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The Effect of the Dental Stem Cell Secretome on Tissue Regeneration: A Systematic Review






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Abstract

Secretome therapy is a promising approach in tissue regeneration because it can reproduce most of the advantages of cell-based therapies. This review aims to investigate the most prominent effect of using dental-derived secretome on tissue regeneration using a systematic review approach. A systematic electronic search was conducted via the PubMed, Scopus and Wiley online library databases for studies published in English up to October 2020. All the articles from the databases were screened, and the criteria for inclusion and exclusion were applied. Forty papers were included in the study, whereby there were 16 in vitro studies and 11 in vivo studies with different animal models. No clinical trial has been reported yet. The most studied DSCs were human SHEDs (12 studies), followed by human DPSCs (11) and human PDLSCs (5). The majority of the studies used secretome from human SHEDs and DPSCs. TGF-ß 1 is the most frequently detected protein in the secretome, which comes from six types of DSCs, followed by NGF and NT-3, which were found in five different types of DSC secretome. The compositions of the secretome were found to promote the regeneration of the tissues through their neurogenic, angiogenic, osteogenic and odontogenic effects, with the majority of studies reviewed reporting using them for nondental tissue regeneration. From this review, DSC-CM reported favorable tissue regeneration potential; however, many factors need to be explored in future research with regard to the application of secretome delivery, particularly DSC-CM, in the clinical setting.

Introduction

In regenerative medicine, tissue engineering has arisen as a promising approach for the restoration, repair and healing of organ and tissue functions, especially in tissues susceptible to disease, injury, and degeneration. At present, tissue engineering studies are focused on adult mesenchymal stem cells, which have become among the most frequently explored types of cells in this field 1 . Mesenchymal stem cells (MSCs) are undifferentiated multipotent cells that possess self-renewal capabilities and can differentiate into various mesoderm cell lineages, such as osteogenic, adipogenic and chondrogenic lines. Aside from bone marrow and adipose tissue, cells possessing stem cell characteristics have also been successfully isolated from different parts of the tooth. These isolated cells are known as dental stem cells and include dental pulp stem cells (DPSCs) 2 , 3 , stem cells from exfoliated deciduous teeth (SHED) 4 , periodontal ligament stem cells (PDLSCs) 5 , stem cells from apical papilla (SCAP) 6 , 7 , dental follicle progenitor cells (DFCs) 8 and gingival tissues derived from mesenchymal stem cells (GMSCs) 9 , 10 .

The majority of dental-derived stem cells (DSCs) can be obtained from human exfoliated deciduous teeth and orthodontically extracted premolars and third molars. These sources of stem cells are considered biological waste in dentistry despite containing multipotent stem cells 4 , 11 . Premolars are the most common teeth indicated for extraction in orthodontics and are often ideal for the relief of anterior and posterior crowding. However, the decision of extracting between the first or second premolars depends on several factors, including the anchorage requirement, the severity of crowding, and the amount of overbite and overjet 12 . Extraction of the third molar for orthodontic reasons is rare, as both orthodontists and oral surgeons must make appropriate decisions and consider the potential risks and benefits of the procedure specifically pertaining to the surgical removal of asymptomatic impacted third molars 13 . There are several orthodontic reasons for the extraction of third molars that aim to prevent late mandibular incisor crowding 14 , to allow molar distalization 15 and to prepare for orthognathic surgery 16 .

Experimental research using stem cells showed that they produce reliable and effective tissue regeneration. However, there are several shortcomings in terms of the clinical application of therapy using MSCs 17 : (i) the host immune response might cause rejection of transplanted MSCs in the long term, (ii) there could be an imbalance and disturbance in the homeostasis of local tissue, (iii) the risk for tumor formation may increase due to long-term ex vivo expansion and/or due to immunosuppression of the local tissue, and (iv) the chances for ectopic tissue formation by the transplanted MSCs become higher 13 .

To overcome these drawbacks of using MSCs, an increasing number of studies have reported the use of the MSC secretome 18 . Secretome are various cellular products, such as cytokines, growth factors and enzymes secreted by MSCs 19 , 20 . These biologically active chemical products play significant roles in diverse aspects of tissue function, repair and homeostasis 21 , 22 . The function of the secretome is to suppress immune responses 23 , reduce oxidative stress 13 , stimulate angiogenesis 24 , and induce the recruitment, proliferation and differentiation of endogenous stem cells 25 . Secretome are easily obtained via in vitro culture of various cells, where they are contained or extracted from the culture media, often referred to as conditioned media (CM). In various studies, CM from stem cells has shown promising results in regenerative medicine and tissue engineering 26 , including CM from SHED and CM from healthy and inflamed periodontal tissue 27 , 28 .

When compared to stem cell therapy, secretome therapy offers potential benefits because it can reproduce most of the advantages of cell-based therapies with minimal side effects. Furthermore, using the secretome as therapy provides many practical advantages, such as ease of preservation, sterilization, and packaging 1 . Apart from that, they also have an extended duration of storage without losing their properties 29 , 30 , ease in gauging proper dosages and can be produced in mass 20 as well as a noninvasive extraction procedure that may save both time and cost of production 24 . Despite the potential benefits of the secretome, the effect of the dental-derived secretome on specific types of tissue has not been systematically reviewed. The focus question is to systematically review in vitro , in vivo and clinical studies on the effect of the dental-derived secretome in terms of tissue regeneration potential. Thus, we aim to identify the most prominent effect of using a dental-derived secretome on tissue regeneration using a systematic review approach.

Methods

The Preferred Reporting Items for Systematic Review (PRISMA) checklist was used as a guideline in conducting this review 31 . A comprehensive and systematic electronic search of MEDLINE via PubMed, Scopus and Wiley online library databases was conducted for studies published in English up to October 2020 ( Figure 1 ).

