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Application of Stem Cells and Cellular Engineering in Musculoskeletal Tissue...
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Application of Stem Cells and Cellular Engineering in Musculoskeletal Tissue Regeneration

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Stem Cells".

Deadline for manuscript submissions: 26 February 2027 | Viewed by 2044

Editor

Dr. Alessandra Colombini

E-Mail Website
Guest Editor
Orthopaedic Biotechnology Lab, IRCCS Ospedale Galeazzi-Sant'Ambrogio, Via Cristina Belgioioso 173, 20157 Milan, Italy
Interests: orthopedics; musculoskeletal field; mesenchymal stem/stromal cells; regenerative medicine; clinical biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Musculoskeletal tissues, including bone, cartilage, tendon, ligament, and muscle, possess limited intrinsic regenerative capacity, making their repair a major clinical challenge. In recent years, stem cell–based therapies and cellular engineering strategies have emerged as promising approaches to enhance tissue regeneration and restore functional integrity. Mesenchymal stem/stromal cells (MSCs), induced pluripotent stem cells, and tissue-specific progenitors have demonstrated significant potential due to their regenerative capacity, immunomodulatory properties, and paracrine activity. In parallel, advances in cellular engineering—such as gene editing, biomaterial-based scaffolds, bioreactors, and three-dimensional culture systems—have enabled the development of more sophisticated and physiologically relevant regenerative strategies. The integration of stem cells with engineered microenvironments allows precise control over cell fate, matrix deposition, and tissue organization, ultimately improving repair outcomes. Moreover, emerging insights into mechanobiology, cell–matrix interactions, and extracellular vesicle signaling are further expanding the therapeutic landscape. This Special Issue aims to highlight cutting-edge research and translational advances in the application of stem cells and cellular engineering for musculoskeletal tissue regeneration. Original research articles and comprehensive reviews addressing basic mechanisms, preclinical models, and clinical perspectives are welcomed, with the goal of fostering interdisciplinary collaboration and accelerating the translation of innovative regenerative therapies into clinical practice.

Topics of interest include, but are not limited to:

  • Stem cell therapies for musculoskeletal tissues;
  • Mesenchymal stem/stromal cells and progenitors;
  • Cellular and gene engineering approaches;
  • Biomaterials, scaffolds, and 3D culture systems;
  • Mechanobiology and cell–matrix interactions;
  • Preclinical animal models for musculoskeletal regeneration;
  • Extracellular vesicles and secretome‑based therapies.

Dr. Alessandra Colombini
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • mesenchymal stem cells (MSCs)
  • tissue specific progenitors
  • cellular engineering
  • musculoskeletal tissue regeneration
  • tissue engineering
  • biomaterials
  • 3D culture systems
  • mechanobiology
  • extracellular vesicles
  • translational regenerative medicine

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Published Papers (3 papers)

