PTPσ inhibitors promote hematopoietic stem cell regeneration

Yurun Zhang, Martina Roos, Heather Himburg, Christina M. Termini, Mamle Quarmyne, Michelle Li, Liman Zhao, Jenny Kan, Tiancheng Fang, Xiao Yan, Katherine Pohl, Emelyne Diers, Hyo Jin Gim, Robert Damoiseaux, Julian Whitelegge, William McBride, Michael E. Jung and John P. Chute ()
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Yurun Zhang: University of California, Los Angeles (UCLA)
Martina Roos: Department of Medicine, UCLA
Heather Himburg: Department of Medicine, UCLA
Christina M. Termini: Department of Medicine, UCLA
Mamle Quarmyne: Department of Medicine, UCLA
Michelle Li: Department of Medicine, UCLA
Liman Zhao: Department of Medicine, UCLA
Jenny Kan: Department of Medicine, UCLA
Tiancheng Fang: Department of Medicine, UCLA
Xiao Yan: Department of Medicine, UCLA
Katherine Pohl: Department of Medicine, UCLA
Emelyne Diers: UCLA
Hyo Jin Gim: UCLA
Robert Damoiseaux: Jonsson Comprehensive Cancer Center, UCLA
Julian Whitelegge: UCLA
William McBride: Jonsson Comprehensive Cancer Center, UCLA
Michael E. Jung: UCLA
John P. Chute: Department of Medicine, UCLA

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Receptor type protein tyrosine phosphatase-sigma (PTPσ) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPσ is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPσ that promote HSC regeneration in vivo. Systemic administration of the PTPσ inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in mice treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPσ and antagonizes PTPσ via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-XL. Furthermore, treatment of irradiated human HSCs with DJ001 promotes the regeneration of human HSCs capable of multilineage in vivo repopulation. These studies demonstrate the therapeutic potential of selective, small-molecule PTPσ inhibitors for human hematopoietic regeneration.

Date: 2019
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DOI: 10.1038/s41467-019-11490-5

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