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Cells
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Biochemical Mechanisms and Physiological Implication of Stem Cell Differentiation
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Biochemical Mechanisms and Physiological Implication of Stem Cell Differentiation

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

Deadline for manuscript submissions: 10 December 2026 | Viewed by 4404

Editors

Dr. Giuliana Mannino

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy
Interests: adipose-derived stem cells; neural differentiation; conditioned media; Schwann cells; olfactory ensheathing cells
Special Issues, Collections and Topics in MDPI journals
Dr. Floriana D'Angeli

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Enna “Kore”, 94100 Enna, Italy
Interests: cell signaling; metabolic remodeling; differentiation pathways, oxidative stress
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Stem cells (SCs) can be isolated from various sources and are capable of differentiating into different cell types. They have garnered significant interest due to their key role in regenerative medicine. Numerous diseases and tissue injuries affect humans, such as sarcopenia, fractures, neurodegeneration, spinal cord injury, diabetes, and osteochondral defects. These conditions induce the loss or dysfunction of tissue cells and can compromise stem cells residing in tissue niches, reducing their regenerative capacity. Therefore, it is necessary to gain a deeper understanding of the mechanisms behind differentiation processes to develop appropriate therapeutic strategies, aiming to enhance the differentiation potential of resident stem cells or improve the efficacy of treatments based on differentiated cells, including adult, induced pluripotent, and embryonic stem cells.

This Special Issue, “Biochemical Mechanisms and Physiological Implication of Stem Cell Differentiation”, focuses on the cell biology, physiology, molecular biology, biophysics, and biochemical mechanisms underlying the various stages of differentiation. We particularly seek studies that compare different stem cell sources or differentiation strategies that may explain diverse physiological responses and those that develop an organoid as a potential in vitro model.

This Special Issue welcomes bioinformatic analyses, review articles and original data pertaining to its scope.

Dr. Giuliana Mannino
Dr. Floriana D'Angeli
Guest Editors

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

  • stem cells
  • differentiation
  • 3D cultures
  • co-cultures
  • biochemistry
  • physiology
  • epigenetics

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Published Papers (3 papers)

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Research

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20 pages, 30536 KB  
Article
Role of the Wnt/β-Catenin Signaling Pathway in Mediating Outer Root Sheath Stem Cells to Promote Hair Follicle Regeneration and Skin Wound Healing in Mice
by Hangzhen Zhou, Jiaxin Liu, Lie Yang, Shan Li and Shuwei Li
Cells 2026, 15(11), 1038; https://doi.org/10.3390/cells15111038 - 5 Jun 2026
Viewed by 810
Abstract
Hair follicle (HF) stem cells are multipotent adult stem cells that play a key role in the hair follicle cycle. However, it remains poorly understood how the outer root sheath (ORS)—specifically, the stem cells in the bulge region of the hair follicle—promotes skin [...] Read more.
Hair follicle (HF) stem cells are multipotent adult stem cells that play a key role in the hair follicle cycle. However, it remains poorly understood how the outer root sheath (ORS)—specifically, the stem cells in the bulge region of the hair follicle—promotes skin repair. This study aims to investigate the role of bulge stem cells in tissue growth and repair and to determine whether the ORS of transplanted hair follicles can facilitate skin repair. We further seek to elucidate the mechanisms by which bulge stem cells contribute to hair follicle development, regeneration, and skin wound healing. In this study, hair follicle samples were obtained from neonatal mice using microdissection. Hair follicle morphology was assessed by Sirius red staining, H&E staining, and transmission electron microscopy. Immunofluorescence staining was used to detect changes in CD34 and SOX9 protein expression. Additionally, microdissection-based hair follicle transplantation and Western blotting were employed to investigate protein activation and inhibition in the Wnt/β-catenin signaling pathway. The results show that the hair follicle bulge, inner root sheath, and dermal papilla all increase in size as hair follicles grow, with each structure growing relatively rapidly on day 7. Treatment with Teplinovivint effectively inhibits the expression of Wnt/β-catenin signaling pathway-related proteins and hair follicle stem cell markers. Damaged hair follicle tissues cultured in vitro are capable of self-repair. At the transplantation site, the skin gradually closes as the outer root sheath wound heals. In contrast, the central region of the outer root sheath becomes progressively filled with numerous dividing cells and extracellular matrix. The inner portion of the outer root sheath is densely populated with cells, and the markers CD34 and SOX9 are also widely distributed. This indicates that activation of the Wnt/β-catenin signaling pathway enhances the proliferation and differentiation of hair follicle stem cells, thereby promoting hair follicle growth, repair of damaged follicles, and healing of skin wounds. Furthermore, this study demonstrates the feasibility of using transplanted outer root sheath (ORS) to repair skin wounds—specifically, the potential to achieve large-scale hair regeneration from a limited number of hair follicle stem cells—providing a new approach for the clinical treatment of skin injury disorders. Nevertheless, achieving long-term, stable, and scalable clinical translation of ORS stem cells for hair follicle regeneration remains a major challenge. Full article
(This article belongs to the Special Issue Biochemical Mechanisms and Physiological Implication of Stem Cell Differentiation)
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19 pages, 2732 KB  
Article
Dextromethorphan Modulates the Osteogenic–Adipogenic Balance in Rat Bone Marrow Mesenchymal Stem Cells
by Jian-Hong Lin, Yu-Po Luo, Pei-Ching Ting, Min-Pei Ko and Kun-Ta Yang
Cells 2026, 15(11), 995; https://doi.org/10.3390/cells15110995 - 28 May 2026
Viewed by 648
Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) maintain skeletal homeostasis by balancing adipogenic and osteogenic differentiation, yet clinically used drugs that bias this fate choice and their mechanisms remain incompletely defined. Here, we investigated whether dextromethorphan (DXM), a widely used antitussive, modulated lineage commitment [...] Read more.
Bone marrow-derived mesenchymal stem cells (BMSCs) maintain skeletal homeostasis by balancing adipogenic and osteogenic differentiation, yet clinically used drugs that bias this fate choice and their mechanisms remain incompletely defined. Here, we investigated whether dextromethorphan (DXM), a widely used antitussive, modulated lineage commitment in rat BMSCs and interrogated candidate upstream signaling modules. Rat BMSCs were induced with adipogenic medium or osteogenic medium in the presence of DXM (30 μM). Adipogenesis and osteogenesis were quantified using Oil Red O and Alizarin Red S staining with elution-based quantification, and lineage markers were measured by RT-qPCR. Intracellular Ca2+ and ROS were analyzed using flow cytometry, and the levels of p-AKT and p-ERK were assessed through Western blotting analysis. Under adipogenic induction, DXM increased lipid droplet accumulation and the mRNA levels of Pparγ and Fabp4. Although DXM elevated Ca2+ and ROS, the chelation of intracellular Ca2+ and pharmacological inhibition of Sig-1R/PLC–IP3R signaling, redox/ROS, NMDA receptors, AKT/ERK, Kv channels, bitter taste receptor-related signaling, and mTOR did not attenuate the DXM-enhanced adipogenesis. DXM reduced p-ERK without increasing p-AKT; U0126 lowered basal adipogenesis but did not block the DXM effect. Under osteogenic induction, DXM reduced matrix mineralization and downregulated Runx2 and Bglap mRNA levels, while Wwtr1 mRNA levels were not significantly changed. DXM also partially reversed the osteogenic induction-associated reduction in Mtor mRNA. Separately, under adipogenic induction, rapamycin attenuated baseline adipogenesis but did not prevent the additional lipid accumulation induced by DXM. Collectively, DXM shifted the osteogenic–adipogenic balance toward adipogenesis through a non-canonical mechanism. Full article
(This article belongs to the Special Issue Biochemical Mechanisms and Physiological Implication of Stem Cell Differentiation)
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Review

