Angelica sinensis Polysaccharides Ameliorate Stress-Induced Premature Senescence of Hematopoietic Cell via Protecting Bone Marrow Stromal Cells from Oxidative Injuries Caused by 5-Fluorouracil.

Hanxianzhi Xiao,Yaping Wang,Lu Wang,Pengwei Jin,Hui Yao,Xiongbin Chen,Linbo Chen,Xiaoying Song,Lirong Xiong

doi:10.3390/ijms18112265

Abstract

Myelosuppression is the most common complication of chemotherapy. Decline of self-renewal capacity and stress-induced premature senescence (SIPS) of hematopoietic stem cells (HSCs) induced by chemotherapeutic agents may be the cause of long-term myelosuppression after chemotherapy. Whether the mechanism of SIPS of hematopoietic cells relates to chemotherapeutic injury occurred in hematopoietic microenvironment (HM) is still not well elucidated. This study explored the protective effect of Angelica sinensis polysaccharide (ASP), an acetone extract polysaccharide found as the major effective ingredients of a traditional Chinese medicinal herb named Chinese Angelica (Dong Quai), on oxidative damage of homo sapiens bone marrow/stroma cell line (HS-5) caused by 5-fluorouracil (5-FU), and the effect of ASP relieving oxidative stress in HM on SIPS of hematopoietic cells. Tumor-suppressive doses of 5-FU inhibited the growth of HS-5 in a dose-dependent and time-dependent manner. 5-FU induced HS-5 apoptosis and also accumulated cellular hallmarks of senescence including cell cycle arrest and typical senescence-associated β-galactosidase positive staining. The intracellular reactive oxygen species (ROS) was increased in 5-FU treated HS-5 cells and coinstantaneous with attenuated antioxidant capacity marked by superoxide dismutase and glutathione peroxidase. Oxidative stress initiated DNA damage indicated by increased γH2AX and 8-OHdG. Oxidative damage of HS-5 cells resulted in declined hematopoietic stimulating factors including stem cell factor (SCF), stromal cell-derived factor (SDF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), however, elevated inflammatory chemokines such as RANTES. In addition, gap junction channel protein expression and mediated intercellular communications were attenuated after 5-FU treatment. Significantly, co-culture on 5-FU treated HS-5 feeder layer resulted in less quantity of human umbilical cord blood-derived hematopoietic cells and CD34+ hematopoietic stem/progenitor cells (HSPCs), and SIPS of hematopoietic cells. However, it is noteworthy that ASP ameliorated SIPS of hematopoietic cells by the mechanism of protecting bone marrow stromal cells from chemotherapeutic injury via mitigating oxidative damage of stromal cells and improving their hematopoietic function. This study provides a new strategy to alleviate the complication of conventional cancer therapy using chemotherapeutic agents.

Highlights

Myelosuppression is a primary complication concern in patients undergoing chemotherapy
The hematopoietic system is organized in a hierarchical manner, in which the rare hematopoietic stem cells (HSCs) initiate the hierarchy and have the ability to self-renew, proliferate and differentiate into different lineages of peripheral blood cells through hematopoietic progenitor cells (HPCs) [1,2,3]
The role of BMSCs toxicity in drug-induced myelosuppression, rejection of stem cell transplants, and cell adhesion-mediated drug resistance suggests that in addition to HSC itself, the bone marrow (BM) microenvironment may be impaired by chemotherapeutic agents, and this may be another reason for hematopoietic dysfunction [7,15,16,17,18]

Summary

Introduction

Myelosuppression is a primary complication concern in patients undergoing chemotherapy. If HSCs undergo senescence with the ability of self-renewal impaired, a long-term damage to the hematopoietic system occurs [7,8]. The role of BMSCs toxicity in drug-induced myelosuppression, rejection of stem cell transplants, and cell adhesion-mediated drug resistance suggests that in addition to HSC itself, the BM microenvironment may be impaired by chemotherapeutic agents, and this may be another reason for hematopoietic dysfunction [7,15,16,17,18]. Recent literature reported that in vitro expansion of hBMSCs combined with HSCs transfusion is an effective method of bone marrow hematopoietic reconstitution [19,20,21,22,23], the mechanism of chemotherapy-induced bone marrow hematopoietic microenvironment (HM) injury and its effect on the function of hematopoietic cells still need to be evaluated. Exploring the possibility and the underlying mechanisms to alleviate toxicity of chemotherapy in HM might be pivotal for long-term myelosuppression, and it might lead to new strategies for the screening of chemotherapeutic preventive agents

Methods

Results

Conclusion