Cellular therapies, including hematopoietic stem cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cell therapy, have undergone significant advancements, leading to broader indications and improved patient outcomes. Despite the progress, access remains inequitable, driven by disparities related to socioeconomic factors, healthcare infrastructure, and limitations associated with the products themselves. This review provides an overview of the current state of access to cellular therapies in the United States, with a focus on identifying barriers and exploring potential solutions. Many of these barriers are shared globally, including in low- and middle-income countries, but are not necessarily mirrored in other developed nations, where healthcare systems and funding models differ. Addressing these disparities will require action at many levels, including expanding community-based access, innovation in the manufacturing process, enhancing financial support, and implementing equity-focused initiatives. As cellular therapies continue to evolve, ensuring equitable access must remain a central priority to foster inclusiveness in medical innovation.

Over the past decade, there has been no clear evidence regarding the comparative effectiveness of bone-marrow mononuclear cell (BMMNC) therapy in patients with chronic heart failure (HF).

Cardiac tissue macrophages are crucial components of the immune system and tissue homeostasis. Traditionally, these macrophages have been classified into three primary lineages: yolk sac blood island-derived erythromyeloid progenitor (EMP), yolk sac hemogenic endothelial-derived late-EMP, and hematopoietic stem cell (HSC)-derived macrophages. These classifications have shaped our understanding of the developmental origin of macrophages in the heart. However, recent studies have significantly shifted this perspective by revealing that the heart itself possesses an intrinsic source of macrophages, independent of the traditionally recognized hematopoietic sources. This discovery has added a new dimension to our understanding of macrophage biology in the context of cardiac development. Our recent work has provided compelling evidence that endocardial cells exhibit hematopoietic potential during embryonic day (E)8.5 to E10. This discovery challenges the previously held belief that macrophages in the heart are exclusively derived from EMP or HSC. Endocardial cells give rise to a distinct population of cardiac tissue macrophages that play vital roles in heart morphogenesis. These findings open up new avenues for understanding how macrophages contribute to heart formation, homeostasis, and their disruption. This review summarizes the latest findings on the role of endocardial-derived macrophages, along with other macrophage lineages, in contributing to heart development and the maintenance of cardiac homeostasis.

Myeloid innate immune cells, including macrophages, neutrophils, myeloid-derived suppressor cells, and dendritic cells, represent major components of the tumor microenvironment (TME), exhibiting remarkable plasticity and dual roles in cancer progression and immune regulation. In recent years, microbial-induced innate immune memory, also termed "trained immunity" (TRIM), has emerged as a novel strategy to reprogram myeloid cells into an immunostimulatory, antitumor state. In this review, we explore the intricate landscape of myeloid cells in cancer and examine how microbial ligands, such as the Bacillus Calmette-Guérin vaccine and β-glucan, reprogram both bone marrow progenitors and tissue-resident myeloid cells to enhance inflammatory and antitumor responses. Notable findings include the hematopoietic stem and progenitor cell reprogramming by Bacillus Calmette-Guérin for sustained anticancer immunity, and the enhanced granulopoiesis and neutrophil-mediated tumor killing mediated by β-glucan-induced TRIM. These mechanisms synergize with immunotherapies, such as immune checkpoint inhibitors, by reshaping the immunosuppressive TME and enhancing adaptive immunity. However, challenges remain, including the structural complexity of microbial products, the lack of predictive biomarkers, and the need for optimized dosing and delivery strategies. Addressing these gaps by introducing precise characterization of microbial-derived ligands, biomarker-driven patient selection through large-scale clinical trials, as well as the development of novel approaches for targeted therapy will be essential to harness the full potential of microbial-induced TRIM, ultimately paving the way for more effective and durable cancer immunotherapies. SIGNIFICANCE STATEMENT: Tumor-promoting myeloid cells within the tumor microenvironment remain a major barrier to effective cancer immunotherapy. Microbial-induced trained immunity offers a novel strategy to reprogram myeloid cells into an antitumor state. This review provides a comprehensive overview of myeloid cell populations in cancer and the mechanisms underlying microbial-induced trained immunity. It also highlights preclinical and clinical evidence demonstrating the efficacy of microbial-based strategies in overcoming immunosuppression and synergizing with existing immunotherapies, offering a promising approach to improve cancer treatment outcomes.

