The role of complement C5a receptor in DPSC odontoblastic differentiation and in vivo reparative dentin formation

Muhammad Irfan,David A Reed,Ji-Hyun Kim,Anne George,Hassan Marzban,Seung Chung,Lyndon F Cooper

doi:10.1038/s41368-022-00158-4

Muhammad Irfan, David A Reed + Show 5 more

Open Access

https://doi.org/10.1038/s41368-022-00158-4

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Abstract

Therapeutic dentin regeneration remains difficult to achieve, and a majority of the attention has been given to anabolic strategies to promote dentinogenesis directly, whereas, the available literature is insufficient to understand the role of inflammation and inflammatory complement system on dentinogenesis. The aim of this study is to determine the role of complement C5a receptor (C5aR) in regulating dental pulp stem cells (DPSCs) differentiation and in vivo dentin regeneration. Human DPSCs were subjected to odontogenic differentiation in osteogenic media treated with the C5aR agonist and C5aR antagonist. In vivo dentin formation was evaluated using the dentin injury/pulp-capping model of the C5a-deficient and wild-type mice. In vitro results demonstrate that C5aR inhibition caused a substantial reduction in odontogenic DPSCs differentiation markers such as DMP-1 and DSPP, while the C5aR activation increased these key odontogenic genes compared to control. A reparative dentin formation using the C5a-deficient mice shows that dentin regeneration is significantly reduced in the C5a-deficient mice. These data suggest a positive role of C5aR in the odontogenic DPSCs differentiation and tertiary/reparative dentin formation. This study addresses a novel regulatory pathway and a therapeutic approach for improving the efficiency of dentin regeneration in affected teeth.

Highlights

Dental caries is one of the major health issues which affects the majority of the U.S adult population.[1]
We recently identified the role of C5a receptor (C5aR) and C5L2 in dental pulp stem cells (DPSCs) odontoblastic differentiation under hypoxia and inflammatory context using C5aR antagonist and C5L2 siRNA.[22,23]
Differentiating DPSCs express mesenchymal stem cell marker STRO-1 and C5a receptor Human DPSCs were subjected to odontogenic differentiation using the osteogenic medium for 24 days

Summary

Introduction

Dental caries is one of the major health issues which affects the majority of the U.S adult population.[1]. In case of a moderate injury, the surviving odontoblasts produce protective reactionary dentin beneath the injured site,[2,3] while a serious injury may involve full or partial regeneration including vascularization, innervation, and dentin repairment endorsed by the generation of odontoblast-like cells.[4] It causes severe pain if left untreated and requires endodontic therapy or may lead to permanent tooth loss.[5] There could be several culprits behind caries; including bacterial invasion, proteolysis or physicochemical dissolution of teeth components, and direct interaction of bacteria or their toxins with dental pulp stem cells (DPSCs) and odontoblasts trigger a reparative process of tertiary dentin formation which further recruit and differentiate DPSCs.[6]. Post infection, therapeutic dentin regeneration is unclear and the underlying mechanism staging the role of inflammation on dentinogenesis in dentin-pulp regeneration is to be elucidated

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