稀土下转换纳米颗粒标记脂肪间充质干细胞治疗亚急性肝损伤的活体示踪研究

doi:10.12300/j.issn.1674-5817.2025.199

摘要/Abstract

摘要：

目的评估近红外二区（near-infrared-Ⅱ，NIR-Ⅱ）稀土下转换纳米颗粒（down-conversion nanoparticles，DCNPs）作为新型造影剂用于标记脂肪来源间充质干细胞（adipose-derived mesenchymal stem cells，ADSCs）的可行性，并探讨其在亚急性肝损伤小鼠模型中进行活体示踪的潜在应用价值。方法采用高温热分解法合成核壳结构下转换纳米颗粒NaYF₄：Yb³⁺，Er³⁺@NaYF₄，经二硬脂酰磷脂酰乙醇胺-聚乙二醇2000（DSPE-PEG2000）表面修饰后制备水溶性DCNPs，并进一步偶联异硫氰酸荧光素（fluorescein isothiocyanate，FITC）以观察ADSCs对DCNPs的摄取情况。采用CCK-8实验检测DCNPs和ADSCs共孵育24 h、48 h的细胞活力；用激光共聚焦显微镜评估不同探针浓度和培养时间下DCNPs对ADSCs的标记效率；采用NIR-Ⅱ荧光成像检测DCNPs标记的ADSCs在体外连续培养过程中荧光信号随培养时间的动态变化；通过流式细胞术及分化实验分别评估DCNPs标记对ADSCs表面抗原表型及多向分化功能的影响。将DCNPs标记的ADSCs通过尾静脉一次性移植进SPF级雄性SD大鼠体内，1个月后采用血常规、血清生化分析以及多器官病理学检查评估其长期毒性反应。采用四氯化碳（CCl₄）诱导法构建SPF级雄性BALB/c小鼠亚急性肝损伤模型，通过尾静脉回输DCNPs标记的ADSCs后，使用NIR-Ⅱ荧光成像系统示踪ADSCs在动物体内的归巢情况，并采用肝功能指标生化分析和HE染色法检测DCNPs示踪对ADSCs治疗的影响。结果本研究合成的NaYF₄：Yb³⁺/Er³⁺纳米颗粒为球形晶体结构，粒径约20～30 nm，具有较好的水分散稳定性。选用0～500 μg/mL DCNPs标记24 h和48 h均对ADSCs不产生细胞毒性。DCNPs的细胞标记效率随着剂量增加而提高，16 h内细胞摄取量基本稳定。DCNPs的NIR-Ⅱ荧光信号在ADSCs体外培养早期可维持稳定，培养第3天时荧光强度出现下降（P=0.003），但第8天时细胞内仍可检测到明显的荧光信号。DCNPs标记对ADSCs的干细胞表型及多向分化功能无明显影响。标记有DCNPs的ADSCs移植至正常SD大鼠体内1个月后，血常规、血清生化分析和多器官组织病理学检查结果均显示无明显的体内毒性反应。将DCNPs标记的ADSCs通过尾静脉回输给亚急性肝损伤模型小鼠后，血清肝功能指标丙氨酸氨基转移酶（alanine aminotransferase，ALT）和天门冬氨酸氨基转移酶（aspartate aminotransferase，AST）水平明显降低（均P<0.05），肝组织中炎症细胞浸润明显减少；而且活体示踪结果显示其1 h内可归巢、迁移至肝脏，并且随着时间推移，荧光信号逐渐减弱，24 h后富集在肝脏的荧光信号明显减弱。结论 DCNPs具有良好的生物相容性，可用于ADSCs标记，且不影响干细胞治疗，有望实现亚急性肝损伤治疗过程中干细胞归巢与迁移的实时、高信噪比活体示踪。

关键词: 间充质干细胞, 稀土下转换纳米颗粒, 活体示踪, 亚急性肝损伤, SD大鼠, BALB/c小鼠

Abstract:

