From Degeneration to Regeneration: The Evolving Landscape of Cell-Based Tendon Repair
Highlights What are the main findings? Distinct stem cell populations demonstrate differential regenerative potential in tendon repair, with source-dependent variation in tenogenic commitment, hypoxic tolerance, and immunomodulatory capacity emerging as key determinants of therapeutic outcome. Cell-based tendon repair operates through mechanistically distinct paracrine axes, including angiogenesis, collagen remodeling, immunomodulation, and tenogenic differentiation, each governed by discrete and targetable signaling cascades. Limited cell survival, absence of standardized dosing protocols, and lack of large-animal and phase II trial data remain the critical barriers to clinical translation. What are the implications of the main findings? Emerging clinical trial evidence supports the therapeutic potential of cell-based approaches in tendon repair, with outcomes influenced by patient selection, delivery parameters, and post-operative rehabilitation protocols. Patient-specific cell selection (stratified by injury type, anatomical site, age, and metabolic status), and autologous vs. allogeneic selection, represent the defining challenge and opportunity for next-generation tendon regenerative strategies. Abstract Tendinopathies represent a major clinical challenge. Vasculature, neuromuscular junctions, low cellularity, and slow extracellular matrix (ECM) turnover restrict endogenous repair and predispose injured tendons to fibrosis, mechanical weakness, and reinjury. Current therapeutic strategies including rehabilitation protocols, anti-inflammatory medications, platelet-rich plasma (PRP) injections, and surgical repair primarily address symptoms or structural deficits without correcting the underlying biological limitations of tendon healing. Cell-based therapies have emerged as a promising regenerative approach aimed at restoring tissue homeostasis through modulation of angiogenesis, collagen synthesis, immune responses, and tenogenic differentiation. Mesenchymal stem cells (MSCs), adipose-derived stem cells (ADSCs), tendon-derived stem cells (TDSCs), induced pluripotent stem cells (iPSCs), differentiated tenocytes, and extracellular vesicle (EV)-based products have demonstrated the ability to enhance vascularization, promote type I collagen remodeling, suppress excessive inflammation, and stimulate tenocyte lineage commitment. These effects are mediated through paracrine signaling, growth factor secretion, and activation of key pathways, including HIF-1α, TGF-β/SMAD, NF-κB, and PI3K/Akt signaling. Despite promising preclinical data, significant translational challenges remain, including limited cell survival at the injury site, variability in cell sources and dosing, immunogenicity, risk of misdifferentiation, and lack of standardization across clinical protocols. Emerging strategies such as genetic modification, hypoxic preconditioning, scaffold-based delivery systems, and extracellular vesicle engineering aim to enhance therapeutic efficacy and reproducibility. This review synthesizes current evidence on cell-based tendon repair, critically evaluates mechanistic insights, clinical trials, and translational barriers, and outlines future directions toward biologically informed regenerative therapies.