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Frontiers in Biology

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Front. Biol.    2018, Vol. 13 Issue (4) : 263-276    https://doi.org/10.1007/s11515-018-1504-4
REVIEW
Origin of tendon stem cells in situ
Tyler Harvey1,2, Chen-Ming Fan1,2()
1. Department of Embryology, Carnegie Institution for Science, Baltimore, MD, 21218, USA
2. Department of Biology, The Johns Hopkins University, Baltimore, MD, 21218, USA
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Abstract

BACKGROUND: Adult stem cells are surveillance repositories capable of supplying a renewable source of progenitors for tissue repair and regeneration to maintain tissue homeostasis throughout life. Many tissue-resident stem cells have been identified in situ, which lays the foundation for studying them in their native microenvironment, i.e. the niche. Within the musculoskeletal system, muscle stem cells have been unequivocally identified in the mouse, which have led to considerable advances in understanding their role in muscle homeostasis and regeneration. On the other hand, for bone and tendon progenitor cells, mesenchymal stem cells have been used as the main in vitro cell model as they can differentiate into osteogenic, chondrogenic and tenogenic fates. Despite considerable efforts and employment of modern tools, the in vivo origins of bone and tendon stem cells remain debated. Tendon regeneration via stem cells is understudied and deserves attention as tendon damage is noted for a bleak, time-consuming recovery and the repaired tendon seldom regains the structural integrity and strength of the native, uninjured state.

OBJECTIVE: Here we review the past efforts and recent studies toward defining adult tendon stem cells and understanding tendon regeneration instead of tendon development. The focus is on adult tendon resident cells in situ and the uncertainty of their roles in regeneration.

METHODS: A systematic literature search using the Pubmed search engine was conducted encompassing the seminal papers in the tendon field.

CONCLUSIONS: Investigation of tendon stem cells in situ is in its infancy mainly due to lack of necessary tools and standardized injury model. We propose a concerted effort toward establishing a comprehensive cell atlas of the tendon, making genetic tools and choosing a reliable injury model for coordinated studies among different laboratories. Increasing our basic understanding should aid future therapeutic innovations to shorten and enhance the tendon repair/regeneration process.
Keywords Tendon      stem cells      midsubstance      sheath      injury     
Corresponding Author(s): Chen-Ming Fan   
Online First Date: 12 July 2018    Issue Date: 10 September 2018
 Cite this article:   
Tyler Harvey,Chen-Ming Fan. Origin of tendon stem cells in situ[J]. Front. Biol., 2018, 13(4): 263-276.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-018-1504-4
https://academic.hep.com.cn/fib/EN/Y2018/V13/I4/263
Fig.1  Brief overview of adult tendon: A) Cartoon of Achilles tendon and outstanding questions (b) in the tendon regeneration field. Achilles tendon structure shown intact with the Gastrocnemius muscle and inserted into the calcaneus bone. Transitional zones: myotendinous junction (MTJ); pink-white, and enthesis; gray-white, are depicted as gradients. B) Cross-section view of the tendon with anatomical position of resident cell types specified and questions surrounding them; individual tendon fascicles (white units) that contain collagen fibers of varying diameter sizes (green circles). Internal fibroblasts (blue stars) lie in between fibers; zoomed out view depicted. Putative locations of tendon stem cells (red) based off of LRC studies. Perivascular cells (black) surrounding blood vessels (pink circle) are found in the loose connective tissue sheaths (gray) along with fibroblasts (orange). Unsolved and outstanding questions are stated as such in the figure.
Injury paradigm Clinical presentation modeling Advantages Disadvantages
Local collagenase injection (Dahlgren et al., 2002; Urdzikova et al., 2014) Tendinopathy; Matrix/Collagen remodeling Facilitates understanding matrix remodeling; can be locally injected making it minimally invasive Difficult to control diffusion into tissues surrounding tendon, which may complicate the autonomy of the repairing tendon; hypervariable outcomes; not physiologically relevant
Achilles overloading by muscle ablation (Gumucio et al., 2014)
or treadmill running (Runesson et al., 2013)		 To study tension modulation and hypertrophic growth; mimics trauma victims (i.e. muscle injuries) Allows for deciphering consequence of increased/decreased tension Pleiotrophic effects from multi-tissue damage/repair process complicate understanding local response of tendon
Burn injury
(Peterson et al., 2015)		 Mimics tendinopathy; trauma victims Non-invasive approach, not requiring surgery Highly variable; damages many tissues complicating the autonomy of the repairing tendon
Mid-2/3 tendon
incision (horizontal)
or excision
(Beason et al., 2012)		 Acute tendon tear; fibrotic scarring Mimics acute tears presented clinically; allows studying regeneration when tension is maintained; enables understanding of fibrotic scar formation Regeneration success varies depending on which tendon performed; can affect mobility; requires surgery and anesthesia to perform.
Central 1/3 patellar tendon excision
(longitudinal) (Dyment et al., 2014)		 Acute tendon tear; Collagenous bridge formation Maintains tension by lateral struts; often used for ACL reconstruction Form a ‘collagenous bridge’ covering the surface over the wounded region without generating tendon fibrils—‘failure to regenerate’
Complete Achilles tendon tear or transection (Runesson et al., 2015)
(Howell et al., 2017)		 Mimics common clinical presentation Facilitates understanding fibrotic tissue accumulation and scar formation This injury affects mobility, sutures are often used to mechanically stabilize tendon stumps, functioning as a substrate/bridge for regeneration. Suturing technique can affect outcome (Mazzocca et al., 2005; Kim et al., 2006); results in fibrotic scar formation not regeneration.
Biopsy punch
(Lin et al., 2006)		 Mimics minor tear in otherwise intact tendon Reproducible injury model; offers a window to study the repair process at a cellular level and have little impact on mobility Requires surgery and anesthesia to perform
Needle punch
(Schwartz et al., 2017)		 Mimics tendon-bone injuries For enthesis regeneration; different gauge needles can be used Post-op requires microCT to confirm the location of the injury (outside or inside of the enthesis); requires large cohort given the nature of bony defects
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