Extracellular Vesicles Derived from Human Dental Pulp Stem Cells Promote Osteogenesis of Adipose-derived Stem Cells Via the MAPK Pathway

Overview

Journal J Tissue Eng

Date 2020 Dec 14

PMID 33312494

Citations 25

Authors

Qiaoqiao Jin

Peilun Li

Keyong Yuan

Fen Zhao

Xiaohan Zhu

Pengfei Zhang

Zhengwei Huang

Affiliations

Soon will be listed here.

Abstract

Recent studies have shown that co-culture systems play an important role in bone tissue engineering. In this study, human dental pulp stem cells (hDPSCs) were co-cultured with human adipose-derived stem cells (hADSCs), and osteoblastic phenotypes were found to be enhanced in co-cultures compared with monocultures of hDPSCs or hADSCs. Furthermore, GW4869, an inhibitor of extracellular vesicle (EV) formation, suppressed the mineralization of co-cultured cells. Studies indicate that the therapeutic potential of DPSCs is realized through paracrine action, in which EVs play an important role. To study their role, we successfully obtained and identified hDPSC-derived extracellular vesicles (hDPSC-EVs), and further investigated their effects on hADSCs and the underlying mechanism. hADSCs were stimulated with hDPSC-EVs, which were found to promote the migration and mineralization of hADSCs. Moreover, hDPSC-EVs promoted osteogenic differentiation by enhancing the phosphorylation of ERK 1/2 and JNK in hADSCs. To investigate the specific proteins in EVs that might play a role in hADSC osteogenic differentiation, we performed proteomic analysis of hDPSC-EVs. We determined the top 30 enriched pathways, which notably included the insulin signaling pathway. The number of genes enriched in the insulin signaling pathway was the largest, in addition to the "protein processing in endoplasmic reticulum" term. The MAPK cascade is a typical downstream pathway mediating insulin signaling. To further study the effects of hDPSC-EVs on maxillofacial bone regeneration, we used hDPSC-EVs as a cell-free biomaterial in a model of mandibular defects in rats. To assess the therapeutic potential of EVs, we analyzed their proteome. Animal experiments demonstrated that hDPSC-EVs promoted the regeneration of bone defects. Overall, these results highlight the potential of hDPSC-EVs to induce lineage specific differentiation of hADSCs. The results also indicated the importance of considering hDPSC-EVs as biomimetic materials for clinical translation of treatments for oral maxillofacial defects.

Citing Articles

Potentially commercializable nerve guidance conduits for peripheral nerve injury: Past, present, and future.

Liu C, Sun M, Lin L, Luo Y, Peng L, Zhang J Mater Today Bio. 2025; 31:101503.

PMID: 40018056 PMC: 11867546. DOI: 10.1016/j.mtbio.2025.101503.

Emerging roles of extracellular vesicles in oral and maxillofacial areas.

Wang Q, Sun J, Jiang H, Yu M Int J Oral Sci. 2025; 17(1):11.

PMID: 39900916 PMC: 11791077. DOI: 10.1038/s41368-024-00341-9.

Extracellular Vesicles in Periodontitis: Pathogenic Mechanisms and Therapeutic Potential.

Zhang L, Li X, Zhang B, Li R J Inflamm Res. 2025; 18:1317-1331.

PMID: 39897520 PMC: 11786598. DOI: 10.2147/JIR.S504612.

Amino acid-based supramolecular chiral hydrogels promote osteogenesis of human dental pulp stem cells via the MAPK pathway.

Li P, Jin Q, Zeng K, Niu C, Xie Q, Dong T Mater Today Bio. 2024; 25:100971.

PMID: 38347936 PMC: 10859303. DOI: 10.1016/j.mtbio.2024.100971.

Biomaterial scaffolds in maxillofacial bone tissue engineering: A review of recent advances.

Huang X, Lou Y, Duan Y, Liu H, Tian J, Shen Y Bioact Mater. 2023; 33:129-156.

PMID: 38024227 PMC: 10665588. DOI: 10.1016/j.bioactmat.2023.10.031.

References

Tooi M, Komaki M, Morioka C, Honda I, Iwasaki K, Yokoyama N . Placenta Mesenchymal Stem Cell Derived Exosomes Confer Plasticity on Fibroblasts. J Cell Biochem. 2015; 117(7):1658-70. DOI: 10.1002/jcb.25459. View

Bacakova L, Zarubova J, Travnickova M, Musilkova J, Pajorova J, Slepicka P . Stem cells: their source, potency and use in regenerative therapies with focus on adipose-derived stem cells - a review. Biotechnol Adv. 2018; 36(4):1111-1126. DOI: 10.1016/j.biotechadv.2018.03.011. View

Vidane A, Zomer H, Oliveira B, Guimaraes C, Fernandes C, Perecin F . Reproductive stem cell differentiation: extracellular matrix, tissue microenvironment, and growth factors direct the mesenchymal stem cell lineage commitment. Reprod Sci. 2013; 20(10):1137-43. DOI: 10.1177/1933719113477484. View

