Nature communications, 2019-08, Vol.10 (1), p.3667-15, Article 3667
2019
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- Autor(en) / Beteiligte
- Titel
- PTPσ inhibitors promote hematopoietic stem cell regeneration
- Ist Teil von
- Nature communications, 2019-08, Vol.10 (1), p.3667-15, Article 3667
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2019
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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-X . 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-019-11490-5Titel-ID: cdi_doaj_primary_oai_doaj_org_article_a4cd7b0d3b6b453f9917108aabe1cec2
- Format
- –
- Schlagworte
- 5-Fluorouracil, Allosteric properties, Allosteric Regulation, Animals, Antimetabolites, Antineoplastic - pharmacology, Apoptosis, Apoptosis - drug effects, Apoptosis - radiation effects, Bcl-x protein, bcl-X Protein - drug effects, bcl-X Protein - metabolism, Chemotherapy, Clinical medicine, Competition, Enzyme Inhibitors - pharmacology, Enzyme kinetics, Fluorouracil - pharmacology, Growth factors, Hematopoietic stem cells, Hematopoietic Stem Cells - drug effects, Hematopoietic Stem Cells - radiation effects, Humans, In vivo methods and tests, Inhibitors, Mice, Oncology, Phosphatase, Protein-tyrosine-phosphatase, Proteins, rac1 GTP-Binding Protein - drug effects, rac1 GTP-Binding Protein - metabolism, Rac1 protein, Radiation, Radiation effects, Receptor-Like Protein Tyrosine Phosphatases, Class 2 - antagonists & inhibitors, Recovery, Regeneration, Regeneration - drug effects, Regeneration - radiation effects, Repopulation, rho GTP-Binding Proteins - drug effects, rho GTP-Binding Proteins - metabolism, Stem cell transplantation, Stem cells, Tyrosine