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Activation of the kynurenine–aryl hydrocarbon receptor axis impairs the chondrogenic and chondroprotective effects of human umbilical cord-derived mesenchymal stromal cells in osteoarthritis rats

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Abstract

It has been proven that intra-articular injection of mesenchymal stromal cells (MSCs) can alleviate cartilage damage in osteoarthritis (OA) by differentiating into chondrocytes and protecting inherent cartilage. However, the mechanism by which the OA articular microenvironment affects MSCs’ therapeutic efficiency is yet to be fully elucidated. The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor involved in various cellular processes, such as osteogenesis and immune regulation. Tryptophan (Trp) metabolites, most of which are endogenous ligand for AHR, are abnormally increased in synovial fluid (SF) of OA and rheumatoid arthritis (RA) patients. In this study, the effects of kynurenine (KYN), one of the most important metabolites of Trp, were evaluated on the chondrogenic and chondroprotective effects of human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs). hUC-MSCs were cultured in conditioned medium containing different proportions of OA/RA SF, or stimulated with KYN directly, and then, AHR activation, proliferation, and chondrogenesis of hUC-MSCs were measured. Moreover, the chondroprotective efficiency of short hairpin-AHR-UC-MSC (shAHR-UC-MSC) was determined in a rat surgical OA model (right hind joint). OA SF could activate AHR signaling in hUC-MSCs in a concentration-dependent manner and inhibit the chondrogenic differentiation and proliferation ability of hUC-MSCs. Similar results were observed in hUC-MSCs stimulated with KYN in vitro. Notably, shAHR-UC-MSC exhibited superior therapeutic efficiency in OA rat upon intra-articular injection. Taken together, this study indicates that OA articular microenvironment is not conducive to the therapeutic effect of hUC-MSCs, which is related to the activation of the AHR pathway by tryptophan metabolites, and thus impairs the chondrogenic and chondroprotective effects of hUC-MSCs. AHR might be a promising modification target for further improving the therapeutic efficacy of hUC-MSCs on treatment of cartilage-related diseases such as OA.

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Acknowledgements

This study was supported by National Natural Science Foundation of China (Nos. 81573443, 82173824, 81973332, 82003763); Anhui Province Natural Science Fund (outstanding youth) (No. 170808J10); Natural Science Foundation of Anhui Provincial (No. 2108085MH320, 2108085QH383); Collaborative Innovation Project of Key Scientific Research Platform in Anhui Universities (No. GXXT-2020-065); The Open Fund of Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, P.R. China (Anhui Medical University) (No. KFJJ-2020-05); Improvement Program of Scientific Research Basement Construction (2021xkjT043); Scientific Research Fund of Anhui Medical University (No. 2020xkj026).

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  1. Xinwei Wang and Yingjie Zhao have contributed equally to this study.

Authors and Affiliations

  1. The Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Ministry of Education, Anhui Medical University, Hefei, 230032, China

    Xinwei Wang, Susu Li, Yueye Wang, Chengyan Jia, Xuezhi Yang, Siyu Li, Bingjie Zhang, Wei Wei & Yan Chang

  2. Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China

    Yingjie Zhao

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  1. Xinwei Wang
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Wang, X., Zhao, Y., Li, S. et al. Activation of the kynurenine–aryl hydrocarbon receptor axis impairs the chondrogenic and chondroprotective effects of human umbilical cord-derived mesenchymal stromal cells in osteoarthritis rats. Human Cell 36, 163–177 (2023). https://doi.org/10.1007/s13577-022-00811-4

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