文献：Co-delivery of protopanaxatriol/icariin into niche cells restores bone marrow niches to rejuvenate HSCs for chemotherapy-induced myelosuppression

文献链接：https://www.sciencedirect.com/science/article/abs/pii/S0944711324006366

作者：Mengdi Xiao , Shiyi Hong , Pei Peng , Siying Ca , Yutian Huang , Jing Liang , Xue Bai , Qiying Bao , Wei Li , Guilin Cheng , Yang Xiong , Mancang Gu , Chaofeng Mu

相关产品：FITC-Dextra (70 kD)（FITC-葡聚糖70 kD）

原文摘要：

Up to 80 % of chemotherapeutic drugs induce myelosuppression in patients. Chemotherapy not only impairs of hematopoietic stem cells (HSCs) but also damages bone marrow niches (vascular and endosteal). Current treatments for myelosuppression overlook these chemotherapy-induced damages to bone marrow niches and the critical role of niche restoration on hematopoietic regeneration. Ginsenoside protopanaxatriol (PPT) protects vascular endothelium from injury, while icariin (ICA) promotes osteogenic differentiation. The combination of PPT and ICA aims to restore damaged vascular and endosteal niches, thus rejuvenating HSCs for treating myelosuppression.

This study aims to develop effective, bone marrow niche-directed PPT/ICA therapies for treating chemotherapy-induced myelosuppression.

3D cell spheroids were used to investigate the effects of PPT/ICA on cell-cell interactions in vascular niches, osteogenesis, and extracellular matrix (ECM) secretion in endosteal niches. In vitro mimic niche models were designed to access the drug combination's efficacy in rejuvenating and mobilizing in HSCs within bone marrow niches. The delivery capability of PPT/ICA to key niche cell types (mesenchymal stromal cells (MSCs), endothelial cells (ECs), and osteoblasts (OBs)) via nanocarriers has been determined. DSS6 peptide-modified nanoparticles (DSS6-NPs) were prepared for specific co-delivery of PPT/ICA into key niche cell populations in vivo.

PPT can prevent vascular niche injury by restoring vascular EC cell-cell adhesion and the intercellular interactions between ECs and MSCs in 5-fluorouracil (5-FU)-damaged cell spheroids. ICA repaired 5-FU-damaged endosteal niches by promoting osteogenesis and ECM secretion. The combination of PPT and ICA restores key HSC niche factor gene expressions, normalizing HSC differentiation and mobilization. The in vitro cellular uptake efficiency of nanocarriers in a mimic niche is positively correlated with their in vivo delivery into bone marrow niche cells. DSS6-NPs greatly enhance the delivery of PPT/ICA into MSCs and OBs within bone marrow niches. Co-loading of PPT/ICA into DSS6-NPs effectively repairs damaged bone marrow niches and promotes HSC rejuvenation in vivo.

The combination of PPT and ICA effectively prevents injury to the vascular and endosteal niches, thereby promoting hematopoietic regeneration in the bone marrow. This study provides novel niche-directed PPT/ICA therapies for managing chemotherapy-induced myelosuppression.  

FITC-Dextra：FITC-Dextran 是由异硫氰酸荧光素（FITC）通过稳定的硫代氨甲酰键连接到葡聚糖分子上形成的荧光标记物。葡聚糖是一种由葡萄糖分子通过 α-1,6 糖苷键连接而成的多糖，具有良好的水溶性、低poison性和生物相容性。通常每个葡萄糖单位含 0.002~0.008 mol FITC，这种低水平的替换确保了葡聚糖结构变化较小，适用于多种生物学研究。该文献相关介绍如下：

图：FITC结构式

FITC-Dextran 可作为一种荧光标记物，将其与人参皂甙原吻三醇 PPT 和淫羊藿苷 ICA 共同孵育细胞。由于 FITC-Dextran 的荧光特性，通过荧光显微镜或共聚焦显微镜等技术，可以直观地观察到细胞对人参皂甙原吻三醇 PPT 和淫羊藿苷 ICA 的摄取情况，了解化合物在细胞内的转运途径和时间进程。FITC-Dextran 的荧光稳定性使其能够在一定时间内持续发出荧光信号，可用于监测人参皂甙原吻三醇 PPT 和淫羊藿苷 ICA 在体内的代谢过程。

图：机制示意

结论：

人参皂甙原吻三醇（PPT）保护Blood vessels内皮免受损伤，而淫羊藿苷（ICA） 促进成骨分化。该文献研究发现PPT与ICA联合使用可有效防止Blood vessels和内皮壁龛损伤，促进骨髓造血再生，PPT 和 ICA 的结合旨在恢复受损的Blood vessels和骨内生位，从而使 HSC 恢复活力以Treatment 骨髓抑制，FITC-Dextran 在其中起到很好的标记作用。