Ahmed Abdal Dayem

Stem cell aging significantly impairs therapeutic efficacy, requiring innovative strategies to restore potency. We present a microfluidic cell‐compressing platform for reactivation (µ‐CPR) designed to apply controlled hydrodynamic deformation to late‐passage stem cells. This mechanical stimulation facilitates functional reactivation without external chemical cues. Within a defined window, µ‐CPR reduces oxidative stress, SA‐β‐gal activity, and γ‐H2A.X foci, while enhancing proliferation and increasing the expression of canonical stemness‐associated markers, including OCT4, SOX2, and KLF4. Mechanical stimulation via µ‐CPR induces coordinated structural remodeling: nuclei become more compact, actin cortex organization is restored, α‐actinin redistributes to focal adhesions, and microtubule networks are restructured, suggesting reorganization of intracellular mechanical architecture. Transcriptomic and proteomic analyses reveal that this process reprograms extracellular matrix remodeling and DNA repair pathways while attenuating pro‐fibrotic and senescence‐associated secretory phenotype (SASP)‐associated pathways. Crucially, this reactivation occurs without compromising fundamental stem cell hallmarks, preserving intrinsic immunophenotypes and multilineage differentiation potential. Functionally, µ‐CPR‐processed stem cells demonstrate enhanced in vitro wound closure and improved tissue repair in vivo, with efficacy dependent on the applied mechanical dose. This platform establishes a non‐genetic, mechanobiological approach to functional stem cell reactivation, offering a scalable strategy for restoring stem cell function and providing a foundation for future cellular rejuvenation strategies.

Background Cartilage has limited self-repair capacity, making it vulnerable to damage from aging, trauma, or mechanical stress, which can progress into severe joint disorders. Stem cell-based therapies offer a promising solution for cartilage regeneration and the development of transplantable cartilage constructs. Methods This review highlights recent advances in stem cell in vitro chondrogenic differentiation and their therapeutic applications. It explores various stem cell sources and the mechanisms guiding chondrogenesis, including dynamic culture conditions, differentiation via intermediate lineages, biomaterial scaffolds, and genetic or epigenetic modulation. Results Results: The roles of small molecules and growth factors in directing stem cells toward functional chondrocytes are also discussed. Additionally, we briefly examine the emerging integration of artificial intelligence (AI) in cartilage tissue engineering. AI applications such as predicting differentiation outcomes, monitoring chondrogenic progression in real-time, and identifying small-molecule enhancers are poised to accelerate discovery and standardization in the field. Conclusion The review concludes with an analysis of current limitations and translational challenges that should be addressed to obtain the clinical potential of stem cell-derived chondrocyte therapies. Graphical Abstract Schematic representation of stem cell types and differentiation strategies for chondrocyte formation in cartilage regeneration. This figure was created with BioRender.com, accessed in May 2025.

Psoriasis is a chronic inflammatory skin disease driven by dysregulated immune responses and aberrant keratinocyte (KC) proliferation, with a profound impact on patient quality of life. Emerging evidence highlights extracellular vesicles (EVs) as promising therapeutic candidates in regenerative medicine, offering new avenues for psoriasis management. This review provides a critical overview of psoriasis pathophysiology and evaluates the mechanistic basis of EV-based therapies, emphasizing their immunomodulatory capacity to restore immune homeostasis. We synthesize findings from preclinical studies, demonstrating the therapeutic potential of EVs derived from diverse cellular sources, including their ability to attenuate inflammation, regulate immune responses, enhance wound repair, and modulate KC function. Finally, we explore future directions aimed at optimizing EV therapeutic efficacy and translating these findings into clinical practice. Collectively, this review underscores EVs as a novel, targeted, and cell-free therapeutic strategy with the potential to transform psoriasis treatment.

Extracellular vesicles (EVs) play a crucial role in cell-to-cell communication by transporting functionally active molecules, including proteins, lipids, and nucleic acids. While extensive research has focused on EVs generated from traditional two-dimensional (2D) monolayer cultures (2D-EVs), the emergence of three-dimensional (3D) organoid systems has led to the development of organoid-derived EVs (OEVs), which more closely mimic the physiological conditions of native tissues. In contrast to 2D cultures, 3D systems offer improved EV yield and cargo specificity, enhancing their translational potential. This review discusses the distinctive features of OEVs, including their enhanced tissue relevance, diverse molecular composition, and promising therapeutic applications in areas like disease modeling, regenerative therapies, and targeted drug delivery. We also present an overview of the current organoid-based platforms used to produce OEVs, recent innovations in EV modification and bioengineering, and the practical barriers to their clinical adoption. By comparing the strengths and limitations of OEVs with those of 2D-EVs, we provide a comprehensive perspective on their future role in precision healthcare, biomarker identification, and advanced therapeutic strategies.

Organoids, self-organizing, three-dimensional (3D) multicellular structures derived from tissues or stem cells, offer physiologically relevant models for studying human development and disease. Compared to conventional two-dimensional (2D) cell cultures and animal models, organoids more accurately recapitulate the architecture and function of human organs. Among the critical microenvironmental cues influencing organoid behavior, hypoxia and multilineage communication are particularly important for guiding cell fate, tissue organization, and pathological modeling. Hypoxia, primarily regulated by hypoxia-inducible factors (HIFs), modulates cellular proliferation, differentiation, metabolism, and gene expression, making it a key component in disease modeling. Similarly, multilineage communication, facilitated by intercellular interactions and extracellular matrix (ECM) remodeling, enhances organoid complexity and immunological relevance. This review explores the dynamic interplay between hypoxia and multilineage signaling in 3D organoid-based disease models, emphasizing recent advances in engineering hypoxic niches and co-culture systems to improve preclinical research fidelity. We also discuss their translational implications for drug screening, regenerative medicine, and precision therapies, while highlighting current challenges and future opportunities. By integrating biophysical, biochemical, and computational approaches, next-generation organoid models may be further optimized for translational research and therapeutic innovation.

