Traditional root canal treatment removes the infection successfully, but the vitality of pulp-dentin complex cannot be restored. The birth of regenerative endodontics is a biologically driven technique that seeks to restore pulp vitality, coax the root into forming, and maintain long-term functionality of the tooth. This review critically appraises the available evidence regarding regenerative endodontics and stem cell-based therapies in clinical practice. PRISMA guidelines were adopted for a comprehensive search of the literature in PubMed, Scopus, Web of Science, Cochrane Library, and Embase. Human trials reporting cellular transplantation-based or cell-homing regenerative approaches were considered. Five eligible human studies were included. Stem cell sources comprised dental pulp stem cells and stem cells from human exfoliated deciduous teeth, while platelet concentrates and collagen scaffolds were commonly used. Clinical outcomes included restoration of pulp vitality, apical closure, dentin wall thickening, and periapical healing, with no major adverse events reported. Stem cell-based regenerative endodontics demonstrates promising clinical potential but remains constrained by small sample sizes, protocol heterogeneity, and limited follow-up. Standardized methodologies and long-term randomized controlled trials are needed before integration into routine practice.

Given the limitations of current treatments for Alzheimer's disease (AD), this study aims to comprehensively evaluate the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) in AD mouse models through a systematic review and meta-analysis. Additionally, we explore the impact of transplantation dose and route on treatment outcomes to identify the optimal window for clinical application.

Over the last few decades, cell and cell-based therapies emerged as treatment options for equine tendinopathy and desmopathy. The objective of this study was to critically evaluate outcomes following treatment of equine tendinopathy or desmopathy with adult multipotent stromal/stem cells (MSCs).

The objective of the study is to systematically evaluate the efficacy and mechanisms of action of stem cell-derived exosomes from various sources (including adipose tissue [AD-MSCs] and bone marrow [BM-MSCs]) in treating diabetic foot ulcers (DFUs) based on preclinical evidence.

Systematic review and meta-analysis.

Incurable hereditary diseases such as Duchenne muscular dystrophy (DMD), Huntington's disease (HD), and myotonic dystrophy type 1 (DM1) fall into the nucleotide repeat expansion disorder (NRED) category. The discovery of CRISPR-Cas genome editing has paved the way toward hopeful strategies for accurate DNA-level repair. This systematic review presents preclinical data on the efficacy, molecular effects, and limitations of CRISPR-based treatments for NREDs.

Hypoxia is an inevitable consequence of surgical interventions such as bone augmentation and soft tissue transplantation in oral and maxillofacial surgery. Cellular adaptation to hypoxic conditions critically influences regenerative processes, including osseointegration, angiogenesis and tissue integration. This systematic review investigated the effects of hypoxic conditions and hypoxia-regulating strategies on tissue regeneration, with the aim of identifying mechanisms to enhance clinical outcomes.

Knee osteoarthritis (KOA) remains a leading cause of disability, and mesenchymal stem cells (MSCs) show potential for KOA treatment. However, existing studies demonstrate conflicting results on the optimal dose and tissue source of MSCs for KOA treatment. This gap limits evidence-based treatment decisions.

Human brown adipocytes (BAs) derived from stem cells are increasingly recognized as valuable in-vitro models for investigating thermogenesis and metabolic regulation. Despite this promise, existing differentiation strategies show wide variation in cell sources, methodology and validation approaches, limiting reproducibility and translational potential. This systematic review evaluated current protocols for differentiating human pluripotent stem cells (hPSCs) and human adipose-derived stem cells (hADSCs) into brown adipocytes, assessing methodological consistency, differentiation outcomes, and key limitations. A comprehensive search of PubMed and Google Scholar up to May 2024 was conducted following PRISMA 2020 guidelines. Twenty-six studies met inclusion criteria. Protocols using hPSCs revealed broad mechanistic potential but generally yielded immature adipogenic and thermogenic phenotypes, while hADSC-derived models demonstrated more reliable lipid accumulation and UCP1 expression yet remained constrained by procedural variability. Most studies emphasized marker-based validation, with limited incorporation of functional assays. The pronounced methodological heterogeneity across studies precluded quantitative synthesis. Overall, current in-vitro differentiation systems produce only partially functional human brown adipocytes. Establishing standardized validation criteria and reproducible culture frameworks will be critical to enhance comparability, reproducibility, and translational relevance in future research.

Successful return to sport after anterior cruciate ligament reconstruction (ACLR) depends on rapid, robust "ligamentization" of the tendon graft. Preclinical and early clinical studies suggest that biologic augmentation with stem cells may accelerate this remodeling process, but the magnitude and consistency of benefit remain uncertain. Therefore, this study systematically reviewed and quantitatively synthesized the available evidence on the efficacy of stem cell-based interventions in enhancing intra-articular ligamentization of tendon grafts following primary ACLR.

