMP group at the 6-mo follow-up[63].
Two case reports indicated that DPSCs combined with TCP could increase the bone regeneration of bone defects caused by osteoradionecrosis and ameloblastoma[59,60]. A case report by Brunelli et al[61] demonstrated that pulp micrografts + collagen sponges increased the BD in newly formed bone when applied for sinus lifting.
Other conditions
Koga et al[64] reported a case series that applied SHED conditioned medium (SHED-CM) to treat erectile dysfunction. In this study, the international index of erectile function (IIEF-5), which is clinically used to screen for erectile function and to assess treatment efficacy, was increased after SHED-CM injection into the corpus cavernosum of erectile dysfunction patients[64]. A case report indicated that SHED intravenous administrations could decrease the scale of unified Huntington’s disease rating, which is designed to assess clinical performance and capacity in patients with Huntington’s disease[65,66]. Meanwhile, the patient with Huntington’s disease also suffered from preexisting pulmonary nodules, and SHED injection did not result in long-term tropism or homing for the patient’s lung adenocarcinoma[65]. In a case report by Wang et al[30], GMSCs were used to treat plaque psoriasis via bolus injection, and they observed fully cleared psoriatic lesions without recurrence.
Three clinical study protocols using DSCs have been published in recent years, including the treatment of acute ischemic stroke, chronic disability after stroke, and COVID-19[67-69].
To date, there have been 21 clinical trials registered on ClinicalTrials.gov evaluating the use of DSCs in treating periodontitis (33.3%, 7/21), post-extraction sockets (4.8%, 1/21), edentulous alveolar ridge (4.8%, 1/21), cleft lip and palate (9.5%, 2/21), knee osteoarthritis (4.8%, 1/21), dental pulp necrosis (4.8%, 1/21), liver cirrhosis (4.8%, 1/21), type 1 diabetes (4.8%, 1/21), acute ischemic stroke (4.8%, 1/21), Huntington’s disease (14.3%, 3/21), and COVID-19 (9.5%, 2/21) (Table 3). In addition to the 6 studies reported in ClinicalTrials.gov, 7 clinical trials were registered on the ICTRP using DSCs in the treatment of periodontitis (57.1%, 4/7), wrinkles (28.6%, 2/7), and hair loss (14.3%, 1/7) (Table 4). In all, 28 clinical trials were registered on these two platforms.
Table 3 Dental stem cell-based clinical trials registered at clinicaltrials.gov.
DPSCs (1 × 107 cells) for once; DPSCs (1 × 107 cells) for twice
Saline
90, 180, 360 d
Phage 0
-
ChiCTR2100049178
Pending
Periodontitis
Randomized; parallel assignment; double-blind
Dental pulp
Local injection
36
DPSCs (1 × 106 cells) for single injection; DPSCs (5 × 106 cells) for single injection; DPSCs (1 × 107 cells) for single injection; DPSCs (1 × 107 cells) for single injection in 2 locations; DPSCs (1 × 107 cells) for single injection in 3-4 locations
All-in-one gel containing immortalized DPSC-CM solution and the latest peptide raw materials
No treatment
4 wk
Not applicable
-
JPRN-UMIN000045897
Complete: Follow-up continuing
Hair loss
Nonrandomized; parallel assignment; open label
Deciduous pulp
Injection
22
SHED-CM; after SHED-CM injection, one dose of micrografts (Rigenera) followed by another SHED-CM injection; SHED-CM injection after one dose of micrografts (Rigenera)
None
6 mo
Not applicable
Several registered clinical trials applied two stages in one work. The most frequently appearing trial phases were phase 1 (42.9%, 12/28), followed by phase 2 (25%, 7/28), Phase 3 (7.1%, 2/28), and Phase 0 (3.6%, 1/28). There were 10 trials (35.7%) in which the phase design was not applied or not selected. One clinical trial reported the outcomes both on the registry platform and in a published article[63] (NCT01932164), and the published articles of seven trials stated the registered ID[29,42,62,63,67,69-71], while other trials did not publish any data.