Extracellular vesicles (EVs) are crucial mediators of intercellular communication, transporting biologically active materials such as proteins, lipids, and nucleic acids. Although EVs derived from 2-dimensional (2D) monolayer cell cultures (2D-EVs) have been extensively studied, recent advancements in 3-dimensional (3D) organoid technology have enabled the generation of organoid-derived EVs (OEVs), which more closely replicate native tissue environments. The 2D culture system has significant limitations for EV production, including low yield and limited enrichment of therapeutic cargo, thereby restricting clinical translation compared to 3D-EVs. This review explores how OEVs provide enhanced tissue specificity, greater molecular complexity, and superior therapeutic potential, particularly in disease modeling, regenerative medicine, and drug delivery. Here, we outline various organoid platforms used to produce OEVs and highlight their potential therapeutic applications. Additionally, we examine recent advances in EV engineering, biofabrication techniques, and the translational challenges related to clinical implementation. By critically assessing the advantages and limitations of OEVs relative to 2D-EVs, this review offers key insights into their potential roles in precision medicine, biomarker discovery, and next-generation therapeutics.

Arthritic diseases are a significant global health challenge, highlighting the urgent need for innovative therapeutic strategies. Extracellular vesicles (EVs) have emerged as promising candidates for treating various intractable diseases. This review explores the therapeutic potential of engineered EVs in joint diseases, particularly in comparison to their parental stem cells. Recent research underscores the efficacy of EVs in treating joint diseases, especially Osteoarthritis (OA). We discuss EV engineering strategies aimed at overcoming the limitations of natural EVs. Data from preclinical trials, clinical studies, and in vitro and in vivo reports are analyzed to evaluate the effectiveness of EVs in treating joint conditions. In addition to their role in intercellular communication, EVs influence various biological processes crucial for bone remodeling, cartilage regeneration, immunomodulation, and inflammation control. EVs are rich in vital biomolecules such as proteins, microRNAs (miRNA), lipids, and nucleic acids, which enhance their therapeutic potential compared to parental stem cells. This understanding is key to developing targeted and effective engineered EVs for OA and other joint diseases. A comprehensive grasp of EV engineering and underlying mechanisms will pave the way for novel and efficient therapies for arthritic diseases and related conditions.This article is categorized under: Implantable Materials and Surgical Technologies > Nanotechnology in Tissue Repair and Replacement Nanotechnology Approaches to Biology > Cells at the Nanoscale Biology‐Inspired Nanomaterials > Peptide‐Based Structures

Flavonoids enhance the self-renewal and differentiation potential of mesenchymal stem cells (MSCs) and have therapeutic activities, including regenerative, anti-oxidative, and anti-inflammatory effects. Recent studies have revealed that MSC-derived extracellular vesicles (MSC-EVs) have therapeutic effects on tissue regeneration and inflammation. To facilitate further research on the therapeutic potential of MSC-EVs derived from flavonoid-treated MSCs, we surveyed the production of EVs and their therapeutic applications in wound regeneration. MSCs treated with flavonoids enhanced EV production twofold compared with naïve MSCs. EVs produced by MSCs treated with flavonoids (Fla-EVs) displayed significant anti-inflammatory and wound-healing effects in vitro. The wound-healing capacity of EVs was mediated by the upregulation of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling. Interestingly, the protein level of p-ERK under inhibition of MEK signals was maintained in Fla-EV-treated fibroblasts, suggesting that Fla-EVs have a higher therapeutic potential than naïve MSC-EVs (Cont-EVs) in wound healing. Moreover, the in vivo wound closure effect of the Fla-EVs showed significant improvement compared with that of the flavonoid-only treatment group and the Cont-EVs. This study provides a strategy for the efficient production of EVs with superior therapeutic potential using flavonoids.

The expression of GPR50 in CSLC and several breast cancer cell lines was assessed by RT-PCR and online platform (UALCAN, GEPIA, and R2 gene analysis). The role of GPR50 in driving CSLC, sphere formation, cell proliferation, and migration was performed using shGPR50 gene knockdown, and the role of GPR50-regulated signaling pathways was examined by Western blotting and Luciferase Assay. Herein, we confirmed that the expression of G protein-coupled receptor 50 (GPR50) in cancer stem-like cells (CSLC) is higher than that in other cancer cells. We examined that the knockdown of GPR50 in CSLC led to decreased cancer properties, such as sphere formation, cell proliferation, migration, and stemness. GPR50 silencing downregulates NF-kB signaling, which is involved in sphere formation and aggressiveness of CSLC. In addition, we demonstrated that GPR50 also regulates ADAM-17 activity by activating NOTCH signaling pathways through the AKT/SP1 axis in CSLC. Overall, we demonstrated a novel GPR50-mediated regulation of the NF-κB-Notch signaling pathway, which can provide insights into CSLC progression and prognosis, and NF-κB-NOTCH-based CSLC treatment strategies.