Nerve injury often results in neuropathic pain, marked by spontaneous pain, hyperalgesia, and allodynia. Current treatments have moderate efficacy and have side effects, prompting interest in alternative approaches. Mesenchymal stem cell (MSC) therapy has shown promise in preclinical studies for reducing neuropathic pain and inflammation. However, the precise mechanisms underlying MSC-mediated pain reduction remain unclear. Investigating these mechanisms is crucial for optimizing MSC-based therapies for neuropathic pain. This article provides a brief overview of the MSC administration, animal models of neuropathic pain, and treatment regimens used in 25 preclinical studies, focusing on the potential mechanisms of action underlying the neuropathic pain-reducing effect of MSCs. Importantly, 23 out of the 25 studies demonstrated a reduction in neuropathic pain following MSC therapy, despite differences in MSC sources and treatment regimens. Neuropathic pain relief was associated with decreased inflammation, suggesting that MSCs may act through immune modulation. However, the resolution of inflammation does not always correlate with complete neuropathic pain relief, indicating the involvement of additional mechanisms.

Background: The individual and social burden of endometriosis is high, and the diagnosis is usually delayed by 7-10 years. Menstrual effluent (ME) represents an accessible and uniquely informative biofluid. This systematic review evaluated the pathophysiological relevance and diagnostic potential of ME in endometriosis. Methods: Following PRISMA 2020 guidelines, we systematically searched PubMed/MEDLINE, EBSCOhost (Academic Search Premier, APA PsycArticles, APA PsycInfo, CINAHL, and MEDLINE), Semantic Scholar, and Google Scholar from inception to 30 November 2025. Original studies analyzing human ME or ME-derived cells in women with endometriosis versus controls were eligible. We extracted study design, analytic methods, diagnostic accuracy metrics (AUC, sensitivity, and specificity), mechanistic pathways, and risk of bias (QUADAS-2 for diagnostic, and NIH tools for mechanistic studies). Results: Thirty-five studies were included. ME consistently captured key pathophysiological mechanisms of endometriosis, including impaired decidualization and progesterone resistance, immune dysregulation with diminished cytotoxic clearance, pro-angiogenic and invasive phenotypes, heightened stem/progenitor cell survival, cellular senescence and DNA damage, and altered extracellular-vesicle signaling. Diagnostic accuracy was reported in nine studies. Aromatase mRNA showed the highest performance (AUC 0.977), followed by TGF-β1 (AUC 0.973) and IGFBP1 (AUC 0.92). A lipidomic two-marker model achieved an AUC of 0.87. All diagnostic assessments were based on case-control studies; none conducted prospective validation. Conclusions: ME is a biologically relevant, non-invasive, and patient-acceptable biospecimen reflecting core endometriosis mechanisms and yielding promising diagnostic accuracy. The highest diagnostic performance was achieved for assays reflecting steroidogenic and growth-factor pathways (e.g., aromatase and TGF-β1). Standardization and prospective validation are needed before clinical adoption.