Consistent with the literature, the proportion of clinical trials using DSCs to treat periodontitis was the highest. Eleven registered clinical trials researched the effect of DSCs on periodontitis (39.3%, 11/28). In these trials, various amounts, types, and injection times of DSCs and different application modes (such as DSCs, micrografts, cell sheet pellets, and cell sheet fragments) were applied. In addition, several scaffolds were used in combination with DSCs, including collagen sponges, deproteinized bovine bone minerals, β-TCP scaffolds, and hydroxyapatite-collagen scaffolds.
SAFETY ISSUES REGARDING DSC-BASED THERAPY
Although encouraging treatment effects on diseases have been achieved, the safety issues of stem cell-based therapy remain controversial, especially in long-term follow-up[72]. At present, the limitations of stem cell-based therapy are mainly focused on non-directional differentiation, accelerating tumor progression.
In addition, uncontrolled non-directional differentiation may have a great impact on the safety of stem cell transplantation. Breitbach et al[73] found that the encapsulated structures in the infarcted areas contained calcifications and/or ossifications in myocardial infarction mice after MSC injection. In another study, unselected bone marrow cells injected directly induced significant intramyocardial calcification in acutely infarcted myocardium[74].
Similar to the regeneration of damaged tissue, tumors exert chemotactic effects on MSCs, affecting their recruitment to tumor sites[75-77]. Current studies have shown that MSCs have bidirectional, anti-cancer and pro-cancer, regulatory effects, which raises safety concerns for clinical application. On the one hand, MSCs are the major component of the tumor microenvironment and can be reprogrammed to the pro-tumorigenic phenotype by the tumor[78]. MSCs have been revealed to participate in the initiation, development, progression, and metastasis of multiple cancers[79]. The pro-cancer effect of stem cells may be achieved by secreting molecules that affect the phenotype of tumor cells, promoting tumor angiogenesis, cancer-associated fibroblast differentiation, cell-to-cell contact, or cell engulfment[76]. In recent studies, DPSCs and their conditioned medium were reported to promote the proliferation and carcinogenic properties of prostate cancer, oral cancer, breast cancer, and melanoma cellsin vitro[80-82].
On the other hand, there is also evidence that MSCs can inhibit the growth of a variety of tumors, including breast cancer, Kaposi’s sarcoma, hepatoma, glioma, and melanoma[76,83-85]. DPSCs and their conditioned medium also showed a suppressive effect on the development and migration of colorectal cancer cells through mitogen-activated protein kinase pathways[86]. In fact, there are few reports of primary pulp malignancies[87]. In a genome-wide RNA-seq study, phosphatase and tensin homolog (PTEN) expression in DPSCs was higher than that in BMSCs[88]. PTEN, a phosphatase, can metabolize phosphatidylinositol 3,4,5-triphosphate and directly oppose the activation of the oncogenic PI3K/AKT/mTOR signaling network[89]. At present, the regulatory effects of stem cells on cancer are still controversial, and the difference in results may be related to cell lines, cell doses, animal models, cancer types, treatment duration time, and other factors.
In conclusion, no adverse events were reported in the published clinical articles or clinical trials using DSCs, which suggested the safety of DSC-based therapy. However, based on current concerns about the safety of stem cell therapy, more in vivo studies on the safety of DSC-based therapies are of great significance.
CURRENT LIMITATIONS AND PERSPECTIVES
Harvesting DSCs from inflamed tissue
Most studies applied stem cells extracted from healthy dental tissue for treatment, but additional surgery (such as third molar extraction) might increase patient suffering. Harvesting stem cells from inflamed dental tissue could be an alternative method, although stem cell abilities might be affected[36,90,91].
Several studies have researched the different biological properties of DPSCs derived from normal and inflamed pulps (iDPSCs), and the results are still in dispute[92-98]. In some studies, DPSCs showed better self-renewal ability[92,93] and multidirectional differentiation capacities than iDPSCs[92], while in other studies, no significant difference was observed[94,95,98]. A study by Nie et al[97] indicated that DPSCs showed higher colony-forming, proliferative, and osteo/dentinogenesis abilities, while iDPSCs demonstrated enhanced chondrogenesis, neurogenesis, angiogenesis, and adipogenesis capacities. Park et al[96] reported that iDPSCs appear to have higher osteogenic differentiation potential and lower neurogenic differentiation potential than DPSCs.
