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Molecular Mechanisms of Stem Cell-Mediated Tendon Regeneration: From Signaling Pathways to Therapeutic Applications

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 June 2026 | Viewed by 914

Special Issue Editor


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Guest Editor
Unit of Basic and Applied Biosciences, Faculty of Bioscience and Agro-Food and Environmental Technology, University of Teramo, 64100 Teramo, Italy
Interests: tendon; tissue engineering; regenerative medicine; amniotic epithelial stem cells; adipose-derived stem cells; 3D bioengineering scaffolds; tendon regeneration; immunomodulation; in vitro models; mechanotransduction; electrospinning

Special Issue Information

Dear Colleagues,

Tendon injuries present significant clinical challenges due to this tissue’s limited intrinsic healing capacity and predisposition toward fibrotic repair rather than functional regeneration. While stem cell-based therapeutic approaches offer promising solutions, their efficacy depends on complex molecular mechanisms including tenogenic differentiation pathways, immune modulation cascades, and vascular integration processes that remain incompletely characterized.

This Special Issue addresses the fundamental molecular basis of stem cell-mediated tendon repair through advanced tissue engineering methodologies. Central focus will be placed on 3D engineered microenvironments and scaffold systems that accurately recapitulate native tendon architecture, enabling the precise investigation of signaling networks, gene expression profiles, and protein interactions governing cellular behavior. These platforms facilitate the mechanistic exploration of paracrine signaling cascades and extracellular matrix remodeling processes that cannot be adequately studied using conventional 2D culture systems.

This issue will emphasize studies on intercellular crosstalk mechanisms, scaffold-guided molecular differentiation pathways, and advanced genomic/proteomic characterization of tendon-specific regenerative networks, providing essential molecular insights for translating stem cell therapies into clinical applications.

Dr. Mohammad El Khatib
Guest Editor

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Keywords

  • regenerative medicine
  • tissue engineering
  • stem cells
  • scaffolds
  • 3D in vitro models
  • tenogenic differentiation
  • tendon regeneration
  • molecular mechanisms
  • intercellular crosstalk
  • paracrine signaling
  • extracellular matrix remodeling

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Published Papers (1 paper)

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Research

32 pages, 3948 KB  
Article
Immuno-Instructive 3D Tendon Biomimetic Scaffolds Functionalized with Amniotic Epithelial Stem Cell Secretome for Controlled Inflammation and Targeted Macrophage Polarization
by Mohammad El Khatib, Annunziata Mauro, Giuseppe Prencipe, Oriana Di Giacinto, Valeria Giovanna Festinese, Carola Agostinone, Maura Turriani, Paolo Berardinelli, Barbara Barboni and Valentina Russo
Int. J. Mol. Sci. 2026, 27(4), 2029; https://doi.org/10.3390/ijms27042029 - 20 Feb 2026
Viewed by 535
Abstract
Tendon healing is often hindered by unresolved inflammation and dysregulated immune responses, highlighting the need for innovative regenerative strategies. This study developed an immune-informed platform by functionalizing validated 3D tendon-mimetic poly(lactide-co-glycolide) (PLGA) scaffolds with immunomodulatory conditioned media (CM), referred to as CMINF [...] Read more.
Tendon healing is often hindered by unresolved inflammation and dysregulated immune responses, highlighting the need for innovative regenerative strategies. This study developed an immune-informed platform by functionalizing validated 3D tendon-mimetic poly(lactide-co-glycolide) (PLGA) scaffolds with immunomodulatory conditioned media (CM), referred to as CMINF to emphasize its anti-inflammatory and immunomodulatory properties, derived from ovine amniotic epithelial stem cells (AECs), offering a potential cell-free therapeutic solution. Three functionalization methods were compared: physical adsorption, and hydrochloric acid (HCl) or sodium hydroxide (NaOH) pre-treatments. FT-IR spectroscopy and protein adsorption analyses identified NaOH as the most effective method, enhancing retention and release of Amphiregulin (AREG), an AEC key immunomodulatory protein. Kinetic studies revealed a sustained, controlled release of AREG over 7 days (d) from CMINF-functionalized scaffolds (3D-CMINF), preserving bioactivity. Functionally, 3D-CMINF scaffolds significantly suppressed T-cell activation and peripheral blood mononuclear cell (PBMC) proliferation. The released CM from 3D-CMINF (CMR) exhibited time-dependent immunomodulatory effects: early T-cell inhibition (6–72 h) and delayed suppression of PBMC proliferation (48 h–7 d). Macrophage polarization analysis revealed a shift towards the pro-regenerative M2 phenotype, with increased expression of M2 over M1 markers in 3D-CMINF-adherent cells. Flow cytometry confirmed a preferential induction of regulatory M2b macrophages alongside reductions in pro-inflammatory M1 and pro-fibrotic M2a subsets. These results demonstrate that 3D-CMINF scaffolds can finely modulate immune responses, balancing inflammatory and reparative cues relevant to early tendon healing processes. This platform, integrating structural and immunomodulatory elements, presents a promising, cell-free, and translational immunoengineering strategy to control inflammation and support tendon repair. Full article
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