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28 pages, 1177 KB  
Review
Extracellular Vesicles in Osteogenesis: Comparative Analysis of Stem Cell Sources, Conditioning Strategies, and In Vitro Models Toward Advanced Bone Regeneration
by Luca Dalle Carbonare, Arianna Minoia, Michele Braggio, Francesca Cristiana Piritore, Anna Vareschi, Mattia Cominacini, Alberto Gandini, Franco Antoniazzi, Daping Cui, Maria Grazia Romanelli and Maria Teresa Valenti
Cells 2026, 15(1), 27; https://doi.org/10.3390/cells15010027 - 23 Dec 2025
Cited by 3 | Viewed by 2406
Abstract
Extracellular vesicles (EVs) derived from stem cells have emerged as promising mediators of osteogenesis, suggesting cell-free alternatives for bone tissue engineering and regenerative medicine. This review provides a comprehensive analysis of the main stem cell sources used for EV production, including bone marrow [...] Read more.
Extracellular vesicles (EVs) derived from stem cells have emerged as promising mediators of osteogenesis, suggesting cell-free alternatives for bone tissue engineering and regenerative medicine. This review provides a comprehensive analysis of the main stem cell sources used for EV production, including bone marrow mesenchymal stem cells (BM-MSCs), adipose-derived stem cells (ADSCs), umbilical cord MSCs (UC-MSCs), induced pluripotent stem cells (iPSCs), and alternative stromal populations. Particular attention is given to the ways in which different conditioning and differentiation strategies, such as osteogenic induction, hypoxia, and mechanical stimulation, modulate EV cargo composition and enhance their therapeutic potential. We further discuss the in vitro models employed to evaluate EV-mediated bone regeneration, ranging from 2D cultures to complex 3D spheroids, scaffold-based systems, and bone organoids. Overall, this review emphasizes the current challenges related to standardization, scalable production, and clinical translation. It also outlines future directions, including bioengineering approaches, advanced preclinical models, and the integration of multi-omics approaches and artificial intelligence to optimize EV-based therapies. By integrating current knowledge, this work aims to guide researchers toward more consistent and physiologically relevant strategies to harness EVs for effective bone regeneration. Finally, this work uniquely integrates a comparative analysis of EVs from multiple stem cell sources with engineering strategies and emerging clinical perspectives, thereby providing an updated and translational framework for their application in bone regeneration. Full article
(This article belongs to the Special Issue Biochemical Mechanisms and Physiological Implication of Stem Cell Differentiation)
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