PTPI? inhibitors promote hematopoietic stem cell regeneration. Nat Commun 2019 08 14;10(1):3667
Date
08/16/2019Pubmed ID
31413255Pubmed Central ID
PMC6694155DOI
10.1038/s41467-019-11490-5Scopus ID
2-s2.0-85070740613 13 CitationsAbstract
Receptor type protein tyrosine phosphatase-sigma (PTPI?) is primarily expressed by adult neurons and regulates neural regeneration. We recently discovered that PTPI? is also expressed by hematopoietic stem cellsA (HSCs). Here, we describe small molecule inhibitors of PTPI? that promote HSC regeneration in vivo. Systemic administration of the PTPI? inhibitor, DJ001, or its analog, to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, DJ001 administration accelerates hematologic recovery in miceA treated with 5-fluorouracil chemotherapy. DJ001 displays high specificity for PTPI? and antagonizes PTPI? 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 PTPI? inhibitors for human hematopoietic regeneration.
Author List
Zhang Y, Roos M, Himburg H, Termini CM, Quarmyne M, Li M, Zhao L, Kan J, Fang T, Yan X, Pohl K, Diers E, Jin Gim H, Damoiseaux R, Whitelegge J, McBride W, Jung ME, Chute JPAuthor
Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Allosteric RegulationAnimals
Antimetabolites, Antineoplastic
Apoptosis
Enzyme Inhibitors
Fluorouracil
Hematopoietic Stem Cells
Humans
Mice
Radiation
Receptor-Like Protein Tyrosine Phosphatases, Class 2
Regeneration
bcl-X Protein
rac1 GTP-Binding Protein
rho GTP-Binding Proteins
