Bioactive Materials
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2022
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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
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再生医学
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辐射生物学
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组织工程
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DOI
PubMed
高影响因子
TOXICOLOGY
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2025
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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
Toxicology Research
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2025
·Vol. 14
·期 1
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IF 2.1
Zhang Yan,Zhou Jin,Zhao Jianxin,Cheng Xiurong,Xing Caihong
In this study, we aimed to investigate the effects of chronic benzene exposure on the self-renewal capacity of C57BL/6 bone marrow HSPCs. Twenty-four male C57BL/6 mice were randomly divided into two groups: the control group and the benzene-exposed group. Mice in the benzene-exposed group inhaled 1,000 mg/m3 (308 ppm; conversion factor: 20 °C, 101 kPa, 1 ppm = 3.25 mg/m3) benzene for 32 weeks and the control group mice inhaled clean air. The peripheral blood hematological alterations were monitored every two weeks. Competitive bone marrow transplantation was performed to assess the self-renewal capacity of bone marrow HSPCs and the donor cell chimerism was quantified through flow cytometry. By the fourth week of benzene exposure, significant reductions in leukocytes, erythrocytes, and hemoglobin levels (P < 0.05) were observed, suggesting the development of benzene poisoning in mice. In the B6.SJL recipient mice, the chimerism ratio of bone marrow cells from C57BL/6 donors exposed to benzene for 20 weeks significantly decreased after transplantation (16 weeks post-transplant: 52.58% ± 17.38% in controls vs. 3.89% ± 1.96% in the benzene group, P < 0.05). Furthermore, the chimerism ratio in recipients of 32-week benzene-exposed donors approached zero by week 84 post-transplant, suggesting a loss of self-renewal capacity in bone marrow HSPCs due to benzene exposure. The study concludes that bone marrow suppression and the diminished self-renewal ability of C57BL/6 bone marrow HSPCs may lead to bone marrow failure in mice, contributing to the potential occurrence of MDS.
研究领域:
毒理学
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血液学
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实验医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports
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2023
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IF 8.8
Dan Zhong,Haowei Jiang,Chengzhuo Zhou,Abrar Ahmed,Hongji Li,Xiaona Wei,Qiuyu Lian,Melodi Tastemel,Hongyi Xin,Mei Ge,Chenhong Zhang,Lili Jing
The commensal microbiota regulates the self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) in bone marrow. Whether and how the microbiota influences HSPC development during embryogenesis is unclear. Using gnotobiotic zebrafish, we show that the microbiota is necessary for HSPC development and differentiation. Individual bacterial strains differentially affect HSPC formation, independent of their effects on myeloid cells. Early-life dysbiosis in chd8 -/- zebrafish impairs HSPC development. Wild-type microbiota promote HSPC development by controlling basal inflammatory cytokine expression in kidney niche, and chd8 -/- commensals elicit elevated inflammatory cytokines that reduce HSPCs and enhance myeloid differentiation. We identify an Aeromonas veronii strain with immuno-modulatory activities that fails to induce HSPC development in wild-type fish but selectively inhibits kidney cytokine expression and rebalances HSPC development in chd8 -/- zebrafish. Our studies highlight the important roles of a balanced microbiome during early HSPC development that ensure proper establishment of lineal precursor for adult hematopoietic system.
研究领域:
免疫学
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血液学
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微生物学
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发育生物学
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DOI
PubMed
高影响因子
BIOMATERIALS
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2023
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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
✓ 已验证
DOI
PubMed
高影响因子
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