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Nat Commun. 2019 Aug 14;10(1):3667. doi: 10.1038/s41467-019-11490-5.

PTPσ inhibitors promote hematopoietic stem cell regeneration.

Author information

1
Molecular Biology Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA.
2
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA, 90095, USA.
3
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, 90095, USA.
4
Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095, USA.
5
Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, 90095, USA.
6
Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, 90095, USA.
7
California Nanosystems Institute, UCLA, Los Angeles, CA, 90095, USA.
8
Department of Psychiatry and Behavioral Sciences, UCLA, Los Angeles, CA, 90095, USA.
9
Department of Radiation Oncology, UCLA, Los Angeles, CA, 90095, USA.
10
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA, 90095, USA. jchute@mednet.ucla.edu.
11
Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, 90095, USA. jchute@mednet.ucla.edu.
12
Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, CA, 90095, USA. jchute@mednet.ucla.edu.
13
Department of Radiation Oncology, UCLA, Los Angeles, CA, 90095, USA. jchute@mednet.ucla.edu.

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.

PMID:
31413255
PMCID:
PMC6694155
DOI:
10.1038/s41467-019-11490-5
[Indexed for MEDLINE]
Free PMC Article

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