Nature Communications
·
2025
·Vol. 16
·期 1
·1-20
·
IF 15.7
Li Lei,Lei Yufei,Li Yan,Xie Yuxin,Hui Pusheng,Zang Xiaoyan,Wu Weiru,Wu Feng,Fan Jiankun,Wang Jianming,Chen Jieping,Chen Zhe,Hou Yu
The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. Emp1 deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of a class of sphingolipids, dihydroceramides (dhCers). DhCers accumulate in Emp1 -deficient HSCs and induce protein aggregation. Furthermore, Emp1 deficiency renders HSCs more susceptible to IR, while overexpression of Emp1 or inhibition of CERS2 protects HSCs against IR-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential.
研究领域:
细胞生物学
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分子生物学
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遗传学
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放射医学
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产品关联
DOI
PubMed
高影响因子
MACROMOLECULAR MATERIALS AND ENGINEERING
·
2019
·Vol. 304
·期 4
·1800630
·
IF 3.038
Yuanhao Zhang,Yudong Tong,Xiuwei Pan,Haibo Cai,Yun Gao,Weian Zhang
Reactive oxygen species (ROS) level is closely associated with the physiological function of hematopoietic stem cells (HSCs) in ex vivo culture systems. Previously developed hydrogels in use of HSCs culture have generally failed in considering their antioxidant property. In the present work, antioxidant hydrogels are constructed to evaluate the biological effect of ROS on HSCs proliferation by suppressing oxidative stress damage. Functionalized carbon nanotubes (CNTs), which act as potential antioxidants, are physically encapsulated in biocompatible hyaluronic acid (HA) hydrogels to achieve long-term antioxidant activity. Consequently, these hybrid hydrogels exhibit enhanced physical properties and superior scavenging capability on oxides and peroxides compared to the pure HA hydrogel. The results indicate that ROS significantly inhibit the biological characteristics of HSCs. Nevertheless, the proliferation ability and pluripotency are dramatically improved when the culture system is supplied with the antioxidant hydrogel, revealing that the CNT-incorporated hydrogel can effectively relieve oxidative stress response in HSCs and reduce apoptosis from ROS. Therefore, the HA/CNT hydrogel can provide a novel strategy to establish an artificial microenvironment with a low ROS level for HSCs proliferation.
研究领域:
生物材料学
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细胞生物学
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再生医学
✓ 已验证
DOI
高影响因子
TOXICOLOGY
·
2025
·
IF 4.6
Jin Zhou,Pinpin Sui,Jianxin Zhao,Xiurong Cheng,Tao Yu,Shiwei Cui,Xiangrong Song,Caihong Xing
Patients with benzene-induced leukemia undergo a continuous transformation from myelosuppression to malignant proliferation. However, the underlying mechanisms in this process remain unknown. Our previous studies have shown that the pathways involved in self-renewal capacity of bone marrow (BM) cells in Mll-Af9 mice exposed to benzene for life are significantly activated after severe blood toxicity. In order to investigate the hematotoxicity effects of benzene on the self-renewal capacity of HSCs, Mll-Af9 chimeric mice were exposed to benzene and hematological parameters were dynamically monitored after benzene exposure. Transcriptomic analysis were used to analyze different time points during benzene exposure and after competitive bone marrow transplantation (BMT). Results showed that despite severe hematotoxicity in mice, but the chimerism rate of Mll-Af9 cells in peripheral blood (PB) cells was significantly increased after 10 weeks benzene exposure ( P < 0.001). After competitive BMT, the chimerism rate of Mll-Af9 cells from 10 weeks benzene-exposed mice was gradually increased and significantly surpassed that of the control at 26 weeks of bone marrow reconstruction (benzene group 86 % VS control group 78 %, P = 0.03). Transcriptome analysis revealed that the expression levels of self-renewal related genes, such as Hox genes ( Hoxb4 , Hoxa7 , Hoxa10 ), Mecom and Ms4a in BM cells of 10 weeks benzene-exposed mice were relatively higher compared to those in the control group, but no significant difference were observed. Interestingly, Hoxa7 , Hoxa10 and Mecom were significantly up-regulated at 26 weeks after bone marrow transplantation. In conclusion, our study suggests that abnormal expression of self-renewal-related genes may be potential early biomarkers for benzene-induced hematotoxicity. This hematotoxicity may contribute to the acquisition of evolutionary advantages by leukemic precursor cells and accelerate malignant transformation.