Figure 1 . Flow diagram for the papers selection.

Study design

This study systematically reviewed and summarized all the published studies regarding the use of dental stem cell-derived conditioned media in tissue regeneration by searching electronic databases.

Inclusion criteria

The included studies were in vivo, in vitro and clinical studies on the dental stem cell secretome and tissue regeneration. Language was limited to English, and no manual or gray literature search was included.

Exclusion criteria

All studies on embryonic stem cells, bone marrow stem cells, induced pluripotent stem cells, other types of mesenchymal stem cells, cell therapy, secretome derived from ameloblasts, odontoblasts, dental epithelium, narrative reviews, systematic reviews and/or meta-analyses.

Information sources and search strategies

A comprehensive search of online databases was implemented through MEDLINE via PubMed, SCOPUS and Wiley Online Library. All studies published up to October 2020 were included. A Boolean operator was used for the search strategy by combining terms and free text words: “dental stem cells” AND secretome, “dental secretome” OR “paracrine therapy” AND regeneration, “dental stem cells” AND “conditioned medium” AND regeneration, dental AND “paracrine mediated therapy”. Then, all duplicate papers were removed by the reference manager software (Mendeley).

Study selection

The data were extracted independently by four authors (N.S. N, M.M. D, F. and M.H. with an extraction form specifically designed for this study. Then, any disagreement on the data extracted was resolved through discussion and mutual consensus between the authors. Interrater reliabilities were calculated using Cohen’s Kappa (Ƙ = 0.704, which indicates substantial agreement).

Data collection process

For data collection, necessary information was extracted as follows: the characteristics of the study (authors, year of publication, country of the study conducted), type of study design ( in vitr o, in vivo , clinical studies), source of dental stem cell secretome, test for dental stem cell markers, test and growth factors identified from the secretome, test and analysis for regeneration with the findings, clinical test used, and any biomaterials used for regeneration.

Results

Study overview

A total of 40 studies were selected after thorough screening by the authors, as listed in Table 1 . Of these, 16 are in vitro studies, and 11 are in vivo studies with various types of animal models. The remaining 13 studies were combinations of in vitro and in vivo intervention studies. There were no clinical trials reported. Nine studies were excluded because the studies used CM from Hertwig’s epithelial root sheath (HERS) (2), study on genetically modified dental stem cells (1), study on differentiated human dental pulp (1), regeneration studies done using stem cells not the CM (3), not a tissue regeneration study (1), and insufficient information (1).

The source of dental-derived stem cell secretome is from either humans or animals. There were 29 studies that used human dental stem cells as the source of the conditioned media, while nine studies used animal dental stem cells, such as stem cells from rats, pigs and dogs. One study used both dental stem cells from humans and porcines, whereby they utilized tooth germ cells. Another study did not specify the source of tooth germ cells used.

The source of the secretome used in all the studies varies from dental pulp stem cells (DPSCs), human exfoliated deciduous teeth (SHEDs), stem cells from apical papilla (SCAPs), dental follicle stem cells (DFSCs), periodontal ligament stem cells (PDLSCs), gingival mesenchymal cells (GCMs) and tooth germ cells (TGCs). TGCs can be further subcategorized into apical tooth germ cells (APTGCs), embryonic tooth germ cells (ETGCs) and neonatal tooth germ cells (NTGCs). Human SHEDs are the most studied DSCs (12 studies), followed by human DPSCs (11) and human PDLSCs (5). Secretome from human SHEDs and DPSCs contributed to the majority of the studies.

Table 1 Summary of studies selected

To ensure that the secretome obtained is of stem cell origin, most studies would need to show the presence of stem cell markers on the cells used. However, from this review, there were only 18 studies reporting on stem cell markers, whereas the remaining studies did not. Among studies that reported stem cell markers, 15 used flow cytometry, while the remaining studies did not state the technique used.

Proteomic analysis of the DSC secretome

Sixteen studies reported proteomic analysis of CM. The techniques used in identifying the secreted factors from the DSCs are ELISA (8 studies), Western blot (1), multiplex analysis (5) and liquid chromatography tandem mass spectrometry (LC‒MS/MS) (2).

The most frequently detected protein is transforming growth factor-β1 (TGF-β1), which is present in the secretome of six types of DSCs: human SHEDs, SCAPs, DPSCs, DFCs, and GMSCs as well as rat DPSCs. This was followed by nerve growth factor (NGF) and neurotrophin-3 (NT-3), which were found in five different types of DSC secretome. Brain-derived neurotrophic factor (BDNF), tissue inhibitor of metalloproteinase-1 (TIMP-1) and vascular endothelial growth factor (VEGF) were detected in the secretome from four different sets of DSCs. Further details of the proteins detected in the DSC secretome are presented in Table 2 .

Table 2 List of frequently reported protein contents of the DSC secretome

Functional analysis using the DSC secretome

Overview

Despite using DSCs to obtain the secretome, the majority of studies we reviewed reported using the cells for nondental applications, with neuroregeneration being the most frequently studied (12 out of 40 studies). Others include regeneration of bone tissue, blood vessels, salivary duct, lung, and liver. Among the studies reporting using secretome for dental tissue regeneration (15 studies), three areas were examined: (i) dental pulp, (ii) periodontal, and (iii) dentin. The effects of the secretome are summarized below.