Objective To evaluate the feasibility of using near-infrared-Ⅱ (NIR-Ⅱ) rare-earth down-conversion nanoparticles (DCNPs) as a novel contrast agent for labeling adipose-derived mesenchymal stem cells (ADSCs), and to explore their potential application for in vivo tracking in a mouse model of subacute liver injury. Methods Core-shell DCNPs (NaYF₄:Yb³⁺,Er³⁺@NaYF₄) were synthesized via a high-temperature thermal decomposition method. Water-soluble DCNPs were prepared through surface modification with DSPE-PEG2000, and further conjugated with fluorescein isothiocyanate (FITC) to observe cellular uptake. The CCK-8 assay was used to detect cell viability after co-incubation of ADSCs with DCNPs at 24 h and 48 h. Confocal laser scanning microscopy was employed to evaluate the labeling efficiency of DCNPs in ADSCs across various probe concentrations and incubation periods. Flow cytometry and differentiation assays were employed to evaluate the effects of DCNPs labeling on ADSCs surface antigen phenotype and multidirectional differentiation potential. NIR-Ⅱ fluorescence imaging was adopted to evaluate the dynamic changes of NIR‑Ⅱ fluorescence signals of labeled ADSCs during continuous in vitro culture. The in vivo toxicity of DCNP-labeled ADSCs transplanted via a single tail vein injection into SPF-grade male Sprague-Dawley (SD) rats was evaluated one month after transplantation through complete blood count, serum biochemical analysis, and multi-organ histopathological examination. A subacute liver injury model was induced in SPF-grade male BALB/c mice using carbon tetrachloride (CCl₄) administration. DCNP-labeled ADSCs were administered via tail vein injection, and the homing of ADSCs in vivo was monitored using NIR-Ⅱ fluorescence imaging. The effects of tracking on ADSC therapy were assessed using biochemical analysis of liver function indicators and hematoxylin and eosin (HE) staining. Results The NaYF₄:Yb³⁺/Er³⁺ nanoparticles synthesized in this study exhibited a spherical crystal structure with particle sizes ranging from approximately 20 to 30 nm, and demonstrated good dispersion stability in water. CCK-8 results showed that DCNPs labeling exerted no cytotoxic effect on ADSCs viability after 24 and 48 h of labeling within the concentration range of 0 to 500 μg/mL used in this study. The cell labeling efficiency of DCNPs increased with dosage, while the cellular uptake remained essentially stable within 16 h. The NIR-Ⅱ fluorescence signal of DCNPs remained stable during the early stage of in vitro ADSCs culture. Although the fluorescence intensity decreased on day 3 of culture (P=0.003), detectable fluorescence signals were still observed in the cells on day 8. Flow cytometry and differentiation assays confirmed that DCNPs labeling had no significant adverse effects on the phenotype and differentiation capacity of ADSCs. One month after the transplantation of DCNP-labeled ADSCs into normal SD rats, blood routine tests, serum biochemical analysis, and multi-organ histopathological examination all revealed no obvious toxic reactions in the body. After the DCNP-labeled ADSCs were injected via the tail vein into mice with subacute liver injury, the serum levels of the liver function indicators alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly reduced (both P<0.05), and the infiltration of inflammatory cells in the liver tissue was markedly decreased. Moreover, in vivo tracing results showed that the labeled ADSCs could home and migrate to the liver within 1 h, with the fluorescence signal gradually weakening over time. By 24 h, the fluorescence signal enriched in the liver had significantly decreased. Conclusion DCNPs possess good biocompatibility for ADSC labeling without affecting stem cell therapy. They may enable real-time, high signal-to-noise ratio in vivo tracking of stem cell homing and migration in ADSC therapy for subacute liver injury.

Key words: Mesenchymal stem cells, Rare-earth down-conversion nanoparticles, In vivo tracking, Subacute liver injury, SD rats, BALB/c mice

中图分类号:

练荣贵,廖乃顺. 稀土下转换纳米颗粒标记脂肪间充质干细胞治疗亚急性肝损伤的活体示踪研究[J]. 实验动物与比较医学, 2026, 46(5): 716-726. DOI: 10.12300/j.issn.1674-5817.2025.199.

LIAN Ronggui,LIAO Naishun. In Vivo Tracking of Adipose-Derived Mesenchymal Stem Cell Therapy for Subacute Liver Injury Using Rare-Earth Down-Conversion Nanoparticles[J]. Laboratory Animal and Comparative Medicine, 2026, 46(5): 716-726. DOI: 10.12300/j.issn.1674-5817.2025.199.

