血液科学(英文)最新文献

Hemophilia A, caused by a deficiency in factor VIII (F8), is a promising target for gene therapy. This study aims to enhance the efficacy of adeno-associated virus serotype 8 (AAV8) vectors, specifically those encoding B-domain-deleted F8 (BDDF8), to treat the condition. We focused on improving therapeutic outcomes by strategically deleting amino acids at the furin cleavage site (RHQR), a modification that is crucial for increasing F8 expression and reducing capsid stress during vector packaging. Using computational modeling with AlphaFold2, combined with western blotting and in vivo clotting assays, we developed and tested several AAV8-BDDF8 variants in a hemophilia A mouse model. The AAV8-BDDF8-ΔRHQR10 variant, which includes a 10-amino acid deletion at the RHQR site, demonstrated a 2- to 3-fold increase in F8 activity, with sustained expression and no hepatotoxicity. This variant also showed reduced capsid stress and enhanced protein expression. However, the observed decline in long-term efficacy highlights the ongoing challenges in AAV-F8 gene therapy, emphasizing the need for continuous improvements. Our findings offer valuable insights for refining AAV-mediated gene therapy in hemophilia A, showing that targeted molecular modifications can significantly enhance therapeutic performance while ensuring safety.

Anemia is a condition marked by a shortage of red blood cells or hemoglobin, resulting in a diminished ability of the blood to carry oxygen. In response to anemia or hypoxia, the body activates a compensatory mechanism known as stress erythropoiesis. This crucial physiological process results in increased erythrocyte production, particularly in extramedullary sites such as the spleen and liver, to restore adequate oxygen levels. Unlike steady-state erythropoiesis, which primarily occurs in the bone marrow, stress erythropoiesis depends on distinct progenitor cells and signaling pathways within a specialized erythroid niche in adult spleen and liver. This niche provides essential support for the proliferation, differentiation, and maturation of erythroid progenitors during anemic stress. The dynamics within this niche under stress conditions involve complex interactions between progenitor and niche cells. These interactions are regulated by specific molecular signals that adapt to the body's physiological demands, ensuring an appropriate response to stress. This review explores the cellular and molecular mechanisms governing these processes, highlighting the extrinsic pathways and cellular interactions during stress erythropoiesis. In addition, it underscores the need for future research to translate findings from murine models into therapeutic strategies for treating anemia-related diseases.

Due to global blood shortages and restricted donor blood storage, the focus has switched to the in vitro synthesis of red blood cells (RBCs) from induced pluripotent stem cells (iPSCs) as a potential solution. Many processes are required to synthesize RBCs from iPSCs, including the production of iPSCs from human or animal cells, differentiation of iPSCs into hematopoietic stem cells, culturing, and maturation of the hematopoietic stem cells (HSC) to make functional erythrocytes. Previous investigations on the in vitro production of erythrocytes have shown conflicting results. Some studies have demonstrated substantial yields of functional erythrocytes, whereas others have observed low yields of enucleated cells. Before large-scale in vitro RBC production can be achieved, several challenges which have limited its application in the clinic must be overcome. These issues include optimizing differentiation techniques to manufacture vast amounts of functional RBCs, upscaling the manufacturing process, cost-effectiveness, and assuring the production of RBCs with good manufacturing practices (GMP) before they can be used for therapeutic purposes.

Irradiation with X-rays has been widely utilized in the clinical treatment of solid tumors and certain hematopoietic malignancies. However, this method fails to completely distinguish between malignant and normal cells. Prolonged or repeated exposure to radiation, whether due to occupational hazards or therapeutical interventions, can cause damage to normal tissues, particularly impacting the hematopoietic system. Therefore, it is important to investigate the effects of total body irradiation on the hematopoietic system of mice and to compare the inhibitory effects of various doses of irradiation on this system. In this study, we primarily employed flow cytometry to analyze mature lineage cells in the peripheral blood, as well as immature hematopoietic stem and progenitor cells (HSPCs) in the bone marrow and spleen. Additionally, we evaluated the multilineage differentiation capacity of HSPCs through colony-forming cell assays. Our results indicated that peripheral B and T cells demonstrated increased sensitivity to irradiation, with significant cell death observed 1-day post-irradiation. Common lymphoid progenitor cells exhibited greater radiotolerance compared to other progenitor cell types, enabling them to maintain a certain population even at elevated doses. Moreover, notable differences were observed between intramedullary and extramedullary hematopoietic stem cells and common lymphoid progenitor cells regarding the extent of damage and recovery rate following irradiation. The multilineage differentiation capacity of HSPCs was also compromised during radiation exposure. In conclusion, different types of mature blood cells, along with immature HSPCs, exhibited varying degrees of sensitivity and tolerance to irradiation, resulting in distinct alterations in cell percentages and numbers.

γδ T cells are a unique subset of lymphocytes with both innate and adaptive features. They recognize and eradicate various hematological malignancies through different mechanisms, employing factors including γδ TCR, NKR, NKG2D, TRAIL, and perforin/granzyme. They also modulate other immune cells to enhance their antitumor activity. Moreover, γδ T cells have potent antiviral functions after hematopoietic stem cell transplantation (HSCT), which may improve the outcome of patients with hematological malignancies. In this review, we summarize the current knowledge on γδ T cell biology and function in hematological malignancies and HSCT complications. We also discuss the challenges and limitations of the clinical application of γδ T cells, such as their low frequency in peripheral blood and heterogeneity among different subsets. We then highlight some promising strategies for γδ T cell-based therapy, such as using agonist antibodies, cell engagers, or genetic modification technology. Furthermore, we review the recent clinical trials evaluating the safety and efficacy of γδ T-cell therapy in different hematological malignancies. In conclusion, γδ T cells represent a promising immunotherapeutic tool for hematological malignancies that deserves further exploration.

Megakaryocytes (MKs) constitute a small portion of bone marrow cells and are primarily responsible for producing platelets, which are essential for hemostasis and wound healing. Recent studies have revealed that MKs and platelets perform diverse functions in various physiological and pathological contexts. This comprehensive review highlights the functional diversity of MKs beyond thrombopoiesis, including their roles in regulating hematopoietic stem cells, modulating immune responses, contributing to hematological malignancies, and influencing aging processes.