Molecular Mechanisms of Immunoregulatory Function of DPSCs: Comparison
View Latest Version
Please note this is a comparison between Version 3 by Conner Chen and Version 2 by Conner Chen.

Dental pulp stem cells (DPSCs) are mesenchymal stem cells (MSCs) derived from dental pulp tissue, which have high self-renewal ability and multi-lineage differentiation potential. With the discovery of the immunoregulatory ability of stem cells, DPSCs have attracted much attention because they have similar or even better immunomodulatory effects than MSCs from other sources. DPSCs and their exosomes can exert an immunomodulatory ability by acting on target immune cells to regulate cytokines. DPSCs can also migrate to the lesion site to differentiate into target cells to repair the injured tissue, and play an important role in tissue regeneration.

  • dental pulp stem cells
  • immunoregulatory mechanisms
  • immune-mediated diseases

1. Soluble Factors Secreted by DPSCs

1.1. Transforming Growth Factor Beta (TGF-β) Is a Major Soluble Factor Mediating Immune Tolerance by Dental pulp stem cells (DPSCs)

In a study by Ding et al., through examining the key soluble factors mediating the immunosuppressive function of DPSCs, it was found that TGF-β1 was significantly up-regulated after DPSCs were co-cultured with peripheral blood mononuclear cells (PBMCs) and phytohemagglutinin (PHA) [1]. Moreover, the anti-TGF-β1 monoclonal antibody could restore the proliferation of T cells inhibited by DPSCs, indicating that TGF-β1 is essential in the process of DPSC-mediated immune regulation. Its down-regulation may lead to the inhibition of the immunoregulatory function of DPSCs [1]. This finding was also supported by an investigation by Tomic et al. [2]. In later study, it was found that TGF-β secreted by DPSCs was a major contributor to immunosuppression induced by DPSCs in acute allogeneic immune responses [3]. TGF-β completely abrogated the production of IgM and IgG by allogeneic activation of responder B lymphocytes. Numerous studies have shown that TGF-β secreted by DPSCs can increase CD4+CD25+Foxp3+ regulatory T cells (Tregs) [4] and inhibit the proliferation of allogeneic lymphocytes [5].

1.2. Other Soluble Factors

Mesenchymal stem cells secrete many soluble molecules with immunomodulatory effects and act on immune cells. Following contents summarized the immunomodulatory soluble factors secreted by DPSCs from a large number of studies, including interleukin (IL)-6, IL-10, IL-13, IL-29, tumor necrosis factor (TNF-α), macrophage colony stimulating factor (M-CSF), HLA-G, intercellular cell adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM-1), insulin growth factor (IGF)-1, granulocyte macrophage colony stimulating factor (GM-CSF), adiponectin, keratinocyte growth factor, hepatocyte growth factor (HGF), stem cell factor (SCF), vascular endothelial growth factor (VEGF), nitric oxide (NO), and prostaglandin E2 (PGE2) [5][6][7][8][9][10]. These soluble factors are involved in the differentiation and recruitment of lymphocytes and macrophages to varying degrees, as well as the regulation of other related cells, and have made a huge contribution to the immunomodulatory capacity of DPSCs (Table 1).
Table 1. Effects of soluble factors secreted by DPSCs on target cells.
Soluble Factors Target Cells Mediated Effects References
TGF-β1, IL-6, IL-10, IL-29, IL-13, HLA-G, IDO, ICAM-1, VCAM-1, HGF, VEGF, NO, PGE2 Lymphocyte Inhibit lymphocyte proliferation [5][6][8]
TGF-β1, IL-29, TNF-α, HGF, IDO Macrophage Inhibit macrophage function [8][11][12]
IL-6, IL-10, IL-13, M-CSF, IGF-1, GM-CSF, PGE2 Macrophage Induce m1 differentiation into m2 [8][9][13]
HGF Hepatocytes Promotes hepatocyte regeneration [14]
SCF, VEGF Endothelial cells Promote neo-vascularization [9][15]
TGF-β1: transforming growth factor beta 1; IL: interleukin; HLA-G: human leukocyte antigen; IDO: indoleamine-2,3-dioxygenase; ICAM-1: intercellular cell adhesion molecule; VCAM-1: vascular cell adhesion molecule; HGF: hepatocyte growth factor; VEGF: vascular endothelial growth factor; NO, nitric oxide; PGE2: prostaglandin E2; TNF-α: tumor necrosis factor; M-CSF: macrophage-colony stimulating factor; IGF-1: insulin growth factor-1; GM-CSF: granulocyte macrophage colony-stimulating factor; SCF: stem cell factor.