Osteosarcoma (OS), chondrosarcoma (CHS), and Ewing sarcoma (EwS) are the most common primary bone cancers (BCs). Among primary malignant tumors of the bones, OS is the most common, mainly affecting young people (4.8 per 1,000,000). The treatment of bone cancer (BC) is challenging for current medicine owing to its substantial incidence and the vast heterogeneity of malignant lesions within bone tissue. Due to the limitations of current therapies, researchers developed new strategies to treat BC. Exosomes (EXOs) play a crucial role in the development, progression, metastasis, and drug delivery of BCs, such as OS, EwS, and CHS. Hierarchical translation via tissue-specific reactions and cell-specific molecular signaling pathways accounts for the various therapeutic effects of EXOs produced from stem cells. The aim of this review is to highlight the critical role of EXOs derived from multiple cells, such as mesenchymal stem cells, immune cells, and tumor cells, in BCs, including OS, CHS, and EwS. Additionally, we provide a concise overview of how tumor-derived EXOs induce BCs. To lessen the adverse effects of EXOs on patients with BC and to provide more effective and focused treatments, it is necessary to understand these pathways. Moreover, we reviewed the potential of using EXOs as drug delivery systems for the treatment of BCs. Finally, we discussed the pros and cons of this therapeutic approach for BCs.

Periodontal and craniofacial regeneration presents significant challenges owing to the complex tissue architecture, inadequate vascularization, and diminished stem cell populations within damaged tissues. Traditionally, autologous bone grafts or alternative bone substitute materials have been employed to address these conditions; however, these approaches are constrained by donor site morbidity, limited availability, and suboptimal regenerative efficacy. The advancement of mesenchymal stem/stromal cell (MSC) biology has accelerated the development of cell-based therapies in modern dentistry, which now focuses on biologically driven approaches to regenerate tissues. MSC-based therapies currently under investigation, both preclinically and clinically, show promise for improving tissue integration and healing processes of both soft and hard tissues, attributable to their multipotent nature, immunomodulatory properties, and paracrine signaling capabilities. Nevertheless, obstacles persist, including inconsistent standardization, limited scalability, regulatory hurdles, a paucity of controlled studies, and restricted biomaterial options. This review evaluates MSC-based treatments for periodontal and craniofacial reconstruction by discussing recent research findings and existing obstacles. This review also examines future prospects, such as advanced biofabrication methods, including 3D printing and bioprinting, which have the potential to improve personalized cell therapy for periodontal and craniofacial regeneration.

For many corneal diseases, transplantation is the gold standard for curative treatment and restoration of vision. Penetrating keratoplasty (PKP), performed by Zirm in 1905, was the first successful corneal transplantation procedure. Since then, relentless advancement in the field has occurred, most importantly with the development of deep anterior lamellar keratoplasty (DALK), Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK), which have been rapidly increasing in usage and are poised to take over PKP in prevalence and effectiveness in treating specific stromal and endothelial pathologies. The biggest issues currently facing this field are the lack of availability of donor corneas and lack of accessibility of the procedure to many areas of the world. Recent and future advancements are focused on substitutes to increase the amount of graft material for use and technological developments to streamline keratoplasty techniques, making them more effective, easier to perform and associated with less complications. Bio-engineered corneas, cell-based therapies and regenerative medicine can create grafts through various mechanisms: acellular, synthetic scaffolds and medical therapies to promote endogenous cell regeneration or exogenous cultivation of corneal tissues from stem-cells. Keratoplasty has also been refined by the introduction of femtosecond laser (FSL), which when combined with intra-operative optical coherence tomography (iOCT) allows for finer cuts and novel techniques which can improve the outcomes from PKP, DALK and DMEK.

