PLoS ONE (Jan 2023)

Remnant tissue enhances early postoperative biomechanical strength and infiltration of Scleraxis-positive cells within the grafted tendon in a rat anterior cruciate ligament reconstruction model.

  • Junki Kawakami,
  • Satoshi Hisanaga,
  • Yuki Yoshimoto,
  • Tomoji Mashimo,
  • Takehito Kaneko,
  • Naoto Yoshimura,
  • Masaki Shimada,
  • Makoto Tateyama,
  • Hideto Matsunaga,
  • Yuto Shibata,
  • Shuntaro Tanimura,
  • Kosei Takata,
  • Takahiro Arima,
  • Kazuya Maeda,
  • Yuko Fukuma,
  • Masaru Uragami,
  • Katsumasa Ideo,
  • Kazuki Sugimoto,
  • Ryuji Yonemitsu,
  • Kozo Matsushita,
  • Masaki Yugami,
  • Yusuke Uehara,
  • Takayuki Nakamura,
  • Takuya Tokunaga,
  • Tatsuki Karasugi,
  • Takanao Sueyoshi,
  • Chisa Shukunami,
  • Nobukazu Okamoto,
  • Tetsuro Masuda,
  • Takeshi Miyamoto

DOI
https://doi.org/10.1371/journal.pone.0293944
Journal volume & issue
Vol. 18, no. 11
p. e0293944

Abstract

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When ruptured, ligaments and tendons have limited self-repair capacity and rarely heal spontaneously. In the knee, the Anterior Cruciate Ligament (ACL) often ruptures during sports activities, causing functional impairment and requiring surgery using tendon grafts. Patients with insufficient time to recover before resuming sports risk re-injury. To develop more effective treatment, it is necessary to define mechanisms underlying ligament repair. For this, animal models can be useful, but mice are too small to create an ACL reconstruction model. Thus, we developed a transgenic rat model using control elements of Scleraxis (Scx), a transcription factor essential for ligament and tendon development, to drive GFP expression in order to localize Scx-expressing cells. As anticipated, Tg rats exhibited Scx-GFP in ACL during developmental but not adult stages. Interestingly, when we transplanted the flexor digitorum longus (FDP) tendon derived from adult Scx-GFP+ rats into WT adults, Scx-GFP was not expressed in transplanted tendons. However, tendons transplanted from adult WT rats into Scx-GFP rats showed upregulated Scx expression in tendon, suggesting that Scx-GFP+ cells are mobilized from tissues outside the tendon. Importantly, at 4 weeks post-surgery, Scx-GFP-expressing cells were more frequent within the grafted tendon when an ACL remnant was preserved (P group) relative to when it was not (R group) (P vs R groups (both n = 5), p<0.05), and by 6 weeks, biomechanical strength of the transplanted tendon was significantly increased if the remnant was preserved (P vsR groups (both n = 14), p<0.05). Scx-GFP+ cells increased in remnant tissue after surgery, suggesting remnant tissue is a source of Scx+ cells in grafted tendons. We conclude that the novel Scx-GFP Tg rat is useful to monitor emergence of Scx-positive cells, which likely contribute to increased graft strength after ACL reconstruction.