Neurogenic effects

Among studies reporting favorable neurogenic effects (total of 15), all but two used the DSC secretome obtained from humans instead of animal cells. Most of the studies using the human DSC secretome were sourced from SHED, followed by secretome from DPSCs, PDLSCs, SCAP, and GMSCs. When looking from the experimental design perspective, most of the neurogenic studies were performed in both cell culture and animal models of various neurodegenerative diseases (such as hemorrhagic stroke, Alzheimer’s disease or diabetic neuropathy), with only six studies reporting the effects of cell culture experiments exclusively. The most frequently reported in vitro finding is enhanced neurite outgrowth, followed by increased neuronal proliferation. Three out of eight studies reporting neurite outgrowth also reported increased expression of BDNF with secretome treatment.

Angiogenic effects

Most of the data on the angiogenic effects of the DSC secretome were obtained from work on human umbilical vein endothelial cells (HUVECs), with only one from human dermal microvascular endothelial cells. From a total of nine studies, four of them reported only in vitro findings, whereas the remainder also reported effects in animal models. The secretome were obtained from either DPSCs (6 studies; 4 of which were human cells) or SHED (all 3 from humans). Looking at the in vitro studies, five of them reported enhanced vascular network formation, three studies reported increased cell proliferation/viability, while two reported observing HUVECs differentiating into VE-cadherin-positive endothelial cells.

Osteogenic/odontogenic effects

Odontogenic effects are seen when cellular differentiation indicates that the formation of odontoblasts is imminent. Odontoblasts are cells that lay down the dentin layer during tooth formation and are usually found in the dental pulp. During in vitro experimentation, Alizarin red staining used to detect intracellular mineralization was used to detect odontogenic or osteogenic processes. In our review, we found 12 studies looking at the osteogenic/odontogenic effects of the secretome, of which only four were sourced from humans, while the rest were obtained from rats and pigs. There were multiple cell types from which the secretome were obtained, with TGCs being the most used (in four studies), followed by DPSCs, DFSCs (three each), SCAP and SHED. In determining the osteogenic/odontogenic effects of the secretome, the parameters reported were enhanced intracellular mineralization (6 studies), increased expression of mineralization markers such as ALP, BSP and CAP (5), and increased odontoblastic differentiation (4). The single study that used the SHED secretome reported inhibition of osteoclastic activity in vitro , which was reflected as a reduction in bone resorption under radiography in vivo .

Discussion

Most of the studies reviewed here were preclinical in vitro and animal studies reporting possible mechanisms of secretome effects, which can be grouped into neurogenic, angiogenic, osteogenic and odontogenic. When compared to the list of proteins detected in the secretome, a correlation can be observed between the type of protein found and the effects seen. As an example, TGF-ß1 is a mediator of osteogenic differentiation and was repeatedly reported to be a component of secretome from various DSCs. Furthermore, NGF, NT-3 and BDNF are well-known neurotrophic factors 70 , 71 , 72 that correlate with the neuroregenerative effects seen in a large proportion of the studies here.

While there are various sources of the DSC secretome, those obtained from the culture of DSCs acquired from permanent teeth (such as DPSCs and PDLSCs) as well as deciduous teeth (called SHEDs) were mostly reported. This is well explained by the fact that such cells are the most easily accessible for the isolation of stem cells 73 . However, not all studies confirmed their claim that the cells they used are stem cells, as only 19 studies reported performing stem cell marker analysis. Other studies that did not report performing this analysis referred to previous publications in their methodology sections. This step is crucial, as it confirmed the stemness of the cells obtained from the various intraoral sources 74 .

At present, clinical studies reporting the effectiveness of the DSC secretome in clinical tissue regeneration are still absent. Until June 2021, there were only three ongoing clinical trials using the MSC secretome registered with the US National Institute of Health (https://clinicaltrial.gov), with the secretome used in all three studies reported to be from bone marrow MSCs. This could be due to a number of reasons. First, the potential of the DSC secretome to instigate an adverse reaction may not have been well studied. This is reflected in an article search on Scopus using the terms “secretome OR (conditioned media)” AND “toxic*”, which returned a result set that was overwhelmingly positive in nature. While this is encouraging, the lack of reports on the propensity of the secretome to cause any adverse biological response will hinder their clinical translation, as the content of the secretome varies and is likely to be antigenic in nature when administered 75 .

Hence, the important nonclinical studies that need to be investigated further are on the inflammatory reaction at the local and systemic levels. Although the PDLSC secretome was found to be able to suppress the proinflammatory cytokine expression (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β) of the surrounding healing tissues after 5 days of implantation in an in vivo periodontal defect, the findings were not statistically significant compared to the control group 45 . In another study in which the PDLSC secretome was used on the spinal cord of a multiple sclerosis animal model, there was reduced expression of proinflammatory mediators (IL-17 and interferon gamma (IFN-γ)) 48 . Other studies that showed immunosuppression of proinflammatory cytokines in animal models include the secretome originating from human SHEDs 65 , 40 ; 43 , human DPSCs 52 and human GMSCs 53 . However, one study showed a contradictory finding that the DPSC secretome caused increased expression of proinflammatory cytokines such as IL-1α, IL-6 and IL-8 39 . To advance knowledge regarding the secretome’s biocompatibility, more similar studies are needed to help with efforts to test the secretome in preclinical and clinical human studies.

Another possible reason for the lack of clinical studies would probably be the difficulty in determining the exact preparation of the secretome to be used. The preparation needs to ensure that the contents of the secretome are properly preserved with minimal protein degradation and that it has adequate shelf life. As mentioned in our results section, multiple lines of evidence were found with regard to the composition of the secretome, which includes a vast range of growth factors and cytokines 76 .