Cell-based therapies are promising for treating solid tumors, but challenges like tumor heterogeneity, antigen escape, and immunosuppressive microenvironments hinder their efficacy. Inducible suicide gene systems, often viewed solely as safety mechanisms, offer an underappreciated opportunity to enhance cellular therapies. These systems, triggered by various mechanisms (prodrugs, ligands, antibodies, or small molecules), enable controlled elimination of therapeutic cells. Recent developments demonstrate that this controlled cell death, especially when inducing immunogenic cell death (ICD), can kill even resistant tumor cells and reshape the tumor microenvironment (TME) from suppressive to stimulatory. This review highlights the transformative potential of integrating these suicide systems into cell therapies, overcoming key limitations, and amplifying antitumor responses while ensuring safety.

Liver diseases pose a major global health burden, and progress in understanding liver pathophysiology and therapeutic development is hampered by the lack of predictive human models. Hepatic organoids (i.e 3D in vitro structures derived from primary, progenitor, or pluripotent stem cells) offer a physiologically relevant alternative to traditional 2D cultures and animal models. This review provides a comprehensive overview of hepatic organoid systems and their translational potential.

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer marked by aggressive growth and therapeutic resistance. A growing body of research highlights substantial spatial heterogeneity within GBM tumors as a critical factor contributing to treatment failure. Advanced molecular techniques, including third-generation genomics, high-resolution metabolomics, and single-cell and spatial transcriptomics, have illuminated the detailed genetic and epigenetic landscape, revealing a complex interplay of molecular modifications. A key determinant of spatial heterogeneity is differential perfusion, which leads to the formation of distinct microenvironmental niches characterized by varying oxygen, nutrient, and growth factor availability. This ITH impacts not only GBM cancer cells but also the entire tumor microenvironment, including immune and other stromal cells. Interactions between cancer cells and the surrounding stroma significantly modulate immune surveillance, frequently promoting tumor malignancy. Perfusion further dictates the plasticity in GBM, enabling their transformation into the aggressive mesenchymal subtype. This review examines how such perfusion-driven differences affect GBM intra-tumoral heterogeneity, focussing on the aspects of immune regulation, and treatment resistance. We discuss emerging therapeutic strategies that target perfusion-induced heterogeneity, including anti-angiogenic and immunotherapeutic approaches. Further, the review emphasizes the importance of the tumor microenvironment and highlights the complex interplay of factors driving GBM progression, paving the way for more effective and personalized treatment strategies aimed at enhancing patient survival.

Multiciliated ependymal and neural stem cells are key cell populations of the subventricular zone. Recent findings revealed that at least a subpopulation of radial glial cells during embryogenesis can be bipotent and produce both neural stem cells and ependymal cells. The balance between these cell populations is orchestrated by Geminin superfamily, ensuring optimal niche function. However, whether cell fate decisions are definitive or dynamic and whether potential regional differences exist remain elusive. In this review, we delve into the shared origins of different subventricular zone cell populations, and we explore the potential interplay among them. Moreover, we compile evidence on the de-differentiation capacity of ependymal cells and their controversial neural stem cell function under specific conditions, with emphasis on the possible implication of a rare population of biciliated (E2) ependymal cells. Understanding the mechanisms regulating cell fate decisions may unravel ependymal cells' therapeutic potential in therapies targeting various human diseases.

Canine periodontal disease, a progressive and irreversible condition, impacts dental health, posing a significant challenge in veterinary medicine. While current treatments focus on managing progression, canine periodontal ligament stem cells (cPDLSCs) offer regenerative potential through their self-renewal capacity, expression of stemness markers and multilineage differentiation. Autologous cPDLSCs have successfully regenerated alveolar bone, cementum, and Sharpey's fibres, while allogeneic cell transplants have demonstrated immunomodulatory benefits without triggering inflammatory reactions. cPDLSCs also show potential for mitigating inflammation and promoting regeneration in experimentally induced canine periodontal disease. Despite promising preclinical results, challenges such as limited clinical studies, disease variability, high costs, and low owner awareness hinder progress in the use of cPDLSCs in veterinary dental clinical settings. Advancing clinical veterinary science requires conducting clinical trials involving dogs with naturally occurring periodontal disease. Interdisciplinary collaboration can lower costs and expand access to these studies. Additionally, educating pet owners about hygiene practices, early disease detection, and the advantages of regenerative therapies will increase their compliance and improve the outcomes. Ultimately, bridging the gap between research and clinical application through real-world studies is essential for advancing accessible and effective periodontal therapies for dogs. Our review aims to explore the potential of cPDLSCs in both in vitro and in vivo contexts, advancing knowledge of the periodontal microenvironment and paving the way for innovative regenerative therapies.