研究领域:
血液学
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毒理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOMATERIALS
·
2023
·
IF 14
Wenjing Li,Haiwei Liang,Yanxiao Ao,Baixue Tang,Junyang Li,Ning Li,Jianwei Wang,Yanan Du
Hematopoietic stem cells (HSCs) are adult multipotential stem cells with the capacity to differentiate into all blood cells and immune cells , which are essential for maintaining hematopoietic homeostasis throughout the lifespan and reconstituting damaged hematopoietic system after myeloablation. However, the clinical application of HSCs is hindered by the imbalance of its self-renewal and differentiation during in vitro culture. Considering the fact that HSC fate is uniquely determined by natural bone marrow microenvironment , various elaborate cues in this hematopoietic micro-niche provide an excellent reference for the regulation of HSCs. Inspired by the bone marrow extracellular matrix (ECM) network, we designed degradable scaffolds by orchestrating the physical parameters to investigate the decoupling effects of Young's modulus and pore size of three-dimensional (3D) matrix materials on the fate of hematopoietic stem and progenitor cells (HSPCs). We ascertained that the scaffold with larger pore size (80 μm) and higher Young's modulus (70 kPa) was more favorable for HSPCs proliferation and the maintenance of stemness related phenotypes. Through in vivo transplantation, we further validated that scaffolds with higher Young's modulus were more propitious in maintaining the hematopoietic function of HSPCs. We systematically screened an optimized scaffold for HSPC culture which could significantly improve the cell function and self-renewal ability compared with traditional two-dimensional (2D) culture. Together, these results indicate the important role of biophysical cues in regulating HSC fate and pave the way for the parameter design of 3D HSC culture system.
研究领域:
血液学
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干细胞生物学
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组织工程
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再生医学
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DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Yongai Xiong,Tingting Chen,Lei Chen,Rongshan Cai
Introduction Radiotherapy and chemotherapy are the fundamental causes of myelosuppression in cancer patients, which usually induce a serious hematopoietic system toxicity, causing the hemocytes and immunity decline of patients. Ziyuglycoside I (ZgI), an active ingredient isolated from traditional Chinese medicine Sanguisorba officinalis L, has been demonstrated to increase the leucocytes and protect hematopoietic stem cells, which is related to its promotion of autophagy in hematopoietic stem cells.Methods In the present study, we formulated the SH-PEG-NH2-coated gold nanoparticles loading ZgI (ZgI-AuNPs) with a enhanced autophagy promotion in hematopoietic stem cells. ZgI-AuNPs were prepared by HAuCl4-sodium citrate reduction method, and the synthesis of ZgI-AuNPs was validated by XRD, FT-IR, DSC, and TEM findings. Furthermore, the drug loading rate and the release of ZgI were evaluated, and the ZgI-AuNPs’ effects on autophagy and immunofluorescence staining for LC3B were tested. Finally, the effect of ZgI-AuNPs on the autophagy and hematopoietic ability of HSCs in vivo was also carried out.Results The prepared ZgI-AuNPs have an irregular cubic crystal structure by TEM observation, and the average particle size was 340 ± 16.5 nm determined by DLS. The XRD, FT-IR and DSC detection showed that the ZgI had been well loaded in AuNPs, and the AuNPs can load the ZgI at a content of 160.63 ± 1.35 μg·mg−1. Meanwhile, the AuNPs can reduce the drug release rate of ZgI. Importantly, the ZgI-AuNPs enhanced autophagy of HSCs both in vitro and in vivo. At the same time, the gold nanoparticles enhance the hematopoietic effect of ZgI on mice HSCs.Conclusion Our research suggests that SH-PEG-NH2-coated gold nanoparticles loading ZgI has potential application in myelosuppression therapy.