Background. NOTCH receptors play a pivotal role in carcinogenesis. Upon ligand binding, a cascade of proteolytic cleavages mediated by ADAM proteases and the γ-secretase complex activates the receptor, ultimately releasing the NOTCH intracellular domain (NICD). NICD translocates to the nucleus, where it regulates gene expression. This review mainly aims to evaluate γ-secretase inhibitors (GSIs) as anticancer agents in preclinical and clinical settings, with a focus on their ability to block tumor progression, target cancer stem cells, and overcome resistance to standard therapies. Methods. A systematic search was conducted in the ISI Web of Science, PubMed, and Scopus databases, following PRISMA guidelines. The review included preclinical in vitro and in vivo studies, as well as clinical trials, investigating GSIs, either as monotherapy or in combination with other treatments, in TNBC, metastatic melanoma, PDAC, gastric cancer, and NSCLC. Exclusion criteria included duplicates, non-English articles, studies published before 2010, studies on non-cancer conditions, research unrelated to NOTCH signaling, and studies outside the selected cancer types. Overall, 69 articles were included and categorized into the five types of cancer analyzed (20 on NSCLC, 22 on TNBC, 11 on metastatic melanoma, 7 on GC, and 9 on PDAC). Of these, 60 studies corresponded to preclinical research in the types of cancer, and 9 studies corresponded to clinical trials in the types of cancer except for GC. Two independent authors screened and extracted relevant data, with disagreements resolved by the corresponding author. Findings were synthesized qualitatively across cancer types under study. Results. This review summarizes therapeutic advances involving GSIs in cancers driven by oncogenic NOTCH signaling, based on the 69 articles included. Preclinical studies show that GSIs synergize with chemotherapy and radiotherapy, particularly in NSCLC, melanoma, and TNBC, and block EMT, overcome therapeutic resistance, and improve prognosis. Commonly used GSIs include DAPT and RO4929097, which enhance the efficacy of agents, such as gemcitabine (PDAC), paclitaxel, osimertinib, erlotinib, and crizotinib (NSCLC), and 5-FU (gastric cancer, TNBC). Promising strategies include combining GSIs with SAHA, ATRA, CB-103, and other NOTCH signaling targeting molecules, either alone or with chemo- and radiotherapy. Clinical trials with GSIs, however, remain limited. RO4929097 is the most extensively tested GSI in clinical settings. PDAC trials combining GSIs with gemcitabine showed no benefit; melanoma trials yielded modest outcomes; and TNBC trials demonstrated partial responses to GSIs but overall low efficacy and significant adverse events. Discussion and Conclusions. Despite encouraging preclinical evidence, clinical trials with GSIs have underperformed, largely due to tumor heterogeneity, dosing limitations, and the non-selective nature of γ-secretase inhibition. Other NOTCH inhibitors, such as DLL4 antibodies, also resulted in partial responses and secondary effects. Future strategies should prioritize receptor-specific NOTCH inhibitors, patient stratification based on NOTCH pathway activation, and optimized combination regimens. Emerging approaches include integrating immunotherapy with advanced technologies such as CRISPR, CAR-T cells, and bispecific antibodies, as well as targeted delivery systems to enhance efficacy and reduce toxicity. Additional research directions include addressing the tumor microenvironment and EMT-driven resistance, elucidating the mechanisms of immune evasion, and inhibiting tumor angiogenesis. Finally, leveraging artificial intelligence and big-data-driven personalized medicine, including sex-specific considerations, will be essential for improving patient outcomes.

Stress urinary incontinence (SUI), characterized by involuntary urine leakage, significantly impairs quality of life and often stems from urethral sphincter insufficiency. While conventional treatments offer relief for many, they have limitations or may be unsuitable for certain patient populations. Regenerative medicine offers a transformative approach by focusing on the restoration of damaged tissue integrity and physiological function.

Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein 9 (CRISPR/Cas9) technology has become a revolutionary tool in medicine, offering substantial potential for treating a wide range of diseases, including hematological disorders, cancers, genetic conditions, and ophthalmological diseases. This systematic review evaluates the efficacy, safety, and applicability of CRISPR/Cas9 in clinical trials. A comprehensive search of the PubMed, Scopus, Web of Science, and Cochrane databases was conducted. All studies, up to November 2024, meeting the eligibility criteria assessing the application of CRISPR for the treatment of diseases were included. A quality assessment of the included studies was conducted using the Cochrane risk of bias tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement for systematic reviews and meta-analyses was followed, and a total of 17 studies were included. This systematic review of CRISPR/Cas9 technology focused on its effectiveness and safety across various diseases. In nonmalignant hematological disorders, CRISPR successfully treated β-thalassemia and sickle cell disease, resulting in high transfusion independence and the elimination of disease crises. In malignant hematological disorders, B-cell acute lymphoblastic leukemia, CRISPR-engineered chimeric antigen receptor T (CAR-T) cells achieved an 83.3% complete remission rate. Furthermore, CRISPR-based CAR-T cells showed promising results in B-cell non-Hodgkin's lymphoma. In oncology, lung cancer and other solid tumors are among the diseases that have been safely engineered using CRISPR gene editing technology. For genetic disorders, CRISPR improved vision in retinal degeneration and reduced symptoms in hereditary angioedema and transthyretin amyloidosis with mild side effects. The results demonstrated CRISPR's potential across a wide range of conditions. In conclusion, the findings underscore the potential role of CRISPR/Cas9 technology across a wide range of diseases. However, challenges remain, including optimizing delivery systems, minimizing off-target effects, addressing immunogenicity concerns, and ethical considerations.

perianal fistulas (PFs) are often refractory to standard management. Cell therapy strategies using mesenchymal stem cells (MSCs) carried in fibrin glue (FG) have shown promising results in regenerative medicine. Thus, the objective of our study was to assess the efficacy and safety of local FG combined with MSCs for PFs.

