PTP? inhibitors promote hematopoietic stem cell regeneration.

ABSTRACT: Receptor type protein tyrosine phosphatase-sigma (PTP?) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTP? is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTP? that promote HSC regeneration in vivo. Systemic administration of the PTP? 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 PTP? and antagonizes PTP? 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 PTP? inhibitors for human hematopoietic regeneration.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC6694155 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature