Speaker: Kostandin Pajcini, University of Illinois at Chicago College of Medicine associate professor, director of Graduate Studies, Department of Pharmacology & Regenerative Medicine

Title: Dynamic roles of Notch signaling in fetal and adult hematopoietic niches

Abstract: Notch signaling is critical for many aspects of mammalian development. Vascular development and regeneration as well as fetal hematopoietic development are two such processes that are directly affected by the Notch signaling pathway. Hematopoietic stem cells (HSCs) emerge from the hemogenic endothelium in a Notch dependent process and migrate to the fetal liver where they expand and mature. We have shown that Notch signaling is required for the functional potential of fetal hematopoietic stem and progenitor cells in the fetal liver niche and that the key activation niche mechanism is one of hematopoietic-to-hematopoietic activation. We show that the ligand Jagged1 promotes activation of Notch signaling in fetal HSCs. Deletion of Jag1 from fetal hematopoietic cells (Jag1^-/-VavCre⁺) does not affect vascular development but critically limits the engraftment and functional potential of fetal HSCs. Failure of robust Notch signaling in fetal HSCs limits the expression of key self-renewal factors such as Mllt3, Gata2 and HoxA7. We are utilizing our knowledge of the hematopoietic fetal liver niche to build bioengineered platforms for extended study and expansion of fetal, cord blood or adult HSCs. Notch ligands on surface of hematopoietic cells continue to play key roles in regenerative hematopoiesis.  Combined chemotherapy and irradiation are a well-established preconditioning treatment to ensure the engraftment of healthy HSCs. However, these treatments inflict severe damage to the bone marrow endothelium, thus reducing long-term transplantation efficiency and potentially contributing to cases of non-relapse mortality.   Notch signaling plays an essential role in facilitating cell-to-cell interactions to promote endothelial cell (EC) survival and HSC regeneration in the bone marrow niche, but this interaction is severely disrupted after myeloablative treatments. We show that transgenic deletion of Notch ligand Jag1 from the surface of hematopoietic causes severe hematopoietic and endothelial damage and poor overall survival following sub-lethal irradiation or chemotherapy. We found a novel damage-resistant myeloid-derived progenitor (DR-MDP) population that upregulates Jag1 ligand during chemotherapy and irradiation. When transfused, DR-MDPs enhance survival, endothelial cell viability, and HSC recovery by promoting active Notch signaling in the bone marrow ECs. Single cell transcriptomics before and after irradiation treatment show that DR-MDPs are heterogenous and that loss of Jag1 negatively affects their proliferation and immunomodulatory functions. Cell-free activation of endothelial Notch signaling using Jag1 membrane-coated nanoparticles is sufficient to enhance EC viability and to promote hematopoietic recovery. Together, these findings reveal a critical role for myeloid-to-endothelial Notch signaling and identify a cellular population that plays an important early role toward therapeutic restoration of the hematopoietic niche and maintenance of vascular integrity. 

Hosts: Clyde Campbell and Raquel Espin Palazon, GDCB assistant professors