Exosome therapy represents an emerging regenerative medicine approach for optimizing wound healing and reducing scarring. Extensive pre-clinical research on human placental mesenchymal stem cell-derived exosomes (hpMSC-exosomes) demonstrates significant therapeutic potential in aesthetic and reconstructive surgery applications. Despite compelling preclinical evidence supporting the efficacy of exosomes in wound healing, human clinical studies remain scarce. The author's current study includes 738 patients treated with hpMSC-exosomes over a 7-year period across multiple aesthetic and reconstructive indications, with 175 cases involving wound healing and 118 cases involving scar therapy. The objective of this systematic review and meta-analysis is to comprehensively evaluate the current evidence for hpMSC-exosomes in wound healing and scar therapy, analyzing their mechanisms of action, clinical applications, and safety profiles through a review of preclinical studies, safety data, and clinical case series in both animals and humans. Analysis of the author's series will be included. Information sources included PubMed, Cochrane Library, EMBASE, Web of Science, and ClinicalTrials.gov resulting in a meta-analysis of 21 global preclinical studies (323 animals) which demonstrated superior outcomes compared with controls across multiple parameters: wound healing rate, neovascular density, re-epithelialization rate, and collagen deposition. hpMSC-exosomes demonstrated accelerated wound healing through enhanced angiogenesis, reduced inflammation, improved collagen production, and immunomodulatory effects. Most studies utilized rodent models, with limited translation to human trials. Current human evidence is predominantly based on early-phase trials, case series, and observational studies. Large-scale, well-designed clinical trials are essential to advancing exosome therapy in wound healing and scar management. hp-MSC-exosomes represent a promising therapeutic modality for wound healing and scar therapy with demonstrated safety and efficacy. Standardization of manufacturing processes and FDA approval remain critical for widespread clinical implementation. Level of Evidence: 3 (Therapeutic).

Postnatal skeletal growth in childhood and adolescence depends on cartilage organs called (epiphyseal) growth plates. Studies in the last decade have identified populations of skeletal stem cells within mouse growth plates' resting zones. While cellular quiescence is vital for the maintenance of many tissue-resident stem cell populations, the resting zone chondrocytes have been labelled "quiescent" for decades. However, the features of cellular quiescence that have been reported in the postnatal resting zone, how they were defined or experimentally assessed, and knowledge gaps relative to other quiescent cell types, remain to be well described. To address this, we conducted a systematic review, using the PRISMA guidelines, to identify studies of resting zone chondrocytes including the prefix "quiescen*". Definitions, keywords, chronological data and experimental findings were extracted. Our analysis demonstrated that, compared to those in other well-studied tissues, features of cellular quiescence in RZ chondrocytes remain poorly reported and underexplored, with limited molecular and functional characterization. Furthermore, while most identified studies reported changes in cell division parameters, integration between cues controlling resting zone cell quiescence is incomplete and heterogeneity among the various sub-populations of RZ cells/potential quiescent states is yet to be fully determined. This review identifies consensuses and knowledge gaps between studies and between quiescent RZ cells and those in other tissues and can act to enhance consistency and comparability in future studies of "quiescence" in the RZ chondrocytes.

Growing evidence has supported the potential method of umbilical cord mesenchymal stem cell (UCMSC) therapy for diabetic foot and lower extremity peripheral artery disease (PAD), but their results are not consistent. Thus, the authors conducted the first meta-analysis concerning the safety and efficacy of UCMSC treatment in diabetic foot patients. 8 English and Chinese databases were searched to identify randomized controlled trials regarding UCMSC therapy in diabetic foot patients. Two independent investigators carried out literature inclusion, data extraction, and quality assessment. Meta-analysis was performed using ReviewManager 5.4.1., 6 RCT studies involving 380 patients were included. Primary endpoints included ulcer healing, transcutaneous oxygen pressure (TcPO2), ankle-brachial index (ABI), and intermittent claudication. Compared with conventional treatment, patients who accepted UCMSC therapy had a better ulcer healing rate (Odds Ratio (OR) = 2.88 [1.20-6.91]), TcPO2 (standardized mean difference (SMD) = 1.39, [0.01-2.77]), and ABI improvement (SMD=1.22 [0.30-2.13]). Moreover, they also experienced significantly better improvements in pain amelioration, skin temperature, and ulcer area reduction. Whereas, intermittent claudication cannot be ameliorated by UCMSC therapy (SMD=0.83 [-0.45-2.10]). Additionally, neovascularization, examined by angiography, was significantly promoted after UCMSC administration. Moreover, two studies recorded adverse events during follow-up, which were considered to be transient, minor, and regional. The present meta-analysis validated that UCMSC treatment enhances diabetic foot ulcer healing and circulation recovery, and has a promising safety profile, though limited by incomplete reporting. Larger-sample multicenter randomized controlled trials and longer-term follow-up are urgently needed to further explore the safety and efficacy of UCMSC treatment in diabetic foot patients. The meta-analysis was prospectively registered on PROSPERO.