The results from the proteomic analysis in this review reveal that insulin growth factor-1 (IGF-1) was found only in rat DPSC-CM 56 , while no IGF-1 was detected in human DSC-CM. IGF-1 is a small peptide with 70 amino acids and has autocrine, paracrine and endocrine effects. The synthesis of IGF-1 mainly comes from the liver 77 , and it is an essential mediator of cell growth, differentiation and transformation 78 , 79 . The findings from this review are in line with the results from Caseiro et al., who performed a study to compare the profiles of metabolomic and bioactive factors of the human umbilical cord and DPSC secretome 80 . The profiling revealed that no IGF-1 was found from the secretome analysis. The lack of IGF-1 expression in the human stem cell secretome, particularly DSC-CM, might contribute to the binding of this hormone with IGF-binding proteins (IGFBPs). IGFBP expression depends on the tissue site and developmental stage at different concentrations in different body compartments 81 . As shown by the results from this review, IGFBP-2, IGFBP-3, IGFBP-4 and IGFB-6 were expressed by different types of DSC-CM, such as human DPSCs, SHEDs and PDLSCs.

In addition, the difference in the expression and concentration of the factors may be due to the difference in the methods used to collect the conditioned medium. The current study also found that even when the CM is derived from the same type of cells, the expression of the growth factors varied. This result may be explained by the difference in cell numbers, culture medium and condition as well their CM processing method 82 .

Apart from various growth factors and cytokines produced by the DSC secretome, this review focused on the effect of the DSC secretome on tissue regeneration. The most abundant evidence was shown in neuroregeneration studies, which was supported by the release of numerous growth factors (NGF, BDNF, NT-3, NTF, GDNF and HGF). These neurotrophins promote the differentiation and growth of neurons and are paramount in treating neurodegenerative diseases as well as neural injuries 51 41 48 43 . Other than neuroregeneration, the DSC secretome has the potential to promote bone regeneration, probably due to the increase in the migration and mineralization potential of the surrounding osteoprogenitor cells by TGF-β1 83 . The TGF-β1-BMP (bone morphogenic protein) signaling pathway has a pivotal role in osseous regeneration through the elevated expression of osteogenic genes in the targeted cells 84 , 85 . This review also found the potential of DSC secretome in dentine formation for pulp protection, periodontal regeneration and other tissue regeneration, such as cartilage, salivary duct cells, liver and lung tissues, but the mechanism of action is still inconclusive.

Conclusion

In conclusion, evidence showing the effectiveness of the DSC secretome in neuroregeneration and bone regeneration is encouraging. However, data from human studies are still lacking, which could impede the translation of such works into the clinical perspective. Furthermore, the potential for the secretome to be used in the regeneration of other tissue types, such as smooth and skeletal muscle, needs to be explored, as secretome content analysis has shown the presence of the relevant factors.

Abbreviations

BDNF – brain derived neurotrophic factor

Acknowledgments

None

Author’s contributions

All authors were involved in the selection of the papers for this study. All authors read and approved the final manuscript.

Funding

The study was personally funded.