Differences in inflammation levels may explain the discrepancy in the biological properties of DPSCs and iDPSCs in various studies. Intense and rapid inflammatory stimulation irreversibly initiates pulp necrosis, while low insult levels of inflammation are able to cause reversible pulpitis and promote dentine regeneration[99]. DPSCs are a suitable source of stem cells for pulp nerve regeneration because of their neuronal differentiation potential. It was reported that acute inflammation with a high level of proinflammatory cytokines could reduce neural precursor cell (NPC) survival and inhibit the neuronal differentiation of NPCs, while chronic inflammation expressed a potentially neuroprotective phenotype and supported neuronal differentiation[100]. Meanwhile, age, sex, tooth position, and sample size are also confounding factors affecting the function of DPSCs, which should be considered in subsequent studies and clinical practice.
DSC-CM and DSC-EVs
The culture medium collected from cells in culture is known as CM. CM is applied as an alternative therapy for tissue regeneration, which is a less ethical issue because it uses cells indirectly. Koga et al[64] applied SHED-CM in the treatment of erectile dysfunction, which is the only record of its clinical use to the best of our knowledge.
DSC-CM contains a variety of cytokines associated with vascular and nerve tissue regeneration, such as VEGF, BDNF, β-NGF, GDNF and neurotrophin-3 (NT-3)[101,102]. To date, DSC-CM has been reported to have the potential to promote bone regeneration[103], periodontal regeneration[104], angiogenesis[105], pulp regeneration[106], and nerve protection/regeneration[105,107-109] with great possibilities for clinical application.
In addition, DSC-CM showed satisfactory anti-inflammatory and immunoregulatory effects. Several in vivo studies based on various animal models reported that intravenous injection or intranasal administration of SHED-CM improved liver fibrosis[110], acute liver failure[111], acute lung injury[112], Alzheimer’s disease, temporomandibular joint osteoarthritis[113], Sjögren’s syndrome[114], and rheumatoid arthritis[115] by exerting anti-inflammatory effects. Meanwhile, studies have also reported the effect of SHED-CM on promoting Treg cell differentiation[114] and M2-like macrophage induction[111,112], as well as inhibiting Th17 cell differentiation[114] and inflammatory macrophage activation[116].
In addition to DSC-CM, DSC-EVs harvested from cell-culture medium have also been deeply studied in recent years. Multiple studies have indicated the promotion effect of DSC-EVs on jawbone and calvarial bone regeneration[117,118], angiogenesis and cutaneous wound healing in vivo[119,120]. Li et al[121] also reported that DSC-EVs could alleviate cerebral ischemia-reperfusion by suppressing the inflammatory response, which is related to the inhibition of the HMGB1/TLR4/MyD88/NF-κB pathway.
The poor survival rate of implanted DSCs and host immunogenic reactions are the main drawbacks of applying DSCs directly. In some comparative studies, stem cell-derived CM showed similar and even better treatment effects on acute lung injury, Parkinsonism, and type 1 diabetes than the direct use of stem cells[112,122,123]. DSC-CM and its components (such as EVs) provide several key advantages over cell-based applications, including avoiding the risk of host immunogenic reactions, cost-effectiveness, long-term storage capacity, and simpler evaluation of safety and efficacy[104,124]. Accumulating evidence indicates the great potential of DSC-CM/DSC-EV-based treatment in clinical applications.
Expanding-free strategy
Despite encouraging results of differentiation and tissue regeneration, DSCs still require rigorous cell-expanding procedures to obtain a sufficient number of cells for treatment, which is costly with great technique sensitivity, often taking tens of days. The ex vivo expansion of stem cells often reduces their self-renewal and proliferation abilities[125]. Direct mechanical digestion or tissue transplantation are promising solutions to these limitations.
