PMID- 36224488 OWN - NLM STAT- MEDLINE DCOM- 20230118 LR - 20230118 IS - 1749-0774 (Electronic) IS - 0914-7470 (Linking) VI - 36 IP - 1 DP - 2023 Jan TI - 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. PG - 163-177 LID - 10.1007/s13577-022-00811-4 [doi] AB - 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. CI - (c) 2022. The Author(s) under exclusive licence to Japan Human Cell Society. FAU - Wang, Xinwei AU - Wang X AD - 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. FAU - Zhao, Yingjie AU - Zhao Y AD - Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China. FAU - Li, Susu AU - Li S AD - 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. FAU - Wang, Yueye AU - Wang Y AD - 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. FAU - Jia, Chengyan AU - Jia C AD - 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. FAU - Yang, Xuezhi AU - Yang X AD - 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. FAU - Li, Siyu AU - Li S AD - 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. FAU - Zhang, Bingjie AU - Zhang B AD - 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. FAU - Wei, Wei AU - Wei W AD - 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. wwei@ahmu.edu.cn. FAU - Chang, Yan AU - Chang Y AUID- ORCID: 0000-0001-6684-5960 AD - 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. yychang@ahmu.edu.cn. LA - eng GR - 2108085MH320/Natural Science Foundation of Anhui Provincial/ GR - 2108085QH383/Natural Science Foundation of Anhui Provincial/ PT - Journal Article DEP - 20221012 PL - Japan TA - Hum Cell JT - Human cell JID - 8912329 RN - 343-65-7 (Kynurenine) RN - 0 (Ligands) RN - 0 (Receptors, Aryl Hydrocarbon) RN - 8DUH1N11BX (Tryptophan) SB - IM MH - Animals MH - Humans MH - Rats MH - *Arthritis, Rheumatoid/metabolism MH - Cell Differentiation MH - Chondrogenesis MH - Kynurenine/metabolism/pharmacology MH - Ligands MH - Mesenchymal Stem Cell Transplantation MH - *Mesenchymal Stem Cells/metabolism MH - *Osteoarthritis/metabolism/therapy MH - *Receptors, Aryl Hydrocarbon/agonists/metabolism MH - Tryptophan/metabolism/pharmacology MH - Umbilical Cord/cytology OTO - NOTNLM OT - Aryl hydrocarbon receptor OT - Chondrogenesis OT - Chondroprotective effects OT - Human umbilical cord-derived mesenchymal stromal cells OT - Osteoarthritis EDAT- 2022/10/13 06:00 MHDA- 2023/01/07 06:00 CRDT- 2022/10/12 23:36 PHST- 2022/04/26 00:00 [received] PHST- 2022/10/06 00:00 [accepted] PHST- 2022/10/13 06:00 [pubmed] PHST- 2023/01/07 06:00 [medline] PHST- 2022/10/12 23:36 [entrez] AID - 10.1007/s13577-022-00811-4 [pii] AID - 10.1007/s13577-022-00811-4 [doi] PST - ppublish SO - Hum Cell. 2023 Jan;36(1):163-177. doi: 10.1007/s13577-022-00811-4. Epub 2022 Oct 12.