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Extracellular vesicles derived from human dental pulp stem cells promote osteogenesis of adipose-derived stem cells via the MAPK pathway.

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.

SUBMITTER: Jin Q

PROVIDER: S-EPMC7716067 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Extracellular vesicles derived from human dental pulp stem cells promote osteogenesis of adipose-derived stem cells via the MAPK pathway.

Jin Qiaoqiao Q Li Peilun P Yuan Keyong K Zhao Fen F Zhu Xiaohan X Zhang Pengfei P Huang Zhengwei Z

Journal of tissue engineering 20200101

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 ...[more]

PMID: 33312494

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Project description:BACKGROUND:Although dental pulp stem cells (DPSCs) isolated from periodontally compromised teeth (P-DPSCs) have been demonstrated to retain pluripotency and regenerative potential, their use as therapeutics remains largely unexplored. In this study, we investigated the proangiogenic effects of extracellular vesicles (EVs) secreted by P-DPSCs using in vitro and in vivo testing models. METHODS:Patient-matched DPSCs derived from periodontally healthy teeth (H-DPSCs) were used as the control for P-DPSCs. Conditioned media (CMs) derived from H-DPSCs and P-DPSCs (H-CM and P-CM), CMs derived from both cell types pretreated with the EV secretion blocker GW4869 (H-GW and P-GW), and EVs secreted by H-DPSCs and P-DPSCs (H-EVs and P-EVs) were prepared to test their proangiogenic effects on endothelial cells (ECs). Cell proliferation, migration, and tube formation were assessed using the Cell Counting Kit-8 (CCK-8), transwell/scratch wound healing, and Matrigel assays, respectively. Specifically, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and western blot analysis were used to examine the expression levels of angiogenesis-related genes/proteins in ECs in response to EV-based incubation. Finally, a full-thickness skin defect model was applied to test the effects of EVs on wound healing and new vessel formation. RESULTS:Both H-CM and P-CM promoted EC angiogenesis, but the proangiogenic effects were compromised when ECs were incubated in H-GW and P-GW, wherein the EV secretion was blocked by pretreatment with GW4869. In EV-based incubations, although both H-EVs and P-EVs were found to enhance the angiogenesis-related activities of ECs, P-EVs exerted a more robust potential to stimulate EC proliferation, migration, and tube formation. In addition, P-EVs led to higher expression levels of angiogenesis-related genes/proteins in ECs than H-EVs. Similarly, both P-EVs and H-EVs were found to accelerate wound healing and promote vascularization across skin defects in mice, but wounds treated with P-EVs resulted in a quicker healing outcome and enhanced new vessel formation. CONCLUSIONS:The findings of the present study provide additional evidence that P-DPSCs derived from periodontally diseased teeth represent a potential source of cells for research and therapeutic use. Particularly, the proangiogenic effects of P-EVs suggest that P-DPSCs may be used to promote new vessel formation in cellular therapy and regenerative medicine.

Dataset Information

Extracellular vesicles derived from human dental pulp stem cells promote osteogenesis of adipose-derived stem cells via the MAPK pathway.

Publications

Extracellular vesicles derived from human dental pulp stem cells promote osteogenesis of adipose-derived stem cells via the MAPK pathway.

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