2. Role of Indoleamine 2,3-Dioxygenase (IDO)

IDO is a heme-containing cytosolic enzyme that acts as a rate-limiting catalyst in the metabolism of an essential amino acid (tryptophan) of the canine uric acid pathway [11]. IDO degrades the essential amino acid tryptophan into kynurenine, which leads to tryptophan depletion, resulting in the suppression of T-cell proliferation or induction of apoptosis in activated T cells and consequently the induction of tolerance [16]. It has already been reported that the immunosuppressive activity of DPSCs is abolished after the inhibition of IDO-1 expression [2]. In another report, IDO was expressed in DPSCs co-cultured with allogeneic PBMCs and inhibited the proliferation of allogeneic PBMCs for immune regulation [5]. In addition, IDO has also been demonstrated to mediate the inhibitory effect of DPSCs on macrophages. Lee et al. showed that the IDO expression level in DPSCs increased with lipopolysaccharide (LPS) or TNF-α stimulation in a time-dependent manner. The results of co-culture experiments showed that DPSCs can inhibit TNF-α secreted by LPS-triggered macrophages via an IDO-dependent mechanism for immune regulation [11].

3. Role of Fas/FasL

Activation of the Fas/FasL pathway typically occurs following exposure to an inflammatory microenvironment and induces T cell apoptosis [17]. Mechanistically, upon the binding of FasL to the Fas receptor (CD95), the extrinsic apoptotic pathway is activated, with Pro-Caspase 8 and Fas-associated death domain (FADD) being recruited to form the death-inducing signaling complex (DISC), in which Pro-Caspase 8 undergoes activation. Then, Caspase 8 leaves the DISC, activates caspase 3/7 and induces apoptosis. Alternatively, c-FLIP, a protease-deficient caspase homolog, can interact with FADD and act as an apoptosis inhibitor [18]. MSC-mediated immunotherapy has been found to be associated with FasL expression, and FasL-expressing MSCs are able to induce apoptosis to trigger immune tolerance [19]. Similarly, DPSCs can suppress the activation of allogeneic T lymphocytes by Fas/Fas ligand (Fas/FasL) interaction and the up-regulation of Tregs [20]. In addition, DPSCs improve disease symptoms by expressing FasL in a variety of diseases; for example, knockdown of FasL in DPSCs leads to a reduced ability to improve the colitis phenotype, indicating that FasL is required for DPSC-mediated immune regulation [20]. In another study, DPSCs were able to modulate CD4+ T lymphocyte responses in monocytes from patients with primary Sjögren’s syndrome (pSS) by increasing Fas ligand expression [21].