研究领域:
纳米技术
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药理学
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血液学
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肿瘤学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF PHARMACOLOGICAL AND TOXICOLOGICAL METHODS
·
2025
·
IF 1.8
Jinxingyi Wang,Ruyu Tao,Hanshuai Hu,Xue Lan,Jiejie Gao,Yanping Guan,Qian Liu
Background Busulfan and cyclophosphamide (Bu-Cy) is a widely used conditioning regimen for hematopoietic stem cell transplantation (HSCT) in the treatment of hematologic malignancies. To explore the exposure-efficiency relationships of Bu-Cy regimen and evaluate the necessity of relative therapeutic drug monitoring (TDM), we developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to simultaneously quantify the busulfan and cyclophosphamide in human plasma. Methods A simple LC-MS/MS bioassay for simultaneous determination of busulfan and cyclophosphamide using isotope dilution internal standardization has been established. Plasma samples were subjected to protein precipitation prior to their injection into a column for subsequent separation (Thermo Accucore aQ C 18 , 50 × 2.1 mm, 2.6 μm). Positive electrospray ionization (ESI) mode with selected reaction monitoring (SRM) was used for analytes determination. Results Busulfan and cyclophosphamide could be measured within 3 min, with the calibration ranges of 80–4000 ng/mL for busulfan and 25–2000 ng/mL for cyclophosphamide. The validated method showed good sensitivity and linearity. Accuracies and precisions were less than 15 %. The results of stability showed that busulfan and cyclophosphamide were stable in the plasma under room temperature for 16 h, 4 °C for 24 h, −80 °C for 2 weeks, and after three freeze-thaw processes. Conclusion The bioassay was simple, sensitive and successfully implemented in the realm of TDM for Bu-Cy, ultimately leading to improved dosing precision.
研究领域:
药理学
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临床化学
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肿瘤学
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分析化学
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血液学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL BIOCHEMISTRY AND BIOPHYSICS
·
2014
·Vol. 71
·期 2
·945-950
·
IF 2.38
Chen Qing-quan,Han Xuesong,Wang Wan-ming,Zhao Liangyu,Chen Aimin
Danggui Sini decoction (DSD), a famous Chinese medicine, has been used therapeutically in various diseases. In this study, we tried to investigate whether and how DSD could ameliorate myelosuppression in an animal model, in which myelosuppression is induced by cyclophosphamide treatment. The myelosuppression model was established by intraperitoneal injection of 100 mg/kg cyclophosphamide in mice. Flow cytometry was used to assess cell numbers and evaluate the bone marrow cell cycle distribution. Spleen samples were collected, and the mRNA expression levels of thrombopoietin (TPO) and c - Mpl were analyzed by RT-PCR. Our results demonstrated that DSD could significantly elevate the level of bone marrow hematopoietic stem progenitor cells in myelosuppression mice model. DSD also accelerated cell proliferation by switching cell cycles from G0/G1 phase to S and G2/M phase. Moreover, DSD significantly elevated the mRNA expression level of TPO , but not c - Mpl in spleen. Overall, the present results indicated that DSD is a promising Chinese medicine that is highly potent to ameliorate myelosuppression induced by chemotherapy by upregulating TPO expression.
研究领域:
药理学
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血液学
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肿瘤学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Environmental Sciences
·
2024
·
IF 5.9
Lingyu Ren,Yue Wang,Ying Ren,Guangke Li,Nan Sang
Phenanthrene (Phe) is one of the common polycyclic aromatic hydrocarbons in the environment, and recent studies show that it can cause cardiac developmental toxicity and immunotoxicity. However, it is still unknown whether it can affect the hematopoietic development in aquatic organisms. To address this question, zebrafish ( Danio rerio ) were chronically exposed to Phe at different concentrations. We found that Phe caused structural damage to the renal tubules in the kidney, induced malformed erythrocyte in peripheral blood, and decreased proportion of myeloid cells in adult zebrafish, suggesting possible negative impacts that Phe posed to hematopoietic development. Then, using in situ hybridization technology, we found that Phe decreased the expression of primitive hematopoietic marker genes, specifically gata1 and pu.1 , accompanied by an obstruction of primitive erythrocyte circulation. Furthermore, Phe impaired definitive hematopoiesis, increased aberrations of the transient hematopoietic site (PBI), and reduced the generation of hematopoietic stem cells, ultimately influencing the number of erythrocytes and myeloid cells. The findings suggested that Phe could induce hematopoietic toxicity in zebrafish embryos and pose unknown ecological risks.
