Characterization of a GSK-3 inhibitor in culture of human cord blood primitive hematopoietic cells - 08/09/10

Doi : 10.1016/j.biopha.2010.01.005

Junfen Jiang ^a,^{^{1
These authors contributed equally to this work.}}, Mei Zhao ^a,^b,^{^{1
These authors contributed equally to this work.}}, Aiying Zhang ^c,^{^{1
These authors contributed equally to this work.}}, Mingfeng Yu ^c, Xiaojuan Lin ^a, Mingyuan Wu ^a, Xiaonong Wang ^d, Huili Lu ^a, Shunying Zhu ^a, Yan Yu ^e, Zhenmin Mao ^c,^⁎ , Wei Han ^a,^⁎
^a Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
^b Department of Pharmacy, Shanghai Institute of Health Sciences, Shanghai 201318, China
^c Heterocyclic Chemistry and Antitumor Drugs Laboratory, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China
^d Haematological Sciences, Medical School, University of Newcastle upon Tyne, NE1 7RU, United Kingdom
^e Shanghai Municipality Key Laboratory of Veterinary Biotechnology, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China

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Abstract

Wnt signaling pathway plays important roles in the biology of stem cells in maintaining their self-renewal property. Glycogen synthase kinase-3 (GSK-3) inhibitors, the Wnt signaling agonists, maintain the pluripotency of embryonic stem cells. We report here that a synthetic GSK-3 inhibitor, 6-bromoindirubin-3′-oxime (BIO), showed opposite effects on the expansion of human primitive hematopoietic cells isolated from umbilical cord blood (UCB). In combination with human c-kit ligand (KL), BIO at low concentration (0.2μM) enhanced the expansion of UCB CD34⁺ cells, which was BIO structure and exposure time dependent; however, at high concentration (2μM) it inhibited the expansion of the cells. Furthermore, hematopoietic stem cells (HSCs) were exhausted when the UCB CD34⁺ cells were exposed to 0.2μM BIO and KL longer than 2 days. In conclusion, the use of BIO in expansion of UCB HSCs remains a significant challenge.

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Keywords : Human umbilical cord blood, CD34⁺ cells, GSK-3 inhibitor, BIO

Plan

Introduction

Materials and methods

Synthesis of 6-bromoindirubin-3′-oxime and 1-methyl-6-bromoindirubin-3′-oxime

Preparation of 6-bromoindirubin-3′-oxime/1-methyl-6-bromoindirubin-3′-oxime solution

Isolation of human umbilical cord blood CD34⁺ cells

Culture expansion of umbilical cord blood CD34⁺ cells

Sequential dilution culture assessing the number of primitive hematopoietic cells

Flow-cytometric analysis

Progenitor assay

Statistical analysis

Results

Dose-dependent opposite effect of 6-bromoindirubin-3′-oxime in expansion of umbilical cord blood CD34⁺ cells

Expansion of umbilical cord blood CD34⁺ cells by 6-bromoindirubin-3′-oxime is structure specific and c-kit ligand dependent

6-bromoindirubin-3′-oxime expands umbilical cord blood primitive hematopoietic cells in combination with c-kit ligand

Discussion

Conflict of interest

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Vol 64 - N° 7

P. 482-486 - septembre 2010 Retour au numéro

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Characterization of a GSK-3 inhibitor in culture of human cord blood primitive hematopoietic cells - 08/09/10

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