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The critical role of Hedgehog-responsive mesenchymal progenitors in meniscus development and injury repair

Author

Elife. 2021 Jun 4;10:e62917. doi: 10.7554/eLife.62917.

Yulong Wei # 1 2Hao Sun # 1 3Tao Gui # 1 4Lutian Yao 1Leilei Zhong 1Wei Yu 1 2Su-Jin Heo 1 5Lin Han 6Nathaniel A Dyment 1Xiaowei Sherry Liu 1Yejia Zhang 1 5 7Eiki Koyama 8Fanxin Long 8Miltiadis H Zgonis 1Robert L Mauck 1 5Jaimo Ahn 1 9Ling Qin 1

Author Information

1 Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.

2 Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

3 Department of Orthopedics, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.

4 Department of Bone and Joint Surgery, Institute of Orthopedic Diseases, The First Affiliated Hospital, Jinan University, Guangzhou, China.

5 Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, United States.

6 School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, United States.

7 Department of Physical Medicine and Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States.

8 Translational Research Program in Pediatric Orthopaedics, The Children's Hospital of Philadelphia, Philadelphia, United States.

9 Department of Orthopaedic Surgery, University of Michigan Medical School, Ann Arbor, United States.

#Contributed equally.

Abstract

Meniscal tears are associated with a high risk of osteoarthritis but currently have no disease-modifying therapies. Using a Gli1 reporter line, we found that Gli1+ cells contribute to the development of meniscus horns from 2 weeks of age. In adult mice, Gli1+ cells resided at the superficial layer of meniscus and expressed known mesenchymal progenitor markers. In culture, meniscal Gli1+ cells possessed high progenitor activities under the control of Hh signal. Meniscus injury at the anterior horn induced a quick expansion of Gli1-lineage cells. Normally, meniscal tissue healed slowly, leading to cartilage degeneration. Ablation of Gli1+ cells further hindered this repair process. Strikingly, intra-articular injection of Gli1+ meniscal cells or an Hh agonist right after injury accelerated the bridging of the interrupted ends and attenuated signs of osteoarthritis. Taken together, our work identified a novel progenitor population in meniscus and proposes a new treatment for repairing injured meniscus and preventing osteoarthritis.