4. Role of Programmed Cell Death(PD)-1/PD-L1

The PD-1 pathway plays an important role in maintaining central and peripheral immune tolerance [22]. PD-L1 binds to the receptor PD-1 on activated T cells and suppresses antitumor immunity by counteracting T cell-activating signals. Currently, a blockade of PD-1 has been identified as a promising immunotherapeutic approach for cancer and chronic infectious diseases [23]. Previously, it has been found that not only DPSCs express PD-L1 and PD-1, but also PD-1 is important to maintain stem cell properties in hDPSCs [24]. DPSCs can modulate the inflammatory microenvironment by activating PD-1/PD-L1 immunomodulation [25]. When exposed to CD3/CD28-costimulated PBMCs, DPSCs were able to up-regulate PD-L1 through both direct and indirect interaction-dependent mechanisms to suppress immune responses [25]. Pignatti et al. showed that PD-L1 expression was increased in DPSCs after stimulation with activated PBMCs and was involved in the regulation of the immune response, resulting in the increased expression of cleaved caspase3 and decreased expression of IL-2 in PBMCs [26]. The PD-1/PD-L1 signaling pathway is widely involved in a series of processes such as the activation, proliferation, and apoptosis of T cells and inhibits T cell-mediated cellular immune responses [27][28][29]. Further study of the PD-1/PD-L1 signaling pathway may contribute to the clinical application of DPSCs in immune-mediated diseases.

5. Role of Toll-Like Receptor (TLR) 4

TLR4 is expressed in the odontoblastic cell layer and in areas that associate with blood vessels. When TLR4 is activated, it can regulate the proliferation and migration of DPSCs in deep caries, and it is believed that TLR4 may play an important role in the immune response of DPSCs [30]. The immunomodulatory properties of DPSCs are mentioned to be susceptible to TLR receptor activation, according to a study by Tomic et al. [2]. For example, when DPSCs were exposed to LPS, DPSCs showed enhanced TLR4 expression, mediated increased expression of the anti-inflammatory factor IL-8 through the TLR4 pathway [31], and promoted Wnt5a expression through the TLR4/MyD88/PI3-kinase/AKT pathway [32]. A recent study reported that dental pulp stem cells-derived exosomes (DPSC-exo) could ameliorate cerebral ischemia-reperfusion-induced brain injury in mice, and its anti-inflammatory mechanism may be related to the inhibition of the HMGB1/TLR4/MyD88/NF-κB pathway [33].

6. Role of PGE2

PGE2 is one of the major effectors of MSC-mediated immunosuppression [34]. PGE2 is a catabolite of arachidonic acid, and during inflammation, PGE2 is thought to act as an anti-inflammatory agent, modulating the inflammatory response and helping to restore tissue homeostasis [35]. PGE2 is an important regulatory molecule that normally synergizes with other immunomodulatory factors such as inducible nitric oxide synthase (iNOS) or IDO to inhibit the proliferation of immune cells and the production of inflammatory factors [36]. DPSCs inhibit the proliferation of allogeneic PBMCs by secreting cytokines such as PGE2 and IL-6 [5]. When stimulated by TNF-α or IL-1β, MSCs secreted significantly more PGE2 [34]. Furthermore, PGE2 has an inhibitory effect on the proliferation of T and NK cells, causes an increase in the pool of Treg, reprograms macrophages to produce the anti-inflammatory cytokine IL-10, and prevents the differentiation of monocytes into DCs [34]. Immunosuppressive factors have been reported to cooperate to exert their regulatory role within inflamed synovium, and PGE2 co-exerts regulatory activity by up-regulating IL-6 [37], reducing local inflammation. It is suggested that PGE2 may play an important role in the immune dysregulation and bone remodeling in the treatment of osteoarthritis by DPSCs [5].