Availability of data and materials

Not applicable.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

  1. El Moshy S, Radwan IA, Rady D, Abbass MMS, El-Rashidy AA, Sadek KM, Dörfer CE, Fawzy El-Sayed KM. Dental Stem Cell-Derived Secretome/Conditioned Medium: The Future for Regenerative Therapeutic Applications. Stem Cells Int. 2020 Jan 31;2020:7593402. . ;:. View Article PubMed Google Scholar
  2. Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13625-30. . ;:. View Article PubMed Google Scholar
  3. Laino G, d'Aquino R, Graziano A, Lanza V, Carinci F, Naro F, Pirozzi G, Papaccio G. A new population of human adult dental pulp stem cells: a useful source of living autologous fibrous bone tissue (LAB). J Bone Miner Res. 2005 Aug;20(8):1394-402. . ;:. View Article PubMed Google Scholar
  4. Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG et al. SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A. 2003;100(10):5807-12. . ;:. View Article PubMed Google Scholar
  5. Seo BM, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, Young M, Robey PG, Wang CY, Shi S. Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet. 2004 Jul 10-16;364(9429):149-55. . ;:. View Article PubMed Google Scholar
  6. Sonoyama W, Liu Y, Fang D, Yamaza T, Seo BM, Zhang C, Liu H, Gronthos S, Wang CY, Wang S, Shi S. Mesenchymal stem cell-mediated functional tooth regeneration in swine. PLoS One. 2006 Dec 20;1(1):e79. . ;:. View Article PubMed Google Scholar
  7. Sonoyama W, Liu Y, Yamaza T, Tuan RS, Wang S, Shi S, Huang GT. Characterization of the apical papilla and its residing stem cells from human immature permanent teeth: a pilot study. J Endod. 2008 Feb;34(2):166-71. . ;:. View Article PubMed Google Scholar
  8. Morsczeck C, Götz W, Schierholz J, Zeilhofer F, Kühn U, Möhl C, Sippel C, Hoffmann KH. Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth. Matrix Biol. 2005 Apr;24(2):155-65. . ;:. Google Scholar
  9. Tang Liang, Li Nan, Xie Han, Jin Yan. Characterization of mesenchymal stem cells from human normal and hyperplastic gingiva. Journal of cellular physiology. 2011;226(3):832-842. Google Scholar
  10. Tomar Geetanjali B, Srivastava Rupesh K, Gupta Navita, Barhanpurkar Amruta P, Pote Satish T, Jhaveri Hiral M, Mishra Gyan C, Wani Mohan R. Human gingiva-derived mesenchymal stem cells are superior to bone marrow-derived mesenchymal stem cells for cell therapy in regenerative medicine. Biochemical and biophysical research communications. 2010;393(3):377-383. Google Scholar
  11. Lo Monaco M, Gervois P, Beaumont J, Clegg P, Bronckaers A, Vandeweerd JM et al. Therapeutic potential of dental pulp stem cells and leukocyte- and platelet-rich fibrin for osteoarthritis. Cells. 2020;9(4). . ;:. View Article PubMed Google Scholar
  12. Travess H, Robert-Harry D, SJ. Orthodontics. Part 8: Extraction in orthodontics. Br Dent J. 2004;4(196):195-203. . ;:. View Article PubMed Google Scholar
  13. Kim SJ, Hwang CJ, Park JH, Kim HJ, Yu H. Surgical removal of asymptomatic impacted third molars: considerations for orthodontists and oral surgeons. Semin Orthod. 2016;22(1):75-83. . ;:. View Article Google Scholar
  14. Lindqvist B, Thilander B. Extraction of third molars in cases of anticipated crowding in the lower jaw. Am J Orthod. 1982;81(2):130-9. . ;:. View Article Google Scholar
  15. Choi YJ, Lee JS, Cha JY, Park YC. Total distalization of the maxillary arch in a patient with skeletal Class II malocclusion. Am J Orthod Dentofacial Orthop. 2011;139(6):823-33. . ;:. View Article PubMed Google Scholar
  16. Verweij JP, Mensink G, Fiocco M, van Merkesteyn JP. Presence of mandibular third molars during bilateral sagittal split osteotomy increases the possibility of bad split but not the risk of other post-operative complications. J Craniomaxillofac Surg. 2014 Oct;42(7):e359-63. . ;:. Google Scholar
  17. Yoshida T, Washio K, Iwata T, Okano T, Ishikawa I. Current status and future development of cell transplantation therapy for periodontal tissue regeneration. Int J Dent. 2012;2012:307024. . ;:. Google Scholar
  18. Daneshmandi L, Shah S, Jafari T, Bhattacharjee M, Momah D, Saveh-Shemshaki N, Lo KW, Laurencin CT. Emergence of the Stem Cell Secretome in Regenerative Engineering. Trends Biotechnol. 2020 Dec;38(12):1373-1384. . ;:. View Article PubMed Google Scholar
  19. Baraniak Priya R, McDevitt TC. Paracrine actions in stem cells and tissue regeneration. Regen Med. 2010;5(1):121-43. Google Scholar
  20. Vizoso Francisco J, Eiro Noemi, Cid Sandra, Schneider Jose, Perez-Fernandez Roman. Mesenchymal stem cell secretome: toward cell-free therapeutic strategies in regenerative medicine. International journal of molecular sciences. 2017;18(9):1852. Google Scholar
  21. Crigler Lauren, Robey Rebecca C, Asawachaicharn Amy, Gaupp Dina, Phinney Donald G. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Experimental neurology. 2006;198(1):54-64. Google Scholar
  22. Majumdar Manas K, Banks Valerie, Peluso Diane P, Morris Elisabeth A. Isolation, characterization, and chondrogenic potential of human bone marrow-derived multipotential stromal cells. Journal of Cellular Physiology. 2000;185(1):98-106. Google Scholar
  23. Wada Naohisa, Menicanin Danijela, Shi Songtao, Bartold P Mark, Gronthos Stan. Immunomodulatory properties of human periodontal ligament stem cells. Journal of cellular physiology. 2009;219(3):667-676. Google Scholar
