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Biomedicines
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Stem Cell Therapy: Traps and Tricks
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Stem Cell Therapy: Traps and Tricks

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Biomedical Engineering and Materials".

Deadline for manuscript submissions: closed (31 March 2026) | Viewed by 11444

Editors

Dr. Martina Perše

E-Mail Website
Guest Editor
Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Interests: challenges in animal model research; translation; unbiased reporting of animal model characteristics and results; ethical justification
Special Issues, Collections and Topics in MDPI journals
Dr. Željka Večerić-Haler

E-Mail Website
Guest Editor
1. Department of Nephrology, University Medical Center Ljubljana, 1000 Ljubljana, Slovenia
2. Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia
Interests: kidney transplantation; regenerative medicine and substitutive therapies of acute and end-stage kidney failure; transplanted stem cells; nephrology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the years, stem cell therapy has garnered significant interest as a treatment for various diseases. The therapeutic potential of mesenchymal stem cells (MSCs) has been explored in numerous animal models and veterinary patients. While preclinical research has reported beneficial treatment effects, these findings have led to the initiation of several clinical trials, which have yielded inconsistent results. Additionally, recent experiences have highlighted numerous reports of adverse events and side-effects associated with MSC therapy.

This experience underscores that there are many challenges and pitfalls in regenerative medicine that are often overlooked in the literature, hindering progress in the field and leading to unnecessary financial costs and safety concerns. A comprehensive understanding of these limitations, challenges, and pitfalls is essential for fostering advancements in stem cell therapy.

Therefore, this Special Issue aims to compile articles and reviews addressing the current obstacles, limitations, and side-effects that impede progress in the field, as well as potential strategies and solutions to overcome these issues.

Dr. Martina Perše
Dr. Željka Večerić-Haler
Guest Editors

Manuscript Submission Information

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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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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
  • MSC therapy
  • preclinical research
  • regenerative medicine

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Related Special Issue

Published Papers (5 papers)

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Research

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23 pages, 3422 KB  
Article
Therapeutic Exosomes Carrying VEGFA siRNA Inhibit Pathological Corneal Angiogenesis via PI3K–Akt–Caspase-3 Signaling
by Woojune Hur, Basanta Bhujel, Seorin Lee, Seheon Oh, Ho Seok Chung, Hun Lee and Jae Yong Kim
Biomedicines 2026, 14(1), 246; https://doi.org/10.3390/biomedicines14010246 - 21 Jan 2026
Viewed by 1620
Abstract
Background/Objectives: Neovascularization, defined as the sprouting of new blood vessels from pre-existing vasculature, is a critical pathological feature in ocular diseases such as pathological myopia and represents a leading cause of corneal vision loss. Vascular endothelial growth factor A (VEGFA) plays a pivotal [...] Read more.
Background/Objectives: Neovascularization, defined as the sprouting of new blood vessels from pre-existing vasculature, is a critical pathological feature in ocular diseases such as pathological myopia and represents a leading cause of corneal vision loss. Vascular endothelial growth factor A (VEGFA) plays a pivotal role in endothelial cell proliferation, migration, survival by anti-apoptotic signaling, and vascular permeability. Dysregulation of VEGFA is closely linked to pathological neovascularization. Exosomes, nanosized phospholipid bilayer vesicles ranging from 30 to 150 nm, have emerged as promising gene delivery vehicles due to their intrinsic low immunogenicity, superior cellular uptake, and enhanced in vivo stability. This study aimed to investigate whether highly purified mesenchymal stem cell (MSC)-derived exosomes loaded with VEGFA siRNA labeled with FAM can effectively suppress pathological corneal neovascularization (CNV) via targeeted cellular transduction and VEGFA inhibition. Furthermore, we examined whether the therapeutic effect involves the modulation of the PI3K–Akt–Caspase-3 signaling axis. Methods: Exosomes purified by chromatography were characterized by electronmicroscopy, standard marker immunoblotting, and nanoparticle tracking analysis. In vitro, we assessed exosome uptake and cytoplasmic release, suppression of VEGFA mRNA/protein, cell viability, and apoptosis. In a mouse CNV model, we evaluated tissue reach and stromal retention after repeated intrastromal injections; anterior segment angiogenic indices; CD31/VEGFA immunofluorescence/immunoblotting; phosphorylated PI3K and Akt; cleaved caspase-3; histology (H&E); and systemic safety (liver, kidney, and spleen). Results: Exosomes were of high quality and showed peak efficacy at 48 h, with decreased VEGFA mRNA/protein, reduced viability, and increased apoptosis in vitro. In vivo, efficient delivery and stromal retention were observed, with accelerated inhibition of neovascularization after Day 14 and maximal effect on Days 17–19. Treatment reduced CD31 and VEGFA, decreased p-PI3K and p-Akt, and increased cleaved caspase-3. Histologically, concurrent reductions in neovascularization, inflammatory cell infiltration, and inflammatory epithelial thickening were observed, alongside a favorable systemic safety profile. Conclusions:VEGFA siRNA-loaded exosomes effectively reduce pathological CNV via a causal sequence of intracellular uptake, cytoplasmic release, targeted inhibition, and phenotypic suppression. Supported by consistent PI3K–Akt inhibition and caspase-3–mediated apoptosis induction, these exosomes represent a promising local gene therapy that can complement existing antibody-based treatments. Full article
(This article belongs to the Special Issue Stem Cell Therapy: Traps and Tricks)
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18 pages, 4023 KB  
Article
Evaluation of Platelet Lysate-Based Medium and Protein Substrate for HUVEC Culture and Expansion
by Juan Manuel Duarte Rojas, Luz Marina Restrepo Múnera and Sergio Estrada Mira
Biomedicines 2025, 13(5), 1187; https://doi.org/10.3390/biomedicines13051187 - 13 May 2025
Cited by 1 | Viewed by 2058
Abstract
Background/Objectives: Endothelial cell (EC) culture relies on specialized and commercial media with distinct growth supplement compositions. These media are expensive and must be imported, increasing the time to effective use. Human platelet lysate (PL) and platelet lysate serum (PLS) supplemented media are emerging [...] Read more.
Background/Objectives: Endothelial cell (EC) culture relies on specialized and commercial media with distinct growth supplement compositions. These media are expensive and must be imported, increasing the time to effective use. Human platelet lysate (PL) and platelet lysate serum (PLS) supplemented media are emerging alternatives to commercial media. Methods: Umbilical cords were collected, and human umbilical vein endothelial cells (HUVEC) were isolated and cultured using different media formulations, using Endothelial Cell Growth, Promocell® (ECGM-Promocell®) commercial medium, and media supplemented with PL and PLS. Results: A mixed medium combining DMEM-F12 + PLS and ECGM-Promocell® maintained EC viability, adhesion, and proliferation. Introducing a PL-derived protein substrate enhanced cell adhesion and proliferation by simulating an extracellular matrix. Flow cytometry revealed positive CD31, CD144, and CD146 markers in cells cultured with ECGM-Promocell® and the mixed medium, with or without the PL-protein substrate. Conclusions: These findings suggest that the mixed medium, especially with the PL protein substrate, offers a cost-effective and efficient approach for EC culture and proliferation, holding promise for research and therapeutic applications. Full article
(This article belongs to the Special Issue Stem Cell Therapy: Traps and Tricks)
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Review