研究领域:
环境毒理学
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发育生物学
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水生毒理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Materials Chemistry B
·
2024
·
IF 6.1
Jing Hong,Zhanchi Zhu,Leisha Cui,Zhaojun Wang,Ying Hao,Xiaopeng Tian,Guosheng Cheng
Hematopoietic stem cell (HSC) expansion offers a key strategy to address the source limitation and donor shortages of HSCs for the treatment of various blood disorders. Specific remodeling of the complex bone marrow microenvironment that contributes to efficient in vitro expansion of HSCs remains challenging. Here, inspired by the regions with different stiffness levels in the bone marrow niche, a three dimensional (3D) bone marrow-mimicking composite scaffold created based on gelatin–hyaluronic acid (Gel–HA) hydrogels and graphene foams (GFs) was engineered to support the in vitro expansion of HSCs. The composite scaffold was prepared by forming a photo-cross-linked Gel–HA hydrogel surrounding the GF. The “soft” Gel–HA hydrogel and “stiff” GF replicate the structure and stiffness of the vascular niche and endosteal niche in the bone marrow, respectively. Furthermore, HSCs cultured in the Gel–HA/GF scaffold proliferated well and retained the CD34+CD38− immunophenotype and pluripotency, suggesting that the Gel–HA/GF composite scaffold supported the in vitro expansion of HSCs, maintaining the primitive phenotype and the ability to differentiate into functional blood cells. Thus, the hydrogel/graphene composite scaffold offers a means of facilitating HSC expansion through structurally and mechanically mimicking bone marrow niches, demonstrating great promise for HSC transplantation.
研究领域:
生物材料
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组织工程
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干细胞生物学
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生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELLULAR & MOLECULAR BIOLOGY LETTERS
·
2023
·Vol. 28
·期 1
·1-23
·
IF 8.3
Adzraku Seyram Yao,Wang Guozhang,Cao Can,Bao Yurong,Wang Yizhou,Smith Alhaji Osman,Du Yuwei,Wang Haiyang,Li Yue,Xu Kailin,Qiao Jianlin,Ju Wen,Zeng Lingyu
Background Hematopoietic stem cell transplantation involves irradiation preconditioning which causes bone marrow endothelial cell dysfunction. While much emphasis is on the reconstitution of hematopoietic stem cells in the bone marrow microenvironment, endothelial cell preservation is indispensable to overcome the preconditioning damages. This study aims to ascertain the role of Roundabout 4 (Robo4) in regulating irradiation-induced damage to the endothelium.Methods Microvascular endothelial cells were treated with γ-radiation to establish an endothelial cell injury model. Robo4 expression in the endothelial cells was manipulated employing lentiviral-mediated RNAi and gene overexpression technology before irradiation treatment. The permeability of endothelial cells was measured using qPCR, immunocytochemistry, and immunoblotting to analyze the effect on the expression and distribution of junctional molecules, adherens junctions, tight junctions, and gap junctions. Using Transwell endothelial monolayer staining, FITC-Dextran permeability, and gap junction-mediated intercellular communication (GJIC) assays, we determined the changes in endothelial functions after Robo4 gene manipulation and irradiation. Moreover, we measured the proportion of CD31 expression in endothelial cells by flow cytometry. We analyzed variations between two or multiple groups using Student’s t-tests and ANOVA.Results Ionizing radiation upregulates Robo4 expression but disrupts endothelial junctional molecules. Robo4 deletion causes further degradation of endothelial junctions hence increasing the permeability of the endothelial cell monolayer. Robo4 knockdown in microvascular endothelial cells increases the degradation and delocalization of ZO-1, PECAM-1, occludin, and claudin-5 molecules after irradiation. Conversely, connexin 43 expression increases after silencing Robo4 in endothelial cells to induce permeability but are readily destroyed when exposed to 10 Gy of gamma radiation. Also, Robo4 knockdown enhances Y731-VE-cadherin phosphorylation leading to the depletion and destabilization of VE-cadherin at the endothelial junctions following irradiation. However, Robo4 overexpression mitigates irradiation-induced degradation of tight junctional proteins and stabilizes claudin-5 and ZO-1 distribution. Finally, the enhanced expression of Robo4 ameliorates the irradiation-induced depletion of VE-cadherin and connexin 43, improves the integrity of microvascular endothelial cell junctions, and decreases permeability.Conclusion This study reveals that Robo4 maintains microvascular integrity after radiation preconditioning treatment by regulating endothelial permeability and protecting endothelial functions. Our results also provided a potential mechanism to repair the bone marrow vascular niche after irradiation by modulating Robo4 expression.
