Levistilide A Promotes Expansion of Human Umbilical Cord Blood Hematopoietic Stem Cells by Enhancing Antioxidant Activity.

Mei He,Yahui Ding,Yafang Li,Chaoqun Wang,Xiaolei Liu,Yiran Zhang,Guangju Liu,Yinghui Li,Wenshan Zhang,Quan Zhang,Hexiao Zhang,Yingdai Gao,Shiqi Xu,Hui Xu,Ming Yang

doi:10.3389/fphar.2022.806837

Abstract

Several approaches to expand human hematopoietic stem cells (hHSCs) clinically along with retainable capability of multipotential differentiation have been reported, but only a few have advanced to evaluation in clinical trials, which limits the application of HSC-based therapy. Here we show a phthalide derivative, Levistilide A (LA), can serve as a promising molecule to expand functional human umbilical cord blood (UCB) HSCs ex vivo. An in-house screen identified LA out of nine natural products as an outstanding candidate for hHSCs expansion. Additionally, our data indicated that LA treatment not only increased the numbers of phenotype-defined HSCs, but also enhanced their colony formation ability. Xenotransplantation assays showed that LA treatment could maintain unaffected engraftment of hHSCs with multilineage differentiation capacity. Further experiments revealed that LA enhanced the antioxidant activity of hHSCs by reducing intracellular and mitochondrial reactive oxygen species (ROS) levels. The identification of LA provides a new strategy in solving the clinical issue of limited numbers of UCB HSCs.

Highlights

Development and maintenance of the hematopoietic system rely on a small heterogeneous pool of HSCs which are characterized by the capability of self-renewal and multipotent differentiation (Seita and Weissman, 2010)
It is noteworthy that dimer 2 illustrates that the 6,7-alkene unit undergoes 4 + 2 cycloaddition as the dienophile with the monomer 8 1,3-diene system, while dimer 9 is derived from 4 + 2 cycloaddition of the cross-conjugated 3,8-alkene
We identified Levistilide A (LA), a dimeric phthalide derivative that could be a promising candidate to expand Hematopoietic stem and progenitor cells (HSPCs) ex vivo

Summary

Introduction

Development and maintenance of the hematopoietic system rely on a small heterogeneous pool of HSCs which are characterized by the capability of self-renewal and multipotent differentiation (Seita and Weissman, 2010). Superior to bone marrow (BM) and mobilized peripheral blood (mPB), UCB collections can be cryopreserved for over 20 years with efficient recovery of HSPCs after being thawed, and require lower human leukocyte antigen (HLA)-matching (Ballen et al, 2013). Widespread use of UCB is still limited by two major obstacles: an insufficient dose of HSPCs in a single UCB collection, and subsequent delay of immune recovery post-transplantation (Ballen et al., Levistilide A Expands UCB HSCs. 2013; Huang et al, 2019). The top priority at present for UCB transplantation is to develop efficient methods to expand HSPCs ex vivo functionally and in turn improve the outcomes of transplantation

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Conclusion