PTPσ inhibitors promote hematopoietic stem cell regeneration
| Autor: | Michelle Li, Liman Zhao, Heather A. Himburg, Tiancheng Fang, Yurun Zhang, Katherine Pohl, Martina Roos, Christina M. Termini, William H. McBride, Mamle Quarmyne, Robert Damoiseaux, Hyo Jin Gim, Michael E. Jung, Xiao Yan, John P. Chute, Julian P. Whitelegge, Emelyne Diers, Jenny Kan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
rac1 GTP-Binding Protein rho GTP-Binding Proteins Antimetabolites General Physics and Astronomy Receptor-Like Protein Tyrosine Phosphatases Apoptosis 02 engineering and technology Stem cells Regenerative Medicine Mice Stem Cell Research - Nonembryonic - Human Tyrosine Enzyme Inhibitors lcsh:Science Cancer Multidisciplinary Radiation Chemistry Haematopoietic stem cells Receptor-Like Protein Tyrosine Phosphatases Class 2 Hematopoietic stem cell Hematology 021001 nanoscience & nanotechnology Antineoplastic 3. Good health Cell biology Haematopoiesis medicine.anatomical_structure 5.1 Pharmaceuticals Systemic administration Stem Cell Research - Nonembryonic - Non-Human Fluorouracil Development of treatments and therapeutic interventions 0210 nano-technology Antimetabolites Antineoplastic 1.1 Normal biological development and functioning Science Allosteric regulation bcl-X Protein RAC1 General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Allosteric Regulation Underpinning research medicine Animals Humans Regeneration Transplantation Regeneration (biology) General Chemistry Class 2 Stem Cell Research Hematopoietic Stem Cells 030104 developmental biology lcsh:Q |
| Zdroj: | Nature Communications, Vol 10, Iss 1, Pp 1-15 (2019) Nature Communications Nature communications, vol 10, iss 1 |
| ISSN: | 2041-1723 |
| Popis: | 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-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 PTPσ inhibitors for human hematopoietic regeneration. Protein tyrosine phosphatase sigma (PTPσ) deficient haematopoietic stem cells (HSCs) demonstrate increased engraftment following transplantation. Here the authors identify a small molecule inhibitor of PTPσ that promotes murine and human haematopoietic stem cell regeneration via induction of the RAC pathway and BCL-XL. |
| Databáze: | OpenAIRE |
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