Inhibition of Protein Tyrosine Phosphatase-Sigma Promotes Hematopoietic Stem Cell Regeneration
- Author(s): Zhang, Yurun
- Advisor(s): Chute, John P
- et al.
Receptor tyrosine kinases, such as c-Kit, Flt-3, and Tie 2, regulate hematopoietic stem cell (HSC) proliferation, differentiation, and maintenance. Substantially less is known regarding the function of protein tyrosine phosphatases (PTPs) in regulating HSC fate. We recently discovered that receptor type protein tyrosine phosphatase-sigma (PTPσ) is highly expressed by murine and human HSCs. PTPσ was originally discovered in adult neurons and has shown to regulate neural regeneration. In the hematopoietic system, constitutive deletion of PTPσ in mouse bone marrow (BM) cells significantly increased HSC repopulating capacity compared to the wildtype. Furthermore, negative selection of human cord blood (CB) HSCs for PTPσ surface expression conferred more than 10-fold increase in human CB hematopoietic engraftment through 20 weeks in transplanted NSG mice. Additionally, PTPσ-deficient mice displayed significantly augmented recovery of BM colony forming cells at day +10 following 600 cGy total body irradiation. Based on these observations, we hypothesized that PTPσ may function as a negative regulator of HSC self-renewal and regeneration. Here we describe novel small molecule inhibitors of PTPσ that promote hematopoietic stem cell (HSC) regeneration in vivo. Systemic administration of DJ001, a PTPσ inhibitor, or its analog to irradiated mice promotes HSC regeneration, accelerates hematologic recovery, and improves survival. Similarly, following chemotherapy, DJ001 administration accelerates hematologic recovery in mice. 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.