  24. Osugi Masashi, Katagiri Wataru, Yoshimi Ryoko, Inukai Takeharu, Hibi Hideharu, Ueda Minoru. Conditioned media from mesenchymal stem cells enhanced bone regeneration in rat calvarial bone defects. Tissue engineering part A. 2012;18(13-14):1479-1489. Google Scholar
  25. Kaigler Darnell, Krebsbach Paul H, Polverini Peter J, Mooney David J. Role of vascular endothelial growth factor in bone marrow stromal cell modulation of endothelial cells. Tissue engineering. 2003;9(1):95-103. Google Scholar
  26. Caplan Arnold I. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. Journal of cellular physiology. 2007;213(2):341-347. Google Scholar
  27. Shimojima Chiaki, Takeuchi Hideyuki, Jin Shijie, Parajuli Bijay, Hattori Hisashi, Suzumura Akio, Hibi Hideharu, Ueda Minoru, Yamamoto Akihito. Conditioned medium from the stem cells of human exfoliated deciduous teeth ameliorates experimental autoimmune encephalomyelitis. The Journal of Immunology. 2016;196(10):4164-4171. Google Scholar
  28. Xia Yu, Tang Hao-Ning, Wu Rui-Xin, Yu Yang, Gao Li-Na, Chen Fa-Ming. Cell responses to conditioned media produced by patient-matched stem cells derived from healthy and inflamed periodontal ligament tissues. Journal of periodontology. 2016;87(5):e53-e63. Google Scholar
  29. Bermudez Maria A, Sendon-Lago Juan, Eiro Noemi, Trevino Mercedes, Gonzalez Francisco, Yebra-Pimentel Eva, Giraldez Maria Jesus, Macia Manuel, Lamelas Maria Luz, Saa Jorge. Corneal epithelial wound healing and bactericidal effect of conditioned medium from human uterine cervical stem cells. Investigative ophthalmology & visual science. 2015;56(2):983-992. Google Scholar
  30. Bermudez Maria A, Sendon-Lago Juan, Seoane Samuel, Eiro Noemi, Gonzalez Francisco, Saa Jorge, Vizoso Francisco, Perez-Fernandez Roman. Anti-inflammatory effect of conditioned medium from human uterine cervical stem cells in uveitis. Experimental Eye Research. 2016;149:84-92. Google Scholar
  31. Moher D, Liberati A, Tetzlaff J, Altman DG, Altman D, Antes G et al. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement. PLOS Med. 2009, July;6(7). . ;:. View Article PubMed Google Scholar
  32. Wakayama H, Hashimoto N, Matsushita Y, Matsubara K, Yamamoto N, Hasegawa Y et al. Factors secreted from dental pulp stem cells show multifaceted benefits for treating acute lung injury in mice. Cytotherapy. 2015;17(8):1119-29. . ;:. View Article PubMed Google Scholar
  33. Nakayama H, Iohara K, Hayashi Y, Okuwa Y, Kurita K, Nakashima M. Enhanced regeneration potential of mobilized dental pulp stem cells from immature teeth. Oral Dis. 2017;23(5):620-8. . ;:. View Article PubMed Google Scholar
  34. Murakami M, Hayashi Y, Iohara K, Osako Y, Hirose Y, Nakashima M. Trophic effects and regenerative potential of mobilized mesenchymal stem cells from bone marrow and adipose tissue as alternative cell sources for pulp/dentin regeneration. Cell Transplant. 2015;24(9):1753-65. . ;:. View Article PubMed Google Scholar
  35. Sugimura-Wakayama Y, Katagiri W, Osugi M, Kawai T, Ogata K, Sakaguchi K et al. Peripheral nerve regeneration by secretomes of stem cells from human exfoliated deciduous teeth. Stem Cells Dev. 2015;24(22):2687-99. . ;:. View Article PubMed Google Scholar
  36. Yang ZH, Zhang XJ, Dang NN, Ma ZF, Xu L, Wu JJ et al. Apical tooth germ cell-conditioned medium enhances the differentiation of periodontal ligament stem cells into cementum/periodontal ligament-like tissues. J Periodont Res. 2009;44(2):199-210. . ;:. View Article PubMed Google Scholar
  37. Aranha AMF, Zhang Z, Neiva KG, Costa CAS, Hebling J, Nör JE. Hypoxia enhances the angiogenic potential of human dental pulp cells. J Endod. 2010;36(10):1633-7. . ;:. View Article PubMed Google Scholar
  38. Huo N, Tang L, Yang Z, Qian H, Wang Y, Han C et al. Differentiation of dermal multipotent cells into odontogenic lineage induced by embryonic and neonatal tooth germ cell-conditioned medium. Stem Cells Dev. 2010;19(1):93-104. . ;:. View Article PubMed Google Scholar
  39. Wen X, Nie X, Zhang L, Liu L, Deng M. Adipose tissue-deprived stem cells acquire cementoblast features treated with dental follicle cell conditioned medium containing dentin non-collagenous proteins in vitro. Biochem Biophys Res Commun. 2011;409(3):583-9. . ;:. View Article PubMed Google Scholar
  40. Wang YX, Ma ZF, Huo N, Tang L, Han C, Duan YZ et al. Porcine tooth germ cell conditioned medium can induce odontogenic differentiation of human dental pulp stem cells. J Tissue Eng Regen Med. 2011;5(5):354-62. . ;:. View Article PubMed Google Scholar
  41. Murakami M, Horibe H, Iohara K, Hayashi Y, Osako Y, Takei Y et al. The use of granulocyte-colony stimulating factor induced mobilization for isolation of dental pulp stem cells with high regenerative potential. Biomaterials. 2013;34(36):9036-47. . ;:. View Article PubMed Google Scholar
  42. Kawamura R, Hayashi Y, Murakami H, Nakashima M. EDTA soluble chemical components and the conditioned medium from mobilized dental pulp stem cells contain an inductive microenvironment, promoting cell proliferation, migration, and odontoblastic differentiation. Stem Cell Res Ther. 2016;7(1):77. . ;:. View Article PubMed Google Scholar
  43. Nagata M, Iwasaki K, Akazawa K, Komaki M, Yokoyama N, Izumi Y et al. Conditioned medium from periodontal ligament stem cells enhances periodontal regeneration. Tissue Eng Part A. 2017;23(9-10):367-77. . ;:. View Article PubMed Google Scholar
  44. Qiu J, Wang X, Zhou H, Zhang C, Wang Y, Huang J et al. Enhancement of periodontal tissue regeneration by conditioned media from gingiva-derived or periodontal ligament-derived mesenchymal stem cells: a comparative study in rats. Stem Cell Res Ther. 2020;11(1):42. . ;:. View Article PubMed Google Scholar