References

  1. Ding, G.; Niu, J.; Liu, Y. Dental pulp stem cells suppress the proliferation of lymphocytes via transforming growth factor-β1. Hum. Cell 2015, 28, 81–90.
  2. Tomic, S.; Djokic, J.; Vasilijic, S.; Vucevic, D.; Todorovic, V.; Supic, G.; Colic, M. Immunomodulatory properties of mesenchymal stem cells derived from dental pulp and dental follicle are susceptible to activation by toll-like receptor agonists. Stem Cells Dev. 2011, 20, 695–708.
  3. Kwack, K.H.; Lee, J.M.; Park, S.H.; Lee, H.W. Human Dental Pulp Stem Cells Suppress Alloantigen-induced Immunity by Stimulating T Cells to Release Transforming Growth Factor Beta. J. Endod. 2017, 43, 100–108.
  4. Hong, J.W.; Lim, J.H.; Chung, C.J.; Kang, T.J.; Kim, T.Y.; Kim, Y.S.; Roh, T.S.; Lew, D.H. Immune Tolerance of Human Dental Pulp-Derived Mesenchymal Stem Cells Mediated by CD4+CD25+FoxP3+ Regulatory T-Cells and Induced by TGF-β1 and IL-10. Yonsei Med. J. 2017, 58, 1031–1039.
  5. Hossein-Khannazer, N.; Hashemi, S.M.; Namaki, S.; Ghanbarian, H.; Sattari, M.; Khojasteh, A. Study of the immunomodulatory effects of osteogenic differentiated human dental pulp stem cells. Life Sci. 2019, 216, 111–118.
  6. Demircan, P.C.; Sariboyaci, A.E.; Unal, Z.S.; Gacar, G.; Subasi, C.; Karaoz, E. Immunoregulatory effects of human dental pulp-derived stem cells on T cells: Comparison of transwell co-culture and mixed lymphocyte reaction systems. Cytotherapy 2011, 13, 1205–1220.
  7. Matsubara, K.; Matsushita, Y.; Sakai, K.; Kano, F.; Kondo, M.; Noda, M.; Hashimoto, N.; Imagama, S.; Ishiguro, N.; Suzumura, A.; et al. Secreted ectodomain of sialic acid-binding Ig-like lectin-9 and monocyte chemoattractant protein-1 promote recovery after rat spinal cord injury by altering macrophage polarity. J. Neurosci. 2015, 35, 2452–2464.
  8. Ogata, K.; Matsumura-Kawashima, M.; Moriyama, M.; Kawado, T.; Nakamura, S. Dental pulp-derived stem cell-conditioned media attenuates secondary Sjogren’s syndrome via suppression of inflammatory cytokines in the submandibular glands. Regen. Ther. 2021, 16, 73–80.
  9. Omi, M.; Hata, M.; Nakamura, N.; Miyabe, M.; Kobayashi, Y.; Kamiya, H.; Nakamura, J.; Ozawa, S.; Tanaka, Y.; Takebe, J.; et al. Transplantation of dental pulp stem cells suppressed inflammation in sciatic nerves by promoting macrophage polarization towards anti-inflammation phenotypes and ameliorated diabetic polyneuropathy. J. Diabetes Investig. 2016, 7, 485–496.
  10. Wakayama, H.; Hashimoto, N.; Matsushita, Y.; Matsubara, K.; Yamamoto, N.; Hasegawa, Y.; Ueda, M.; Yamamoto, A. Factors secreted from dental pulp stem cells show multifaceted benefits for treating acute lung injury in mice. Cytotherapy 2015, 17, 1119–1129.
  11. Lee, S.; Zhang, Q.Z.; Karabucak, B.; Le, A.D. DPSCs from Inflamed Pulp Modulate Macrophage Function via the TNF-α/IDO Axis. J. Dent. Res. 2016, 95, 1274–1281.
  12. Li, P.L.; Wang, Y.X.; Zhao, Z.D.; Li, Z.L.; Liang, J.W.; Wang, Q.; Yin, B.F.; Hao, R.C.; Han, M.Y.; Ding, L.; et al. Clinical-grade human dental pulp stem cells suppressed the activation of osteoarthritic macrophages and attenuated cartilaginous damage in a rabbit osteoarthritis model. Stem Cell Res. Ther. 2021, 12, 260.
