Novel Model of Tendon Regeneration Reveals Distinct Cell Mechanisms Underlying Regenerative and Fibrotic Tendon Healing.
To date, the cell and molecular mechanisms regulating tendon healing are poorly understood. Here, we establish a novel model of tendon regeneration using neonatal mice and show that neonates heal via formation of a 'neo-tendon' that differentiates along the tendon specific lineage with functional restoration of gait and mechanical properties. In contrast, adults heal via fibrovascular scar, aberrant differentiation toward cartilage and bone, with persistently impaired function. Lineage tracing identified intrinsic recruitment of Scx-lineage cells as a key cellular mechanism of neonatal healing that is absent in adults. Instead, adult Scx-lineage tenocytes are not recruited into the defect but transdifferentiate into ectopic cartilage; in the absence of tenogenic cells, extrinsic αSMA-expressing cells persist to form a permanent scar. Collectively, these results establish an exciting model of tendon regeneration and uncover a novel cellular mechanism underlying regenerative vs non-regenerative tendon healing.
Dept. of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
Kristen
K
Howell
Dept. of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
Chun
C
Chien
Dept. of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853 USA.
Rebecca
R
Bell
Dept. of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
Damien
D
Laudier
Micro-Imaging Center, Shriners Hospital for Children, Portland, OR 97209, USA.
Sara F
SF
Tufa
Micro-Imaging Center, Shriners Hospital for Children, Portland, OR 97209, USA.
Douglas R
DR
Keene
Dept. of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853 USA.
Nelly
N
Andarawis-Puri
Dept. of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY 10029 USA.
Alice H
AH
Huang
D000125:Achilles Tendon / Q000293:injuries; D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D051379:Mice; D012038:Regeneration; D013708:Tendon Injuries / Q000473:pathology*; D000070916:Tenocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology*
D000199:Actins; D051792:Basic Helix-Loop-Helix Proteins; C503815:Scx protein, mouse