  45. Ogasawara N, Kano F, Hashimoto N, Mori H, Liu Y, Xia L et al. Factors secreted from dental pulp stem cells show multifaceted benefits for treating experimental temporomandibular joint osteoarthritis. Osteoarthr Cartil. 2020;28(6):831-41. . ;:. View Article PubMed Google Scholar
  46. Zheng Jian-mao, Kong Yuan-yuan, Li Yao-yin, Zhang Wen. MagT1 regulated the odontogenic differentiation of BMMSCs induced byTGC-CM via ERK signaling pathway. Stem cell research & therapy. 2019;10(1):1-13. Google Scholar
  47. Liu N, Gu B, Liu N, Nie X, Zhang B, Zhou X et al. Wnt/β-catenin pathway regulates cementogenic differentiation of adipose tissue-deprived stem cells in dental follicle cell-conditioned medium. PLOS ONE. 2014;9(5):e93364. . ;:. View Article PubMed Google Scholar
  48. Yang H, Li G, Han N, Zhang X, Cao YYY, Cao YYY et al. Secreted frizzled-related protein 2 promotes the osteo/odontogenic differentiation and paracrine potentials of stem cells from apical papilla under inflammation and hypoxia conditions. Cell Prolif. 2020;53(1):e12694. . ;:. View Article PubMed Google Scholar
  49. Takeuchi H, Takahashi H, Tanaka A. Effects of human dental pulp stem cell-derived conditioned medium on atrophied submandibular gland after the release from ligation of the main excretory duct in mice. J Hard Tissue Biol. 2020;29(3):183-92. . ;:. View Article Google Scholar
  50. Muhammad SA, Nordin N, Hussin P, Mehat MZ, Abu Kasim NHA, Fakurazi S. Protective effects of stem cells from human exfoliated deciduous teeth derived conditioned medium on osteoarthritic chondrocytes. PLOS ONE. 2020;15(9) (september 9):e0238449. . ;:. View Article PubMed Google Scholar
  51. Yamamoto T, Osako Y, Ito M, Murakami M, Hayashi Y, Horibe H et al. Trophic effects of dental pulp stem cells on Schwann cells in peripheral nerve regeneration. Cell Transplant. 2016;25(1):183-93. . ;:. View Article PubMed Google Scholar
  52. Giacoppo S, Thangavelu SR, Diomede F, Bramanti P, Conti P, Trubiani O et al. Anti-inflammatory effects of hypoxia-preconditioned human periodontal ligament cell secretome in an experimental model of multiple sclerosis: a key role of IL-37. FASEB J. 2017;31(12):5592-608. . ;:. View Article PubMed Google Scholar
  53. Hong H, Chen X, Li K, Wang N, Li M, Yang B et al. Dental follicle stem cells rescue the regenerative capacity of inflamed rat dental pulp through a paracrine pathway. Stem Cell Res Ther. 2020;11(1):333. . ;:. View Article PubMed Google Scholar
  54. Fujio M, Xing Z, Sharabi N, Xue Y, Yamamoto A, Hibi H et al. Conditioned media from hypoxic-cultured human dental pulp cells promotes bone healing during distraction osteogenesis. J Tissue Eng Regen Med. 2017;11(7):2116-26. . ;:. View Article PubMed Google Scholar
  55. Hiraki T, Kunimatsu R, Nakajima K, Abe T, Yamada S, Rikitake K et al. Stem cell-derived conditioned media from human exfoliated deciduous teeth promote bone regeneration. Oral Dis. 2020;26(2):381-90. . ;:. View Article PubMed Google Scholar
  56. Chen YR, Lai PL, Chien Y, Lee PH, Lai YH, Ma HI et al. Improvement of impaired motor functions by human dental exfoliated deciduous teeth stem cell-derived factors in a rat model of Parkinson's disease. Int J Mol Sci. 2020;21(11). . ;:. View Article PubMed Google Scholar
  57. Kano F, Matsubara K, Ueda M, Hibi H, Yamamoto A. Secreted ectodomain of sialic acid-binding Ig-like Lectin-9 and monocyte chemoattractant Protein-1 synergistically regenerate transected rat peripheral nerves by altering macrophage polarity. Stem Cells. 2017;35(3):641-53. . ;:. View Article PubMed Google Scholar
  58. Kolar MK, Itte VN, Kingham PJ, Novikov LN, Wiberg M, Kelk P. The neurotrophic effects of different human dental mesenchymal stem cells. Sci Rep. 2017;7(1):12605. . ;:. View Article PubMed Google Scholar
  59. Aghamohamadi Z, Kadkhodazadeh M, Torshabi M, Tabatabaei F. A compound of concentrated growth factor and periodontal ligament stem cell-derived conditioned medium. Tissue Cell. 2020;65:101373. . ;:. View Article PubMed Google Scholar
  60. Miura-Yura E, Tsunekawa S, Naruse K, Nakamura N, Motegi M, Nakai-Shimoda H et al. Secreted factors from cultured dental pulp stem cells promoted neurite outgrowth of dorsal root ganglion neurons and ameliorated neural functions in streptozotocin-induced diabetic mice. J Diabetes Investig. 2020;11(1):28-38. . ;:. View Article PubMed Google Scholar
  61. Gervois P, Ratajczak J, Wolfs E, Vangansewinkel T, Dillen Y, Merckx G et al. Preconditioning of human dental pulp stem cells with leukocyte- and platelet-rich fibrin-derived factors does not enhance their neuroregenerative effect. Stem Cells Int. 2019;2019:8589149. . ;:. View Article PubMed Google Scholar
  62. Cara SPHM, Origassa CST, de Sá Silva F, Moreira MSNAA, de Almeida DC, Pedroni ACF et al. Angiogenic properties of dental pulp stem cells conditioned medium on endothelial cells in vitro and in rodent orthotopic dental pulp regeneration. Heliyon. 2019;5(4):e01560. . ;:. View Article PubMed Google Scholar
  63. Kumar A, Kumar V, Rattan V, Jha V, Bhattacharyya S. Secretome cues modulate the neurogenic potential of bone marrow and dental stem cells. Mol Neurobiol. 2017;54(6):4672-82. . ;:. View Article PubMed Google Scholar
  64. Mita T, Furukawa-Hibi Y, Takeuchi H, Hattori H, Yamada K, Hibi H et al. Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer's disease. Behav Brain Res. 2015;293:189-97. . ;:. View Article PubMed Google Scholar
