Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-019-11490-5
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Funding
- NIAID [AI-067769-12]
- NHLBI [HL-086998-08, U54-HL-119893]
- California Institute for Regenerative Medicine Leadership Awards [LA1-08014, DISC2-09624]
- Tower Cancer Research Foundation Career Development Grant
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [U54HL119893] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI067769] Funding Source: NIH RePORTER
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Receptor type protein tyrosine phosphatase-sigma (PTPs) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPs is also expressed by hematopoietic stem cells (HSCs). Here, we describe small molecule inhibitors of PTPs that promote HSC regeneration in vivo. Systemic administration of the PTPs 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 PTPs and antagonizes PTPs via unique non-competitive, allosteric binding. Mechanistically, DJ001 suppresses radiation-induced HSC apoptosis via activation of the RhoGTPase, RAC1, and induction of BCL-X-L. 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 PTPs inhibitors for human hematopoietic regeneration.
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