Stem cell technology for tendon regeneration: current status, challenges, and future research directions

Stem Cells and Cloning: Advances and Applications Dovepress open access to scientific and medical research Review Stem Cells and Cloning: Advances and Applications downloaded from https://www.dovepress.com/ by 54.37.117.73 on 12-Jul-2018 For personal use only. Open Access Full Text Article Stem cell technology for tendon regeneration: current status, challenges, and future research directions This article was published in the following Dove Press journal: Stem Cells and Cloning: Advances and Applications 11 December 2015 Number of times this article has been viewed Pauline Po Yee Lui Headquarter, Hospital Authority, Hong Kong SAR, People’s Republic of China Introduction Correspondence: Pauline Po Yee Lui Headquarter, Hospital Authority, 9/F, Rumsey Street Carpark Building, 2 Rumsey Street, Sheung Wan, Hong Kong SAR, People’s Republic of China Tel +852 9809 4026 Email Tendon and ligament injuries are common clinical problems as a result of either overuse or aging. There are more than 30 million tendon and ligament injuries occurring annually worldwide.1 These injuries often upset the balance between mobility and stability of the joint which results in abnormal loading that could damage other soft tissues in and around the joint that can progress into early onset of osteoarthritis, pain, disability, and eventually the need for joint replacement.2 Their occurrence is particularly devastating to the elite athletes as it can be career-ending. The social and economic burden associated with these injuries presents a compelling argument to better understand their pathophysiology and develop appropriate treatments. Tendon injury is currently managed by two approaches: 1) conservative treatment which aims to relieve pain and 2) surgical excision and repair. Irrespective of the approaches used, the treated tendon heals slowly and fails to regain its full function due to the formation of mechanically inferior scar tissue, ectopic bone, and adhesion or the lack of regeneration of fibrocartilage at the tendon to bone junction (TBJ). Repeated ruptures, joint stiffness, and restricted movement are common problems encountered even after repair. The inability of tendon to self-repair and the inefficiency of current treatment regimens used clinically have sparked the exploration of alternative treatment strategies. The use of stem cells to repair tendon is particularly exciting and promising as stem cells 163 submit your manuscript | www.dovepress.com Stem Cells and Cloning: Advances and Applications 2015:8 163–174 Dovepress © 2015 Lui. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/SCCAA.S60832 Powered by TCPDF (www.tcpdf.org) Abstract: Tendon injuries are a common cause of physical disability. They present a clinical challenge to orthopedic surgeons because injured tendons respond poorly to current treatments without tissue regeneration and the time required for rehabilitation is long. New treatment options are required. Stem cell-based therapies offer great potential to promote tendon regeneration due to their high proliferative, synthetic, and immunomodulatory activities as well as their potential to differentiate to the target cell types and undergo genetic modification. In this review, I first recapped the challenges of tendon repair by reviewing the anatomy of tendon. Next, I discussed the advantages and limitations of using different types of stem cells compared to terminally differentiated cells for tendon tissue engineering. The safety and efficacy of application of stem cells and their modified counterparts for tendon tissue engineering were then summarized after a systematic literature search in PubMed. The challenges and future research directions to enhance, optimize, and standardize stem cell-based therapies for augmenting tendon repair were then discussed. Keywords: stem cells, tendon repair, tendon tissue engineering, tendon injuries Dovepress Stem Cells and Cloning: Advances and Applications downloaded from https://www.dovepress.com/ by 54.37.117.73 on 12-Jul-2018 For personal use only. Lui have the potential to differentiate into tenocytes, show high proliferative and synthetic activities, and can secrete paracrine factors and exhibit immunomodulatory effects to promote tendon regeneration. However, a number of challenges have to be overcome before they can be used as a safe and effective therapeutic option for promoting tendon repair. In this review, I aimed to present the recent advances, challenges, and future research directions of application of stem cells for tendon regeneration. I first recapped the anatomy of tendon. Then, I discussed the advantages and limitations of using different types of stem cells compared to terminally differentiated cells for tendon tissue engineering. Next, I summarized the literature regarding the safety and efficacy of application of stem cells and their modified counterparts for the promotion of tendon repair. Finally, I presented the challenges and future research directions to enhance, optimize, and standardize stem cell-based therapies for the augmentation of tendon repair. Why are tendons difficult to heal? A review of tendon anatomy Tendon consists of collagen (mostly type I collagen) and elastin embedded in a proteoglycan-rich matrix. Collagen and elastin account for 65%–80% and 1%–2%, respectively, while proteoglycans account for 1%–5% of the tendon dry mass.3 The tendon matrix is produced by tenoblasts and tenocytes that lie parallel between the longitudinally-arranged collagen fibers. The cellularity of tendon tissue is low (as opposed to epithelial tissue which has high cellularity), explaining the low turnover and poor self-healing capacity of the tissue. Recent studies have shown that tendon also contains resident stem cells which function to maintain tendon homeostasis during growth and repair.4,5 Recent reports have also suggested that the change of tendon microenvironment after injury may induce erroneous differentiation of stem cells in tendon and cause pathological tendon ossification and failed tendon healing.6–8 The collagen molecules form cross-links and are packed in a quarter staggered fashion to form microfibrils, which are further aggregated together to form collagen fibrils. The staggering of collagen microfibrils and collagen fibrils produces the characteristic banding pattern of tendon under polarized microscopy. The collagen fibri (...truncated)