Bone is an incredibly robust tissue thanks to its high blood supply, rapid cell turnover, and continuous remodeling. A significant body of research investigates strategies to improve osteogenesis, angiogenesis, and immunomodulation for bone regeneration, facilitated by numerous various therapeutic approaches (e.g. pharmacologics, biomaterials, stem cell therapy, and more). However, a critically understudied but recently emerging area of research lies in the inflammatory cascade and the cleanup of apoptotic cells during repair, aging, and disease. Termed "efferocytosis," this natural and efficient cleaning up of cells at the end of their lifespan is a crucial step in resolving injury, controlling disease, maintaining homeostasis, and tissue repair. Currently, the primary mechanism(s) driving efferocytosis in most tissue but especially bone, is unknown. Despite this knowledge gap, mounting evidence suggests that impaired efferocytosis plays a significant role in many chronic illnesses and impairs tissue regeneration. Biomaterials-based interventions are well-positioned to interrogate mechanisms of efferocytosis due to their ability to provide local support and guide cellular activity not only in combination with but also without additional pharmaceutical aid. This review will highlight the current understanding of efferocytosis in bone and discuss cutting-edge biomaterials-based strategies to engineer efferocytosis for improved outcomes in bone regeneration.

Glioma, a prevalent primary brain tumor, arises from the supporting cells of the central nervous system (CNS) and is categorized into grades I-IV. Despite advancements in therapeutic strategies, including surgery, chemotherapy, radiotherapy, and targeted therapies, glioma remains associated with high mortality and recurrence rates, often leading to poor patient outcomes. The pathogenesis of glioma is influenced by a combination of environmental factors, genetic mutations, and lifestyle choices. Transforming growth factor-beta (TGF-β) signaling plays a pivotal role in glioma progression by regulating cell proliferation, survival, and differentiation. TGF-β activates Small mothers against decapentaplegic 2/3 (Smad2/3) proteins through specific receptors, forming a complex with Smad4 that translocate to the nucleus to modulate gene expression. In addition, TGF-β-activated kinase 1 (TAK1) initiates mitogen-activated protein kinase (MAPK) cascades, further contributing to tumorigenesis. The TGF-β/Smad pathway can be negatively regulated by inhibitory Smad6/7. Elevated expression of TGF-β isoforms (Ι-Ш) is correlated with increased glioma risk. TGF-β promotes tumor growth by sustaining glioma stem cell self-renewal and suppressing antitumor immune responses. Preclinical studies demonstrate that TGF-β signaling inhibitors reduce glioma viability and invasion in animal models, highlighting their potential as promising therapeutic agents for glioma treatment.

Acute myeloid leukemia (AML) is a blood cancer caused by genetic mutations in hematopoietic precursor cells, leading to abnormal cell production in the bone marrow (BM) and results in complications like anemia, leukopenia, and thrombocytopenia. Treatments, such as chemotherapy and hematopoietic stem cell transplantation carry risks like graft-versus-host disease (GVHD) and infections due to immune suppression. Recently, treatment with natural killer (NK) cells has emerged as a novel approach for treating AML. NK cells can identify and destroy leukemic cells, and methods like NK cell transfer and cytokine activation show promise as effective treatments. This article evaluates the feasibility and safety of NK cell-based therapies for AML patients. This article is a systematic review that registered its protocol in PROSPERO. A strategic search was conducted in the PubMed, Scopus, Google Scholar, and Web of Science databases using the keywords "Natural killer cell, " "Acute myeloid leukemia" and "Immunotherapy". After removing duplicates and applying inclusion/exclusion criteria, 1623 articles were selected. Two reviewers screened titles and abstracts, followed by a full-text review. Disagreements were resolved by a third reviewer, resulting in 17 articles for inclusion. Data were organized in Excel, and study quality was assessed using the Cochrane risk-of-bias tool. Data analysis was performed using R software. Out of 1623 initially identified records, 17 clinical studies comprising 402 AML patients aged between 1 and 82 years were included. Most studies used allogeneic or homologous NK cells, sometimes combined with chemotherapy or interleukin-2. The pooled complete remission (CR) rate was 48.22% (95% CI 31.75-65.09%), with significant heterogeneity (I2 = 76%). Immune response prevalence across 14 studies was 69.34% (95% CI 49.18-84.09%). Adverse events were generally mild and manageable, with no consistent reports of severe toxicity. Although study quality varied, eight studies demonstrated low risk of bias. Publication bias was detected for CR outcomes, adjusting the CR rate to 36.94% after correction. We conducted a systematic review that demonstrates that NK cell therapy shows promising efficacy and acceptable safety in treating AML patients, with a pooled complete remission rate of 48.22% and encouraging immune response rates. Despite heterogeneity across studies and varying methodological quality, the consistent observation of anti-leukemic effects and manageable adverse events supports the potential role of NK cell therapy as a complementary treatment. Further high-quality, large-scale trials are warranted to validate these findings and optimize clinical protocols.

Inflammatory bowel disease (IBD) is a complex disorder characterized by chronic gastrointestinal inflammation. This paper examines the use of Drosophila melanogaster as a model organism to investigate interactions among the gut microbiota, intestinal stem cells (ISCs), and signaling pathways involved in IBD pathogenesis. Key findings indicate that dysbiosis of the gut microbiota significantly contributes to IBD by altering immune responses and inflammatory signaling, leading to increased intestinal damage. Additionally, ISCs are crucial for intestinal regeneration; their dysregulation exacerbates injury, highlighting their role in maintaining gut homeostasis. Natural compounds, particularly those derived from traditional herbal medicines, show promise in alleviating IBD symptoms by targeting oxidative stress, regulating inflammation, and modulating autophagy, thus promoting ISC homeostasis and restoring microbial balance. This review underscores the intricate relationships among the gut microbiota, ISCs, and inflammatory pathways in IBD, as elucidated through Drosophila studies. The studies summarized here emphasize the need to address microbial imbalances, ISC dysregulation, and inflammatory mechanisms to develop effective therapeutic strategies. Further research is essential to fully elucidate these interactions and inform innovative treatments that improve patient outcomes in IBD management.

Inflammatory bowel disease (IBD), which encompasses ulcerative colitis and Crohn's disease, poses significant treatment difficulties because of its persistent course and underlying inflammatory mechanisms. Existing treatments primarily focus on alleviating symptoms, while novel biological drugs that target specific molecular pathways could address the root causes of the disease. One such pathway involves the farnesoid X receptor (FXR), a nuclear receptor essential for bile acid metabolism, intestinal homeostasis and modulation of inflammation. Activating FXR can reduce intestinal inflammation and improve gut barrier function, highlighting its potential as a treatment target for IBD. However, using synthetic agonists to directly activate FXR has drawbacks, including off‑target effects and limited effectiveness. Exosomes, tiny nanoscale vesicles involved in cell‑to‑cell communication, have emerged as promising therapeutic tools for regulating FXR signaling in IBD. Exosomes, particularly those derived from mesenchymal stem cells, can deliver bioactive molecules that promote FXR activation, reduce inflammation, and enhance tissue regeneration. The present review examines how exosomes regulate FXR signaling and their potential therapeutic use in IBD. It covers exosome biogenesis, therapeutic benefits and their molecular mechanisms in IBD.

