Molecular Biology Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, 90095, USA.
Division of Hematology/Oncology, Department of Medicine, UCLA, Los Angeles, CA, 90095, USA.
Nat Commun. 2019 Aug 14;10(1):3667. doi: 10.1038/s41467-019-11490-5.
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.
受体型蛋白酪氨酸磷酸酶-σ（PTPσ）主要在成年神经元中表达，调节神经再生。我们最近发现 PTPσ 也在造血干细胞（HSCs）中表达。在这里，我们描述了小分子 PTPσ 抑制剂，可促进体内 HSC 再生。PTPσ 抑制剂 DJ001 或其类似物的全身给药可促进辐射小鼠的 HSC 再生，加速血液学恢复并提高存活率。同样，DJ001 给药可加速接受氟尿嘧啶化疗的小鼠的血液学恢复。DJ001 对 PTPσ 具有高度特异性，并通过独特的非竞争性变构结合拮抗 PTPσ。在机制上，DJ001 通过激活 RhoGTPase RAC1 和诱导 BCL-X 来抑制辐射诱导的 HSC 凋亡。此外，用 DJ001 处理辐照的人 HSC 可促进体内多谱系重建的人 HSC 的再生。这些研究表明，选择性小分子 PTPσ 抑制剂在人类造血再生方面具有治疗潜力。