研究领域:
细胞生物学
·
放射生物学
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血液学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
International Journal of Nanomedicine
·
2023
·
IF 8
Tingting Song,Hong Wang,Yue Liu,Rongshan Cai,Dezhi Yang,Yongai Xiong
Background Ziyuglycoside I (ZgI), an active ingredient isolated from traditional Chinese medicine Sanguisorba officinalis L, has been demonstrated to increase the leucocytes and protect hematopoietic stem cells. However, the poor solubility and a short half-life of ZgI limit its bioavailability and efficacy. The D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) has been widely used to increase the solubility, improve the encapsulation rate, and extend the half-life of drugs.Methods Here, we formulated the TPGS-modified long-circulating liposomes loading ZgI with a sustained drug release and enhanced therapy for myelosuppression. ZgI-TPGS-liposomes were manufactured using a thin-film hydration technique, followed by characterizations of physicochemical properties, including the particle size, zeta potential, TEM, SEM, FTIR, XRD, stability, drug loading (DL), encapsulation efficiency (EE). The in vitro and in vivo delivery efficiency were further evaluated by cellular uptake, in vitro drug release and in vivo pharmacokinetics. Finally, therapeutic effect on myelosuppression was investigated.Results The ZgI-TPGS-liposomes had an particle size of 97.89 ± 1.42 nm and ZP of −28.65 ± 0.16 mV. It exhibited DL of 9.06 ± 0.76% and EE of 92.34 ± 3.83%, along with excellent storage stability, cellular uptake and sustained drug release to free ZgI and liposomes without TPGS. Additionally, the TPGS modified liposomes significantly enhanced the therapeutic effect of ZgI on CTX induced myelosuppression, which can be confirmed in the apoptosis inhibition and cell viability promotion of CTX injured HSPC-1 cells. Also, the mice in vivo pharmacodynamics demonstrated that TPGS liposomes promoted ZgI increasing the numbers of leucocytes and neutrophils in myelosuppression mice induced by CTX.Conclusion Our research suggest that TPGS-modified long-circulating liposomes loading ziyuglycoside I has potential application in myelosuppression therapy.
研究领域:
药剂学
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药理学
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纳米技术
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中药学
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药物递送系统
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Bioactive Materials
·
2022
·
IF 16.874
Haiwei Liang,Yanxiao Ao,Wenjing Li,Kaini Liang,Baixue Tang,Junyang Li,Jianwei Wang,Xiaoyu Zhu,Yanan Du
Hematopoietic syndrome of acute radiation syndrome (h-ARS) is an acute illness resulted from the damage of bone marrow (BM) microenvironment after exposure to radiation. Currently, the clinical management of h-ARS is limited to medication-assisted treatment, while there is still no specific therapy for the hematopoietic injury from high-dose radiation exposure. Our study aimed to assemble biomimetic three-dimensional (3D) BM microniches by co-culture of hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stem cells (MSCs) in porous, injectable and viscoelastic microscaffolds in vitro . The biodegradable BM microniches were then transplanted in vivo into the BM cavity for the treatment of h-ARS. We demonstrated that the maintenance of HSPCs was prolonged by co-culture with MSCs in the porous 3D microscaffolds with 84 μm in pore diameter and 11.2 kPa in Young's modulus compared with 2D co-culture system. Besides, the minimal effective dose and therapeutic effects of the BM microniches were investigated on a murine model of h-ARS, which showed that the intramedullary cavity-injected BM microniches could adequately promote hematopoietic reconstitution and mitigate death from acute lethal radiation with a dose as low as 1000 HSPCs. Furthermore, the mRNA expression of Notch1 and its downstream target gene Hes1 of HSPCs were increased when co-cultured with MSCs, while the Jagged1 expression of the co-cultured MSCs was upregulated, indicating the significance of Notch signaling pathway in maintenance of HSPCs. Collectively, our findings provide evidence that biomimetic and injectable 3D BM microniches could maintain HSPCs, promote hematopoiesis regeneration and alleviate post-radiation injury, which provides a promising approach to renovate conventional HSPCs transplantation for clinical treatment of blood and immune disorders.
研究领域:
干细胞研究
·
再生医学
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辐射生物学
·
组织工程
✓ 已验证
DOI
PubMed
高影响因子
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