  13. Zayed, M.; Iohara, K. Immunomodulation and Regeneration Properties of Dental Pulp Stem Cells: A Potential Therapy to Treat Coronavirus Disease 2019. Cell Transplant. 2020, 29, 963689720952089.
  14. Li, N.; Zhang, Y.; Nepal, N.; Li, G.; Yang, N.; Chen, H.; Lin, Q.; Ji, X.; Zhang, S.; Jin, S. Dental pulp stem cells overexpressing hepatocyte growth factor facilitate the repair of DSS-induced ulcerative colitis. Stem Cell Res. Ther. 2021, 12, 30.
  15. Mu, X.; Shi, L.; Pan, S.; He, L.; Niu, Y.; Wang, X. A Customized Self-Assembling Peptide Hydrogel-Wrapped Stem Cell Factor Targeting Pulp Regeneration Rich in Vascular-Like Structures. ACS Omega 2020, 5, 16568–16574.
  16. Tas, S.W.; Vervoordeldonk, M.J.; Hajji, N.; Schuitemaker, J.H.; van der Sluijs, K.F.; May, M.J.; Ghosh, S.; Kapsenberg, M.L.; Tak, P.P.; de Jong, E.C. Noncanonical NF-kappaB signaling in dendritic cells is required for indoleamine 2,3-dioxygenase (IDO) induction and immune regulation. Blood 2007, 110, 1540–1549.
  17. Riccio, M.; Carnevale, G.; Cardinale, V.; Gibellini, L.; De Biasi, S.; Pisciotta, A.; Carpino, G.; Gentile, R.; Berloco, P.B.; Brunelli, R.; et al. The Fas/Fas ligand apoptosis pathway underlies immunomodulatory properties of human biliary tree stem/progenitor cells. J. Hepatol. 2014, 61, 1097–1105.
  18. Pisciotta, A.; Bertani, G.; Bertoni, L.; Di Tinco, R.; De Biasi, S.; Vallarola, A.; Pignatti, E.; Tupler, R.; Salvarani, C.; de Pol, A.; et al. Modulation of Cell Death and Promotion of Chondrogenic Differentiation by Fas/FasL in Human Dental Pulp Stem Cells (hDPSCs). Front. Cell Dev. Biol. 2020, 8, 279.
  19. Akiyama, K.; Chen, C.; Wang, D.; Xu, X.; Qu, C.; Yamaza, T.; Cai, T.; Chen, W.; Sun, L.; Shi, S. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 2012, 10, 544–555.
  20. Zhao, Y.; Wang, L.; Jin, Y.; Shi, S. Fas ligand regulates the immunomodulatory properties of dental pulp stem cells. J. Dent. Res. 2012, 91, 948–954.
  21. Genç, D.; Günaydın, B.; Sezgin, S.; Aladağ, A.; Tarhan, E.F. Immunoregulatory effects of dental mesenchymal stem cells on T and B lymphocyte responses in primary Sjögren’s syndrome. Immunotherapy 2022, 14, 225–247.
  22. Sharpe, A.H.; Pauken, K.E. The diverse functions of the PD1 inhibitory pathway. Nat. Rev. Immunol. 2018, 18, 153–167.
  23. Sun, C.; Mezzadra, R.; Schumacher, T.N. Regulation and Function of the PD-L1 Checkpoint. Immunity 2018, 48, 434–452.
  24. Liu, Y.; Jing, H.; Kou, X.; Chen, C.; Liu, D.; Jin, Y.; Lu, L.; Shi, S. PD-1 is required to maintain stem cell properties in human dental pulp stem cells. Cell Death Differ. 2018, 25, 1350–1360.
  25. Di Tinco, R.; Bertani, G.; Pisciotta, A.; Bertoni, L.; Pignatti, E.; Maccaferri, M.; Bertacchini, J.; Sena, P.; Vallarola, A.; Tupler, R.; et al. Role of PD-L1 in licensing immunoregulatory function of dental pulp mesenchymal stem cells. Stem Cell Res. Ther. 2021, 12, 598.