In recent years, using mechanical disaggregation of dental tissues instead of cell-expending procedures was successful for harvesting autologous pulp micrografts rich in progenitor cells[41,126]. In 2016, Monti et al[126] indicated that DSCs harvested by mechanical digestion (Rigenera® system, HBW, Turin, Italy) were fully comparable to stem cells obtained after enzymatic digestion. In this study, mechanical digestion-obtained DPSCs showed osteogenic, adipogenic, and chondrogenic differentiation abilitiesin vitro and were able to increase the regeneration of post-extraction sockets in vivo when applied with the collagen sponge[126].
Pulp micrografts harvested by mechanical digestion were also applied in the treatment of sinus lifting, post-extraction sockets, and periodontal intrabony defects[46,47,49,57,61,62]. One clinical trial using pulp micrografts was also designed for periodontitis management (NCT03386877), but the outcome was not reported. Different systems of mechanical disaggregation were applied in these studies, including BD Medimachine (BD Biosciences San Jose, CA, United States)[62], the Rigenera® system (HBW, Turin, Italy)[46,57,61], and the Medimachine System (Consul TS, Orbassano, Italy)[47,49]. In brief, dental pulp is first collected from extracted teeth and then sent to the mechanical disaggregation system to obtain pulp micrografts. After filtration or without filtration, pulp micrografts are combined with the scaffold for transplantation.
In addition, Vandana et al[125] described a novel approach using stem cell assistance in the periodontal regeneration technique (SAI-PRT), which contained periodontal ligament soft tissue gelatin sponge scaffolds and cementum scrapings. In their research, SAI-PRT successfully bypassedin vitro culture and expanded PDLSCs, resulting in satisfactory defect filling of periodontal intrabony defects[125].
Embryonic stem cells, PSCs, and DSCs
Embryonic stem cells (ESCs) are pluripotent cells of great significance to developmental biology. They give rise to all types of germ layer cells in the embryo. The self-renewal ability and plasticity of ESCs make it possible to generate unlimited numbers of different types of cells in vitro[127]. Similar to embryonic cells, PSCs derived from different somatic cells also have the ability to immortalize and differentiate into the three germ layers[128]. The properties of these two cell types make them promising sources for stem cell-based therapy for various diseases and injuries. However, due to the limitations of ESCs and PSCs, adult stem cells (such as DSCs) still possess high application value.
First, ethical issues regarding the use of ESCs make their clinical application challenging[128]. Second, the preparation of autologous PSCs takes a long time (more than 3 mo) and has high medical cost, and the immune rejection issue of allotransplantation should be considered[129]. In addition, teratomas are germ cell tumors containing cells of two or three germ lines that always occur via uncontrollable stem cell proliferation and differentiation[130,131]. In experimental studies, stem cell transplants (especially ESC and PSC transplants) have been found to increase the risk of teratomas, raising safety concerns[131-133]. Previously, viral vector integration and contamination of animal-derived components also posed obstacles to the use of PSCs, but these problems have been addressed by innovative techniques, such as integration-free methods and xeno-free culture[134-136].
DSCs did not show unlimited proliferation potential and demonstrated poorer differentiation ability than PSCs and ESCs[137]. However, the advantages of DSCs over ESCs and PSCs, such as fewer ethical issues and lower teratoma risk[87,88,138], lower cost and shorter preparation period, harvesting from medical waste, and implementing therapeutic effects without gene editing, grant them greater potential for clinical applications in the future.
CONCLUSION
Many clinical articles and clinical trials of autologous and allogeneic DSCs have aimed to evaluate their therapeutic effects on various diseases, such as pulpitis, periapical lesions, periodontitis, cleft lip and palate and Huntington’s disease. In most studies, satisfactory clinical treatment results were obtained, while clinical benefits of using DSCs were not found in some research. Although safety risks exist for stem cell-based therapies, safety issues have not been reported in the clinical applications of DSCs. In the future, in addition to continuing to study the efficacy and safety of DSC-based treatment, harvesting DSCs from inflammatory tissues, expanding-free strategies, and applying DSC-CM or DSC-EVs should be studied, as they have strong research value and application potential. Taken together, DSC-based therapy is a promising tool for the treatment of various diseases and can be further promoted.
ACKNOWLEDGEMENTS
We thank our friend Han-Yi Dong for designing and drawing Figure 1.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Dentistry, oral surgery and medicine
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