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21 pages, 559 KB  
Review
Stem Cell Therapies for Gastrointestinal and Liver Diseases: Translational Barriers, Clinical Heterogeneity, and Future Directions
by Georgi Nikolaev, Stefan Lozenov, Marina Konaktchieva, Borislav Arabadzhiev, Ivelina Vassileva, Radko Sotirov and Rossitza Konakchieva
Biomedicines 2026, 14(5), 1102; https://doi.org/10.3390/biomedicines14051102 - 13 May 2026
Viewed by 547
Abstract
Gastrointestinal and liver diseases remain major contributors to global morbidity and mortality, with limited options for curative or regenerative treatment. Innovative cell-based platforms for liver regeneration and treatment include advanced therapy medicinal products (ATMPs) based on mesenchymal stem cells (MSCs), induced pluripotent stem [...] Read more.
Gastrointestinal and liver diseases remain major contributors to global morbidity and mortality, with limited options for curative or regenerative treatment. Innovative cell-based platforms for liver regeneration and treatment include advanced therapy medicinal products (ATMPs) based on mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and organoids produced by them, while cell-free systems like extracellular vesicles (EVs) offer a new approach to restore tissue function and homeostasis. This review summarizes key advances from 2020 to 2025 in the translational development of these platforms. MSCs have achieved clinical validation in perianal Crohn’s disease and show encouraging antifibrotic and immunomodulatory effects in cirrhosis and acute-on-chronic liver failure. iPSC and iPSC-derived organoids now enable disease modeling and, in early trials, have shown direct epithelial repair. Emerging cell-free approaches based on EVs promise safer, scalable products. Despite rapid progress, challenges remain in potency standardization, manufacturing, and long-term efficacy assessment. International harmonization through the EMA, FDA, and PMDA frameworks is accelerating the translation of stem cell-based advanced therapy medicinal products. The integration of bioengineering, data science, and ethical governance will determine whether these regenerative approaches evolve into accessible standard-of-care interventions for gastrointestinal and hepatic diseases. Full article
(This article belongs to the Special Issue Stem Cell Therapy: Traps and Tricks)
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28 pages, 1795 KB  
Review
Transcription Factor-Based Differentiation of Pluripotent Stem Cells: Overcoming the Traps of Random Neuronal Fate
by Georgie McDaid, Jaime Vanek, Brett Cromer and Huseyin Sumer
Biomedicines 2025, 13(11), 2783; https://doi.org/10.3390/biomedicines13112783 - 14 Nov 2025
Cited by 1 | Viewed by 2362
Abstract
Developing robust methods to differentiate pluripotent stem cells (PSCs) into specific neuronal subtypes is crucial for advancing neuroscience research, including disease modelling and regenerative medicine. Research in this area has primarily focused on generating and studying excitatory neurons, often in co-culture with primary [...] Read more.
Developing robust methods to differentiate pluripotent stem cells (PSCs) into specific neuronal subtypes is crucial for advancing neuroscience research, including disease modelling and regenerative medicine. Research in this area has primarily focused on generating and studying excitatory neurons, often in co-culture with primary astrocytes to support maturation. Due to the shared ectodermal lineage of these cell types, any mesoderm derived cells, such as microglia, are absent using traditional methods of culture. To more accurately model the intricate complexity of the brain and its normal neuronal physiology, it is important to incorporate other critical neural subtypes, such as inhibitory interneurons and various glial cells. This review highlights recent progress in using transcription factor-based in vitro differentiation strategies to generate these diverse neural populations. A major advantage of this approach is the ability to rapidly produce highly specific cell types in a controlled manner, allowing for the precise seeding of cells at defined anatomical and physiological ratios. This controlled methodology enables the creation of more accurate and reproducible in vitro models, including two-dimensional (2D) and three-dimensional (3D) cultures and organoids, thereby moving beyond the limitations of random differentiation from neuronal progenitor cells. Despite these advances, key challenges remain, including reproducibility between pluripotent stem cell lines, off-target transcriptional effects of exogenous factors, and incomplete phenotypic maturation of derived cells. Addressing these constraints is essential for translating transcription factor-based approaches into robust and clinically relevant neural models. Full article
(This article belongs to the Special Issue Stem Cell Therapy: Traps and Tricks)
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Other