图/表 5

图1 DCNPs的表征、水合粒径、Zeta电位变化及修饰后稳定性

注：A，透射电子显微镜检测图；B，X射线衍射图谱［PDF 27-0689为标准六方相氟化钠铒（β-NaErF₄），作为对照］；C，荧光发射光谱；D，稀土下转换纳米颗粒（DCNPs）与DCNPs@PEG（即经DSPE-PEG2000-COOH修饰后的DCNPs）的水合粒径变化；E，DCNPs与DCNPs@PEG的Zeta电位变化情况；F，DCNPs@PEG室温静置于超纯水5 d内的水合粒径变化情况。

Figure 1 Characterization， hydrodynamic diameter and zeta potential changes as well as post-modification stability of DCNPs

Note： A， Transmission electron microscopy image； B， X-ray diffraction pattern［PDF 27-0689， standard hexagonal-phase sodium erbium fluoride （β-NaErF₄）as the positive control］； C， Fluorescence emission spectrum； D， Changes in hydrodynamic diameter of down-conversion nanoparticles （DCNPs） and DCNPs@PEG （DCNPs after modification with DSPE-PEG2000-COOH）； E， Changes in zeta potential of DCNPs and DCNPs@PEG； F， Changes in hydrodynamic diameter of DCNPs@PEG during static storage at room temperature in ultrapure water over 5 days.

图2 DCNPs标记ADSCs的细胞毒性、摄取情况和稳定性验证

注：A～B，不同质量浓度的稀土下转换纳米颗粒（DCNPs）对脂肪来源间充质干细胞（ADSCs）存活率的影响（A，DCNPs与ADSCs共孵育24 h；B，DCNPs与ADSCs共孵育48 h）；C，激光扫描共聚焦显微镜拍摄不同质量浓度DCNPs与ADSCs细胞共孵育不同时间的摄取情况（比例尺为20 μm）。D，980 nm激发下DCNPs标记ADSCs的荧光信号随时间变化情况（单因素方差分析，^** P<0.01，^*** P<0.001，^**** P<0.000 1）。

Figure 2 Verification of the cytotoxicity， uptake， and stability of DCNP-labeled ADSCs

Note： A-B， Effects of different concentrations of down-conversion nanoparticles （DCNPs） on adipose-derived mesenchymal stem cells （ADSCs） viability （A， Co-incubation of DCNPs with ADSCs for 24 h； B， Co-incubation for 48 h）； C， Confocal laser scanning microscope images（CLSM） showing uptake following co-incubation of DCNPs with ADSCs at different concentrations and time points （scale bar=20 μm）； D， Time-dependent changes in the fluorescence signal of DCNP-labeled ADSCs under 980 nm excitation（one-way analysis of variance， ^** P<0.01， ^*** P<0.001， ^**** P<0.000 1）

图3 DCNPs标记对ADSCs表型及多向分化能力的影响

注：A，流式细胞术检测脂肪来源间充质干细胞（ADSCs）表型（PE-A为藻红蛋白荧光染料-面积，FITC-A为异硫氰酸荧光素荧光染料-面积；CD29、CD90、CD105为ADSCs细胞阳性标志物，CD31、CD34为ADSCs细胞阴性标志物）；B，ADSCs多向分化能力验证（Osteogenesis为细胞成骨诱导分化，使用茜素红S染色；Chondrogenesis为细胞成软骨诱导分化，使用阿尔辛蓝染色；Adipogenesis为细胞成脂诱导分化，使用油红O染色；比例尺为100 μm）。ADSCs组，未加入稀土下转换纳米颗粒（DCNPs）的ADSCs细胞；ADSCs+DCNPs组，ADSCs细胞与DCNPs共孵育24 h；Negative control组，阴性对照样品。

Figure 3 Effects of DCNPs labeling on the phenotype and multilineage differentiation potential of ADSCs

Note： A， Flow cytometric characterization of surface markers in adipose-derived mesenchymal stem cells （ADSCs）（PE-A，phycoerythrin fluorescence area； FITC-A， fluorescein isothiocyanate fluorescence area. CD29， CD90， and CD105 are positive markers of ADSCs， while CD31 and CD34 are negative markers）. B， Verification of the multilineage differentiation potential of ADSCs （Osteogenesis， osteogenic differentiation confirmed by alizarin red S staining； Chondrogenesis， chondrogenic differentiation confirmed by alcian blue staining； Adipogenesis， adipogenic differentiation confirmed by oil red O staining； the scale bar=100 μm）. ADSCs group， ADSCs not incubated with down-conversion nanoparticles （DCNPs）； ADSCs+DCNPs group， ADSCs co-incubated with DCNPs for 24 h； Negative control group， the negative control sample.

