Li Chen

Induction of fetal hemoglobin (HbF) expression is a promising therapeutic approach for hemoglobinopathies. HbF is primarily regulated by hypoxia-inducible

Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are important components of bone marrow, possessing multipotent differentiation potential and the ability to support hematopoiesis. Exposure to ionizing radiation (IR) induces cellular damage in BM-MSCs, such as DNA lesions and mitochondrial dysfunction. Despite their relative radioresistance, most surviving BM-MSCs enter senescence post-irradiation. This senescent state disrupts the bone marrow niche, impairs stem cell proliferation and differentiation, and contributes to acute radiation syndrome (ARS) and myelosuppression. To clarify the impact of IR on BM-MSCs, this review systematically summarizes the general mechanisms of radiation-induced cellular senescence, examines the effects of different radiation types (e.g., gamma rays, X-rays, and heavy-ion radiation) and doses on BM-MSCs senescence, and outlines senotherapeutic strategies targeting BM-MSCs senescence. The analysis indicates that the senescence of BM-MSCs caused by IR is type- and dose-dependent. The review identifies key factors in IR-induced BM-MSCs senescence to guide targeted interventions, highlighting the need for future studies to elucidate the underlying mechanisms of IR-induced BM-MSCs senescence.

Red blood cell (RBC) plays a vital role in the adaptations to hypoxia at high altitudes, however, the metabolic pattern of RBC under long-term hypoxia remains unknown. Here, we employed broad- and energy-targeted metabolomics approaches to study the differences in the RBC among the three groups: lowlanders living in plain areas, lowlanders acclimatized to plateaus for more than 10 years, and native Tibetans. Compared with lowlanders, the glycolytic flux remained stable in acclimatized lowlanders and adapted Tibetans, and purine metabolism did not correspondingly increase. Notably, the oxidative pentose phosphate pathway was reduced in both acclimatized lowlanders and adapted Tibetans, and a consistent decrease was observed in the reduced glutathione, a key metabolite of the redox system. Next, reduced Superoxide dismutase activity and enhanced catalase activity exhibited distinct pattern in the antioxidant system. Further validation using proteomics confirmed that the major antioxidant enzymes have undergone extensive adaptive changes under long-term hypoxia, including a decrease in Superoxide dismutase 1, peroxiredoxin 1/2, and thioredoxin reductase 1, while catalase has increased. In conclusion, metabolomics and validation measurements reveal a distinct remodeling of the antioxidant defense system in erythrocytes under long-term hypoxia and suggest a pronounced influence of environmental factors on erythrocyte metabolism, offering new insights into hypoxic adaptations.

BACKGROUND Thrombocytopenia 2, an autosomal dominant inherited disease characterized by moderate thrombocytopenia, predisposition to myeloid malignancies and normal platelet size and function, can be caused by 5’-untranslated region (UTR) point mutations in ankyrin repeat domain containing 26 (ANKRD26). Runt related transcription factor 1 (RUNX1) and friend leukemia integration 1 (FLI1) have been identified as negative regulators of ANKRD26 . However, the positive regulators of ANKRD26 are still unknown. AIM To prove the positive regulatory effect of GATA binding protein 2 (GATA2) on ANKRD26 transcription. METHODS Human induced pluripotent stem cells derived from bone marrow (hiPSC-BM) and urothelium (hiPSC-U) were used to examine the ANKRD26 expression pattern in the early stage of differentiation. Then, transcriptome sequencing of these iPSCs and three public transcription factor (TF) databases (Cistrome DB, animal TFDB and ENCODE) were used to identify potential TF candidates for ANKRD26 . Furthermore, overexpression and dual-luciferase reporter experiments were used to verify the regulatory effect of the candidate TFs on ANKRD26 . Moreover, using the GENT2 platform, we analyzed the relationship between ANKRD26 expression and overall survival in cancer patients. RESULTS In hiPSC-BMs and hiPSC-Us, we found that the transcription levels of ANKRD26 varied in the absence of RUNX1 and FLI1. We sequenced hiPSC-BM and hiPSC-U and identified 68 candidate TFs for ANKRD26 . Together with three public TF databases, we found that GATA2 was the only candidate gene that could positively regulate ANKRD26 . Using dual-luciferase reporter experiments, we showed that GATA2 directly binds to the 5’-UTR of ANKRD26 and promotes its transcription. There are two identified binding sites of GATA2 that are located 2 kb upstream of the TSS of ANKRD26 . In addition, we discovered that high ANKRD26 expression is always related to a more favorable prognosis in breast and lung cancer patients. CONCLUSION We first discovered that the transcription factor GATA2 plays a positive role in ANKRD26 transcription and identified its precise binding sites at the promoter region, and we revealed the importance of ANKRD26 in many tissue-derived cancers.