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14 pages, 1679 KB  
Article
Pulsed Electromagnetic Fields Modulate Inflammatory and Tenogenic Responses in Human Tenocytes: Insights from Acute and Prolonged Inflammation Models
by Michela Maria Taiana, Paola De Luca, Giulio Grieco, Enrico Ragni, Simona Salati, Antonio Marmotti, Valerio Pascale and Laura de Girolamo
Cells 2026, 15(17), 1529; https://doi.org/10.3390/cells15171529 - 25 Aug 2026
Abstract
Tendinopathy is a prevalent musculoskeletal condition characterised by chronic inflammatory and degenerative changes. Pulsed electromagnetic fields (PEMFs) represent a promising biophysical therapeutic modality, yet their effects across different inflammatory states of tendinopathy remain poorly characterised. To evaluate PEMF biological effects on human tenocytes, [...] Read more.
Tendinopathy is a prevalent musculoskeletal condition characterised by chronic inflammatory and degenerative changes. Pulsed electromagnetic fields (PEMFs) represent a promising biophysical therapeutic modality, yet their effects across different inflammatory states of tendinopathy remain poorly characterised. To evaluate PEMF biological effects on human tenocytes, three in vitro models differing in IL-1β dose and duration were tested: acute low-dose (0.1 ng/mL, 96 h), acute high-dose (1 ng/mL, 96 h), and prolonged (0.1 ng/mL, 9 days). At the transcriptional level, PEMFs significantly reduced IL-6 and IL-8 mRNA overexpression in the acute low-dose model and CCL2 upregulation in the prolonged model. At the secretome level, PEMFs reduced GM-CSF and IL-8 secretion in the acute high-dose model, and suppressed CCL2 and CCL5 protein secretion in the prolonged model. MMP activity was not modulated by PEMFs in any condition. PEMFs consistently increased tenocyte proliferation across both the acute models. Finally, in wound healing assays, non-inflamed tenocytes exposed to PEMFs showed significantly enhanced wound closure compared to IL-1β-treated cells across all models; in the acute low-dose model, PEMFs also significantly improved wound closure in IL-1β-treated cells at an early timepoint, whereas no such effect was observed in cells exposed to high-dose or prolonged inflammation. PEMFs exert context-dependent effects, promoting healing primarily during acute or mild inflammation. These findings suggest that the inflammatory stage of tenocytes may influence PEMF responsiveness in vitro, highlighting the importance of considering this variable in the design of future clinical studies evaluating PEMF therapy for tendinopathy. Full article
(This article belongs to the Special Issue Application of Stem Cells and Cellular Engineering in Musculoskeletal Tissue Regeneration)
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16 pages, 3885 KB  
Article
Preclinical Tumorigenicity Study of an Advanced Therapy Medicinal Product for Diffuse Cartilage Lesions in an Osteoarthritic Environment
by Alessandra Colombini, Vincenzo Raffo, Vincenzo Pennone, Katia Mareschi, Luciana Labanca, Laura Mangiavini, Matteo Moretti, Camilla Recordati, Federico Armando, Laura de Girolamo and Arianna B. Lovati
Cells 2026, 15(5), 429; https://doi.org/10.3390/cells15050429 - 28 Feb 2026
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Abstract
Background: Advanced therapy medicinal products require rigorous preclinical testing to exclude tumorigenicity. Human articular cartilage cells expanded at low density with human platelet lysate show enhanced proliferation, matrix production, and immunomodulatory properties, supporting their use for diffuse cartilage lesions in osteoarthritic joints. This [...] Read more.
Background: Advanced therapy medicinal products require rigorous preclinical testing to exclude tumorigenicity. Human articular cartilage cells expanded at low density with human platelet lysate show enhanced proliferation, matrix production, and immunomodulatory properties, supporting their use for diffuse cartilage lesions in osteoarthritic joints. This study evaluated tumorigenicity and biodistribution of cartilage cell spheroids generated using two platelet lysate sources. Methods: Cartilage cells were expanded at low density with two platelet lysates and assembled into spheroids. Cytogenetic stability was assessed by metaphase karyotyping following expansion. Immunodeficient mice received subcutaneous implantation and were monitored for 180 days. Human colon carcinoma cells and mouse fibroblasts were used as controls. Clinical follow-up, full organ histopathology, and immunohistochemistry were performed to detect human cell persistence. Results: Expanded cartilage cells showed predominantly normal karyotypes, with rare low-level mosaic chromosomal alterations not detected at the previous passage. Cartilage cell spheroids were well tolerated in vivo, with complete survival and no evidence of tumorigenicity, inflammation, or human cell persistence at implantation sites or distant organs. Control experiments confirmed the sensitivity of the model, and no systemic toxicity was observed. Conclusions: Spheroids derived from cartilage cells are non-tumorigenic, non-migratory, and biologically safe in immunodeficient mice. These findings support their development as cell-based cartilage therapies and align with regulatory recommendations for non-clinical safety evaluation. Full article
(This article belongs to the Special Issue Application of Stem Cells and Cellular Engineering in Musculoskeletal Tissue Regeneration)
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24 pages, 2793 KB  
Perspective
Perspective: Optimizing Host Environments to Enhance MSK Tissue Repair and Complement Use of Cellular Therapies Is Critical for Improving Outcome Success—An Unmet Need
by David A. Hart
Cells 2026, 15(15), 1317; https://doi.org/10.3390/cells15151317 - 23 Jul 2026
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Abstract
Since the discovery and characterization of mesenchymal stem cells (MSC) some 40 years ago and the development of induced pluripotent stem cells (iPSC), opportunities to advance repair and potentially regenerate injured or diseased connective tissues of the musculoskeletal (MSK) system have been intensely [...] Read more.
Since the discovery and characterization of mesenchymal stem cells (MSC) some 40 years ago and the development of induced pluripotent stem cells (iPSC), opportunities to advance repair and potentially regenerate injured or diseased connective tissues of the musculoskeletal (MSK) system have been intensely investigated. While some advances have been made with some tissues, progress has not been as great as was hoped following the availability of such stem-like cells. Optimizing cell-biomaterial composites in vitro for features such as cell state or extracellular vesicle cargo, structure, composition, biomechanical integrity are likely to be only part of the story and optimizing the environments where such composites have been implanted has not received the same attention. Thus, implanting optimized or near optimized cell-biomaterial composites in acutely or chronically affected implantation sites can compromise the efficacy of such composites to effectively repair/regenerate MSK tissues. This may be due to inflammatory processes, alterations to the remaining tissues in the injury site during development of chronicity, waiting too long to repair residual tissue, or other host factors. Thus, success in realizing the potential of MSC and iPSC may depend, in significant part, on the environment at the implantation site. Further attention to optimizing the implantation site may enhance outcome success with long-term return to tissue function. Furthermore, heterogeneity in patient populations regarding natural factors influencing healing outcomes after injury may also require changes to clinical trial design to assess efficacy of cell therapies. Full article
(This article belongs to the Special Issue Application of Stem Cells and Cellular Engineering in Musculoskeletal Tissue Regeneration)
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