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Stepwise Differentiation of Human Embryonic Stem Cells Promotes Tendon Regeneration by Secreting Fetal Tendon Matrix and Differentiation Factors
Xiao Chen 1, Xing-Hui Song 1, Zi Yin 1, Xiao-Hui Zou 2, Lin-Lin Wang 1, Hu Hu 3, Tong Cao 4, Minghao Zheng 5, Hong Wei Ouyang 1 6 *§
1Center for Stem Cells and Tissue Engineering, Zhejiang University School of Medicine, Hangzhou, China
2Womens Hospital, Zhejiang University School of Medicine, Hangzhou, China
3Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, China
4Stem Cell Laboratory, Faculty of Dentistry, National University of Singapore, Singapore
5Centre for Orthopaedic Research, School of Surgery and Pathology, University of Western Australia, Perth; Australia Perth Bone and Tissue Bank, Nedlands, Australia
6Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
Human embryonic stem cells (hESCs) are ideal seed cells for tissue regeneration, but no research has yet been reported concerning their potential for tendon regeneration. This study investigated the strategy and efficacy of using hESCs for tendon regeneration as well as the mechanism involved.
hESCs were first induced to differentiate into mesenchymal stem cells (MSCs), which had the potential to differentiate into the three mesenchymal lineages and were positive for MSC surface markers. hESC-derived MSCs (hESC-MSCs) regenerated tendon tissues in both an in vitro tissue engineering model and an in vivo ectopic tendon regeneration model, as confirmed by the expression of tendon-specific genes and structure. In in-situ rat patellar tendon repair, tendon treated with hESC-MSCs had much better structural and mechanical properties than controls. Further, hESC-MSCs remained viable at the tendon wound site for at least 4 weeks and secreted human fetal tendon-specific matrix components and differentiation factors, which then activated the endogenous regeneration process in tendon. Moreover, no teratoma was found in any samples.
These findings demonstrate a safe and practical strategy of applying ESCs for tendon regeneration and may assist in future strategies to treat tendon diseases.