Inherited thrombocytopenia (IT) is a group of hereditary disorders characterized by a reduced platelet count as the main clinical manifestation, and often with abnormal platelet function, which can subsequently lead to impaired hemostasis. In the past decades, humanized mouse models (HMMs), that are mice engrafted with human cells or genes, have been widely used in different research areas including immunology, oncology, and virology. With advances of the development of immunodeficient mice, the engraftment, and reconstitution of functional human platelets in HMM permit studies of occurrence and development of platelet disorders including IT and treatment strategies. This article mainly reviews the development of humanized mice models, the construction methods, research status, and problems of using humanized mice for the in vivo study of human thrombopoiesis.

Nanomedicines are considered one of the promising strategies for anticancer therapy; however, the low targeting efficiency of nanomedicines in vivo is a great obstacle to their clinical applications. Camouflaging nanomedicines with either platelet membrane (PM) or platelet would significantly prolong the retention time of nanomedicines in the bloodstream, enhance the targeting ability of nanomedicines to tumor cells, and reduce the off-target effect of nanomedicines in major organs during the anticancer treatment. In the current review, the advantages of using PM or platelet as smart carriers for delivering nanomedicines to inhibit tumor growth, metastasis, and recurrence were summarized. The opportunities and challenges of this camouflaging strategy for anticancer treatment were also discussed.

Cancer is still a leading cause of death worldwide and liquid biopsy is a powerful tool that can be applied to different stages of cancer screening and treatment. However, as the second most abundant cell type in the bloodstream, platelets are isolated through well-established and fast methods in clinic but their value as a BioSource of cancer biomarkers is relatively recent. Many studies demonstrated the bidirectional interaction between cancer cells and platelets. Platelets transfer various proteins (e.g., growth factors, cytokine, chemokines) and RNAs (e.g., mRNA, lncRNA, miRNA, circRNA) into the tumor cells and microenvironment, leading the stimulation of tumor growth and metastasis. In turn, the platelet clinical characteristics (e.g., count and volume) and contents (e.g., RNA and protein) are altered by the interactions with cancer cells and this enables the early cancer detection using these features of platelets. In addition, platelet-derived microparticles also demonstrate the prediction power of being cancer biomarkers. In this review, we focus on the clinical applications of platelet detection using the platelet count, mean platelet volume, platelet RNA and protein profiles for human cancers and discuss the gap in bringing these implementations into the clinic.

Megakaryocytes (MKs) are the unique non-pathological cells that undergo polyploidization in mammals. The polyploid formation is critical for understanding the MK biology, and transcriptional regulation is involved in the differentiation and maturation of MKs. However, little is known about the functions of transcriptional elongation factors in the MK polyploidization. In this study, we investigated the role of transcription elongation factor EloA in the polyploidy formation during the MK differentiation. We found that EloA was highly expressed in the erythroleukemia cell lines HEL and K562. Knockdown of EloA in HEL cell line was shown to impair the phorbol myristate acetate (PMA) induced polyploidization process, which was used extensively to model megakaryocytic differentiation. Selective over-expression of EloA mutants with Pol II elongation activity partially restored the polyploidization. RNA-sequencing revealed that knockdown of EloA decelerated the transcription of genes enriched in the ERK1/2 cascade pathway. The phosphorylation activity of ERK1/2 decreased upon the EloA inhibition, and the polyploidization process of HEL was hindered when ERK1/2 phosphorylation was inhibited by PD0325901 or SCH772984. This study evidenced a positive role of EloA in HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity.

Inherited thrombocytopenia 2 (THC2) is difficult to diagnose due to the lack of specific clinical characteristics and diagnostic methods. To identify potential plasma protein biomarkers for THC2, we collected the plasma samples from a THC2 family (9 THC2 and 15 non-THC2 members), enriched the medium and low abundant proteins using Proteominer and analyzed the protein profiles using the liquid chromatography-mass spectrometry in data independent acquisition mode. Initially, we detected 784 proteins in the plasma samples of this family and identified 27 up-regulated and 36 down-regulated in the THC2 group compared to the non-THC2 group (|log₂ ratio| >1 and p-value <0.05). To improve the predictive power, top eight dysregulated proteins (B7Z2B4, LTF, HP, ERN1, IGHV1-8, A0A0X9V9C4, VH6DJ, and D3JV41) were selected by an area under the curve-based random forest process to construct a clinical model. Multivariate analysis with random forest and support vector machine showed that the prediction model provided high discrimination ability for THC2 diagnosis (AUC: 1.000 and 0.967, respectively). The potential plasma protein biomarkers will be tested in more THC2 patients and other thrombocytopenia patients to further validate their specificity and sensitivity.