  26. Pignatti, E.; Pisciotta, A.; Bertani, G.; Di Tinco, R.; Bertoni, L.; Croci, S.; Bonacini, M.; Azzoni, P.; De Pol, A.; Salvarani, C.; et al. Role of mesenchymal stem cells isolated from dental pulp (DPSCs) in immunoregulation processes mediated by programmed death-ligand 1 (PD-L1). Ann. Rheum. Dis. 2020, 79, 1318.
  27. Tripathi, S.; Guleria, I. Role of PD1/PDL1 pathway, and TH17 and treg cells in maternal tolerance to the fetus. Biomed. J. 2015, 38, 25–31.
  28. Germanidis, G.; Argentou, N.; Hytiroglou, P.; Vassiliadis, T.; Patsiaoura, K.; Germenis, A.E.; Speletas, M. Liver FOXP3 and PD1/PDL1 Expression is Down-Regulated in Chronic HBV Hepatitis on Maintained Remission Related to the Degree of Inflammation. Front. Immunol. 2013, 4, 207.
  29. Yogev, N.; Frommer, F.; Lukas, D.; Kautz-Neu, K.; Karram, K.; Ielo, D.; von Stebut, E.; Probst, H.C.; van den Broek, M.; Riethmacher, D.; et al. Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells. Immunity 2012, 37, 264–275.
  30. Liu, Y.; Gao, Y.; Zhan, X.; Cui, L.; Xu, S.; Ma, D.; Yue, J.; Wu, B.; Gao, J. TLR4 activation by lipopolysaccharide and Streptococcus mutans induces differential regulation of proliferation and migration in human dental pulp stem cells. J. Endod. 2014, 40, 1375–1381.
  31. He, W.; Qu, T.; Yu, Q.; Wang, Z.; Lv, H.; Zhang, J.; Zhao, X.; Wang, P. LPS induces IL-8 expression through TLR4, MyD88, NF-kappaB and MAPK pathways in human dental pulp stem cells. Int. Endod. J. 2013, 46, 128–136.
  32. He, W.; Wang, Z.; Zhou, Z.; Zhang, Y.; Zhu, Q.; Wei, K.; Lin, Y.; Cooper, P.R.; Smith, A.J.; Yu, Q. Lipopolysaccharide enhances Wnt5a expression through toll-like receptor 4, myeloid differentiating factor 88, phosphatidylinositol 3-OH kinase/AKT and nuclear factor kappa B pathways in human dental pulp stem cells. J. Endod. 2014, 40, 69–75.
  33. Li, S.; Luo, L.; He, Y.; Li, R.; Xiang, Y.; Xing, Z.; Li, Y.; Albashari, A.A.; Liao, X.; Zhang, K.; et al. Dental pulp stem cell-derived exosomes alleviate cerebral ischaemia-reperfusion injury through suppressing inflammatory response. Cell Prolif. 2021, 54, e13093.
  34. Mancuso, P.; Raman, S.; Glynn, A.; Barry, F.; Murphy, J.M. Mesenchymal Stem Cell Therapy for Osteoarthritis: The Critical Role of the Cell Secretome. Front. Bioeng. Biotechnol. 2019, 7, 9.
  35. Estúa-Acosta, G.A.; Buentello-Volante, B.; Magaña-Guerrero, F.S.; Flores, J.E.; Vivanco-Rojas, O.; Castro-Salas, I.; Zarco-Ávila, K.; García-Mejía, M.A.; Garfias, Y. Human Amniotic Membrane Mesenchymal Stem Cell-Synthesized PGE(2) Exerts an Immunomodulatory Effect on Neutrophil Extracellular Trap in a PAD-4-Dependent Pathway through EP2 and EP4. Cells 2022, 11, 2831.
  36. Braun, D.; Longman, R.S.; Albert, M.L. A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. Blood 2005, 106, 2375–2381.
  37. Bouffi, C.; Bony, C.; Courties, G.; Jorgensen, C.; Noël, D. IL-6-dependent PGE2 secretion by mesenchymal stem cells inhibits local inflammation in experimental arthritis. PLoS ONE 2010, 5, e14247.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback