Stem Cell Reviews and Reports最新文献

Bronchopulmonary dysplasia (BPD) frequently affects extremely preterm and low birth weight infants, with current treatments lacking specificity. Enhancing extra-uterine preterm alveoli development and repairing damage are crucial for BPD management. Here we show that exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs-Exos) can enhance fetal lung development in mice by delivering specific contents. Briefly, hucMSCs-Exos were extracted using ultracentrifugation and identified by transmission electron microscopy (TEM), flow cytometry, Western blot (WB), and nanoparticle tracking analysis (NTA). These exosomes were then administered to pregnant mice via tail vein injection. Embryonic lung tissues were collected at E13.5 and E18.5 via cesarean section and analyzed using hematoxylin-eosin (HE) staining, immunofluorescence, and TEM. Proteomic analysis was conducted to identify protein components in the exosomes, and WB was used to assess protein expression changes. hucMSCs-Exos from full-term infants were more effective in promoting cell proliferation than those from preterm infants. In vivo, full-term hucMSCs-Exos significantly enhanced alveolarization in fetal lung tissues. Proteomic analysis revealed higher Wnt5a expression in full-term hucMSCs-Exos, and further experiments confirmed a direct interaction between Wnt5a and ROCK1. WB also showed increased expression of the autophagy marker LC3B in the lung tissues of mice treated with full-term exosomes. In conclusion, term hucMSCs-Exos may directly regulate the phosphorylation of ROCK1 in mouse lung tissue through naturally enriched Wnt5a, thus promoting autophagy of AT2 cells and lamellar body development, and ultimately enhance the alveolarization and reducing the incidence of BPD in premature infants.

Genetic variations of signaling modulator protein LNK (also called SH2B3) are associated with relatively mild myeloproliferative phenotypes in patients with myeloproliferative neoplasms (MPN). However, these variations can induce more severe MPN disease and even leukemic transformation when co-existing with other driver mutations. In addition to the most prevalent driver mutation JAK2V617F, LNK mutations have been clinically identified in patients harboring CBL inactivation mutations, but its significance remains unclear. Here, using a transgenic mouse model, we demonstrated that mice with the loss of both Lnk and Cbl exhibited severe splenomegaly, extramedullary hematopoiesis and exacerbated myeloproliferative characteristics. Moreover, a population of Mac1⁺ myeloid cells expressed c-Kit in aged mice. Mechanistically, we discovered that LNK could pull down multiple regulatory subunits of the proteosome. Further analysis confirmed a positive role of LNK in regulating proteasome activity, independent of its well-established function in signaling transduction. Thus, our work reveals a novel function of LNK in coordinating with the E3 ligase CBL to regulate myeloid malignancies.

Wound healing is a dynamic, multi-stage process essential for restoring skin integrity. Dysregulated wound healing is often linked to impaired macrophage function, particularly in individuals with chronic underlying conditions. Macrophages, as key regulators of wound healing, exhibit significant phenotypic diversity, ranging from the pro-healing M2 phenotype to the pro-inflammatory M1 phenotype. Imbalances in the M1/M2 ratio or hyperactivation of the M1 phenotype can delay the normal healing. Consequently, strategies aimed at suppressing the M1 phenotype or promoting the shift of local skin macrophages toward the M2 phenotype can potentially treat chronic non-healing wounds. This manuscript provides an overview of macrophages' role in normal and pathological wound-healing processes. It examines various therapeutic approaches targeting M2 macrophages, such as ex vivo-activated macrophage therapy, immunopharmacological strategies, and biomaterial-directed macrophage polarization. However, it also highlights that M2 macrophage therapies and immunopharmacological interventions may have drawbacks, including rapid phenotypic changes, adverse effects on other skin cells, biotoxicity, and concerns related to biocompatibility, stability, and drug degradation. Therefore, there is a need for more targeted macrophage-based therapies that ensure optimal biosafety, allowing for effective reprogramming of dysregulated macrophages and improved therapeutic outcomes. Recent advances in nano-biomaterials have demonstrated promising regenerative potential compared to traditional treatments. This review discusses the progress of biomaterial-assisted macrophage targeting in chronic wound repair and addresses the challenges faced in its clinical application. Additionally, it explores novel design concepts for combinational therapies, such as incorporating regenerative particles like exosomes into dressing materials or encapsulating them in microneedling systems to enhance wound healing rates.

Mesenchymal stem/stromal cells (MSCs) hold immense potential for regenerative medicine due to their remarkable regenerative and immunomodulatory properties. However, their therapeutic application requires large-scale production under stringent regulatory standards and Good Manufacturing Practice (GMP) guidelines, presenting significant challenges. This review comprehensively evaluates automated manufacturing processes and platforms for the scalable production of clinical-grade MSCs. Various large-scale culture vessels, including multilayer flasks and bioreactors, are analyzed for their efficacy in MSCs expansion. Furthermore, automated MSCs production platforms, such as Quantum^® Cell Expansion System, CliniMACS Prodigy^®, NANT001/ XL, CellQualia™, Cocoon^® Platform, and Xuri™ Cell Expansion System W25 are reviewed and compared as well. We also underscore the importance of optimizing culture media specifically emphasizing the shift from fetal bovine serum to humanized or serum-free alternatives to meet GMP standards. Moreover, advances in alternative cryopreservation methods and controlled-rate freezing systems, that offer promising improvements in MSCs preservation, are discussed as well. In conclusion, advancing automated manufacturing processes and platforms is essential for realizing the full potential of MSCs-based regenerative medicine and accomplishing the increasing demand for cell-based therapies. Collaborative initiatives involving industry, academia, and regulatory bodies are emphasized to accelerate the translation of MSCs-based therapies into clinical practice.

Dealing with chronic inflammatory skin conditions like atopic dermatitis and psoriasis can be extremely difficult. Current treatments, such as topical corticosteroids, often have limitations and side effects. However, researchers have discovered that the placenta's remarkable properties may provide a breakthrough in effectively addressing these skin conditions. The placenta comprises three essential tissues: decidua, placental membrane, and umbilical cord. Placental derivatives have shown significant potential in treating psoriasis by reducing inflammatory cytokines and inhibiting keratinocyte proliferation. In the case of atopic dermatitis, umbilical cord stem cells have demonstrated anti-inflammatory effects by targeting critical factors and promoting anti-inflammatory cytokines. The scope of benefits associated with placental derivatives transcends these specific applications. They also potentially address other inflammatory skin diseases, such as vitiligo, by stimulating melanin production. Moreover, these derivatives have been leveraged in the treatment of pemphigus and epidermolysis bullosa (EB), showcasing potential as a wound dressing that could eliminate the necessity for painful dressing changes in EB patients. In summary, the integration of placental derivatives stands to revolutionize our approach to inflammatory skin conditions owing to their distinct properties and the prospective benefits they offer. This comprehensive review delves into the current applications of placental derivatives in addressing inflammatory skin diseases, presenting a novel treatment approach.

Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) are crucial means of intercellular communication and can regulate a range of biological processes by reducing inflammation, decreasing apoptosis and promoting tissue repair. We treated temporomandibular joint (TMJ) disc chondrocytes with TNF-α and performed local injection of sodium iodoacetate (MIA) in the TMJ of rats to establish in vitro and in vivo models of TMJ osteoarthritis (TMJOA). BMSC-Exos were isolated and extracted to evaluate their proliferation and trilineage differentiation abilities, and their antiapoptotic and chondroprotective effects were assessed. This study revealed that BMSC-Exos can be endocytosed by TMJ disc chondrocytes in vitro and that BMSC-Exos pretreatment strongly attenuated the inhibitory effect of TNF-α on the proliferative and chondrogenic potential of TMJ disc chondrocytes. The administration of BMSC-Exos significantly suppressed TNF-α-induced apoptosis in TMJ disc chondrocytes by increasing the phosphorylation level of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) pathway-related proteins, whereas the PI3K inhibitor LY294002 neutralized this antiapoptotic effect. Intradiscal injection of BMSC-Exos alleviated the degeneration and inflammation of TMJ discs in a rat model of TMJOA. Our study revealed that BMSC-Exos can attenuate the apoptosis of TMJ disc chondrocytes and destruction of TMJ discs partially by inhibiting the apoptotic pathway and activating the PI3K/AKT pathway, thereby providing a promising treatment strategy for the regeneration of damaged TMJ discs.

Stemness, giving cancer cells massive plasticity enabling them to survive in dynamic (e.g. hypoxic) environments and become resistant to treatment, especially chemotherapy, is an important property of aggressive tumours. Here, we review some essentials of cancer stemness focusing on triple-negative breast cancer (TNBC), the most aggressive form of all breast cancers. TNBC cells express a range of genes and mechanisms associated with stemness, including the fundamental four "Yamanaka factors". Most of the evidence concerns the transcription factor / oncogene c-Myc and an interesting case is the expression of the neonatal splice variant of voltage-gated sodium channel subtype Nav1.5. On the whole, measures that reduce the stemness make cancer cells less aggressive, reducing their invasive/metastatic potential and increasing/restoring their chemosensitivity. Such measures include gene silencing techniques, epigenetic therapies as well as novel approaches like optogenetics aiming to modulate the plasma membrane voltage. Indeed, simply hyperpolarizing their membrane potential can make stem cells differentiate. Finally, we give an overview of the clinical aspects and exploitation of cancer/TNBC stemness, including diagnostics and therapeutics. In particular, personalised mRNA-based therapies and mechanistically meaningful combinations are promising and the emerging discipline of 'cancer neuroscience' is providing novel insights to both fundamental issues and clinical applications.

The morphogenetic events leading to tissue formation can be recapitulated using organoids, which allows studying new diseases and modelling personalized medicines. In this review, culture systems comparable to human organs are presented, these organoids are created from pluripotent stem cells or adult stem cells. The efficient and reproducible models of human tissues are discussed for biobanking, precision medicine and basic research. Mechanisms used by these model systems with an overview of models from human cells are also covered. As human physiology is different from animals, culture conditions and tissue limits often become challenging. Organoids offer novel approaches for such cases with rapid screening, transplantation studies and in immunotherapy. Discrepancies with large datasets can be handled with an integrated framework of artificial intelligence or AI and machine learning. An attempt has been made to show the improved effectiveness, simplified iterations, along with image analysis that are possible from this synergy. AI-assisted organoids have the potential to transform healthcare by improving disease understanding and accelerating clinical decision-making through personalized and precision medicine.

Background: Cell-free approaches, utilizing mesenchymal stem cell secretome, have promising prospects in various fields of regenerative medicine. In this study, we examined in vitro and in vivo the potential of dental pulp stem cell-conditioned medium (DPSC-CM) for bone regeneration.

Methods: The secretome of undifferentiated stem cells from dental pulp were collected, and the effects of this DPSC-CM were assessed for osteodifferentiation of osteoblast-like cells (MG-63) and osteoblasts deriving from DPSC. Cell proliferation, alkaline phosphatase (ALP) activity, gene expression of Runt-related transcription factor 2 (Runx2), Bone Sialoprotein (BSP), Osteocalcin (OCN), and extracellular matrix mineralization were evaluated. The rat caudal vertebrae critical size defect model was to investigate the effect of DPSC-CM in vivo.

Results: Results showed that DPSC-CM induced cell growth, and increased ALP activity and the expression of key marker genes at an early stage of osteoblastic differentiation compared to control. A rat bone defect model was used to illustrate the effect of DPSC-CM in vivo. The bone density within the defects were improved using conditioned medium, even though there was no significant difference between the control and DPSC-CM groups. The analysis of DPSC-CM by human growth factor antibody array revealed the presence of several factors involved in osteogenesis.

Conclusion: Taken together, these findings indicate that DPSC-CM is a promising therapeutic candidate for bone regenerative therapy, accelerating the maturation of osteoblastic cells. And even though safety and efficiency of DPSC-CM have to be confirmed in preclinical studies, these results represent a first step toward clinical application.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a critical condition resulting from impaired oxygen and blood flow to the brain during birth, leading to neuroinflammation, neuronal apoptosis, and long-term neurological deficits. Despite the use of therapeutic hypothermia, current treatments remain inadequate in fully preventing brain damage. Recent advances in mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) offer a novel, cell-free therapeutic approach, as these EVs can cross the blood-brain barrier (BBB) and deliver functional microRNAs (miRNAs) to modulate key pathways involved in inflammation and neuroprotection. This review examines how specific miRNAs encapsulated in MSC-EVs-including miR-21, miR-124, miR-146, and the miR-17-92 cluster-target the complex inflammatory responses that drive HIE pathology. By modulating pathways such as NF-κB, STAT3, and PI3K/Akt, these miRNAs influence neuroinflammatory processes, reduce neuronal apoptosis, and promote tissue repair. The aim is to assess the therapeutic potential of miRNA-loaded MSC-EVs in mitigating inflammation and neuronal damage, thus addressing the limitations of current therapies like therapeutic hypothermia.