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51 pages, 1664 KB  
Perspective
Stem Cell and Exosome Therapy in Wound Healing: Traps, Paradoxes, and Tricks Transforming Paradigms
by Gordana Velikic, Gordana Supic, Dusica L. Maric, Miljan Puletic, Marija D. Maric, Branko Barac and Dusan M. Maric
Biomedicines 2025, 13(12), 3030; https://doi.org/10.3390/biomedicines13123030 - 10 Dec 2025
Cited by 2 | Viewed by 3530
Abstract
Cell therapies hold great promise for advancing wound healing; however, translating this promise into consistent clinical benefit has proven elusive. Numerous trials have failed to reproduce the robust outcomes suggested by preclinical studies, reflecting a landscape marked by hidden traps. These include the [...] Read more.
Cell therapies hold great promise for advancing wound healing; however, translating this promise into consistent clinical benefit has proven elusive. Numerous trials have failed to reproduce the robust outcomes suggested by preclinical studies, reflecting a landscape marked by hidden traps. These include the hostile wound microenvironment, the cytotoxicity of antimicrobial dressings, poor retention and engraftment, immune clearance, and the paradoxical risk of fibrosis and scarring. Across these challenges emerge paradoxes that redefine how traps are understood. The Scarring Paradox reveals that MSCs and EVs may either suppress or reinforce fibrosis, depending on the niche context. The Immune Double-Edged Sword captures the duality of clearance and regenerative modulation. These paradoxes illustrate that traps are not static obstacles but dynamic inflection points. Recognition of these paradoxes has inspired tricks: protective biomaterial carriers, preconditioning strategies, engineered exosomes, and combinatorial therapies with anti-fibrotic, neuromodulatory, or microbiome-targeted adjuncts. Case studies illustrate how classical traps manifest in clinical practice and how paradoxes guide innovation. Emerging adjuncts, ranging from herbal bioactives and bioelectric modulation to circadian synchronization and digital twins, point toward more unconventional but increasingly plausible frameworks for niche control. This perspective review demonstrates that the future of regenerative wound therapy depends not on avoiding traps but on reframing them through paradoxes and converting them into tricks. Stem cell and exosome therapy is thus moving beyond a linear “promise versus failure” narrative toward a systemic, context-aware, programmable approach in which paradoxes drive conceptual renewal and transformative paradigms in wound care. Full article
(This article belongs to the Special Issue Stem Cell Therapy: Traps and Tricks)
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