Zubkova E, Beloglazova I, Makarevich P, Boldyreva M, Sukhareva O, Shestakova M . Regulation of Adipose Tissue Stem Cells Angiogenic Potential by Tumor Necrosis Factor-Alpha. J Cell Biochem. 2015; 117(1):180-96. DOI: 10.1002/jcb.25263. View

Liu Y, Zheng W, Gao W, Shen Y, Ding W . Function of TGF-beta and p38 MAKP signaling pathway in osteoblast differentiation from rat adipose-derived stem cells. Eur Rev Med Pharmacol Sci. 2013; 17(12):1611-9. View

Li Q, Zhao H, Chen W, Huang P, Bi J . Human keratinocyte-derived microvesicle miRNA-21 promotes skin wound healing in diabetic rats through facilitating fibroblast function and angiogenesis. Int J Biochem Cell Biol. 2019; 114:105570. DOI: 10.1016/j.biocel.2019.105570. View

Niu C, Yuan K, Ma R, Gao L, Jiang W, Hu X . Gold nanoparticles promote osteogenic differentiation of human periodontal ligament stem cells via the p38 MAPK signaling pathway. Mol Med Rep. 2017; 16(4):4879-4886. DOI: 10.3892/mmr.2017.7170. View

Sterzenbach U, Putz U, Low L, Silke J, Tan S, Howitt J . Engineered Exosomes as Vehicles for Biologically Active Proteins. Mol Ther. 2017; 25(6):1269-1278. PMC: 5474961. DOI: 10.1016/j.ymthe.2017.03.030. View

Mu C, Lv T, Wang Z, Ma S, Ma J, Liu J . Mechanical stress stimulates the osteo/odontoblastic differentiation of human stem cells from apical papilla via erk 1/2 and JNK MAPK pathways. Biomed Res Int. 2014; 2014:494378. PMC: 4009119. DOI: 10.1155/2014/494378. View

10.

Ulsamer A, Ortuno M, Ruiz S, Susperregui A, Osses N, Rosa J . BMP-2 induces Osterix expression through up-regulation of Dlx5 and its phosphorylation by p38. J Biol Chem. 2007; 283(7):3816-26. DOI: 10.1074/jbc.M704724200. View

11.

Jaiswal R, Jaiswal N, Bruder S, Mbalaviele G, Marshak D, Pittenger M . Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J Biol Chem. 2000; 275(13):9645-52. DOI: 10.1074/jbc.275.13.9645. View

12.

Zhao P, Xiao L, Peng J, Qian Y, Huang C . Exosomes derived from bone marrow mesenchymal stem cells improve osteoporosis through promoting osteoblast proliferation via MAPK pathway. Eur Rev Med Pharmacol Sci. 2018; 22(12):3962-3970. DOI: 10.26355/eurrev_201806_15280. View

13.

Zhang W, Wang S, Xu L, Zhang M, Wang G, Jin Y . Comparison of the use of adipose tissue-derived and bone marrow-derived stem cells for rapid bone regeneration. J Dent Res. 2013; 92(12):1136-41. DOI: 10.1177/0022034513507581. View

14.

Yin K, Wang S, Zhao R . Exosomes from mesenchymal stem/stromal cells: a new therapeutic paradigm. Biomark Res. 2019; 7:8. PMC: 6450000. DOI: 10.1186/s40364-019-0159-x. View

15.

Liu Y, Chan J, Teoh S . Review of vascularised bone tissue-engineering strategies with a focus on co-culture systems. J Tissue Eng Regen Med. 2012; 9(2):85-105. DOI: 10.1002/term.1617. View

16.

He X, Dong Z, Cao Y, Wang H, Liu S, Liao L . MSC-Derived Exosome Promotes M2 Polarization and Enhances Cutaneous Wound Healing. Stem Cells Int. 2019; 2019:7132708. PMC: 6754952. DOI: 10.1155/2019/7132708. View

17.

Wilhelm M, Schlegl J, Hahne H, Gholami A, Lieberenz M, Savitski M . Mass-spectrometry-based draft of the human proteome. Nature. 2014; 509(7502):582-7. DOI: 10.1038/nature13319. View

18.

Vandomme J, Touil Y, Ostyn P, Olejnik C, Flamenco P, El Machhour R . Insulin-like growth factor 1 receptor and p38 mitogen-activated protein kinase signals inversely regulate signal transducer and activator of transcription 3 activity to control human dental pulp stem cell quiescence, propagation, and differentiation. Stem Cells Dev. 2013; 23(8):839-51. PMC: 3992006. DOI: 10.1089/scd.2013.0400. View

19.

Otero-Ortega L, Laso-Garcia F, Gomez-de Frutos M, Rodriguez-Frutos B, Pascual-Guerra J, Fuentes B . White Matter Repair After Extracellular Vesicles Administration in an Experimental Animal Model of Subcortical Stroke. Sci Rep. 2017; 7:44433. PMC: 5353554. DOI: 10.1038/srep44433. View

20.

Yu Y, Mu J, Fan Z, Lei G, Yan M, Wang S . Insulin-like growth factor 1 enhances the proliferation and osteogenic differentiation of human periodontal ligament stem cells via ERK and JNK MAPK pathways. Histochem Cell Biol. 2012; 137(4):513-25. DOI: 10.1007/s00418-011-0908-x. View