  65. Chen TF, Chen KW, Chien Y, Lai YH, Hsieh ST, Ma HY et al. Dental pulp stem cell-derived factors alleviate subarachnoid hemorrhage-induced neuroinflammation and ischemic neurological deficits. Int J Mol Sci. 2019;20(15). . ;:. Google Scholar
  66. Tsuruta T, Sakai K, Watanabe J, Katagiri W, Hibi H. Dental pulp-derived stem cell conditioned medium to regenerate peripheral nerves in a novel animal model of dysphagia. PLOS ONE. 2018;13(12):e0208938. . ;:. View Article PubMed Google Scholar
  67. Gharaei MA, Xue Y, Mustafa K, Lie SA, Fristad I. Human dental pulp stromal cell conditioned medium alters endothelial cell behavior. Stem Cell Res Ther. 2018;9(1):69. . ;:. View Article PubMed Google Scholar
  68. Rajan TS, Diomede F, Bramanti P, Trubiani O, Mazzon E. Conditioned medium from human gingival mesenchymal stem cells protects motor-neuron-like NSC-34 cells against scratch-injury-induced cell death. Int J Immunopathol Pharmacol. 2017;30(4):383-94. . ;:. View Article PubMed Google Scholar
  69. Hayashi Y, Murakami M, Kawamura R, Ishizaka R, Fukuta O, Nakashima M. CXCL14 and MCP1 are potent trophic factors associated with cell migration and angiogenesis leading to higher regenerative potential of dental pulp side population cells. Stem Cell Res Ther. 2015;6(1):111. . ;:. View Article PubMed Google Scholar
  70. Aloe L, Rocco ML, Bianchi P, Manni L. Nerve growth factor: from the early discoveries to the potential clinical use. J Transl Med. 2012;10:239. . ;:. View Article PubMed Google Scholar
  71. Bathina S, Das UN. Paperbrain-derived neurotrophic factor and its clinical implications. Arch Med Sci. 2015;11(6):1164-78. doi: 10.5114/aoms.2015.56342, PMID 26788077.. . ;:. View Article PubMed Google Scholar
  72. Maisonpierre PC, Belluscio L, Squinto S, Ip NY, Furth ME, Lindsay RM et al. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science. 1990;247(4949 Pt 1):1446-51. . ;:. View Article PubMed Google Scholar
  73. Zeitlin BD. Banking on teeth - stem cells and the dental office. Biomed J. 2020;43(2):124-33. . ;:. View Article PubMed Google Scholar
  74. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-7. . ;:. View Article PubMed Google Scholar
  75. Teixeira FG, Salgado AJ. Mesenchymal stem cells secretome: current trends and future challenges. Neural Regen Res. 2020;15(1):75-7. . ;:. View Article PubMed Google Scholar
  76. Pawitan JA. Prospect of stem cell conditioned medium in regenerative medicine. BioMed Res Int. 2014;2014:965849. . ;:. View Article PubMed Google Scholar
  77. Troncoso R, Ibarra C, Vicencio JM, Jaimovich E, Lavandero S. New insights into IGF-1 signaling in the heart. Trends Endocrinol Metab. 2014, March 1;25(3):128-37. . ;:. View Article PubMed Google Scholar
  78. Delafontaine P, Song YH, Li Y. Expression, regulation, and function of IGF-1, IGF-1R, and IGF-1 binding proteins in blood vessels. Arterioscler Thromb Vasc Biol. 2004, March 1;24(3):435-44. . ;:. View Article PubMed Google Scholar
  79. Delafontaine P. Insulin-like growth factor I and its binding proteins in the cardiovascular system. Cardiovasc Res. 1995;30(6):825-34. . ;:. View Article PubMed Google Scholar
  80. Caseiro AR, Santos Pedrosa S, Ivanova G, Vieira Branquinho M, Almeida A, Faria F et al. Mesenchymal Stem/ stromal Cells metabolomic and bioactive factors profiles: A comparative analysis on the umbilical cord and dental pulp derived Stem/ stromal Cells secretome. PLOS ONE. 2019;14(11):e0221378. . ;:. View Article PubMed Google Scholar
  81. Schneider MR, Lahm H, Wu M, Hoeflich A, Wolf E. Transgenic mouse models for studying the functions of insulin-like growth factor‐binding proteins. FASEB J. 2000;14(5):629-40. . ;:. View Article PubMed Google Scholar
  82. Cho YJ, Song HS, Bhang S, Lee S, Kang BG, Lee JC et al. Therapeutic effects of human adipose stem cell-conditioned medium on stroke. J Neurosci Res. 2012;90(9):1794-802. . ;:. View Article PubMed Google Scholar
  83. Paschalidis T, Bakopoulou A, Papa P, Leyhausen G, Geurtsen W, Koidis P. Dental pulp stem cells' secretome enhances pulp repair processes and compensates TEGDMA-induced cytotoxicity. Dent Mater. 2014;30(12):e405-18. . ;:. View Article PubMed Google Scholar
  84. Diomede F, D'Aurora M, Gugliandolo A, Merciaro I, Ettorre V, Bramanti A et al. A novel role in skeletal segment regeneration of extracellular vesicles released from periodontal-ligament stem cells. Int J Nanomedicine. 2018;13:3805-25. . ;:. View Article PubMed Google Scholar
  85. Pizzicannella J, Gugliandolo A, Orsini T, Fontana A, Ventrella A, Mazzon E et al. Engineered extracellular vesicles from human periodontal-ligament stem cells increase VEGF/VEGFR2 expression during bone regeneration. Front Physiol. 2019;10(APR):512. . ;:. View Article PubMed Google Scholar

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Issue: Vol 9 No 1-2 (2022)
Page No.: 318-336
Published: Nov 14, 2022
Article type: Reviews
DOI: https://doi.org/10.15419/psc.v9i1-2.413

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Copyright: The Authors. This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 How to Cite
Nordin, N., Dasor, M., Ariffin, F., Berahim, Z., & Haron, M. (2022). The Effect of the Dental Stem Cell Secretome on Tissue Regeneration: A Systematic Review. Progress in Stem Cell, 9(1-2), 318-336. https://doi.org/https://doi.org/10.15419/psc.v9i1-2.413

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