Targeting JNK Pathway Expands Human Hematopoietic Stem Cells

The limited number of human hematopoietic stem cells (HSCs) has restrained their widespread clinical application. Despite great efforts in recent years, the in vitro expansion of HSCs remains a challenge due to incomplete understanding of the signaling networks underlying HSC self-renewal. Here we show that culturing human cord blood (CB) CD34+ cells with JNK-IN-8, an inhibitor of the JNK signaling pathway, can enhance the self-renewal of HSCs with a 6-fold increase in number. These expanded CD34+ cells repopulated recipient mice for 20 weeks and can form secondary engraftment that lasted for more than 21 weeks. Knockdown of c-Jun, a major downstream target in the JNK pathway, significantly promoted the expansion of hematopoietic stem and progenitor cells (HSPCs). Our findings demonstrate a critical role of JNK pathway in regulating HSC expansion, provide new insights into HSC self-renewal mechanism, and may lead to improved clinical application of HSCs. The progeny mRNA profiles of cord blood CD34+ cells with a 7-days culture were generated by RNA sequencing, in duplicate, using Illumina hiseq XTen.