PEDF promotes the repair of bone marrow endothelial cell injury and accelerates hematopoietic reconstruction after bone marrow transplantation

Wen Ju,Zhenyu Li,Weiwei Wang,Fei Hong,Lan Ding,Hui Gao,Kunming Qi,Yurong Bao,Guozhang Wang,Yuting Chen,Chunling Fu,Jianlin Qiao,Wenyi Lu,Xi Zhang,Kailin Xu,Lingyu Zeng,Xiaoqi Xu

doi:10.1186/s12929-020-00685-4

Abstract

BackgroundPreconditioning before bone marrow transplantation such as irradiation causes vascular endothelial cells damage and promoting the repair of damaged endothelial cells is beneficial for hematopoietic reconstitution. Pigment epithelium-derived factor (PEDF) regulates vascular permeability. However, PEDF’s role in the repair of damaged endothelial cells during preconditioning remains unclear. The purpose of our study is to investigate PEDF’s effect on preconditioning-induced damage of endothelial cells and hematopoietic reconstitution.MethodsDamaged endothelial cells induced by irradiation was co-cultured with hematopoietic stem cells (HSC) in the absence or presence of PEDF followed by analysis of HSC number, cell cycle, colony formation and differentiation. In addition, PEDF was injected into mice model of bone marrow transplantation followed by analysis of bone marrow injury, HSC number and peripheral hematopoietic reconstitution as well as the secretion of cytokines (SCF, TGF-β, IL-6 and TNF-α). Comparisons between two groups were performed by student t-test and multiple groups by one-way or two-way ANOVA.ResultsDamaged endothelial cells reduced HSC expansion and colony formation, induced HSC cell cycle arrest and apoptosis and promoted HSC differentiation as well as decreased PEDF expression. Addition of PEDF increased CD144 expression in damaged endothelial cells and inhibited the increase of endothelial permeability, which were abolished after addition of PEDF receptor inhibitor Atglistatin. Additionally, PEDF ameliorated the inhibitory effect of damaged endothelial cells on HSC expansion in vitro. Finally, PEDF accelerated hematopoietic reconstitution after bone marrow transplantation in mice and promoted the secretion of SCF, TGF-β and IL-6.ConclusionsPEDF inhibits the increased endothelial permeability induced by irradiation and reverse the inhibitory effect of injured endothelial cells on hematopoietic stem cells and promote hematopoietic reconstruction.

Highlights

Preconditioning before bone marrow transplantation such as irradiation causes vascular endothelial cells damage and promoting the repair of damaged endothelial cells is beneficial for hematopoietic reconstitution
It is known that vascular endothelial cells, as important hematopoietic stromal cells, can promote hematopoietic stem cells (HSC) proliferation which was confirmed by our study (Fig. 1a)
We found that co-culture of damaged endothelial cells and HSC inhibited HSC expansion (Fig. 1a), leading to a decrease in the proportion and total number of HSC (Fig. 1b)

Summary

Introduction

Preconditioning before bone marrow transplantation such as irradiation causes vascular endothelial cells damage and promoting the repair of damaged endothelial cells is beneficial for hematopoietic reconstitution. Hematopoietic microenvironment is an internal environment that regulates and supports the growth and development of hematopoietic cells. It is mainly composed of stromal cells and extracellular matrix [7, 8]. EPC can differentiate into endothelial cells and promote the repair of injured vascular niche, indicating its important role in hematopoietic reconstruction [13]. We previously found that preconditioning regimens prior to HSCT could cause damage to vascular endothelial structure and function and changes in endothelial permeability [17,18,19]. The current underlying mechanisms of endothelial injury and strategies to promote endothelial repair during preconditioning treatment are still lacking [14]

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