Excessive generation of reactive oxygen species (ROS) can lead to oxidative-antioxidative imbalance in the organism, resulting in oxidative stress. Hematopoietic stem/progenitor cells (HSPCs) exhibit high sensitivity to changes in ROS levels, and high levels of ROS can impair self-renewal capacity of HSPCs, leading to oxidative damage and even death. Wnt/β-catenin signaling pathway regulates hematopoiesis and plays an important role in determining the fate of stem cells, such as self-renewal, proliferation and differentiation of HSPCs. Studies have shown that Wnt/β-catenin signaling pathway is also closely related to oxidative stress. This article summarizes the relevant literature, and reviews the role of Wnt/β-catenin signaling pathway in oxidative stress, its impact on hematopoietic system, and the current research status of related mechanisms.

Diminished functional beta-cell mass is a key pathogenic mechanism underlying both type 1 and type 2 diabetes (T1D and T2D), precipitated by the progressive impairment of insulin secretion, loss of cellular identity, and ultimately, beta-cell death. The replenishment of beta-cell deficit through the transplantation of pancreatic islets from cadaveric donors or beta-cells derived from human embryonic stem cells has shown transformative therapeutic potential. However, the regeneration of functional beta-cell mass in vivo remains an important therapeutic goal, as a more physiological and scalable approach. Effective beta-cell replenishment must address the underlying causes of beta-cell loss, such as cellular stress and autoimmunity, while simultaneously promoting beta-cell regeneration, function, and survival. Advances in the mechanistic underpinnings of beta-cell differentiation, growth, and survival, coupled with cutting-edge high-throughput screening methods have accelerated the discovery of novel therapeutic targets and small-molecule interventions. Current strategies for in vivo beta-cell expansion include modulating the cell-cycle to promote replication, reprogramming non-beta-cell lineages into beta-cells, and enhancing beta-cell survival. However, the limited regenerative capacity and inherently high stress sensitivity of beta-cells pose significant barriers to their in vivo expansion, further complicated by the fundamental conflict between replication and functional maintenance, and the high vulnerability of replicating cells in a metabolically stressed environment. There has been tremendous progress in developing approaches that simultaneously promote beta-cell expansion and function. In this review, we discuss the recent advances in beta-cell expansion, along with remaining challenges and emerging opportunities to address them.

The idea of ​​using stem cell therapy to treat neurodegenerative diseases has undergone significant change over the years and has made significant progress recently. Neurotrophins, growth factors, and transcription factors regulate neural stem cell proliferation and differentiation. Disruption of these regulatory mechanisms, including negative feedback, can contribute to neurodegenerative diseases. Contemporary research highlights a growing global concern regarding diverse neurodegenerative disorders affecting both humans and animals. These conditions arise from neuronal cell death, axonal regeneration failure, and impairment of neuronal structure. Current pharmacological treatments primarily offer symptomatic relief without altering disease progression. Consequently, researchers are investigating innovative therapeutic strategies, with neural stem cell therapy emerging as a promising avenue. Adult neural stem cells, embryonic neural stem cells, and induced pluripotent stem cells represent potential cell sources, although challenges such as ethical considerations and technical limitations remain. The therapeutic application of neural stem cells holds significant promise for addressing neurodegenerative diseases, including Alzheimer's disease, stroke, amyotrophic lateral sclerosis, spinal cord injury, and multiple sclerosis. Neural stem cell therapy aims to replenish lost neurons and promote neural regeneration in these conditions. While clinical trials have demonstrated some success in improving cognitive and motor functions in individuals with neurodegenerative impairments, challenges such as immunological rejection, the identification of compatible cell sources, ethical concerns, treatment efficacy, and potential side effects necessitate thorough investigation before widespread clinical implementation. Despite these challenges, neural stem cell-based therapy offers substantial potential for revolutionizing the treatment of neurodegenerative diseases and central nervous system injuries. This paper, therefore, explores adult neurogenesis and the therapeutic potential of neural stem cells within the dynamic field of neurodegenerative disorders.