FDA-Approved Drug Screening for Compounds That Facilitate Hematopoietic Stem and Progenitor Cells (HSPCs) Expansion in Zebrafish.

Zhi Feng,Li Li,Michael Edbert Suryanto,Chung-Der Hsiao,Limei Tu,Chunyu Song,Chenyu Lin,Shengnan Liu,Ming Su

doi:10.3390/cells10082149

Abstract

Hematopoietic stem cells (HSCs) are a specialized subset of cells with self-renewal and multilineage differentiation potency, which are essential for their function in bone marrow or umbilical cord blood transplantation to treat blood disorders. Expanding the hematopoietic stem and progenitor cells (HSPCs) ex vivo is essential to understand the HSPCs-based therapies potency. Here, we established a screening system in zebrafish by adopting an FDA-approved drug library to identify candidates that could facilitate HSPC expansion. To date, we have screened 171 drugs of 7 categories, including antibacterial, antineoplastic, glucocorticoid, NSAIDS, vitamins, antidepressant, and antipsychotic drugs. We found 21 drugs that contributed to HSPCs expansion, 32 drugs’ administration caused HSPCs diminishment and 118 drugs’ treatment elicited no effect on HSPCs amplification. Among these drugs, we further investigated the vitamin drugs ergocalciferol and panthenol, taking advantage of their acceptability, limited side-effects, and easy delivery. These two drugs, in particular, efficiently expanded the HSPCs pool in a dose-dependent manner. Their application even mitigated the compromised hematopoiesis in an ikzf1−/− mutant. Taken together, our study implied that the larval zebrafish is a suitable model for drug repurposing of effective molecules (especially those already approved for clinical use) that can facilitate HSPCs expansion.

Highlights

Hematopoietic stem and progenitor cells (HSPCs) transplantation has been a major stem cell-based curative therapy in the treatment of hematologic diseases, including leukemia, immune deficiencies, hemoglobinopathies, and metabolism-based disorders, since the late 1950s, due to their capacity of reconstructing blood system [1]
Among these 21drugs, we focused on 6 vitamin drugs with limited side-effects and easy delivery, without ruling out that the other 15 drugs had potential functions for therapeutical use in HSPCs expansion ex vivo
The caudal hematopoietic tissue (CHT) region is functionally similar to the mammalian fetal liver, which is an HSPCs expansion site [35]

Summary

Introduction

Hematopoietic stem and progenitor cells (HSPCs) transplantation has been a major stem cell-based curative therapy in the treatment of hematologic diseases, including leukemia, immune deficiencies, hemoglobinopathies, and metabolism-based disorders, since the late 1950s, due to their capacity of reconstructing blood system [1]. Accessibility of bone marrow transplantation for patients is restricted by the short availability of immune-matched donors [2]. Umbilical cord blood (UCB) has become an increasingly popular source of transplantable HSPCs because of its rapid availability with less-stringent immune-matching requirements [3]. Extensive efforts have been put into finding culture conditions that sustain HSCs ex vivo expansion, spurring the improvements in transplantation treatment outcomes through the development of various cellular therapies [9]

Objectives

Methods

Results

Conclusion