图4 DCNPs标记ADSCs移植后的体内生物相容性评估

注：A，脂肪来源间充质干细胞（ADSCs）通过尾静脉注射到正常SD大鼠体内1个月后血清生化指标分析。B，ADSCs细胞移植到正常大鼠体内后主要器官的病理学分析（HE染色，比例尺为200 μm）。Normal，注射相应剂量生理盐水的正常大鼠；ADSCs，注射ADSCs细胞的正常大鼠；ADSCs+DCNPs，注射稀土下转换纳米颗粒（DCNPs）标记的ADSCs细胞的正常大鼠。Crea，肌酐；TBil，总胆红素；PCT，血小板压积；HCT，红细胞压积；LYMPH，淋巴细胞比率；Hgb，血红蛋白；RBC，红细胞计数；GRAN，中性粒细胞计数；WBC，白细胞计数；PLT，血小板计数；ALT，丙氨酸氨基转移酶；AST，天门冬氨酸氨基转移酶；ALP，碱性磷酸酶；TG，甘油三酯；Glu，葡萄糖。

Figure 4 Biocompatibility evaluation of DCNP-labeled ADSCs in vivo

Note： A， Analysis of serum biochemical parameters one month after tail vein injection of adipose-derived mesenchymal stem cells （ADSCs） into normal SD rats. B， Histopathological analysis of major organs from normal rats after ADSCs transplantation （HE staining， scale bar=200 μm）.Normal， normal rats injected with an equivalent volume of normal saline； ADSCs， normal rats injected with ADSCs； ADSCs+DCNPs， normal rats injected with down-conversion nanoparticle （DCNP）-labeled ADSCs. Crea， creatinine； TBil， total bilirubin； PCT， plateletcrit； HCT， hematocrit； LYMPH， lymphocyte percentage； Hgb， hemoglobin； RBC， red blood cell count； GRAN， granulocyte count； WBC， white blood cell count； PLT， platelet count； ALT， alanine aminotransferase； AST， aspartate aminotransferase； ALP， alkaline phosphatase； TG， triglyceride； Glu， glucose.

图4 DCNPs标记ADSCs移植后的体内生物相容性评估
注：A，脂肪来源间充质干细胞（ADSCs）通过尾静脉注射到正常SD大鼠体内1个月后血清生化指标分析。B，ADSCs细胞移植到正常大鼠体内后主要器官的病理学分析（HE染色，比例尺为200 μm）。Normal，注射相应剂量生理盐水的正常大鼠；ADSCs，注射ADSCs细胞的正常大鼠；ADSCs+DCNPs，注射稀土下转换纳米颗粒（DCNPs）标记的ADSCs细胞的正常大鼠。Crea，肌酐；TBil，总胆红素；PCT，血小板压积；HCT，红细胞压积；LYMPH，淋巴细胞比率；Hgb，血红蛋白；RBC，红细胞计数；GRAN，中性粒细胞计数；WBC，白细胞计数；PLT，血小板计数；ALT，丙氨酸氨基转移酶；AST，天门冬氨酸氨基转移酶；ALP，碱性磷酸酶；TG，甘油三酯；Glu，葡萄糖。

Figure 4 Biocompatibility evaluation of DCNP-labeled ADSCs in vivo
Note： A， Analysis of serum biochemical parameters one month after tail vein injection of adipose-derived mesenchymal stem cells （ADSCs） into normal SD rats. B， Histopathological analysis of major organs from normal rats after ADSCs transplantation （HE staining， scale bar=200 μm）.Normal， normal rats injected with an equivalent volume of normal saline； ADSCs， normal rats injected with ADSCs； ADSCs+DCNPs， normal rats injected with down-conversion nanoparticle （DCNP）-labeled ADSCs. Crea， creatinine； TBil， total bilirubin； PCT， plateletcrit； HCT， hematocrit； LYMPH， lymphocyte percentage； Hgb， hemoglobin； RBC， red blood cell count； GRAN， granulocyte count； WBC， white blood cell count； PLT， platelet count； ALT， alanine aminotransferase； AST， aspartate aminotransferase； ALP， alkaline phosphatase； TG， triglyceride； Glu， glucose.

图5 DCNPs标记ADSCs在亚急性肝损伤小鼠中的治疗及示踪效果
注：A，脂肪来源间充质干细胞（ADSCs）治疗BALB/c小鼠亚急性肝损伤的实验示意图（i.p.，腹腔注射，i.v.，静脉注射）；B～C，血清ALT和AST水平检测（单因素方差分析，^* P<0.05，^** P<0.01，^*** P<0.001）；D，肝组织的HE染色评估肝损伤程度及治疗效果（比例尺为200 μm）。Normal，正常小鼠；Model，亚急性肝损伤小鼠；ADSCs，ADSCs治疗亚急性肝损伤小鼠；ADSCs+DCNPs，标记有稀土下转换纳米颗粒（DCNPs）的ADSCs治疗亚急性肝损伤小鼠。E，DCNPs标记ADSCs移植2只亚急性肝损伤小鼠的活体示踪（Bright，未施加激光的明场成像，0～72 h为不同时间节点的小鼠活体成像显示荧光信号强度和体内分布情况）。

Figure 5 Therapeutic efficacy and in vivo NIR-Ⅱ fluorescence imaging of DCNP-labeled ADSCs in mice with subacute liver injury
Note： A， Schematic diagram of adipose-derived mesenchymal stem cells （ADSCs） administration for the treatment of subacute liver injury in BALB/c mice （i.p.， intraperitoneal injection； i.v.， intravenous injection）； B-C， Serum ALT and AST levels （one-way analysis of variance， ^* P<0.05， ^** P<0.01， ^*** P<0.001）； D， Hematoxylin and eosin （HE） staining of liver tissues to evaluate the degree of liver injury and therapeutic efficacy （scale bar=200 μm）. Normal， healthy control mice； Model， mice with induced subacute liver injury； ADSCs， mice with subacute liver injury treated with ADSCs； ADSCs+DCNPs： mice with subacute liver injury treated with down-conversion nanoparticle （DCNP）-labeled ADSCs. E， In vivo tracking of DCNP-labeled ADSCs in two mice with subacute liver injury （Bright， bright-field images acquired without laser excitation； fluorescence signal intensity and in vivo distribution in mice during live imaging at different time points from 0 to 72 h）.

图5 DCNPs标记ADSCs在亚急性肝损伤小鼠中的治疗及示踪效果
注：A，脂肪来源间充质干细胞（ADSCs）治疗BALB/c小鼠亚急性肝损伤的实验示意图（i.p.，腹腔注射，i.v.，静脉注射）；B～C，血清ALT和AST水平检测（单因素方差分析，^* P<0.05，^** P<0.01，^*** P<0.001）；D，肝组织的HE染色评估肝损伤程度及治疗效果（比例尺为200 μm）。Normal，正常小鼠；Model，亚急性肝损伤小鼠；ADSCs，ADSCs治疗亚急性肝损伤小鼠；ADSCs+DCNPs，标记有稀土下转换纳米颗粒（DCNPs）的ADSCs治疗亚急性肝损伤小鼠。E，DCNPs标记ADSCs移植2只亚急性肝损伤小鼠的活体示踪（Bright，未施加激光的明场成像，0～72 h为不同时间节点的小鼠活体成像显示荧光信号强度和体内分布情况）。

Figure 5 Therapeutic efficacy and in vivo NIR-Ⅱ fluorescence imaging of DCNP-labeled ADSCs in mice with subacute liver injury
Note： A， Schematic diagram of adipose-derived mesenchymal stem cells （ADSCs） administration for the treatment of subacute liver injury in BALB/c mice （i.p.， intraperitoneal injection； i.v.， intravenous injection）； B-C， Serum ALT and AST levels （one-way analysis of variance， ^* P<0.05， ^** P<0.01， ^*** P<0.001）； D， Hematoxylin and eosin （HE） staining of liver tissues to evaluate the degree of liver injury and therapeutic efficacy （scale bar=200 μm）. Normal， healthy control mice； Model， mice with induced subacute liver injury； ADSCs， mice with subacute liver injury treated with ADSCs； ADSCs+DCNPs： mice with subacute liver injury treated with down-conversion nanoparticle （DCNP）-labeled ADSCs. E， In vivo tracking of DCNP-labeled ADSCs in two mice with subacute liver injury （Bright， bright-field images acquired without laser excitation； fluorescence signal intensity and in vivo distribution in mice during live imaging at different time points from 0 to 72 h）.

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