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PTPI? inhibitors promote hematopoietic stem cell regeneration. Nat Commun 2019 08 14;10(1):3667

Date

08/16/2019

Pubmed ID

31413255

Pubmed Central ID

PMC6694155

DOI

10.1038/s41467-019-11490-5

Scopus ID

2-s2.0-85070740613   13 Citations

Abstract

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 JP

Author

Heather A. Himburg PhD Associate Professor in the Radiation Oncology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Allosteric Regulation
Animals
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